WO2022261068A1

WO2022261068A1 - Methods and treatment of viral infection with substituted furo-pyrimidines

Info

Publication number: WO2022261068A1
Application number: PCT/US2022/032464
Authority: WO
Inventors: Jane RHODES; Michelle MIGHDOLL; Irene Y. Choi; Brian KOPEC
Original assignee: Verge Analytics, Inc.
Priority date: 2021-06-08
Filing date: 2022-06-07
Publication date: 2022-12-15
Also published as: TW202313051A

Abstract

The present disclosure provides compounds that are useful for the treatment of coronavirus infections.

Description

METHODS AND TREATMENT OF VIRAL INFECTION WITH SUBSTITUTED FURO-PYRIMIDINES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/208,459, filed on June 8, 2021, the disclosure of which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present disclosure relates to methods of i) blocking alpha-coronavirus, beta- coronavirus lineage B, and beta-coronavirus lineage A into a host cell; and ii) preventing and treating an infection caused by alpha-coronavirus, beta-coronavirus lineage B, and beta- coronavirus lineage A with compounds that are phosphoinositide kinase inhibitors, in particular FYVE-type finger-containing phosphoinositide kinase (“PIKfyve”) inhibitors. BACKGROUND OF THE INVENTION [0003] According to the World Health Organization, there have been over 517 million confirmed cases and about 6.3 million deaths worldwide due to COVID-19 as of May 2022. SARS-CoV-2, which is responsible for the COVID-19 (2019 novel coronavirus (2019-nCoV) disease, is an enveloped, positive-sense, RNA virus that belongs to the Betacoronavirus genus. Bouhaddou et al, Cell 182: 1-28 (2020). Improved understanding of key steps in viral entry and ways to disrupt them can lead to the development of effective antiviral drugs, not only for COVID-19, but for future viral outbreaks as well. Treatments for COVID-19 are greatly needed. [0004] Coronavirus entry into susceptible cells is a complex process that requires the concerted action of receptor-binding and proteolytic processing of the coronavirus S protein to promote virus-cell fusion. Heald-Sargent and Gallagher, Viruses 4:557-580 (2012); Millet and Whittaker, Virus Res.202:120-134 (2015). For example, viral entry into cells may be mediated by a viral glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes, and catalyzes fusion between viral and endosomal membranes. Murray, et al, J. Virology 79:11742-11751 (2005). In the case of SARS-CoV-2, its spike (S) protein binds to an ACE2 receptor on the target cell and is subsequently primed by a serine protease, TMPRSS2, that cleaves the S protein and allows fusion of viral and lysosomal membranes. Hoffmann, et al., Cell 181:271-280.e8 (2020). [0005] Like most viruses, coronavirus membrane fusion with host cell membrane takes place within acidified endosomes. Kang, et al, PNAS 117(34):20803-20813 (2020). Coronaviruses are known to interact with phosphatidylinositol (PI) kinases, which are distributed across various subcellular compartments. Beziau et al, Viruses 12, 1124; doi:10.3390/v12101124 (2020). The PI kinase phosphatidylinositol 3-phosphate 5 kinase (PIKfyve) involved in endosomal acidification is required for SARS-CoV-2 to enter the cell. Ou, et al, Nat. Commun.11(1620):1- 12 (2020). PIKfyve inhibition with small molecule inhibitors has been shown to inhibit SARS- CoV-2 infection. Kang et al, PNAS 117(34):20803-20813 (2020); Nelson, et al, PLoS Negl. Trop. Dis.11(4):e0005540 (2017). Ablation of PIKfyve arrests endosomal maturation (Ikonomov et al, J. Biol. Chem.276(28):26141-26147 (2001); Ikonomov et al, J. Biol. Chem. 277(11):9206-9211 (2002); Jefferies et al, EMBO Rep.9(2):164-170 (2008); Rutherford, et al, J. Cell Sci.119(19):3944-3957 (2006); Sbrissa, et al, J. Biol. Chem.277(8):6073-6079 (2002)), which makes PIKfyve a candidate target for new drugs against viruses that exploit the endosomal pathway. SUMMARY OF THE INVENTION [0006] Embodiment 1 is a method of blocking alpha-coronavirus, beta-coronavirus lineage B, and/or beta-coronavirus lineage A entry into a host cell and preventing an infection caused by alpha-coronavirus, beta-coronavirus lineage B, and beta-coronavirus lineage A, comprising administering to a subject in need thereof a compound of (i) Formula (I)

wherein: R^1a and R^1b taken together with the nitrogen to which they are attached form:

wherein X and Y are independently N or CR^a; wherein R^a is H or C_1-4alkyl; and R^b is phenyl, monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three R^d substituents; or R^1a is H or C1-4alkyl; and R^1b is a heteroaryl optionally substituted with R^c; wherein R^c is C1-4alkyl, phenyl, -C1-4alkyl-phenyl, monocyclic cycloalkyl, -C_1-4alkyl-(monocyclic cycloalkyl), monocyclic heterocyclyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, or -C1-4alkyl-(monocyclic heteroaryl), wherein each alkyl, phenyl, cycloalkyl, heterocyclyl, heterocycloalkyl or heteroaryl is optionally substituted with one, two, or three R^d substituents; wherein each R^d substituent is independently C_1-4alkyl, C_1-4alkenyl, C_1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)1-2R^h, -NR^gS(=O)_1-2NR^gR^h, =NSO₂R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)₂R^g, -OS(=O)_1-2R^g, -S(=O)1-2OR^g, or -S(=O)1-2NR^gR^h; wherein R^g and R^h are each independently H or C_1-4alkyl; each of R² and R³ is independently chosen from H, C_1-4alkyl, cycloalkyl, C_1- 4alkylcycloalkyl, heterocyclyl, heterocycloalkyl, and heteroaryl optionally substituted with one, two, or three R^j substituents; or R² and R³ taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one, two, three, or four R^j substituents, or further wherein any of the hydrogens bonded to carbon atoms are optionally replaced by deuterium; wherein each R^j substituent is independently C_1-4alkyl, -OH, oxo, -NR^kR^l, halo, C_1-4haloalkyl, -O-C_1-4alkyl, or -O-C_1-4-haloalkyl; where R^k and R^l are each independently H or C1-4alkyl; R⁴ is H, halo, -C(O)OH, C_1-4alkylNR^xR^y _, or -C(O)NR^xR^y, or is a cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl, wherein each cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one, two, or three R^z substituents; wherein R^x is H or C_1-4alkyl and R^y is H, C_1-4alkyl, -O-C_1-4alkyl, -SO₂-R^r, C_1-4alkyl-SO₂- R^r monocyclic cycloalkyl, -C1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; or R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C1-4alkyl or -OC1-4alkyl; and each R^z substituent is independently C_1-4alkyl, halo, -NR^pR^q, -C(O)NR^pR^q, -OH, or -OC_1-4alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ; wherein R^m and Rⁿ are each independently H, C1-4alkyl, C(O)C1-2alkyl, C(O)C_1-2haloalkyl, C(O)C_1-2alkenyl, or R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl, optionally substituted with one or two R^o substituents; wherein each R^o substituent is independently C1-4alkyl, -OH, -OC1-4alkyl, halo, cyano, methylsulfonyl, -NR^pR^q, or -C(O)NR^pR^q; wherein R^p and R^q are each independently H, C_1-4alkyl, C_1-4alkylNH₂, C1-4alkylNH(C1-4alkyl), or C1-4alkylN(C1-4alkyl)2; wherein each R^r is independently C1-4alkyl or NR^pR^q; and R⁵ is H, C_1-4alkyl, halo, -OH, or -OC_1-4alkyl; or a pharmaceutically acceptable salt or prodrug or prodrug thereof; or (ii) Formula (II)

wherein R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C1-4alkylNR^xR^y or C(O)NR^xR^y; or is phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof; or (iii) Formula (III):

wherein R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C_1-4alkylNR^xR^y or -C(O)NR^xR^y; or is phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof; or (iv) Formula (IV):

wherein R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C_1-4alkyl, -CF₃, fluoro, chloro, -OCH₃, and -OCF₃; and R^4a is C1-4alkylNR^xR^y or -C(O)NR^xR^y; or is phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof. [0007] Embodiment 1a is the method of embodiment 1,wherein: R^1a and R^1b taken together with the nitrogen to which they are attached form:

wherein X and Y are independently N or CR^a; wherein R^a is H or C_1-4alkyl; and R^b is phenyl, monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three R^d substituents; or R^1a is H or C_1-4alkyl; and R^1b is a moncyclic heteroaryl optionally substituted with R^c; wherein R^c is C1-4alkyl, phenyl, -C1-4alkyl-phenyl, monocyclic cycloalkyl, -C1-4alkyl-(monocyclic cycloalkyl), monocyclic heterocyclyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, or -C_1-4alkyl-(monocyclic heteroaryl), wherein each alkyl, phenyl, cycloalkyl, heterocyclyl, heterocycloalkyl or heteroaryl is optionally substituted with one, two, or three R^d substituents; wherein each R^d substituent is independently C_1-4alkyl, C_1-4alkenyl, C_1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)1-2R^h, -NR^gS(=O)_1-2NR^gR^h, =NSO₂R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)₂R^g, -OS(=O)_1-2R^g, -S(=O)1-2OR^g, or -S(=O)1-2NR^gR^h; wherein R^g and R^h are each independently H or C1-4alkyl; R² and R³ taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one, two, three, or four R^j substituents, or further wherein any of the hydrogens bonded to carbon atoms are optionally replaced by deuterium; wherein each R^j substituent is independently C1-4alkyl, -OH, oxo, -NR^kR^l, halo, C1-4haloalkyl, -O-C1-4alkyl, or -O-C1-4-haloalkyl; where R^k and R^l are each independently H or C_1-4alkyl; R⁴ is halo, -C(O)OH, C_1-4alkylNR^xR^y _, or -C(O)NR^xR^y, or is a cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl, wherein each cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one, two, or three R^z substituents; wherein R^x is H or C1-4alkyl and R^y is H, C1-4alkyl, -O-C1-4alkyl, -SO2-R^r, C1-4alkyl-SO2-R^r monocyclic cycloalkyl, -C1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; or R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C_1-4alkyl or -OC_1-4alkyl; and each R^z substituent is independently C_1-4alkyl, halo, -NR^pR^q, -C(O)NR^pR^q, -OH, or -OC1-4alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ; wherein R^m and Rⁿ are each independently H, C_1-4alkyl, C(O)C_1-2alkyl, C(O)C_1-2haloalkyl, C(O)C_1-2alkenyl, or R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl, optionally substituted with one or two R^o substituents; wherein each R^o substituent is independently C_1-4alkyl, -OH, -OC_1-4alkyl, halo, cyano, methylsulfonyl, -NR^pR^q, or -C(O)NR^pR^q; wherein R^p and R^q are each independently H, C1-4alkyl, C1-4alkylNH₂, C1-4alkylNH(C1- 4alkyl), or C_1-4alkylN(C_1-4alkyl)₂; wherein each R^r is independently C1-4alkyl or NR^pR^q; and R⁵ is H, C1-4alkyl, halo, -OH, or -OC1-4alkyl; or a pharmaceutically acceptable salt or prodrug or prodrug thereof. [0008] Embodiment 1b is the method of embodiment 1, wherein R^1b is a monocyclic heteroaryl. [0009] Embodiment 1c is the method of embodiment 1, wherein R² and R³ taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one, two, three, or four R^j substituents, or further wherein any of the hydrogens bonded to carbon atoms are optionally replaced by deuterium.Embodiment 1d is the method of embodiment 1, wherein R⁴ is halo, -C(O)OH, C1-4alkylNR^xR^y, or -C(O)NR^xR^y, or is a cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl, wherein each cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one, two, or three R^z substituents. [0010] Embodiment 2 is the method of embodiment 1, wherein a. the alpha-coronavirus is HCoV 229E; b. the beta-coronavirus lineage B is SARS-CoV2; and c. the beta-coronavirus lineage A is HCoV OC43. [0011] Embodiment 3 is the method of embodiment 2, wherein the infection is caused by SARS-CoV-2, and wherein the infection is COVID-19. [0012] Embodiment 4 is the method of any one of embodiments 1 - 3, wherein R^1a and R^1b are taken together with the nitrogen to which they are attached to form

. [0013] Embodiment 5 is the method of any one of embodiments 1 - 3, wherein R^1a and R^1b are taken together with the nitrogen to which they are attached to form

. [0014] Embodiment 6 is the method of any one of embodiments 1 - 5, wherein X is N and Y is CR^a. [0015] Embodiment 7 is the method of any one of embodiments 1 - 5, wherein X is CR^a and Y is N. [0016] Embodiment 8 is the method of any one of embodiments 1 - 5, wherein X is N and Y is N. [0017] Embodiment 9 is the method of any one of embodiments 1 - 8, wherein R^a is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. [0018] Embodiment 10 is the method of any one of embodiments 1 - 8, wherein R^a is H or methyl. [0019] Embodiment 11 is the method of any one of embodiments 1 - 8, wherein R^a is H. [0020] Embodiment 12 is the method of any one of embodiments 1 - 11, wherein R^b is optionally substituted phenyl. [0021] Embodiment 13 is the method of any one of embodiments 1 - 11, wherein R^b is tolyl. [0022] Embodiment 14 is the method of any one of embodiments 1 - 11, wherein R^b is phenyl. [0023] Embodiment 15 is the method of any one of embodiments 1 - 11, wherein R^b is optionally substituted pyridinyl or pyrimidinyl. [0024] Embodiment 16 is the method of any one of embodiments 1 - 11, wherein R^b is optionally substituted pyridinyl. [0025] Embodiment 17 is the method of any one of embodiments 1 - 11, wherein R^b is substituted with one or two R^d substituents. [0026] Embodiment 18 is the method of any one of embodiments 1 - 11, wherein R^b is methylpryridinyl, phenyl, m-tolyl, chlorophenyl, bromophenyl, methoxyphenyl. [0027] Embodiment 19 is the method of any one of embodiments 1 - 18, wherein R^1a is H or C1-4alkyl; and R^1b is a 5-membered N-containing heteroaryl optionally substituted with R^c. [0028] Embodiment 20 is the method of any one of embodiments 1 - 18, wherein R^1a is H. [0029] Embodiment 21 is the method of any one of embodiments 1 - 18, wherein R^1a is C_1- 4alkyl. [0030] Embodiment 22 is the method of any one of embodiments 1 - 18, wherein R^1a is methyl. [0031] Embodiment 23 is the method of any one of embodiments 1 - 22, wherein R^1b is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazolopyridinyl, or indazolyl, each optionally substituted with R^c. [0032] Embodiment 23a is the method of any one of embodiments 1 – 22, wherein R^1b is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each optionally substituted with R^c. [0033] Embodiment 24 is the method of any one of embodiments 1 - 22, wherein R^1b is pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl or isoxazolyl, each optionally substituted with R^c. [0034] Embodiment 25 is the method of any one of embodiments 1 - 22, wherein R^1b is pyrazolyl, optionally substituted with R^c. [0035] Embodiment 26 is the method of any one of embodiments 1 - 22, wherein R^1b is

[0036] Embodiment 27 is the method of any one of embodiments 1 - 22, wherein R^1b is c

. [0037] Embodiment 28 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted C1-4alkyl. [0038] Embodiment 29 is the method of any one of embodiments 1 - 27, wherein R^c is methyl, ethyl, isopropyl, or trifluoromethyl. [0039] Embodiment 30 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted phenyl. [0040] Embodiment 31 is the method of any one of embodiments 1 - 27, wherein R^c is phenyl or o-, m-, p-tolyl, fluorophenyl, methoxyphenyl, or trifluoromethoxyphenyl. [0041] Embodiment 32 is the method of any one of embodiments 1 - 27, wherein R^c is phenyl. [0042] Embodiment 33 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted monocyclic cycloalkyl. [0043] Embodiment 34 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0044] Embodiment 35 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted cyclopropyl. [0045] Embodiment 36 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted monocyclic heterocycloalkyl. [0046] Embodiment 37 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl. [0047] Embodiment 38 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted monocyclic heterocyclyl. [0048] Embodiment 39 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, or piperazinyl. [0049] Embodiment 40 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted monocyclic heteroaryl. [0050] Embodiment 41 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. [0051] Embodiment 42 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted pyrazole, thiophenyl, imidazolyl, pyridinyl, or pyrimidinyl. [0052] Embodiment 43 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted pyrazolyl. [0053] Embodiment 44 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted pyridinyl. [0054] Embodiment 45 is the method of any one of embodiments 1 - 27, wherein R^c is methylpyridinyl. [0055] Embodiment 46 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted -C1-4alkyl-phenyl, -C1-4alkyl-(monocyclic cycloalkyl), monocyclic heterocycloalkyl, or -C1-4alkyl-(monocyclic heteroaryl). [0056] Embodiment 47 is the method of any one of embodiments 1 - 27, wherein R^c is optionally substituted with one or two R^d substituents and each R^d substituent is independently C1-4alkyl, C1-4alkenyl, C1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C_1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)_1-2R^h, -NR^gS(=O)_1-2NR^gR^h, =NSO₂R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)2R^g, -OS(=O)1-2R^g, -S(=O)1-2OR^g, or -S(=O)1-2NR^gR^h. [0057] Embodiment 48 is the method of any one of embodiments 1 - 47, wherein each R^d substituent is independently C1-4alkyl, -O-C1-4alkyl, C1-4haloalkyl, or halo. [0058] Embodiment 49 is the method of any one of embodiments 1 - 47, wherein each R^d substituent is independently methyl, ethyl, isopropyl, -CF₃, -OCH₃, -OCF₃, or fluoro. [0059] Embodiment 50 is the method of any one of embodiments 1 - 49, wherein R^g and R^h are each independently H or methyl. [0060] Embodiment 51 is the method of any one of embodiments 1 - 50, wherein each of R² and R³ are independently selected from H, pyrrolidinyl, piperidinyl, and piperazinyl, wherein each pyrrolidinyl, piperidinyl, and piperazinyl is optionally substituted with one R^j substituent. [0061] Embodiment 52 is the method of any one of embodiments 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each optionally substituted with one, two, three, or four R^j substituents.Embodiment 53 is the method of any one of embodiments 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form morpholino or piperazinyl, optionally substituted with one, two, three, or four R^j substituents.Embodiment 54 is the method of any one of embodiments 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form 2,2,6,6-tetrafluoro-morpholino, morpholino-2-one, morpholino-3-one, piperazinyl-2-one, piperazinyl-3-one, thiomorpholino-1,1-dioxide. [0062] Embodiment 55 is the method of any one of embodiments 1 - 50, wherein each R^j substituent is independently methyl, oxo, hydroxy, NH₂, -OCH₃, halo, -CF₃, or -OCF₃. [0063] Embodiment 56 is the method of any one of embodiments 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form morpholino in which 1 to 8 hydrogens are replaced with deuterium. [0064] Embodiment 57 is the method of any one of embodiments 1 - 56, wherein R^k and R^l are each independently H or methyl. [0065] Embodiment 58 is the method of any one of embodiments 1 - 57, wherein R⁴ is H. [0066] Embodiment 59 is the method of any one of embodiments 1 - 57, wherein R⁴ is chloro. [0067] Embodiment 60 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted phenyl. [0068] Embodiment 61 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted heteroaryl. [0069] Embodiment 62 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted monocyclic heteroaryl. [0070] Embodiment 63 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. [0071] Embodiment 64 is the method of any one of embodiments 1 - 57, wherein R⁴ is

or each optionally

substituted with 1 or 2 R^z groups. [0072] Embodiment 65 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted pyridinyl or pyrimidinyl. [0073] Embodiment 66 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted pyridinyl. [0074] Embodiment 67 is the method of any one of embodiments 1 - 57, wherein R⁴ is pyridinyl. [0075] Embodiment 68 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted pyrazolyl. [0076] Embodiment 69 is the method of any one of embodiments 1 - 57, wherein R⁴ is optionally substituted with one or two R^z substituents. [0077] Embodiment 70 is the method of any one of embodiments 1 - 57, wherein R⁴ is pyrazolyl optionally substituted with one or two R^z substituents. [0078] Embodiment 71 is the method of any one of embodiments 1 - 57, wherein R⁴ is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C_1-4alkyl, - CF₃, fluoro, chloro, -OCH₃, and -OCF₃. [0079] Embodiment 72 is the method of any one of embodiments 1 - 57, wherein R⁴ is heterocyclyl, optionally substituted with one or two R^z substituents. [0080] Embodiment 73 is the method of any one of embodiments 1 - 57, wherein R⁴ is pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, optionally substituted with one or two R^z substituents. [0081] Embodiment 74 is the method of any one of embodiments 1 - 57, wherein R⁴ is heterocycloalkyl, optionally substituted with one or two R^z substituents. [0082] Embodiment 75 is the method of any one of embodiments 1 - 57, wherein R⁴ is pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinomethyl, or thiomorpholinomethyl, optionally substituted with one or two R^z substituents. [0083] Embodiment 76 is the method of any one of embodiments 1 - 57, wherein R⁴ is 3- methyl-1H-pyrazol-5-yl, 3-methylisothiazol-5-yl, 2-methyl-1H-imidazol-5-yl, 1-methyl-pyrazol- 4-yl, 1-methylpyrazol-3-yl, 1-((1-acetamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1- chloromethylamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1-acrylamido)-eth-2-yl)-5-methyl- pyrazol-3-yl, thiazol-2-yl, pyrazol-4-yl, pyrazol-1-yl, oxazol-2-yl, 3-(1-N,N-dimethyl-eth-2-yl)- 4-methyl-pyrazol-1-yl, or pyridinyl. [0084] Embodiment 77 is the method of any one of embodiments 1 - 57, wherein R⁴ is C1- 4alkylNR^xR^y. [0085] Embodiment 78 is the method of any one of embodiments 1 - 57, wherein R⁴ is CH₂NR^xR^y. [0086] Embodiment 79 is the method of any one of embodiments 1 - 57, wherein R⁴ is - C(O)NR^xR^y. [0087] Embodiment 80 is the method of any one of embodiments 1 - 79, wherein R^x is H. [0088] Embodiment 81 is the method of any one of embodiments 1 - 79, wherein R^x is methyl or ethyl, optionally substituted with one, two, or three R^o substituents. [0089] Embodiment 82 is the method of any one of embodiments 1 - 79, wherein R^x is methyl. [0090] Embodiment 83 is the method of any one of embodiments 1 - 82, wherein R^y is H. [0091] Embodiment 84 is the method of any one of embodiments 1 - 82, wherein R^y is C1- 4alkyl, optionally substituted with one, two, or three R^o substituents. [0092] Embodiment 85 is the method of any one of embodiments 1 - 82, wherein R^y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R^o substituents. [0093] Embodiment 86 is the method of any one of embodiments 1 - 82, wherein R^y is H, methyl, ethyl, methyoxy, or methoxyethyl. [0094] Embodiment 87 is the method of any one of embodiments 1 - 82, wherein R^y is methyl. [0095] Embodiment 88 is the method of any one of embodiments 1 - 82, wherein R^y is -SO2- R^r or C_1-4alkyl-SO₂-R^r. [0096] Embodiment 89 is the method of any one of embodiments 1 - 82, wherein R^y is -SO₂- R^r, C1-4alkyl-SO2-R^r; and R^r is CH3 or NH₂, NHCH3, or N(CH3)2. [0097] Embodiment 90 is the method of any one of embodiments 1 - 82, wherein R^y is -SO2- methyl, C_2-4alkyl-SO₂-N(CH₃)₂. [0098] Embodiment 91 is the method of any one of embodiments 1 - 82, wherein R^y is monocyclic cycloalkyl or -C1-2alkyl(monocyclic cycloalkyl), each optionally substituted with one, two, or three R^o substituents. [0099] Embodiment 92 is the method of any one of embodiments 1 - 82, wherein R^y is monocyclic cycloalkyl, optionally substituted with one, two, or three R^o substituents. [0100] Embodiment 93 is the method of any one of embodiments 1 - 82, wherein R^y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one, two, or three R^o substituents. [0101] Embodiment 94 is the method of any one of embodiments 1 - 82, wherein R^y is cyclopropyl. [0102] Embodiment 95 is the method of any one of embodiments 1 - 82, wherein R^y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2- cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl. [0103] Embodiment 96 is the method of any one of embodiments 1 - 82, wherein R^y is monocyclic heterocyclyl, optionally substituted with one, two, or three R^o substituents. [0104] Embodiment 97 is the method of any one of embodiments 1 - 82, wherein R^y is optionally substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, azocanyl, tetrahydrofuranyl, or tetrahydropyranyl, optionally substituted with methyl. [0105] Embodiment 98 is the method of any one of embodiments 1 - 82, wherein R^y is monocyclic heterocycloalkyl, optionally substituted with one, two, or three R^o substituents. [0106] Embodiment 99 is the method of any one of embodiments 1 - 82, wherein R^y is optionally substituted azetidinylmethyl, oxetanylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, or piperazinylmethyl, optionally substituted with methyl. [0107] Embodiment 100 is the method of any one of embodiments 1 - 79, wherein one of R^x and R^y is H and the other is -CH3. [0108] Embodiment 101 is the method of any one of embodiments 1 - 79, wherein both of R^x and R^y is H. [0109] Embodiment 102 is the method of any one of embodiments 1 - 79, wherein both of R^x and R^y is -CH₃. [0110] Embodiment 103 is the method of any one of embodiments 1 - 79, wherein R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C1-4alkyl. [0111] Embodiment 104 is the method of any one of embodiments 1 - 79, wherein R^x and R^y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally substituted with methyl. [0112] Embodiment 105 is the method of any one of embodiments 1 - 104, wherein each R^z is independently C1-4alkyl, halo, -OH, or -OC1-4alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ. [0113] Embodiment 106 is the method of any one of embodiments 1 - 104, wherein each R^z is independently -CH3, -OH, halo, or -OCH3. [0114] Embodiment 107 is the method of any one of embodiments 1 - 104, wherein R^z is C_2- ₄alkyl substituted with -NR^mRⁿ or OCH₃. [0115] Embodiment 108 is the method of any one of embodiments 1 - 104, wherein each R^z substituent is independently -NR^pR^q, -C(O)NR^pR^q. [0116] Embodiment 109 is the method of any one of embodiments 1 - 104, wherein each R^z substituent is methyl, ethyl, isopropyl, -CF3, fluoro, chloro, -OCH3, -OCF3, methylamino, ethylamino, propylamino, butylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, -C(O)methylamino, -C(O)ethylamino, -C(O)propylamino, - C(O)butylamino, -C(O)dimethylamino, -C(O)dimethylaminomethyl, -C(O)dimethylaminoethyl, -C(O)dimethylaminopropyl, or -C(O)dimethylaminobutyl. [0117] Embodiment 110 is the method of any one of embodiments 1 - 109, wherein R^m and Rⁿ are each independently H, C1-4alkyl, C(O)CH3, C(O)CH₂Cl, or C(O)CH₂CH₂. [0118] Embodiment 111 is the method of any one of embodiments 1 - 109, wherein R^m and Rⁿ are each H. [0119] Embodiment 112 is the method of any one of embodiments 1 - 109, wherein R^m and Rⁿ are each methyl. [0120] Embodiment 113 is the method of any one of embodiments 1 - 109, wherein R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with one or two R^o substituents. [0121] Embodiment 114 is the method of any one of embodiments 1 - 109, wherein R^m and Rⁿ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, or thiomorpholino-1,1-dioxide, each optionally substituted with one or two R^o substituents. [0122] Embodiment 115 is the method of any one of embodiments 1 - 109, wherein R^m and Rⁿ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or morpholino, each optionally substituted with methyl. [0123] Embodiment 116 is the method of any one of embodiments 1 - 115, wherein each R^o substituent is C_1-4alkyl, or -NR^pR^q. [0124] Embodiment 117 is the method of any one of embodiments 1 - 116, wherein R^p and R^q are each independently H, methyl, C1-4alkylNH₂, C1-4alkylNHCH3, or C1-4alkylN(CH3)2. [0125] Embodiment 118 is the method of any one of embodiments 1 - 116, wherein R^p and R^q are each independently H or methyl. [0126] Embodiment 119 is the method of any one of embodiments 1 - 118, wherein R⁵ is H, methyl, ethyl, chloro, bromo, fluoro, -OH, or -OCH₃. [0127] Embodiment 120 is the method of any one of embodiments 1 - 118, wherein R⁵ is H. [0128] Embodiment 121 is the method of any one of embodiments 1 - 3, wherein R^c1 is phenyl or pyridyl, each optionally substituted with methyl, -CF3, Cl, Br, or OCH3. [0129] Embodiment 122 is the method of any one of embodiments 1 - 3, wherein R^c1 is phenyl. [0130] Embodiment 123 is the method of any one of embodiments 1 - 3, wherein R^c1 is tolyl. [0131] Embodiment 124 is the method of any one of embodiments 1 - 3, wherein R^c1 is pyridyl optionally substituted with methyl or -CF₃. [0132] Embodiment 125 is the method of any one of embodiments 1 - 3, wherein R^4a is pyridyl, optionally substituted with one or two R^z groups. [0133] Embodiment 126 is the method of any one of embodiments 1 - 3, wherein R^4a is pyridyl. [0134] Embodiment 127 is the method of any one of embodiments 1 - 3, wherein R^4a is pyrazolyl optionally substituted with one or two R^z groups. [0135] Embodiment 128 is the method of any one of embodiments 1 - 3, wherein R^4a is 3- methyl-1H-pyrazol-5-yl, 3-methylisothiazol-5-yl, 2-methyl-1H-imidazol-5-yl, 1-methyl-pyrazol- 4-yl, 1-methylpyrazol-3-yl, 1-((1-acetamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1- chloromethylamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1-acrylamido)-eth-2-yl)-5-methyl- pyrazol-3-yl, thiazol-2-yl, pyrazol-4-yl, pyrazol-1-yl, oxazol-2-yl, or 3-(1-N,N-dimethyl-eth-2- yl)-4-methyl-pyrazol-1-yl. [0136] Embodiment 129 is the method of any one of embodiments 1 - 3, wherein R^4a is - C(O)NR^xR^y wherein R^x is H or C_1-4alkyl and R^y is H, C_1-4alkyl, -O-C_1-4alkyl, -SO₂-R^r, C1-4alkyl-SO2-R^r monocyclic cycloalkyl, -C1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; and R^r and R^o are as defined herein. [0137] Embodiment 130 is the method of any one of embodiments 1 - 3, wherein R^4a is - C(O)NR^xR^y wherein R^x is H or methyl; and R^y is H, methyl, ethyl, butyl, isopropyl, methoxy, - SO₂-methyl, C_2-4alkyl-SO₂-methyl, C_2-4alkyl-SO₂-N(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted azetidinylmethyl, oxetanylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, or piperazinylmethyl, each optionally substituted with one, two, or three methyl, methoxy, fluoro or amino groups. [0138] Embodiment 131 is the method of any one of the preceding embodiments, wherein the compound is selected from a compound of Table 1 or a pharmaceutically acceptable salt thereof. [0139] Embodiment 132 is the method of any one of embodiments 1 to 131, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms. [0140] Embodiment 133 is the method of any one of the preceding embodiments, wherein the compound and/or the pharmaceutically acceptable salt is in a pharmaceutical composition. [0141] Embodiment 134 is the method of embodiment 133, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS [0142] Figure 1 shows antiviral effect and cell toxicity data for Compound 101 in Vero-E6 cells. Concentration-dependent antiviral effect (i.e., antiviral activity) is shown as percent cell survival (i.e., percent inhibition) on the left axis (data represented by black squares with a solid line). Concentration-dependent cell toxicity is shown as percent cell survival on the right axis (data represented by white squares with a dotted line). [0143] Figure 2 shows antiviral effects of Compound 97 A549-ACE2 cells. Viral titer is shown as Log10 of plaque forming units per mL (PFU/mL) on the left axis (data represented by white circles). Percent cell viability is shown on the right axis (data represented by black circles). [0144] Figures 3A-B show the effects of Compounds 91 and 121 on human alphacoronavirus strain 229E (HCoV 229E). Human bronchial epithelial (16BHE) cells infected with HCoV 229E were compared to uninfected 16HBE cells. Data are presented as mean percentage viral inhibition (EC₅₀; circles) or cell viability (CC₅₀; squares) ± SEM (n=3). Figure 3A shows data for Compound 91; Figure 3B shows data for Compound 121. [0145] Figures 4A-C show the effects of Compounds 91, 114 and 121 on human betacoronavirus strain OC43 (HCoV OC43). Human lung mucoepidermoid (H₂92) cells infected HCoV OC43 were compared to uninfected H₂92 cells. Data are presented as mean percentage viral inhibition (EC50; circles) or cell viability (CC50; squares) ± SEM (n=3). Figure 4A shows data for Compound 91; Figure 4B shows data for Compound 114; Figure 4C shows data for Compound 121. [0146] Figures 5A-C show the activity of Compound 114 (Fig.5A), Compound 163 (Fig.5B), and the remdesivir control (Fig.5C) in a Vero-E6-SARS-CoV-2 cytopathic assay against two SARS-CoV2 strains, Wildtype (WT) and Delta (D). DETAILED DESCRIPTION OF THE INVENTION [0147] The present disclosure provides methods and compositions for the treatment of certain coronavirus infections. In some embodiments, the present disclosure provides methods and compositions for blocking alpha-coronavirus, beta-coronavirus lineage B, and/or beta- coronavirus lineage A into a host cell with compounds that are phosphoinositide kinase inhibitors, in particular FYVE-type finger-containing phosphoinositide kinase (“PIKfyve”) inhibitors. In some embodiments, the present disclosure provides methods and compositions for preventing and/or treating an infection caused by alpha-coronavirus, beta-coronavirus lineage B, or a beta-coronavirus lineage A with compounds that are phosphoinositide kinase inhibitors, in particular PIKfyve inhibitors. [0148] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the described embodiments, it will be understood that such descriptions are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the invention as defined by the appended claims. [0149] Before describing the present teachings in detail, it is to be understood that the disclosure is not limited to specific compositions or process steps, as such may vary. It should be noted that, as used in this specification and the appended claims, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “a surfactant” includes a plurality of surfactants and the like. [0150] Numeric ranges are inclusive of the numbers defining the range. Measured and measurable values are understood to be approximate, taking into account significant digits and the error associated with the measurement. Also, the use of “comprise,” “comprises,” “comprising,” “contain,” “contains,” “containing,” “include,” “includes,” “included,” and “including” are not intended to be limiting. It is to be understood that both the foregoing general description and detailed description are exemplary and explanatory only and are not restrictive of the teachings. [0151] Unless specifically noted in the above specification, embodiments in the specification that recite “comprising” various components are also contemplated as “consisting of” or “consisting essentially of” the recited components; embodiments in the specification that recite “consisting of” various components are also contemplated as “comprising” or “consisting essentially of” the recited components; and embodiments in the specification that recite “consisting essentially of” various components are also contemplated as “consisting of” or “comprising” the recited components (this interchangeability does not apply to the use of these terms in the claims). [0152] The section headings used herein are for organizational purposes only and are not to be construed as limiting the desired subject matter in any way. In the event that any literature incorporated by reference contradicts any term defined in this specification, this specification controls. While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. I. Definitions [0153] Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedence over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. [0154] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings. [0155] As used herein, the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “approximately” can mean within one or more than one standard deviation per the practice in the art. Alternatively, “about” or “approximately” can mean a range of up to 10% (i.e., ±10%) or more depending on the limitations of the measurement system. For example, about 5 mg can include any number between 4.5 mg and 5.5 mg. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the instant disclosure, unless otherwise stated, the meaning of “about” or “approximately” should be assumed to be within an acceptable error range for that particular value or composition. “Or” is used in the inclusive sense, i.e., equivalent to “and/or,” unless the context requires otherwise. [0156] The term “and/or” used herein is to be taken mean specific disclosure of each of the specified features or components with or without the other. For example, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).The terms “or a combination thereof” and “or combinations thereof” as used herein refers to any and all permutations and combinations of the listed terms preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context. [0157] The term “subject” and “patient” as used herein refers to human and non-human animals, including vertebrates, mammals and non-mammals. In one embodiment, the subject can be human, non-human primates, simian, ape, murine (e.g., mice and rats), bovine, porcine, equine, canine, feline, caprine, lupine, ranine or piscine. [0158] The term “administering”, “administered” and grammatical variants refers to the physical introduction of an agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. In one embodiment, the formulation is administered via a non-parenteral route, e.g., orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. [0159] The terms “treat,” “treating,” and “treatment,” as used herein, covers any administration or application of a therapeutic for disease/disorder in a subject, and includes inhibiting the disease/disorder, arresting its development, relieving one or more symptoms of the disease/disorder, or curing the disease/disorder. [0160] The terms “prevent” and “preventing” as used herein, means inhibiting or arresting development of a disease/disorder in a subject deemed to be disease/disorder free. [0161] The terms “block” and “blocking” as used herein with reference to viral entry into a host cell refers to stopping the entry of some or all of a virus, such as a coronavirus, into a host cell or host cells. The blocking may be complete or partial. Partial blocking includes preventing at least some virus from entering host cells, for example, enough virus to prevent the subject from displaying at least one symptom associated with such viral infection. [0162] The terms "effective amount", “therapeutically effective amount” or “effective dose” or related terms may be used interchangeably and refer to an amount of a described PIKfyve inhibitor that when administered to a subject, is sufficient to affect a measurable improvement or prevention of a disease or disorder associated with a virus infection. [0163] A “pharmaceutically acceptable vehicle” for therapeutic purposes is a physical embodiment that can be administered to a subject. Pharmaceutically acceptable vehicles include pills, capsules, caplets, tablets, oral fluids, injection fluids, sprays, aerosols, troches, dietary supplements, creams, lotions, oils, solutions, pastes, powders, steam, Or it may be a liquid, but is not limited to these. An example of a pharmaceutically acceptable vehicle is a buffered isotonic solution such as phosphate buffered saline (PBS). [0164] “Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like. [0165] “Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like. [0166] “Alkylsulfonyl” means a –SO₂R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like. [0167] “Amino” means a -NH₂. [0168] “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. [0169] “Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with an alkoxy group, (in one embodiment one or two alkoxy groups), as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like. [0170] “Alkoxycarbonyl” means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like. [0171] “Acyl” means a -COR radical where R is alkyl, haloalkyl, or cycloalkyl, e.g., acetyl, propionyl, cyclopropylcarbonyl, and the like. When R is alkyl, the radical is also referred to herein as alkylcarbonyl. [0172] “Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms wherein one or two carbon atoms may be replaced by an oxo group, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like. [0173] “Carboxy” means –COOH. [0174] A “coronavirus,” “corona respiratory virus,” and “CoV” are used interchangeably herein to refer to a virus belonging to the family Coronaviridae. Coronaviruses are enveloped, positive-sense RNA viruses of approximately 31 Kb, making these viruses the largest known RNA viruses. Coronaviruses infect a variety of host species, including humans and several other vertebrates. These viruses predominantly cause respiratory and intestinal tract infections and induce a wide range of clinical manifestations. In general, coronaviruses can be classified into low pathogenic CoVs (including human CoVs (hCoVs)) and highly pathogenic CoVs, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV). Low pathogenic hCoV infect upper airways and cause seasonal mild to moderate cold-like respiratory illnesses in healthy individuals. In contrast, the highly pathogenic hCoVs (pathogenic hCoV) infect the lower respiratory tract and cause severe pneumonia, which sometimes leads to fatal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), resulting in high morbidity and mortality. [0175] “Halo” means fluoro, chloro, bromo, or iodo. [0176] “Haloalkyl” means alkyl radical as defined above, which is substituted with one or one to five halogen atoms (in one embodiment fluorine or chlorine,) including those substituted with different halogens, e.g., -CH₂Cl, -CF₃, -CHF₂, -CH₂CF₃, -CF₂CF₃, -CF(CH₃)₂, and the like. In Cx-y-haloalkyl, “Cx-y” means the number of carbon atoms in the alkyl group ranges from x to y. When the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkyl. [0177] “Haloalkoxy” means a –OR radical where R is haloalkyl as defined above e.g., -OCF3, -OCHF₂, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkoxy. [0178] “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2- hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl. Further examples include, but are not limited to, 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymethyl)-2-hydroxyethyl. [0179] “Heterocyclyl” means a saturated or unsaturated monovalent monocyclic or bi-cyclic group (fused bi-cyclic or bridged bi-cyclic) of 4 to 10 ring atoms in which one or two ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO- group. More specifically the term heterocyclyl includes, but is not limited to, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one- yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. [0180] ^“Heterocyclylalkyl” and “heterocycloalkyl” mean an –(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like. [0181] “Heterocycloamino” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C provided that at least one of the ring atoms is N. Additionally, one or two ring carbon atoms in the heterocycloamino ring can optionally be replaced by a –CO- group. When the heterocycloamino ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. [0182] “Heterocycloaminoalkyl” means a –(alkylene)-R radical where R is heterocycloamino as described above. [0183] “Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, (in one embodiment one, two, or three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolopyridinyl, indazolyl, furopyrimidinyl, and the like. [0184] “Oxo” means an =(O) group and “carbonyl” means a >C(O) group. [0185] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocyclyl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl. [0186] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0187] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. [0188] “PIKfyve inhibitor” refers to a molecule that inhibits phosphatidylinositol 3-phosphate 5-kinase (PIKfyve). [0189] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference. II. Methods of Treating, Uses, Administration, and Pharmaceutical Compositions [0190] Provided herein are methods of treating an infection caused by a virus, inhibiting entry of a virus into a host cell, or inhibiting fusion of viral membrane with a host cell membrane comprising administering to a subject in need thereof a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. [0191] In one aspect, the disclosure relates to a method of blocking alpha-coronavirus entry into a host cell and preventing an infection caused by alpha-coronavirus, comprising administering to a subject in need thereof a compound of Formula (I) or any of the embodiments thereof described herein. In some embodiments, the alpha-coronavirus is HCoV 229E. [0192] In another aspect, the disclosure relates to a method of blocking beta-coronavirus lineage B entry into a host cell and preventing an infection caused by beta-coronavirus lineage B, comprising administering to a subject in need thereof a compound of Formula (I) or any of the embodiments thereof described herein. In some embodiments, the beta-coronavirus lineage B is SARS-CoV2. In some embodiments, the infection caused by SARS-CoV-2 is COVID-19. In some embodiments, the methods treat or prevent COVID-19 infection. [0193] In another aspect, the disclosure relates to a method of blocking beta-coronavirus lineage A entry into a host cell and preventing an infection caused by beta-coronavirus lineage A, comprising administering to a subject in need thereof a compound of Formula (I) or any of the embodiments thereof described herein. In some embodiments, the beta-coronavirus lineage A is HCoV OC43. [0194] In some embodiments, a method of inhibiting coronavirus viral membrane fusion with an early endosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with a maturing endosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with a late endosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with an endo-lysosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with a lysosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with an early macropinosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with a macropinosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with a late macropinosomal membrane is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusion with the endoplasmic reticulum (ER) is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In some embodiments, a method of inhibiting coronavirus viral membrane fusing with the plasma membrane directly is provided comprising administering a compound of Formula (I) or any of the embodiments thereof (e.g., compounds of Table 1) described herein. In each such embodiment, the coronavirus may be an alpha-coronavirus, a beta-coronavirus lineage B, or a beta-coronavirus lineage A. [0195] In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. [0196] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. In some embodiments, the manner of administration is nasal using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. [0197] Pharmaceutical compositions can be formulated using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries. The formulation can be modified depending upon the route of administration chosen. The pharmaceutical compositions can also include the compounds described herein in a free base form or a pharmaceutically acceptable salt form. [0198] Methods for formulation of the pharmaceutical compositions can include formulating any of the compounds described herein with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compositions described herein can be lyophilized or in powder form for re- constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug- delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. [0199] The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration. [0200] The pharmaceutical compositions described herein can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution, or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion. [0201] For parenteral administration, the compounds can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently nontoxic, and non-therapeutic. A vehicle can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives). [0202] Sustained-release preparations can also be prepared. Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and γ ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO^TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(–)-3-hydroxybutyric acid. [0203] Pharmaceutical formulations of the compositions described herein can be prepared for storage by mixing a compound with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and/or stabilizers can be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non- ionic surfactants or polyethylene glycol. [0204] Compounds of the present disclosure may be used in methods of treating in combination with one or more other combination agents (e.g., one, two, or three other drugs) that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful. In some embodiments, the combination of the drugs together is safer or more effective than either drug alone. In some embodiments the compounds disclosed herein and the one or more combination agents have complementary activities that do not adversely affect each other. Such molecules can be present in combination in amounts that are effective for the purpose intended. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, in some embodiments, the agents are administered together in a single pharmaceutical composition in unit dosage form. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active agent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. In some embodiments, combination therapy includes therapies in which the compound of the present disclosure and one or more other drugs are administered separately, and in some cases, the two or more agents are administered on different, overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. [0205] The compounds, pharmaceutical compositions, and methods of the present disclosure can be useful for treating and preventing infection in a subject such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a non-domesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig, a horse, a goat, a sheep, or a rabbit. In preferred embodiments, compounds, pharmaceutical compositions, and methods of the present disclosure are used for treating a human. [0206] The compounds, pharmaceutical compositions, and methods described herein can be useful as a therapeutic or preventative, for example a treatment or preventative that can be administered to a subject in need thereof. A therapeutic or preventative effect can be obtained in a subject by prevention (complete or partial), reduction, suppression, remission, or eradication of a disease state, including, but not limited to, a symptom thereof. A therapeutic effect in a subject having a disease or condition, or pre-disposed to have or is beginning to have the disease or condition, can be obtained by a reduction, a suppression, a prevention, a remission, or an eradication of the condition or disease, or pre-condition or pre-disease state. [0207] In practicing the methods described herein, therapeutically effective amounts of the compounds or pharmaceutical compositions described herein can be administered to a subject in need thereof, often for treating and/or preventing a condition or progression thereof. A pharmaceutical composition can affect the physiology of the subject, such as the immune system, inflammatory response, or other physiologic affect. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. [0208] Treat and/or treating can refer to any indicia of success in the treatment or amelioration of the disease or condition. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treat can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely. [0209] Prevent, preventing, and the like can refer to the prevention of the disease or condition in the patient. For example, if an individual at risk of contracting a disease is treated with the methods of the present disclosure and does not later contract the disease, then the disease has been prevented, at least over a period of time, in that individual. In some embodiments the PIKfyve inhibitors described herein can prevent coronavirus infection. In some embodiments the PIKfyve inhibitors described herein can treat a coronavirus infection. [0210] A therapeutically effective amount can be the amount of a compound or pharmaceutical composition or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered. A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment and can be ascertainable by one skilled in the art using known techniques. [0211] The compounds or pharmaceutical compositions described herein that can be used in the methods and uses described herein can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, the condition of the individual patient, the site of delivery of the compound or pharmaceutical composition, the method of administration and other factors known to practitioners. The compounds or pharmaceutical compositions can be prepared according to the description of preparation described herein. [0212] One of ordinary skill in the art would understand that the amount, duration, and frequency of administration of a pharmaceutical composition or compound described herein to a subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the patient, the grade or level of a specific disease or condition of the patient, the additional therapeutics the subject is being or has been administered, and the like. [0213] The methods, uses, compounds, and pharmaceutical compositions described herein can be for administration to a subject in need thereof. Often, administration of the compounds or pharmaceutical compositions can include routes of administration, non-limiting examples of administration routes include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or intraperitoneally. Additionally, a pharmaceutical composition or compound can be administered to a subject by additional routes of administration, for example, by inhalation, oral, dermal, intranasal, or intrathecal administration. [0214] Pharmaceutical compositions or compounds of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations. The one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks, or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days or less than 1 day after the first administration. The one or more administrations can occur more than once per day, more than once per week, or more than once per month. The compounds or pharmaceutical compositions can be administered to the subject in need thereof in cycles of 21 days, 14 days, 10 days, 7 days, 4 days, or daily over a period of one to seven days. [0215] The compounds, pharmaceutical compositions, and methods provided herein can be useful for the treatment of a plurality of diseases or conditions or preventing a disease or a condition in a subject, or other therapeutic applications for subjects in need thereof. III. Viruses Treatable and Preventable with the Disclosed Compositions [0216] The PIKfyve inhibitors described herein can be administered to treat and/or prevent certain coronavirus infection. [0217] The coronaviruses belong to the order Nidovirales, family Coronaviridae, and the subfamily Coronavirinae. They are genetically categorized into four genera: the Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Mahendra et al., Cureus, 12(3):e7423 (2020). The Alphacoronaviruses and the Betacoronaviruses typically infect mammals, whereas the Gammacoronaviruses and the Deltacoronaviruses predominantly infect birds. In some embodiments, the coronavirus is an Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or Deltacoronavirus. [0218] Alphacoronavirus strains that are associated with human disease include HCoV-229E and HCoV-NL63. (Id.) Other examples of alphacoronavirus strains include feline infectious peritonitis virus (FIPV), canine coronavirus (CCoV), porcine respiratory coronavirus (PRCV), porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), Rhinolophus bat coronavirus (Rh-BatCoV) HKU2, Miniopterus bat coronavirus (Mi-BatCoV) HKU8, Mi-BatCoV 1A, Mi-BatCoV 1B, Rousettus bat coronavirus (Ro-BatCoV) HKU10183A, Hipposideros bat coronavirus (Hi-BatCoV) HKU10 LSH5A, and Scotiphilus bat coronavirus (Sc-BatCoV) 512. Lau et al., J. Virol.86(21):11906-11918 (2012); Woo et al., Viruses, 2(8):1804-1820 (2010). In some embodiments, the coronavirus is HCoV-229E or HCoV-NL63. In other embodiments, the coronavirus is FIPV, CCoV, PRCV, PEDV, TGEV, Rh-BatCoV HKU2, Mi-BatCoV HKU8, Mi-BatCoV 1A, Mi-BatCoV 1B, Ro-BatCoV HKU10183A, Hi- BatCoV HKU10 LSH5A, and Sc-BatCoV 512. [0219] Betacoronaviruses are divided into four subgroups: Embecovirus (lineage A), Sarbecovirus (lineage B), Merbecovirus (lineage C), and Nobecovirus (lineage D). Woo et al., Viruses, 2(8):1804-1820 (2010). Examples of Embecovirus (lineage A) include bovine coronavirus (BCoV), human coronavirus OC43 (HCoV-OC43), HCoV-HKU1, porcine hemagglutinating encephalomyelitis virus (PHEV), giraffe coronavirus (GiCoV), and murine hepatitis virus (MHV). Id. Examples of Sarbecovirus (lineage B) include SARS-CoV-1 and SARSr-Rh-BatCoV HKU3. Id. Examples of Merbecovirus (lineage C) include MERS-CoV, Tylonycteris bat coronavirus (Ty-BatCoV) HKU4 and Pipistrellus bat coronavirus (Pi-BatCoV) HKU5. Id. Examples of Nobecovirus (lineage D) include Ro-BatCoV HKU9. Id. Betacoronavirus strains that are associated with human disease include SARS-CoV-1, HCoV- OC43, HCoV-HKU1, and MERS-CoV. [0220] In some embodiments, the coronavirus causes upper respiratory tract disease, lower respiratory tract disease, fever, sore throat, swollen adenoids, colds with minor or major symptoms, malaise, muscle and joint pains, nausea, vomiting, loss of appetite, pneumonia, secondary bacterial infection, bronchitis, dyspnea, diarrhea, shortness of breath, acute respiratory distress syndrome, cytokine storm, multi-organ failure, septic shock, blood clots, loss of smell, or loss of taste. In some embodiments, the coronavirus causes no symptoms at all. [0221] In some embodiments, the disclosed compounds are administered to block an alpha- coronavirus entry into a host cell. In some embodiments, the disclosed compounds are administered to block a beta-coronavirus lineage B entry into a host cell. In some embodiments, the disclosed compounds are administered to block a beta-coronavirus lineage A entry into a host cell. In some embodiments, the disclosed compounds are administered to prevent an alpha- coronavirus infection in a subject. In some embodiments, the disclosed compounds are administered to prevent a beta-coronavirus lineage B infection in a subject. In some embodiments, the disclosed compounds are administered to prevent a beta-coronavirus lineage A infection in a subject. In some embodiments, the disclosed compounds are administered to block an alpha-coronavirus entry into a host cell and prevent an alpha-coronavirus infection in a subject. In some embodiments, the disclosed compounds are administered to block a beta- coronavirus lineage B entry into a host cell prevent a beta-coronavirus lineage B infection in a subject. In some embodiments, the disclosed compounds are administered to block a beta- coronavirus lineage A entry into a host cell prevent a beta-coronavirus lineage A infection in a subject. In some embodiments, the alpha-coronavirus is HCoV 229E. In some embodiments, the beta-coronavirus lineage B is SARS-CoV2. In some embodiments, the beta-coronavirus lineage A is HCoV OC43. In some embodiments, the infection is caused by SARS-CoV-2, and the infection is COVID-19. IV. PIKfyve inhibitor compounds [0222] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active, optically enriched, optically pure, or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. [0223] Certain compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this disclosure. For example, pyrazole tautomers as shown below are equivalent structures. The depiction of one such structure is intended to encompass both structures.

[0224] Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as heteroaryl, heterocyclyl are substituted, they include all the positional isomers. [0225] Pharmaceutically acceptable salts of the compounds of Formula (I) (or any of the embodiments thereof described herein) are within the scope of this disclosure. In addition, the compounds described herein include hydrates and solvates of the compounds or pharmaceutically acceptable salts thereof. [0226] The present disclosure also includes the prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof. The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) (or any of the embodiments thereof described herein) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups in vivo or by routine manipulation. Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) or phosphonates (e.g., -OP(=O)(OH)2 ) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof are also within the scope of this disclosure. [0227] The present disclosure also includes polymorphic forms (amorphous as well as crystalline) and deuterated forms of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof. [0228] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [0229] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of the present disclosure. [0230] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, and ¹²⁵I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0231] In certain embodiments, the compounds disclosed herein have some or all of the ¹H atoms replaced with ²H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [0232] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [0233] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [0234] In one aspect is a compound of Formula (I):

wherein X and Y are independently N or CR^a; wherein R^a is H or C_1-4alkyl; and R^b is phenyl, monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three R^d substituents; or R^1a is H or C1-4alkyl; and R^1b is a heteroaryl optionally substituted with R^c; wherein R^c is C1-4alkyl, phenyl, -C1-4alkyl-phenyl, monocyclic cycloalkyl, -C_1-4alkyl-(monocyclic cycloalkyl), monocyclic heterocyclyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, or -C1-4alkyl-(monocyclic heteroaryl), wherein each alkyl, phenyl, cycloalkyl, heterocyclyl, heterocycloalkyl or heteroaryl is optionally substituted with one, two, or three R^d substituents; wherein each R^d substituent is independently C_1-4alkyl, C_1-4alkenyl, C_1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)1-2R^h, -NR^gS(=O)_1-2NR^gR^h, =NSO₂R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)₂R^g, -OS(=O)_1-2R^g, -S(=O)1-2OR^g, or -S(=O)1-2NR^gR^h; wherein R^g and R^h are each independently H or C_1-4alkyl; each of R² and R³ is independently chosen from H, C_1-4alkyl, cycloalkyl, C_1-4alkylcycloalkyl, heterocyclyl, heterocycloalkyl, and heteroaryl, each optionally substituted with one, two, or three R^j substituents; or R² and R³ taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one, two, three, or four R^j substituents, or further wherein any of the hydrogens bonded to carbon atoms are optionally replaced by deuterium; wherein each R^j substituent is independently C_1-4alkyl, -OH, -NR^kR^l, halo, C_1-4haloalkyl, -O- C_1-4alkyl, or -O-C_1-4-haloalkyl; where R^k and R^l are each independently H or C1-4alkyl; R⁴ is H, halo, -C(O)OH, C_1-4alkylNR^xR^y _, or -C(O)NR^xR^y, or is a cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl, wherein each cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one, two, or three R^z substituents; wherein R^x is H or C_1-4alkyl and R^y is H, C_1-4alkyl, -O-C_1-4alkyl, -SO₂-R^r, C_1-4alkyl-SO₂-R^r monocyclic cycloalkyl, -C1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; or R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C1-4alkyl or -OC1-4alkyl; and each R^z substituent is independently C_1-4alkyl, halo, -NR^pR^q, -C(O)NR^pR^q, -OH, or -OC_1- ₄alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ; wherein R^m and Rⁿ are each independently H, C1-4alkyl, C(O)C1-2alkyl, C(O)C_1-2haloalkyl, C(O)C_1-2alkenyl, or R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl, optionally substituted with one or two R^o substituents; wherein each R^o substituent is independently C1-4alkyl, -OH, -OC1-4alkyl, halo, cyano, methylsulfonyl, -NR^pR^q, or -C(O)NR^pR^q; wherein R^p and R^q are each independently H, C_1-4alkyl, C_1-4alkylNH₂, C_1-4alkylNH(C_1- 4alkyl), or C1-4alkylN(C1-4alkyl)2; wherein each R^r substituent is independently C1-4alkyl or NR^pR^q; and R⁵ is H, C_1-4alkyl, halo, -OH, or -OC_1-4alkyl; or a pharmaceutically acceptable salt or prodrug thereof. [0235] In some embodiments, R^1a and R^1b taken together with the nitrogen to which they are attached form:

wherein X and Y are independently N or CR^a; wherein R^a is H or C_1-4alkyl; and R^b is phenyl, monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three R^d substituents; or R^1a is H or C1-4alkyl; and R^1b is a moncyclic heteroaryl optionally substituted with R^c; wherein R^c is C1-4alkyl, phenyl, -C1-4alkyl-phenyl, monocyclic cycloalkyl, -C_1-4alkyl-(monocyclic cycloalkyl), monocyclic heterocyclyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, or -C1-4alkyl-(monocyclic heteroaryl), wherein each alkyl, phenyl, cycloalkyl, heterocyclyl, heterocycloalkyl or heteroaryl is optionally substituted with one, two, or three R^d substituents; wherein each R^d substituent is independently C_1-4alkyl, C_1-4alkenyl, C_1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)_1-2R^h, -NR^gS(=O)_1-2NR^gR^h, =NSO₂R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)2R^g, -OS(=O)1-2R^g, -S(=O)1-2OR^g, or -S(=O)1-2NR^gR^h; wherein R^g and R^h are each independently H or C_1-4alkyl; R² and R³ taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one, two, three, or four R^j substituents, or further wherein any of the hydrogens bonded to carbon atoms are optionally replaced by deuterium; wherein each R^j substituent is independently C_1-4alkyl, -OH, oxo, -NR^kR^l, halo, C_1-4haloalkyl, -O-C1-4alkyl, or -O-C1-4-haloalkyl; where R^k and R^l are each independently H or C1-4alkyl; R⁴ is halo, -C(O)OH, C1-4alkylNR^xR^y, or -C(O)NR^xR^y, or is a cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl, wherein each cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one, two, or three R^z substituents; wherein R^x is H or C1-4alkyl and R^y is H, C1-4alkyl, -O-C1-4alkyl, -SO2-R^r, C1-4alkyl-SO2- R^r monocyclic cycloalkyl, -C_1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; or R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C_1-4alkyl or -OC_1-4alkyl; and each R^z substituent is independently C1-4alkyl, halo, -NR^pR^q, -C(O)NR^pR^q, -OH, or -OC1-4alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ; wherein R^m and Rⁿ are each independently H, C_1-4alkyl, C(O)C_1-2alkyl, C(O)C1-2haloalkyl, C(O)C1-2alkenyl, or R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl, optionally substituted with one or two R^o substituents; wherein each R^o substituent is independently C_1-4alkyl, -OH, -OC_1-4alkyl, halo, cyano, methylsulfonyl, -NR^pR^q, or -C(O)NR^pR^q; wherein R^p and R^q are each independently H, C_1-4alkyl, C_1-4alkylNH₂, C_1-4alkylNH(C_1- ₄alkyl), or C_1-4alkylN(C_1-4alkyl)₂; wherein each R^r is independently C1-4alkyl or NR^pR^q; and R⁵ is H, C_1-4alkyl, halo, -OH, or -OC_1-4alkyl; or a pharmaceutically acceptable salt or prodrug or prodrug thereof. [0236] In some embodiments, R^1a and R^1b are taken together with the nitrogen to which they are attached to form . In some embodiments, R^1a and R^1b are taken together with

the nitrogen to which they are attached to form In some embodiments, X is N and

Y is CR^a. In some embodiments, X is CR^a and Y is N. In some embodiments, X is N and Y is N. In some embodiments, R^a is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R^a is H or methyl. In some embodiments, R^a is H. [0237] In some embodiments, R^b is optionally substituted phenyl. In some embodiments, R^b is optionally substituted monocyclic heteroaryl. In some embodiments, R^b is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, R^b is optionally substituted pyridinyl or pyrimidinyl. In some embodiments, R^b is optionally substituted pyridinyl. In some embodiments, R^b is phenyl. In some embodiments, R^b is o-, m-, or p-tolyl. In some embodiments, R^b is optionally substituted with one or two R^d substituents. In some embodiments, R^b is optionally substituted with one R^d substituent. In some embodiments, R^b is methylpryridinyl, phenyl, tolyl, chlorophenyl, bromophenyl, or methoxyphenyl. [0238] In some embodiments, R^1a is H or C_1-4alkyl; and R^1b is a 5-membered N-containing heteroaryl optionally substituted with R^c. In some embodiments, R^1a is H. In some embodiments, R^1a is C_1-4alkyl. In some embodiments, R^1a is methyl. [0239] In some embodiments, R^1b is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazolopyridinyl, or indazolyl, each optionally substituted with R^c. In some embodiments, R^1b is a monocyclic heteroaryl. In some embodiments, R^1b is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each optionally substituted with R^c. In some embodiments, R^1b is pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl or isoxazolyl, each optionally substituted with R^c. In some embodiments, R^1b is pyrazolyl, optionally substituted with R^c. In some embodiments, R^1b is

[_{0240] In some embodiments, R} ^1b _is [0241] In some embodiments, R^c

is optionally substituted C_1-4alkyl. In some embodiments, R^c is methyl, ethyl, isopropyl, or trifluoromethyl. In some embodiments, R^c is optionally substituted phenyl. In some embodiments, R^c is phenyl or o-, m-, p-tolyl, fluorophenyl, methoxyphenyl, or trifluoromethoxyphenyl. In some embodiments, R^c is phenyl. In some embodiments, R^c is optionally substituted monocyclic cycloalkyl. In some embodiments, R^c is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R^c is optionally substituted cyclopropyl. In some embodiments, R^c is optionally substituted monocyclic heterocycloalkyl. In some embodiments, R^c is optionally substituted cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl. In some embodiments, R^c is optionally substituted monocyclic heterocyclyl. In some embodiments, R^c is optionally substituted pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, or piperazinyl. In some embodiments, R^c is optionally substituted monocyclic heteroaryl. In some embodiments, R^c is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, R^c is optionally substituted pyrazole, thiophenyl, imidazolyl, pyridinyl, or pyrimidinyl. In some embodiments, R^c is optionally substituted pyrazolyl. In some embodiments, R^c is optionally substituted pyridinyl. In some embodiments, R^c is methylpyridinyl. In some embodiments, R^c is optionally substituted -C_1-4alkyl-phenyl, -C_1- 4alkyl-(monocyclic cycloalkyl), monocyclic heterocycloalkyl, or -C1-4alkyl-(monocyclic heteroaryl). In some embodiments, R^c is optionally substituted benzyl, -CH₂-(monocyclic cycloalkyl), -CH₂-(monocyclic heterocycloalkyl), or -CH₂-(monocyclic heteroaryl). In some embodiments, R^c is optionally substituted benzyl or -CH₂-(monocyclic cycloalkyl), such as -CH₂-cyclopropyl. In some embodiments, each R^c is optionally substituted with one or two R^d substituents. [0242] In some embodiments, each R^d substituent is independently C1-4alkyl, C1-4alkenyl, C1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C_1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)_1-2R^h, -NR^gS(=O)_1-2NR^gR^h, =NSO₂R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)2R^g, -OS(=O)1-2R^g, -S(=O)_1-2OR^g, or -S(=O)_1-2NR^gR^h. In some embodiments, each R^d substituent is independently C_1-4alkyl, -O-C_1-4alkyl, C_1-4haloalkyl, or halo. In some embodiments, each R^d substituent is independently methyl, ethyl, isopropyl, -CF3, -OCH3, -OCF3, or fluoro. [0243] In some embodiments, R^g and R^h are each independently H or methyl. [0244] In some embodiments, R² and R³ taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one, two, three, or four R^j substituents, or further wherein any of the hydrogens bonded to carbon atoms are optionally replaced by deuterium. [0245] In some embodiments, each of R² and R³ are independently selected from H, pyrrolidinyl, piperidinyl, and piperazinyl, wherein each pyrrolidinyl, piperidinyl, and piperazinyl is optionally substituted with one R^j substituent. [0246] In some embodiments, R² and R³ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, or thiomorpholino-1,1-dioxide, each optionally substituted with one, two, three, or four R^j substituents. In some embodiments, R² and R³ taken together with the nitrogen to which they are attached form morpholino or piperazinyl, optionally substituted with one, two, three, or four R^j substituents. In some embodiments, R² and R³ taken together with the nitrogen to which they are attached form 2,2,6,6-tetrafluoro-morpholino, morpholino-2-one, morpholino-3-one, piperazinyl-2-one, piperazinyl-3-one, thiomorpholino-1,1-dioxide. [0247] In some embodiments, each R^j substituent is independently methyl, oxo, hydroxy, -OCH3, NH₂, halo, -CF3, or -OCF3. [0248] In some embodiments, R² and R³ taken together with the nitrogen to which they are attached form morpholino in which 1 to 8 hydrogens are replaced with deuterium. [0249] In some embodiments, R^k and R^l are each independently H or methyl. [0250] In some embodiments, R⁴ is H. In some embodiments, R⁴ is chloro. [0251] In some embodiments, R⁴ is halo, -C(O)OH, C_1-4alkylNR^xR^y _, or -C(O)NR^xR^y, or is a cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl, wherein each cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one, two, or three R^z substituents. [0252] In some embodiments, R⁴ is optionally substituted phenyl. In some embodiments, R⁴ is optionally substituted heteroaryl. In some embodiments, R⁴ is optionally substituted monocyclic heteroaryl. In some embodiments, R⁴ is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, R⁴ is optionally substituted pyridinyl or pyrimidinyl. [0253] In some embodiments, R⁴ is

each optionally substituted with 1 or 2 R^z groups.

[0254] In some embodiments, R⁴ is optionally substituted pyridinyl. In some embodiments, R⁴ is pyridinyl. In some embodiments, R⁴ is 4-pyridyl, 3-pyridyl, or 2-pyridyl. In some embodiments, R⁴ is 4-pyridyl. In some embodiments, R⁴ is optionally substituted with one or two R^z substituents. In some embodiments, R⁴ is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3. [0255] In some embodiments, R⁴ is heterocyclyl, optionally substituted with one or two R^z substituents. In some embodiments, R⁴ is pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, optionally substituted with one or two R^z substituents. In some embodiments, R⁴ is pyrrolidinyl, or piperazinyl, optionally substituted with one C1-4alkyl. In some embodiments, R⁴ is optionally substituted pyrazolyl. In some embodiments, R⁴ is optionally substituted with one or two R^z substituents. In some embodiments, R⁴ is optionally substituted with one R^z substituent. In some embodiments, R⁴ is 3-methyl-1H-pyrazol-5-yl, 3- methylisothiazol-5-yl, 2-methyl-1H-imidazol-5-yl, 1-methyl-pyrazol-4-yl, 1-methylpyrazol-3-yl, 1-((1-acetamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1-chloromethylamido)-eth-2-yl)-5- methyl-pyrazol-3-yl, 1-((1-acrylamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, thiazol-2-yl, pyrazol-4- yl, pyrazol-1-yl, oxazol-2-yl, or 3-(1-N,N-dimethyl-eth-2-yl)-4-methyl-pyrazol-1-yl. [0256] In some embodiments, R⁴ is heterocycloalkyl, optionally substituted with one or two R^z substituents. In some embodiments, R⁴ is pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinomethyl, or thiomorpholinomethyl, optionally substituted with one or two R^z substituents. [0257] In some embodiments, R⁴ is C1-4alkylNR^xR^y. In some embodiments, R⁴ is CH₂NR^xR^y. In some embodiments, R⁴ is -C(O)NR^xR^y. [0258] In some embodiments, R^x is H. In some embodiments, R^x is methyl or ethyl, optionally substituted with one, two, or three R^o substituents. In some embodiments, R^x is methyl. [0259] In some embodiments, R^y is H, methyl, ethyl, methyoxy, or methoxyethyl. In some embodiments, R^y is H. In some embodiments, R^y is C_1-4alkyl, optionally substituted with one, two, or three R^o substituents. In some embodiments, R^y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R^o substituents. In some embodiments, R^y is methyl, ethyl, or methoxyethyl. In some embodiments, R^y is methoxy. In some embodiments, R^y is -SO2-R^r or C1-4alkyl-SO2-R^r. R^y is -SO2-R^r, C1-4alkyl-SO2-R^r; and R^r is CH3 or NH₂, NHCH3, or N(CH3)2. In some embodiments, R^y is -SO2-methyl, C2-4alkyl-SO2-N(CH3)2. In some embodiments, R^y is -SO₂-methyl. In some embodiments, R^y is monocyclic cycloalkyl or -C1-2alkyl(monocyclic cycloalkyl), each optionally substituted with one, two, or three R^o substituents. In some embodiments, R^y is monocyclic cycloalkyl, optionally substituted with one, two, or three R^o substituents. In some embodiments, R^y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one, two, or three R^o substituents. In some embodiments, R^y is cyclopropyl. In some embodiments, R^y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl. In some embodiments, R^y is monocyclic heterocycloalkyl, optionally substituted with one, two, or three R^o substituents. In some embodiments, R^y is optionally substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, azocanyl, tetrahydrofuranyl, or tetrahydropyranyl, optionally substituted with methyl. In some embodiments, R^y is optionally substituted azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl. In some embodiments, R^y is monocyclic heterocycloalkyl, optionally substituted with one, two, or three R^o substituents. In some embodiments, R^y is optionally substituted azetidinylmethyl, oxetanylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, or piperazinylmethyl, optionally substituted with methyl. [0260] In some embodiments, R^x and R^y is H and the other is -CH3. In some embodiments, both of R^x and R^y is H. In some embodiments, both of R^x and R^y is -CH₃. [0261] In some embodiments, R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C1-4alkyl. In some embodiments, R^x and R^y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholino, each optionally substituted with methyl. [0262] In some embodiments, each R^z is independently C1-4alkyl, halo, -OH, or -OC1-4alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ. In some embodiments, each R^z is independently -CH₃, -OH, halo, or -OCH₃. In some embodiments, R^z is C_2-3alkyl substituted with -NR^mRⁿ. In some embodiments, R^z is C2-4alkyl substituted with -NR^mRⁿ or OCH3. In some embodiments, each R^z substituent is independently -NR^pR^q, -C(O)NR^pR^q. [0263] In some embodiments, each R^z substituent is methyl, ethyl, isopropyl, -CF₃, fluoro, chloro, -OCH3, -OCF3, methylamino, ethylamino, propylamino, butylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, -C(O)methylamino, -C(O)ethylamino, -C(O)propylamino, -C(O)butylamino, -C(O)dimethylamino, -C(O)dimethylaminomethyl, -C(O)dimethylaminoethyl, -C(O)dimethylaminopropyl, or -C(O)dimethylaminobutyl. [0264] In some embodiments, R^m and Rⁿ are each independently H, C1-4alkyl, C(O)CH3, C(O)CH₂Cl, or C(O)CH₂CH₂. In some embodiments, R^m and Rⁿ are each H. In some embodiments, R^m and Rⁿ are each methyl. In some embodiments, R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with one or two R^o substituents. In some embodiments, R^m and Rⁿ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholino, or thiomorpholino-1,1-dioxide, each optionally substituted with one or two R^o substituents. In some embodiments, R^m and Rⁿ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or morpholino, each optionally substituted with one or two R^o substituents. In some embodiments, R^m and Rⁿ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with methyl. [0265] In some embodiments, each R^o substituent is C1-4alkyl. In some embodiments, each R^o substituent is -NR^pR^q. In some embodiments, R^p and R^q are each independently H or methyl. [0266] In some embodiments, R^p and R^q are each independently H, methyl, C_1-4alkylNH₂, C1-4alkylNHCH3, or C1-4alkylN(CH3)2. [0267] In some embodiments, R⁵ is H, methyl, ethyl, chloro, bromo, fluoro, -OH, or -OCH₃. In some embodiments, R⁵ is H. [0268] In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a compound of Formula (II):

wherein R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C1-4alkylNR^xR^y or C(O)NR^xR^y wherein R^x and R^y are as defined herein; or phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof. [0269] In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a compound of Formula (III):

wherein R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C1-4alkylNR^xR^y or -C(O)NR^xR^y wherein R^x and R^y are as defined herein; or phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof. [0270] In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a compound of Formula (IV):

wherein R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C1-4alkylNR^xR^y or -C(O)NR^xR^y wherein R^x and R^y are as defined herein; or phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof. [0271] In some embodiments, R^c1 is phenyl or pyridyl, each optionally substituted with methyl, -CF₃, Cl, Br, or OCH_3. In some embodiments, R^c1 is phenyl or m-tolyl. In some embodiments, R^c1 is pyridyl. In some embodiments, R^c1 is 4-pyridyl. [0272] In some embodiments, R^4a is phenyl or pyridyl, each optionally substituted with methyl or -CF3. In some embodiments, R^4a is phenyl. In some embodiments, R^4a is tolyl. In some embodiments, R^4a is m-tolyl. In some embodiments, R^4a is pyridyl. In some embodiments, R^4a is 4-pyridyl. [0273] In some embodiments, R^4a is pyrazolyl optionally substituted with one or two R^z groups. [0274] In some embodiments, each R^z is independently methyl, ethyl, isopropyl, -CF₃, fluoro, chloro, -OCH3, -OCF3, methylamino, ethylamino, propylamino, butylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, -C(O)methylamino, -C(O)ethylamino, -C(O)propylamino, -C(O)butylamino, -C(O)dimethylamino, -C(O)dimethylaminomethyl, -C(O)dimethylaminoethyl, -C(O)dimethylaminopropyl, or -C(O)dimethylaminobutyl. [0275] In some embodiments, R^4a is 3-methyl-1H-pyrazol-5-yl, 3-methylisothiazol-5-yl, 2- methyl-1H-imidazol-5-yl, 1-methyl-pyrazol-4-yl, 1-methylpyrazol-3-yl, 1-((1-acetamido)-eth-2- yl)-5-methyl-pyrazol-3-yl, 1-((1-chloromethylamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1- acrylamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, thiazol-2-yl, pyrazol-4-yl, pyrazol-1-yl, oxazol-2- yl, or 3-(1-N,N-dimethyl-eth-2-yl)-4-methyl-pyrazol-1-yl. [0276] In some embodiments, R^4a is -C(O)NR^xR^y wherein R^x is H or C1-4alkyl and R^y is H, C1- 4alkyl, -O-C1-4alkyl, -SO2-R^r, C1-4alkyl-SO2-R^r monocyclic cycloalkyl, -C1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; and R^r and R^o are as defined herein. In some embodiments, R^4a is -C(O)NR^xR^y wherein R^x is H or methyl; and R^y is H, methyl, ethyl, butyl, isopropyl, methoxy, -SO₂-methyl, C_2-4alkyl-SO₂-methyl, C_2-4alkyl-SO₂-N(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted azetidinylmethyl, oxetanylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, or piperazinylmethyl, each optionally substituted with one, two, or three methyl, methoxy, fluoro or amino groups. [0277] In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a compound of Formula (I):

Formula (II):

Formula (III):

Formula (IV):

as defined herein, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms. [0278] In some embodiments, one or more hydrogen atoms attached to carbon atoms of R¹, R², R³, R⁴, R⁵, R^1a, R^1b, R^1c or R^4a are replaced by deuterium atoms. [0279] In some embodiments, one or more hydrogen atoms attached to carbon atoms of R^a, R^b, R^c, R^d, R^g, R^h, R^j, R^k, R^l, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^x, R^y, or R^z are replaced by deuterium atoms. In some embodiments, one or more R^a, R^b, R^c, R^d, R^g, R^h, R^j, R^k, R^l, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^x, R^y, or R^z group is a C1-4alkyl group wherein one or more hydrogen atoms attached to carbon atoms are replaced by deuterium atoms. In some embodiments, one or more R^a, R^b, R^c, R^d, R^g, R^h, R^j, R^k, R^l, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^x, R^y, or R^z group is a methyl group wherein one or more hydrogen atoms attached to the carbon atom are replaced by deuterium atoms. In some embodiments, one or more R^a, R^b, R^c, R^d, R^g, R^h, R^j, R^k, R^l, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^x, R^y, or R^z group is -CD₃. [0280] In some embodiments, the compound of Formula (I) - (IV) comprises a -D in place of at least one -H, or a -CD3 substituent in place of at least one CH3. [0281] In some embodiments, the compound is a compound selected from those of Table 1: Table 1

and pharmaceutically acceptable salts thereof. I. Kits and Articles of Manufacture [0282] Any of the aforementioned methods can be implemented via kits for the treatment of a coronavirus infection. In various embodiments, the coronavirus is SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-HKU1, HCoV-229E, or HCoV-NL63. [0283] The kit may contain a compound of Formula I (or any of the embodiments thereof described herein), a pharmaceutically acceptable carrier, a physiologically acceptable carrier, instructions for use, a container, a vessel for administration, or any combination thereof. [0284] The disclosure further provides any compounds disclosed herein for use in a method of treatment of the human or animal body by therapy. Therapy may be by any mechanism disclosed herein, such as inhibiting, reducing, or reducing progression of the diseases disclosed herein. The disclosure further provides any compound disclosed herein for prevention or treatment of any condition disclosed herein. The disclosure also provides any compound or pharmaceutical composition thereof disclosed herein for obtaining any clinical outcome disclosed herein for any condition disclosed herein. The disclosure also provides use of any compound disclosed herein in the manufacture of a medicament for preventing or treating any disease or condition disclosed herein. EXAMPLES [0285] The following preparations of compounds of Formula (I) and intermediates are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof. [0286] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. [0287] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78 °C to about 150 °C, or from about 0 °C to about 125 °C or at about room (or ambient) temperature, e.g., about 20 °C. [0288] Compounds of Formula (I) and subformulae and species described herein, including those where the substituent groups as defined herein, can be prepared as illustrated and described below. [0289] Unless otherwise noted, all reagents were used without further purification. ¹H NMR spectra were obtained in CDCl3, DMSO-d6, or CD3OD at room temperature on a Bruker 300 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one is reported. Chemical shifts of ¹H NMR spectra were recorded in parts per million (ppm) on the δ scale from an internal standard of residual solvent. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. LC-MS conditions were as described below: [0290] LCMS Column: Agilent Zorbax XDB C184.6×50 mm, 3.5µm a. Mobile phase: Solvent A: Water (with 0.1% formic acid); Solvent B: MeOH b. Flow rate: 1.0 mL/min, c. Run time: 2 min gradient (20%-90% B), then 3 min @90% B, d. Temperature: 30 °C [0291] HPLC Column: Agilent SB-C184.6×150 mm, 3.5µm a. Mobile phase: Solvent A: water (with 0.02% TFA); Solvent B: MeOH b. Flow rate: 1.0 mL/min, c. Run time: 0.5 min @10% B, 9.5 min gradient (10%-90% B), then 10 min @90% B, d. Temperature: 30 °C [0292] Preparative LC Column: Phenomenex Luna 5u 100A, 21.2×250mm, 5µm a. Mobile phase: Solvent A: Water Solvent B: MeOH b. Flow rate: 10 mL/min, c. Run time: 1 min @20% B, 30 min gradient (20%-80% B), then 10 min @90% B, d. Temperature: Ambient [0293] The following abbreviations are used in the text: PE = petroleum ether, EA or AcOH = acetic acid, EtOAc = ethyl acetate, DMSO = dimethyl sulfoxide, DMF = N, N- dimethylacetamide, MeOH = methanol, i-PrOH = isopropyl alcohol, MTBE = Methyl tert-butyl ether, DCM = dichloromethane, Et3N or TEA = triethylamine, DIPEA = Diisopropylethylamine, DIEA = N,N-Diisopropylethylamine, TFA = trifluoroacetic acid, TLC = thin layer chromatography, (BPin)2 = Bis(pinacolato)diboron, HFIP = 1,1,1,3,3,3-hexafluoropropan-2-ol, DIBAL-H = Diisobutylaluminum hydride, MeI = Iodomethane, n-Hex = n-Hexane, DCE = 1,2- Dichloroethane, TBSCl = tert-Butyldimethylsilyl chloride, Tf₂O = Trifluoromethanesulfonic anhydride, n-BuLi = n-Butyllithium, DMAP = 4-Dimethylaminopyridine, KOAc = Potassium acetate, NaOAc = Sodium acetate, TFAA = Trifluoroacetic anhydride, m-CPBA = meta- Chloroperoxybenzoic acid, DME = 1,2-Dimethoxyethane, PS-TPP = polymer supported triphenylphosphine, MSA = methanesulfonic acid, SEMCl = 2-(Trimethylsilyl)ethoxymethyl chloride, Et2O = diethylether, THF = tetrahydrofuran, NIS = N-Iodosuccinimide, LDA = Lithium diisopropylamide, EDCl = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, TMSCF3 = Trifluoromethyltrimethylsilane, Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, h and hr = hour, rt = room temperature, Ph = phenyl, dppf = 1,1'-Bis(diphenylphosphino)- ferrocene, dba = dibenzylideneacetone, [0294] EXAMPLE 1: Compound 1 using General Synthetic Route 1:

1.1) Synthesis of (Z)-methyl 2-((2-cyano-1-(pyridin-4-yl)vinyl)oxy)acetate [0295] To a solution of triphenylph

osphine (3.5 g, 13.4 mmol) in dry THF was added diethyl azodicarboxylate (DEAD) (2.3 g, 13.4 mmol), 3-oxo-3-(pyridin-4-yl)propanenitrile (1.5 g, 10.3 mmol) and methyl 2-hydroxyacetate (1.2 g, 13.4 mmol) under N2. The reaction was stirred at ambient temperature overnight. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 4.4 g of impure (Z)-methyl2-((2-cyano-1-(pyridin-4- yl)vinyl)oxy)acetate containing triphenylphosphine oxide as a yellow solid. LC-MS (ESI+): m/z 219 (MH⁺). 1.2) Synthesis of methyl 3-amino-5-(pyridin-4-yl)furan-2-carboxylate

[0296] To a solution of impure (Z)-methyl2-((2-cyano-1-(pyridin-4-yl)vinyl)oxy)acetate (4.6 g, 21.1 mmol) in dry THF at 0 °C was added NaH (1.5 g, 31.6 mmol). The reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with a saturated NH4Cl solution and the pH was adjusted to 3 using 2 N HCl aqueous solutions. The aqueous solution was extracted with ethyl acetate (3 x 50 mL) to remove some impurities. To the remaining aqueous solution was added a saturated Na₂CO₃ solution to adjust the pH to 11. The resulting aqueous solution was extracted with DCM/MeOH (10/1, 3 x 60 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated to provide 1.35 g of crude methyl 3-amino-5-(pyridin-4-yl)furan-2-carboxylate as an oil. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 219 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.66 (dd, J = 4.5, 1.5 Hz, 2H), 7.58 (dd, J = 4.8, 1.2 Hz, 2H), 6.58 (s, 1H), 4.67 (brs, 2H), 3.93 (s, 3H). 1.3) Synthesis of methyl 5-(pyridin-4-yl)-3-ureidofuran-2-carboxylate [0297] To a solution of methyl 3-am

ino-5-(pyridin-4-yl)furan-2-carboxylate (1.94 g, 8.9 mmol) in DCM (40 mL) at -78 °C under N₂ was added chlorosulfonyl isocyante (3.79 g, 26.7 mmol) dropwise. After addition, the reaction was warmed to room temperature and stirred for 1 h. After removal of DCM by evaporation, the resulting residue was treated with 6 N HCl (10 mL) aqueous solutions. The mixture was heated to reflux for 30 min. The completion of the reaction was monitored by thin layer chromatography (TLC). The reaction was cooled to room temperature and the pH was adjusted to 9 using a saturated NaHCO3 solution. A large amount of solid was precipitated. After filtration, the filter cake was washed with water and dried to provide 2.7 g of crude methyl5-(pyridin-4-yl)-3-ureidofuran-2-carboxylate as a yellow solid. LC-MS (ESI+): m/z 262 (MH⁺).¹HNMR (300 MHz, CD3OD) δ 8.61 (dd, J = 4.8, 1.5 Hz, 2H), 7.89 (s, 1H), 7.78 (dd, J = 5.1, 1.5 Hz, 2H), 3.95 (s, 3H). 1.4) Synthesis of 6-(pyridin-4-yl)furo[3,2-d]pyrimidine-2,4-diol

[0298] To a solution of crude methyl 5-(pyridin-4-yl)-3-ureidofuran-2-carboxylate (2.7 g, 10.3 mmol) in MeOH (40 mL) was added 1.5 N NaOH (15 mL). The reaction was heated to reflux for 1.5 h. The completion of the reaction was monitored by TLC. The solvent MeOH was removed by evaporation. To the resulting residue were added 6 N HCl solutions until the pH was adjusted to 2. A large amount of solid was precipitated. After filtration, the filter cake was washed with water and dried to provide crude 2.1 g of 6-(pyridin-4-yl)furo[3,2-d]pyrimidine- 2,4-diol as a yellow solid. LC-MS (ESI+): m/z 230 (MH⁺).¹HNMR (300 MHz, DMSO-d₆) δ 11.61 (s, 1H), 11.37 (s, 1H), 8.89 (d, J = 6.6 Hz, 2H), 8.24 (d, J = 6.3 Hz, 2H), 7.63 (s, 1H). 1.5) Synthesis of 2,4-dichloro-6-(pyridin-4-yl)furo[3,2-d]pyrimidine

[0299] To a solution of 6-(pyridin-4-yl)furo[3,2-d]pyrimidine-2,4-diol (1.5 g, 6.54 mmol) in phenylphosphonic dichloride (30 mL) was added DIPEA (8.43 g, 65.4 mmol). The reaction was heated to 120 °C overnight. After the reaction mixture was cooled to room temperature, a saturated NaHCO₃ solution was added to adjust the pH to 8. The aqueous solution was extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 50% EtOAc/PE to 75% EtOAc/PE to provide 2,4- dichloro-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (1.6 g, 6.9 mmol) as a yellow solid. LC-MS (ESI+): m/z 266/268 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.85 (dd, J = 4.8, 1.5 Hz, 2H), 7.82 (dd, J = 4.5, 1.5 Hz, 2H), 7.38 (s, 1H). 1.6) Synthesis of 2-chloro-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine

[0300] To a solution of 2,4-dichloro-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (1.6 g, 6.9 mmol) in DCM/EtOH (1/3, 120 mL) was added morpholine (0.91 g, 10.5 mmol) and K2CO3 (1.91 g, 14 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 3% MeOH/DCM to provide 2-chloro-4-morpholino-6-(pyridin-4-yl) furo[3,2-d]pyrimidine (770 mg, 2.43 mmol) as a yellow solid. LC-MS (ESI+): m/z 317/319 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 6.0 Hz, 2H), 7.97 (d, J = 6.0 Hz, 2H), 7.82 (s, 1H), 4.06-3.97 (m, 4H), 3.82-3.75 (m, 4H). 1.6) Synthesis of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine

[0301] A solution of 2,4-dichloro-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (770 mg, 2.43 mmol) in HBr/AcOH (33 wt.% in Acetic acid, 10 mL) was heated to refluxed for 3.5 h. The completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with a saturated NaHCO₃ solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure to provide 740 mg of crude 2-bromo- 4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine as a brown solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 362/364 (MH⁺). ¹HNMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 4.5 Hz, 2H), 7.98 (d, J = 4.5 Hz, 2H), 7.82 (s, 1H), 4.02-3.95 (m, 4H), 3.83-3.76 (m, 4H). 1.7) Synthesis of 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide [0302] To a solution of 3-pheny

l-1H-pyrazol-5-amine (300 mg, 1.88 mmol) in THF (5 mL) at 0 °C was added NaH (100 mg, 2.82 mmol). After stirring at 0 °C for 1 h, to the solution was added dimethylsulfamoyl chloride (315 mg, 2.20 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 33% EtOAc/PE to provide 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1- sulfonamide (300 mg, 1.13 mmol). LC-MS: m/z 267 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 7.79- 7.76 (m, 2H), 7.42-7.35 (m, 3H), 5.75 (s, 1H), 4.84 (s, 2H), 3.03 (s, 6H). 1.8) Synthesis of N,N-dimethyl-5-((4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidin-2- yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide

[0303] A suspension of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (500 mg, 1.4 mmol), 3-amino-N,N-dimethyl-5-phenyl-1H-pyrazole-1-sulfonamide (554 mg, 2.1 mmol), Cs₂CO₃ (906 mg, 2.8 mmol), Pd(OAc)₂ (30 mg, 0.1 mmol) and Xantphos (80 mg, 0.1 mmol) in DMF/1,4-dioxane (1/7, 16 mL) was heated to 100 °C for 40 min under microwave conditions. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide N,N-dimethyl-5-((4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidin-2-yl)amino)-3-phenyl- 1H-pyrazole-1-sulfonamide (140 mg, 0.26 mmol) as a white solid. LC-MS (ESI+): m/z 547 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.76-8.71 (m, 3H), 7.91 (d, J = 6.9 Hz, 2H), 7.64 (d, J = 5.7 Hz, 2H), 7.47-7.39 (m, 3H), 7.28-7.22 (m, 2H), 4.14-4.08 (m, 4H), 3.94-3.87 (m, 4H), 3.07 (s, 6H). 1.9) Synthesis of 4-morpholino-N-(3-phenyl-1H-pyrazol-5-yl)-6-(pyridin-4-yl)furo[3,2- d]pyrimidin-2-amine hydrochloride

[0304] To a solution of N,N-dimethyl-5-((4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidin- 2-yl)amino) -3-phenyl-1H-pyrazole-1-sulfonamide (140 mg, 0.26 mmol) in DCM (4 mL) was added HCl/Et2O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et₂O (1/20, 2 mL), 4-morpholino-N-(3-phenyl-1H-pyrazol-5- yl)-6-(pyridin-4-yl)furo[3,2-d] pyrimidin-2-amine hydrochloride (Compound 1, 112 mg, 0.22 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 440 (MH⁺).¹HNMR (300 MHz, CD3OD) δ 8.97 (d, J = 6.6 Hz, 2H), 8.55 (d, J = 6.6 Hz, 2H), 8.05 (s, 1H), 7.37 (d, J = 6.9 Hz, 2H), 7.66-7.40 (m, 3H), 6.44 (s, 1H), 4.35-4.27 (m, 4H), 4.01-3.92 (m, 4H). [0305] EXAMPLE 2: Compound 10 using General Synthetic Route 2:

1.1) Synthesis of 5-amino-N,N-dimethyl-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide [0306] To a solution of 3-(pyridin

-4-yl)-1H-pyrazol-5-amine (500 mg, 3.12 mmol) in THF (5 mL) at 0°C was added NaH (374 mg, 9.36 mmol). After stirred at 0°C for 1 h, to the solution was added dimethylsulfamoyl chloride (536 mg, 3.75 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 33% EtOAc/PE to provide 5-amino-N,N-dimethyl-3-(pyridin-4-yl)- 1H- pyrazole-1-sulfonamide (94 mg, 0.35 mmol). LC-MS: m/z 268 (MH⁺).¹HNMR (300 MHz, DMSO-d₆) δ 8.50 (d, J = 6.0 Hz, 2H), 7.60 (dd, J = 4.5, 1.2 Hz, 2H), 6.04 (s, 2H), 5.79 (s, 1H), 2.81 (s, 6H). 1.2) Synthesis of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine [0307] To a solution of 2,4-dichlorofu

ro[3,2-d]pyrimidine (6.46 g, 34.2 mmol mmol) in methanol (100 mL) was added morpholine (5.95 g, 68.4 mmol). The reaction was stirred at room temperature for 30 min. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and the resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 20% EtOAc/PE to provide 2- chloro-4-morpholinofuro [3,2-d]pyrimidine (7.5 g, 40.1 mmol) as a white solid. LC-MS (ESI+): m/z 240/242 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.74 (d, J = 1.8 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.05-4.02 (m, 4H), 3.85-3.82 (m, 4H). 1.3) Synthesis of 2-bromo-4-morpholinofuro[3,2-d]pyrimidine

[0308] A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (180 mg, 0.75 mmol) in HBr/AcOH (33 wt.% in Acetic acid, 3 mL) was heated to reflux for 3.5 h. The completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with a saturated NaHCO₃ solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to provide 175 mg of crude 2-bromo- 4-morpholino- furo[3,2-d]pyrimidine as a yellow solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 284/286 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.72 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.04-4.01 (m, 4H), 3.85-3.81 (m, 4H). 1.4) Synthesis of N,N-dimethyl-5-((4-morpholinofuro[3,2-d]pyrimidin-2-yl)amino)-3-(pyridin-4- yl)-1H-pyrazole-1-sulfonamide

[0309] A suspension of 2-bromo-4-morpholinofuro[3,2-d]pyrimidine (48 mg, 0.17 mmol), 5- amino-N,N-dimethyl-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide (54 mg, 0.20 mmol), Cs2CO3 (126 mg, 0.39 mmol), Pd(OAc)₂ (4 mg, 0.017 mmol) and Xantphos (10 mg, 0.017 mmol) in DMF/1,4-dioxane (1/7, 3 mL) was heated to 100 °C for 40 min under microwave conditions. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N,N-dimethyl-5-((4-morpholinofuro[3,2-d]pyrimidin-2-yl)amino)-3-(pyridin-4-yl)-1H-pyrazole- 1-sulfonamide (27 mg, 0.06 mmol) as a yellow solid. LC-MS (ESI+): m/z 471 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.69-8.67 (m, 3H), 7.77 (d, J = 6.0 Hz, 2H), 7.70 (d, J = 2.1 Hz, 1H), 7.35 (s, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.05-4.02 (m, 4H), 3.87-3.84 (m, 4H), 3.08 (s, 6H). 1.5) Synthesis of 4-morpholino-N-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)furo[3,2-d]pyrimidin-2- amine hydrochloride

[0310] To a solution of N,N-dimethyl-5-((4-morpholinofuro[3,2-d]pyrimidin-2-yl)amino)-3- (pyridin-4-yl) -1H-pyrazole-1-sulfonamide (27 mg, 0.06 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 4-morpholino-N-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride (Compound 10, 21.2 mg, 0.042 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 364 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 8.90 (d, J = 6.9 Hz, 2H), 8.42 (d, J = 6.9 Hz, 2H), 8.17 (d, J = 2.1 Hz, 1H), 7.06-7.04 (m, 2H), 4.22-4.10 (m, 4H), 3.92-3.86 (m, 4H). [0311] EXAMPLE 3: Compound 11 using General Synthetic Route 3:

1.1) Synthesis of 2-bromo-6-chloro-4-morpholinofuro[3,2-d]pyrimidine

[0312] To a solution of 2-bromo-4-morpholinofuro[3,2-d]pyrimidine (1.3 g, 4.59 mmol) in dry THF (4 mL) at -78 °C was added LDA (7.5 mL, 14.7 mmol) dropwise. After addition, the solution was stirred at that temperature for 1 h. Then to the solution was added NCS (733 mg, 5.5 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 25% EtOAc/PE to provide 2-bromo-6-chloro- 4- morpholinofuro[3,2-d]pyrimidine (550 mg, 1.73 mmol) as a light yellow solid. LC-MS (ESI+): m/z 318/320 (MH⁺).¹HNMR (300 MHz, CD3OD) δ6.77 (s, 1H), 3.99-3.95 (m, 4H), 3.82-3.79 (m, 4H). 1.2) Synthesis of 3-((6-chloro-4-morpholinofuro[3,2-d]pyrimidin-2-yl)amino)-N,N-dimethyl-5- phenyl-1H-pyrazole-1-sulfonamide

[0313] A suspension of 2-bromo-6-chloro-4-morpholinofuro[3,2-d]pyrimidine (3 x 50 mg, 0.16 mmol), 3-amino-N,N-dimethyl-5-phenyl-1H-pyrazole-1-sulfonamide (42 mg, 0.16 mmol), Cs₂CO₃ (118 mg, 0.36 mmol), Pd(OAc)₂ (3.5 mg, 0.016 mmol) and Xantphos (9 mg, 0.015 mmol) in DMF/1,4-dioxane (1/7, 3 mL) was heated to 80 °C for 40 min under microwave conditions. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 35% EtOAc/PE to provide the impure product. After further preparative HPLC purification, 26 mg of pure 3-((6-chloro-4- morpholinofuro [3,2-d]pyrimidin-2-yl)amino)-N,N-dimethyl-5-phenyl-1H-pyrazole-1- sulfonamide was obtained. LC-MS (ESI+): m/z 504/506 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 7.89 (dd, J = 8.1, 1.5 Hz, 2H), 7.46-7.39 (m, 3H), 7.21 (s, 1H), 6.60 (s, 1H), 3.99- 3.96 (m, 4H), 3.87-3.84 (m, 4H), 3.06 (s, 6H). 1.3) Synthesis of 6-chloro-4-morpholino-N-(5-phenyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-2- amine hydrochloride

[0314] To a solution of 3-((6-chloro-4-morpholinofuro[3,2-d]pyrimidin-2-yl)amino)-N,N- dimethyl-5- phenyl-1H-pyrazole-1-sulfonamide (26 mg, 0.05 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 6-chloro-4-morpholino-N-(5-phenyl-1H- pyrazol-3-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride (Compound 11, 18.5 mg, 0.043 mmol) was obtained. LC-MS (ESI+): m/z 397/399 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 7.87- 7.69 (m, 2H), 7.51-7.39 (m, 3H), 7.09 (s, 1H), 6.41 (s, 1H), 4.17-4.12 (m, 4H), 3.89-3.84 (m, 4H). [0315] EXAMPLE 4: Compound 12 using General Synthetic Route 4:

1.1) Synthesis of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde

[0316] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (50 mg, 0.21 mmol) in THF at -78 °C under N₂ was added n-BuLi ( 0.1 mL, 0.25 mmol). The mixture was stirred at that temperature for 15 min and then DMF (90 mg, 1.23 mmol) was added. The solution was allowed to warm to room temperature for 10 min. The completion of the reaction was monitored by TLC. The reaction was quenched with water and the aqueous solution was extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 35% EtOAc/PE to provide 2- chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde (26 mg, 0.097 mmol) as a white solid. LC-MS (ESI+): m/z 268/270 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 9.91 (s, 1H), 7.48 (s, 1H), 4.15-4.10 (m, 4H), 3.88-3.85 (m, 4H). 1.2) Synthesis of 2-chloro-4-morpholino-6-(morpholinomethyl)furo[3,2-d]pyrimidine [0317] A solution of 2-chloro-4-

morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde (150 mg, 0.56 mmol) and morpholine (58 mg, 0.67 mmol) in DCM was stirred at room temperature for 15 min. To the solution was added sodium triacetoxyborohydride (356 mg, 1.68 mmol). The mixture was stirred at room temperature for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NaHCO3 solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to EtOAc to provide 2-chloro-4-morpholino-6- (morpholinomethyl)furo[3,2-d]pyrimidine (120 mg, 0.35 mmol). LC-MS (ESI+): m/z 339/341 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 6.63 (s, 1H), 4.13-3.92 (m, 4H), 3.85-3.82 (m, 4H), 3.74- 3.71 (m, 4H), 3.63 (s, 2H), 2.56-2.53 (m, 4H). 1.3) Synthesis of 2-bromo-4-morpholino-6-(morpholinomethyl)furo[3,2-d]pyrimidine

[0318] A solution of 2-chloro-4-morpholino-6-(morpholinomethyl)furo[3,2-d]pyrimidine (120 mg, 0.35 mmol) in HBr/AcOH (33 wt.% in Acetic acid, 5 mL) was heated to refluxed for 3.5 h. The completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with a saturated NaHCO3 solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to provide 80 mg of crude 2-bromo-4-morpholino-6-(morpholinomethyl)furo[3,2-d]pyrimidine as a brown solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 383/385 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 6.71 (s, 1H), 4.03-4.00 (m, 4H), 3.83-3.81 (m, 4H), 3.75 (s, 2H), 3.72-3.68 (m, 4H), 2.57-2.54 (m, 4H). 1.4) Synthesis of N,N-dimethyl-5-((4-morpholino-6-(morpholinomethyl)furo[3,2-d]pyrimidin-2- yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide

[0319] A suspension of 2-bromo-4-morpholino-6-(morpholinomethyl)furo[3,2-d]pyrimidine (60 mg, 0.16 mmol), 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide (50 mg, 0.19 mmol), Cs2CO3 (120 mg, 0.37 mmol), Pd(OAc)2 (3 mg, 0.01 mmol) and Xantphos (6 mg, 0.01 mmol) in DMF/1,4-dioxane (1/7, 8 mL) was heated to 90 °C for 30 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N,N-dimethyl-5-((4- morpholino-6-(morpholinomethyl)furo[3,2-d]pyrimidin-2-yl)amino)-3- phenyl-1H-pyrazole-1-sul-fonamide (23 mg, 0.04 mmol) as a yellow solid. LC-MS (ESI+): m/z 569 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.89 (d, J = 6.9 Hz, 2H), 7.45-7.38 (m, 3H), 7.25 (s, 1H), 6.63 (s, 1H), 4.02-4.00 (m, 4H), 3.87-3.84 (m, 4H), 3.75-3.73 (m, 4H), 3.67 (s, 2H), 3.06 (s, 6H), 2.58-2.55 (m, 4H). 1.5) Synthesis of 4-morpholino-6-(morpholinomethyl)-N-(3-phenyl-1H-pyrazol-5-yl)furo[3,2- d]pyrimidin-2-amine hydrochloride

[0320] To a solution of N,N-dimethyl-5-((4-morpholino-6-(morpholinomethyl)furo[3,2- d]pyrimidin -2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide (23 mg, 0.04 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 4-morpholino-6- (morpholinomethyl)-N-(3-phenyl-1H- pyrazol-5-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride (Compound 12, 21.2 mg, 0.042 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 462 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 7.79-7.70 (m, 2H), 7.52-7.42 (m, 3H), 7.39 (s, 1H), 6.42 (s, 1H), 4.67 (s, 2H), 4.32-4.12 (m, 4H), 4.10-3.86 (m, 8H), 3.55-3.42 (m, 4H). [0321] EXAMPLE 5: Compound 22 using General Synthetic Route 5:

1.1) Synthesis of 3-(2-methylpyridin-4-yl)-3-oxopropanenitrile [0322] To a solution of acetonitrile (1

.63 g, 39.7 mmol) in anhydrous THF (40 mL) at -70 °C under N2 was added n-BuLi (15.9 mL, 39.7 mmol) dropwise. After addition, a solution of methyl 2-methylisonicotinate (2.0 g, 13.2 mmol) in THF (10 mL) was added to the above solution over 10 min. The reaction mixture was stirred at that temperature for 2 h. The completion of the reaction was monitored by TLC. The reaction was quenched with AcOH (6.9 mL) and the solution was concentrated directly under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 3-(2-methylpyridin-4-yl)-3-oxopropanenitrile (1.15 g, 7.2 mmol) as a yellow solid. LC-MS (ESI+): m/z 161 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.77 (d, J = 5.4 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 5.1 Hz, 1H), 4.08 (s, 2H), 2.69 (s, 3H). 1.2) Synthesis of 3-(2-methylpyridin-4-yl)-1H-pyrazol-5-amine

[0323] To a solution of 3-(2-methylpyridin-4-yl)-3-oxopropanenitrile (1.15 g, 7.2 mmol) in EtOH (40 mL) was added NH₂NH₂.H₂O (0.54 g, 10.8 mmol). The mixture was heated to reflux overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 3-(2-methylpyridin-4-yl)-1H-pyrazol-5- amine (0.8 g, 4.6 mmol) as a yellow oil. LC-MS (ESI+): m/z 175 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.47 (d, J = 5.4Hz, 1H), 7.33 (s, 1H), 7.27 (d, J = 5.1 Hz, 1H), 6.00 (s, 1H), 4.70 (brs, 2H), 2.55 (s, 3H). 1.3) Synthesis of 5-amino-N,N-dimethyl-3-(2-methylpyridin-4-yl)-1H-pyrazole-1-sulfonamide [0324] To a solution of 3

-(2-methylpyridin-4-yl)-1H-pyrazol-5-amine (800 mg, 4.6 mmol) in THF (30 mL) at 0 °C was added NaH (413 mg, 6.9 mmol). After stirred at 0 °C for 1 h, to the reaction solution was added dimethylsulfamoyl chloride (854 mg, 5.98 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NH4Cl solution. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 50% EtOAc/PE to 66% EtOAc/PE to provide 5-amino-N,N-dimethyl-3-(2- methylpyridin-4-yl)-1H-pyrazole-1-sulfonamide (220 mg, 0.78 mmol). LC-MS: m/z 282 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 8.51 (d, J = 5.1Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 5.4Hz, 1H), 5.78 (s, 1H), 4.91 (brs, 2H), 3.05 (s, 6H), 2.60 (s, 3H). 1.4) Synthesis of N,N-dimethyl-3-(2-methylpyridin-4-yl)-5-((4-morpholino-6-(pyridin-4- yl)furo[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazole-1-sulfonamide

[0325] A suspension of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (2 x 50 mg, 0.14 mmol), 5-amino-N,N-dimethyl-3-(2-methylpyridin-4-yl)-1H-pyrazole-1-sulfonamide (46.8 mg, 0.17 mmol), Cs2CO3 (90.6 mg, 0.28 mmol), Pd(OAc)2 (3 mg, 0.014 mmol) and Xantphos (6 mg, 0.014 mmol) in DMF/1,4-dioxane (1/7, 4 mL) was heated to 100 °C for 30 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide impure N,N-dimethyl-3-(2-methylpyridin-4-yl)-5-((4-morpholino-6- (pyridin-4-yl)furo [3,2-d]pyrimidin-2-yl)amino)-1H-pyrazole-1-sulfonamide (23.2 mg, 0.04 mmol) as a yellow solid. LC-MS (ESI+): m/z 562 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.76 (d, J = 6.0 Hz, 2H), 8.71 (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 7.66-7.61 (m, 3H), 7.58 (d, J = 4.2 Hz, 1H), 7.35 (s, 1H), 4.10-4.08 (m, 4H), 3.93-3.90 (m, 4H), 3.09 (s, 6H), 2.65 (s, 3H). 1.5) Synthesis of N-(3-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)-4-morpholino-6-(pyridin-4- yl)furo[3,2-d]pyrimidin-2-amine hydrochloride

[0326] To a solution of impure N,N-dimethyl-3-(2-methylpyridin-4-yl)-5-((4-morpholino-6- (pyridin-4-yl) furo[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazole-1-sulfonamide (23 mg, 0.04 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), N-(3-(2- methylpyridin-4-yl)-1H- pyrazol- 5-yl)-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidin-2- amine hydrochloride (Compound 22, 20.8 mg, 0.04 mmol) was obtained as a yellow solid. LC- MS (ESI+): m/z 455 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 8.94 (d, J = 6.6 Hz, 2H), 8.74 (d, J = 6.6 Hz, 1H), 8.51 (d, J = 6.9 Hz, 2H), 8.30 (s, 1H), 8.24 (d, J = 6.3 Hz, 1H), 8.02 (s, 1H), 6.99 (s, 1H), 4.32-4.28 (m, 4H), 3.95-3.94 (m, 4H), 2.85 (s, 3H). [0327] EXAMPLE 6: Compound 28 using General Synthetic Route 6:

1.1) Synthesis of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine [0328] To a solution of 2-chloro

-4-morpholinofuro[3,2-d]pyrimidine (2.0 g, 0.83 mmol) in THF (30 mL) at -78 °C under N2 was added LDA (1.33 mL, 2M, 2.66 mmol). After stirred at - 78 °C for 1 h, to the solution was added NIS (2.25 g, 1.0 mmol) in THF (10 mL). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with DCM (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 10% EtOAc/PE to provide 2-chloro-6-iodo-4- morpholinofuro[3,2-d]pyrimidine (1.6 g, 4.4 mmol) as yellow solid. LC-MS (ESI+): m/z 366/368 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 6.97 (s, 1H), 4.01-3.98 (m, 4H), 3.85-3.82 (m, 4H). 1.2) Synthesis of 2-chloro-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine

[0329] A solution of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (1 g, 2.7 mmol), 2- (tributylstannyl)pyridine (1.2 g, 3.3 mmol) and Pd(PPh₃)₄ (155 mg, 0.14 mmol) in toluene (5 mL) was heated to 90 °C overnight. The completion was monitored by TLC. The reaction mixture was diluted with water and extracted with DCM/MeOH (15/1, 3 x 50mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-chloro-4-morpholino- 6- (pyridin-2-yl)furo[3,2-d]pyrimidine (352 mg, 1.11 mmol) as a yellow solid. LC-MS (ESI+): m/z 317/319 (MH⁺). 1.3) Synthesis of 2-bromo-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine [0330] A solution of 2-chloro-4-

morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (350 mg, 1.11 mmol) in HBr/AcOH (33 wt.% in Acetic acid, 5 mL) was heated to reflux for 3.5 h. The completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with a saturated NaHCO3 solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure to provide 290 mg of crude 2-bromo- 4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine as a yellow solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 361/363 (MH⁺). 1.4) Synthesis of N,N-dimethyl-5-((4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidin-2- yl)amino)-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide

[0331] A suspension of 2-bromo-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (2 x 40 mg, 0.13 mmol), 3-amino-N,N-dimethyl-5-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide (41 mg, 0.15 mmol), Cs2CO3 (95 mg, 0.29 mmol), Pd(OAc)2 (3 mg, 0.013 mmol) and Xantphos (7 mg, 0.013 mmol) in DMF/1,4-dioxane (1/7, 4 mL) was heated to 90 °C for 30 min under microwave conditions. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N,N-dimethyl-5-((4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidin-2-yl)amino)-3-(pyridin-4- yl)-1H-pyrazole-1-sulfonamide (35.6 mg, 0.065 mmol) as a yellow solid. LC-MS (ESI+): m/z 548 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.70-8.68 (m, 3H), 7.81-7.77 (m, 4H), 7.41-7.39 (m, 2H), 7.36-7.26 (m, 1H), 4.11-4.09 (m, 4H), 3.92-3.91 (m, 4H), 3.09 (s, 6H). 1.5) Synthesis of Compound 28, 4-morpholino-6-(pyridin-2-yl)-N-(3-(pyridin-4-yl)-s1H-pyrazol- 5-yl)furo[3,2-d]pyrimidin-2-aminehydrochloride [0332] To a solution o

f N,N-dimethyl-5-((4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidin- 2-yl)amino)- 3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide (35.6 mg, 0.065 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 4-morpholino-6-(pyridin-2-yl)-N- (3-(pyridin-4-yl)-1H-pyrazol-5-yl) furo[3,2-d] pyrimidin-2-aminehydrochloride (Compound 28, 28.8 mg, 0.06 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 441 (MH⁺).¹HNMR (300 MHz, CD3OD) δ 8.92 (d, J = 6.3 Hz, 2H), 8.75 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 6.6 Hz, 2H), 8.17 (d, J = 7.2 Hz, 1H), 8.12- 8.07 (m, 1H), 7.65 (s, 1H), 7.62-7.58 (m, 1H), 7.07 (s,1H), 4.47-4.13 (m, 4H), 3.97-3.85 (m, 4H). [0333] EXAMPLE 7: Compound 34 using General Synthetic Route 7:

1.1) Synthesis of 2-chloro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-morpholinofuro[3,2-d] pyrimidine

[0334] A suspension of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (400 mg, 1.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (244 mg, 1.1 mmol), K2CO3 (454 mg, 3.29 mmol) and Pd(PPh3)4 (127 mg, 0.011 mmol) in 1,4- dioxane/H₂O (8/1, 40 mL) was heated to 50 °C for 2 h under N₂. The completion was monitored by TLC. The reaction was diluted with water and extracted with DCM/MeOH (15/1, 3 x 30 mL). The combined organic phase was dried over Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 2-chloro-6-(1-methyl-1,2,3,6- tetrahydropyridin-4-yl)-4-morpholinofuro[3,2-d]pyrimidine (270 mg, 0.81 mmol) as a yellow solid. LC-MS (ESI+): m/z 335/337 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 6.52 (s, 1H), 6.52-6.47 (m, 1H), 4.03-4.00 (m, 4H), 3.86-3.83 (m, 4H), 3.19-3.18 (m, 2H), 2.70-2.66 (m, 2H), 2.58-2.54 (m, 2H), 2.43 (s, 3H). 1.2) Synthesis of N,N-dimethyl-5-((6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4- morpholinofuro[3,2-d]pyrimidin-2-yl)amino)-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide

[0335] A suspension of 2-chloro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4- morpholinofuro [3,2-d]pyrimidine (120 mg, 0.60 mmol), 5-amino-N,N-dimethyl-3-(pyridin-4- yl)-1H-pyrazole-1- sulfonamide (176 mg, 0.18 mmol), KOAc (176 mg, 1.80 mmol), Pd(OAc)₂ (14.8 mg, 0.066 mmol) and Xantphos (80 mg, 0.18 mmol) in DMF (20 mL) was heated to 80 °C for 3 h. The reaction mixture was diluted with water and extracted with DCM/MeOH (15/1, 3 x 30mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 10% MeOH/DCM to provide N,N-dimethyl-5-((6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-morpholinofuro[3,2- d]pyrimidin-2-yl)amino)-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide (120 mg, 0.21 mmol) as a yellow solid. LC-MS (ESI+): m/z 566 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.68 (d, J = 6.0 Hz, 2H), 7.77 (d, J = 6.0 Hz, 2H), 7.32 (s, 1H), 6.58 (s, 1H), 6.47-6.42 (m, 1H), 4.03-4.00 (m, 4H), 3.88-3.85 (m, 4H), 3.30-3.29 (m, 2H), 3.07 (s, 6H), 2.83-2.79 (m, 2H), 2.62-2.58 (m, 2H), 2.50 (s, 3H). 1.3) Synthesis of N,N-dimethyl-5-((6-(1-methylpiperidin-4-yl)-4-morpholinofuro[3,2- d]pyrimidin- 2-yl)amino)-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide

[0336] To a solution of N,N-dimethyl-5-((6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4- morpholinofuro [3,2-d]pyrimidin-2-yl)amino)-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide (120 mg, 0.21 mmol) in DCM/MeOH (1/1, 10 mL) was added Pd/C under H₂ (balloon). The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was monitored by LC-MS. After filtration, the filtrate was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 10% MeOH/DCM to provide N,N-dimethyl-5- ((6-(1-methylpiperidin-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-2- yl)amino)-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide (71 mg, 0.13 mmol) as a white solid. LC-MS (ESI+): m/z 568 (MH⁺).¹HNMR (300 MHz, CD3OD) δ 8.62 (d, J = 6.3 Hz, 2H), 7.87 (d, J = 6.0 Hz, 2H), 7.29 (s, 1H), 6.54 (s, 1H), 4.03-4.00 (m, 4H), 3.86-3.83 (m, 4H), 3.40-3.34 (m, 2H), 3.06 (s, 6H), 2.82-2.79 (m, 2H), 2.67 (s, 3H), 2.30-2.26 (m, 2H), 1.97-1.95 (m, 2H). 1.4) Synthesis of 6-(1-methylpiperidin-4-yl)-4-morpholino-N-(3-(pyridin-4-yl)-1H-pyrazol- 5- yl)furo[3,2-d]pyrimidin-2-amine hydrochloride

[0337] To a solution of N,N-dimethyl-5-((6-(1-methylpiperidin-4-yl)-4-morpholinofuro[3,2-d] pyrimidin-2-yl)amino)-3-(pyridin-4-yl)-1H-pyrazole-1-sulfonamide (71 mg, 0.13 mmol) in DCM (4 mL) was added HCl/Et2O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 6-(1- methylpiperidin-4-yl)- 4-morpholino-N-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)furo[3,2-d]pyrimidin- 2-amine hydrochloride (Compound 34, 55 mg, 0.11 mmol) was obtained as a yellow solid. LC- MS (ESI+): m/z 461 (MH⁺).¹HNMR (300 MHz, CD3OD) δ 8.90 (d, J = 6.6 Hz, 2H), 8.42 (d, J = 6.6 Hz, 2H), 7.03 (s, 1H), 6.88 (s, 1H), 4.25-4.10 (m, 4H), 3.96-3.85 (m, 4H), 3.69-3.64 (m, 2H), 3.30-3.17(m, 3H), 2.93 (s, 3H), 2.48-2.39 (m, 2H), 2.16-2.02 (m, 2H).

[0338] EXAMPLE 8: Compound 35 using General Synthetic Route 8:

1.1) Synthesis of tert-butyl 3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-5,6- dihydropyridine-1(2H)-carboxylate

[0339] A suspension of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (400 mg, 1.1 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)- carboxylate (339 mg, 1.1 mmol), K₂CO₃ (454 mg, 3.29 mmol) and Pd(PPh₃)₄ (127 mg, 0.011 mmol) in 1,4-dioxane/H₂O (8/1, 40 mL) was heated to 90 °C for 3 h under N₂. The completion of the reaction was monitored by TLC. The reaction was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 33% EtOAc/PE to provide tert- butyl 3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-5,6-dihydropyridine-1(2H)- carboxylate (155 mg, 0.37 mmol) as a yellow solid. LC-MS (ESI+): m/z 421/423 (MH⁺). 1HNMR (300 MHz, CDCl₃) δ 6.68-6.62 (m, 1H), 6.55 (s, 1H), 4.25 (brs, 2H), 4.03-4.00 (m, 4H), 3.86-3.83 (m, 4H), 3.60-3.56 (m, 2H), 2.42-2.38 (m, 2H), 1.50 (s, 9H). 1.2) Synthesis of 2-chloro-4-morpholino-6-(1,2,5,6-tetrahydropyridin-3-yl)furo[3,2- d]pyrimidine H

[0340] To a solution of tert-butyl3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-5,6- dihydropyridine-1(2H)-carboxylate (600 mg, 1.43 mmol) in DCM (15 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 2 h. The completion of the reaction was monitored by TLC. The reaction was quenched with Na2CO3 and extracted with MeOH/DCM (1/15, 3 x 40 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The residue was slurried in MeOH/Et2O (1/20, 10 mL) to provide 2-chloro-4-morpholino-6-(1,2,5,6-tetrahydropyridin-3- yl)furo[3,2-d]pyrimidine (385 mg, 1.20 mmol) as a white solid. LC-MS (ESI+): m/z 321/323 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 6.94-6.91 (m, 1H), 6.82 (s, 1H), 4.25-4.05 (m, 6H), 3.90- 3.83 (m, 4H), 3.59-3.54 (m, 2H), 2.87-2.70 (m, 2H). 1.3) Synthesis of 2-chloro-6-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-4-morpholinofuro[3,2- d]pyrimidine

[0341] A solution of 2-chloro-4-morpholino-6-(1,2,5,6-tetrahydropyridin-3-yl)furo[3,2- d]pyrimidine (385 mg, 1.2 mmol), formaldehyde solution (488 mg, 37%, 6.02 mmol) and CH3COOH (one drop) in DCM was stirred at room temperature for 30 min. To the solution was added sodium triacetoxyborohydride (1.27 g, 6.02 mmol). The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NaHCO3 solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM (3 x 40 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 2-chloro-6-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-4- morpholinofuro[3,2-d]pyrimidine (375 mg, 1.12 mmol) as a brown solid. LC-MS (ESI+): m/z 335/337 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 6.61-6.58 (m, 1H), 6.46 (s, 1H), 4.03-4.00 (m, 4H), 3.86-3.83 (m, 4H), 3.25-3.24 (m, 2H), 2.63-2.59 (m, 2H), 2.48-2.45 (m, 5H). 1.4) Synthesis of N,N-dimethyl-5-((6-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-4- morpholinofuro[3,2-d]pyrimidin-2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide

[0342] A suspension of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (2 x 20 mg, 0.06 mmol), 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide (19 mg, 0.07 mmol), Cs2CO3 (49 mg, 0.15 mmol), Pd(OAc)2 (1 mg, 0.006 mmol) and Xantphos (3 mg, 0.006 mmol) in DMF/1,4-dioxane (1/7, 2 mL) was heated to 100 °C for 25 min under microwave conditions. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide N,N-dimethyl-5-((6-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-4-morpholinofuro[3,2- d]pyrimidin-2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide (50 mg, 0.089 mmol) as a brown solid. LC-MS (ESI+): m/z 565 (MH⁺). ¹HNMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 7.89 (d, J = 6.6 Hz, 2H), 7.45-7.37 (m, 4H), 6.60-6.57 (m, 1H), 6.50 (s, 1H), 4.03-4.00 (m, 4H), 3.88-3.85 (m, 4H), 3.30-3.27 (m, 2H), 3.05 (s, 6H), 2.62-2.60 (m, 2H), 2.50-2.40 (m, 5H). 1.5) Synthesis of N,N-dimethyl-5-((6-(1-methylpiperidin-3-yl)-4-morpholinofuro [3,2- d]pyrimidin-2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide [0343] To a solutio

n of N,N-dimethyl-5-((6-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-4- morpholinofuro [3,2-d]pyrimidin-2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide (50 mg, 0.089 mmol) in DCM/MeOH (1/1, 4 mL) was added Pd/C under H₂ (balloon). The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was monitored by LC-MS. After filtration, the filtrate was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide N,N-dimethyl-5-((6-(1-methylpiperidin -3-yl)-4-morpholinofuro[3,2-d]pyrimidin-2- yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide (28 mg, 0.049 mmol) as a yellow solid. LC-MS (ESI+): m/z 567 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 7.89 (dd, J = 8.1, 1.5 Hz, 2H), 7.46-7.37 (m, 3H), 7.24 (s, 1H), 6.44 (s, 1H), 4.01-3.98 (m, 4H), 3.87-3.84 (m, 4H), 3.09- 3.03 (m, 8H), 2.90-2.80 (m, 1H), 2.35 (s, 3H), 2.13-2.02 (m, 3H), 1.82-1.79 (m, 2H), 1.51-1.46 (m, 1H). 1.6) Synthesis of Compound 35, 6-(1-methylpiperidin-3-yl)-4-morpholino-N-(3-phenyl-1H- pyrazol-5-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride

[0344] To a solution of N,N-dimethyl-5-((6-(1-methylpiperidin-3-yl)-4-morpholinofuro[3,2-d] pyrimidin -2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide (28 mg, 0.049 mmol) in DCM (4 mL) was added HCl/Et2O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 6-(1-methylpiperidin-3-yl)-4- morpholino-N-(3-phenyl -1H-pyrazol-5-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride (Compound 35, 22 mg, 0.044 mmol) was obtained as a white solid. LC-MS (ESI+): m/z 460 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.97 (s, 1H), 7.80 (d, J = 7.5 Hz, 2H), 7.52-7.47 (m, 2H), 7.43-7.38 (m, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 4.20-4.08 (m, 4H), 3.90-3.82 (m, 4H), 3.72-3.61 (m, 1H), 3.53-3.39(m, 2H), 3.22-3.14 (m, 1H), 3.06-2.94 (m, 1H), 2.78 (s, 3H), 2.19-2.08(m,1H), 2.03-1.97(m, 2H),1.69-1.59 (m, 1H).

[0345] EXAMPLE 9: Compound 39 using General Synthetic Route 9:

1.1) Synthesis of tert-butyl 3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate

[0346] A suspension of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (800 mg, 2.2 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (649 mg, 2.2 mmol), K2CO3 (911 mg, 6.6 mmol) and Pd(PPh3)4 (254 mg, 0.022 mmol) in 1,4-dioxane/H₂O (2/1, 60 mL) was heated to 90 °C for 3 h under N₂. The completion of the reaction was monitored by TLC. The reaction was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 50% EtOAc/PE to provide tert- butyl 3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (400 mg, 0.99 mmol) as a yellow solid. LC-MS (ESI+): m/z 407/409 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 6.60 (s, 0.5H), 6.50 (s, 0.5H), 6.40 (s, 0.5H), 6.35 (s, 0.5H), 4.53- 4.35 (m, 4H), 4.05-4.01 (m, 4H), 3.86-3.82 (m, 4H), 1.51 (s, 9H). 1.2) Synthesis of tert-butyl 3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)pyrrolidine-1- carboxylate

[0347] To a solution of tert-butyl 3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-2,5- dihydro-1H- pyrrole-1-carboxylate (50 mg, 0.089 mmol) in DCM/MeOH (1/1, 20 mL) was added Pd/C under H₂ (balloon). The reaction mixture was stirred at room temperature overnight. The completion of the reaction was monitored by LC-MS. After filtration, the filtrate was concentrated directly and purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 33% EtOAc/PE to provide tert-butyl 3-(2-chloro-4-morpholinofuro[3,2- d]pyrimidin-6-yl)pyrrolidine-1- carboxylate (300 mg, 0.74 mmol) as a white solid. LC-MS (ESI+): m/z 409/411 (MH⁺). 1.3) Synthesis of 2-chloro-4-morpholino-6-(pyrrolidin-3-yl)furo[3,2-d]pyrimidine [0348] To a solution of tert-bu

tyl 3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-5,6- dihydropyridine-1(2H)-carboxylate (300 mg, 0.74 mmol) in DCM (15 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 2 h. The completion of the reaction was monitored by TLC. The solution was quenched with Na2CO3 and the pH was adjusted to 8. A large amount of solid was precipitated. After filtration, 2-chloro-4-morpholino- 6- (pyrrolidin-3-yl)furo[3,2-d]pyrimidine (200 mg, 0.65 mmol) was obtained as a white solid. LC-MS (ESI+): m/z 309/311 (MH⁺). 1.4) Synthesis of 2-chloro-6-(1-methylpyrrolidin-3-yl)-4-morpholinofuro[3,2-d]pyrimidine

[0349] A solution of 2-chloro-4-morpholino-6-(pyrrolidin-3-yl)furo[3,2-d]pyrimidine (200 mg, 0.65 mmol), formaldehyde solution (264 mg, 37%, 3.25 mmol) and CH3COOH (one drop) in DCM was stirred at room temperature for 30 min. Then to the reaction was added sodium triacetoxyborohydride (690 mg, 6.02 mmol). The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NaHCO₃ solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM (3 x 40 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-chloro-6-(1-methylpyrrolidin-3-yl)-4-morpholinofuro[3,2- d]pyrimidine (180 mg, 0.56 mmol) as a white solid. LC-MS (ESI+): m/z 323/325 (MH⁺).¹HNMR (300 MHz, CDCl3) δ6.80 (s, 1H), 3.92-3.89 (m, 4H), 3.75-3.74 (m, 4H), 3.69- 3.66 (m, 1H), 3.12-3.05 (m, 1H), 2.90-2.81 (m, 3H), 2.50 (s, 3H), 2.37-2.30 (m, 1H), 2.09-2.01 (m, 1H). 1.5) Synthesis of N,N-dimethyl-5-((6-(1-methylpyrrolidin-3-yl)-4-morpholinofuro[3,2- d]pyrimidin -2-yl)amino)-3-(m-tolyl)-1H-pyrazole-1-sulfonamide

[0350] A suspension of 2-chloro-6-(1-methylpyrrolidin-3-yl)-4-morpholinofuro[3,2- d]pyrimidine (40 mg, 0.12 mmol), 5-amino-N,N-dimethyl-3-(m-tolyl)-1H-pyrazole-1- sulfonamide (45 mg, 0.16 mmol), Cs2CO3 (100 mg, 0.31 mmol), Pd(OAc)2 (3 mg, 0.012 mmol) and Xantphos (7 mg, 0.012 mmol) in DMF/1,4-dioxane (1/7, 5 mL) was heated to 90 °C for 30 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N,N-dimethyl-5-((6-(1-methylpyrrolidin-3-yl)-4-morpholinofuro[3,2- d]pyrimidin-2-yl)amino)-3-(m-tolyl)-1H-pyrazole-1-sulfonamide (60 mg, 0.11 mmol). LC-MS (ESI+): m/z 567 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ7.67-7.62 (m, 2H), 7.35-7.30 (m, 1H), 7.23-7.21 (m, 1H), 7.16 (s, 1H), 6.56 (s, 1H), 4.04-4.01 (m, 4H), 3.87-3.84 (m, 4H), 3.69-3.54 (m, 1H), 3.15-3.05 (m, 2H), 2.90 (s, 6H), 2.85-2.75 (m, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.37- 2.30 (m, 1H), 2.19-2.10 (m, 1H). 1.6) Synthesis of Compound 39, 6-(1-methylpyrrolidin-3-yl)-4-morpholino-N-(3-(m-tolyl)-1H- pyrazol-5-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride [0351] To a solut

ion of N,N-dimethyl-5-((6-(1-methylpyrrolidin-3-yl)-4-morpholinofuro[3,2- d]pyrimidin -2-yl)amino)-3-(m-tolyl)-1H-pyrazole-1-sulfonamide (60 mg, 0.11 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration, the crude product was purified by preparative HPLC to provide 6-(1- methylpyrrolidin -3-yl)-4-morpholino- N-(3-(m-tolyl)-1H-pyrazol-5-yl)furo[3,2-d]pyrimidin-2- amine hydrochloride (Compound 39, 9 mg, 0.018 mmol) as a yellow solid. LC-MS (ESI+): m/z 460 (MH⁺).¹HNMR (300 MHz, D2O) δ 7.17-7.04 (m, 4H), 6.64 (d, J = 3.0 Hz, 1H), 6.03 (s, 1H), 6.41 (s, 1H), 3.99-3.94 (m, 1H), 3.92-3.76 (m, 8H), 3.75-3.68 (m, 1H), 3.66-3.42 (m, 1H), 3.28-3.09 (m, 2H), 2.92 (d, J = 5.1 Hz, 3H), 2.64-2.44 (m, 1H), 2.32-2.22 (m, 1H), 2.17 (s, 3H). [0352] EXAMPLE 10: Compound 42 using General Synthetic Route 10: General procedure 10:

1.1) Synthesis of tert-butyl 4-(m-tolyl)-1H-pyrazole-1-carboxylate [0353] A solution of tert-butyl

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole - 1-carboxylate (1.5 g, 5.1 mmol) 1-bromo-3-methylbenzene (872 mg, 5.1 mmol), Cs2CO3 (91 mg, 0.28 mmol), PdCl₂(PPh₃)₂ (590 mg, 0.051 mmol) and CsF (1.16 g, 7.65 mmol) in 1,4- dioxane/H₂O (2/1, 30 mL) was heated to 80 °C overnight under N₂. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide tert-butyl 4-(m-tolyl)-1H-pyrazole-1-carboxylate (300 mg, 1.16 mmol) as a yellow solid. LC-MS (ESI+): m/z 259 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.29 (s, 1H), 7.99 (s, 1H), 7.34-7.28 (m, 3H), 7.13-7.10 (m, 1H), 2.39 (s, 3H), 1.68 (s, 9H). Synthesis of 4-(m-tolyl)-1H-pyrazole hydrochloride

[0354] To a solution of tert-butyl 4-(m-tolyl)-1H-pyrazole-1-carboxylate (300 mg, 1.16 mmol) in DCM (8 mL) was added HCl/Et2O (3 mL). The reaction mixture was stirred at room temperature for 2 h. A large amount of solid was precipitated. After concentration and slurry in MeOH/Et₂O (1/20, 2 mL), 4-(m-tolyl)-1H-pyrazole hydrochloride (153 mg, 0.79 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 159 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.13 (s, 2H), 7.38-7.20 (m, 4H), 2.42 (s, 3H). 1.2) Synthesis of Compound 42, 4-morpholino-6-(pyridin-4-yl)-2-(4-(m-tolyl)-1H-pyrazol -1- yl)furo[3,2-d] pyrimidine

[0355] A suspension of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (60 mg, 0.17 mmol) and 4-(m-tolyl)-1H-pyrazole hydrochloride (40 mg, 0.20 mmol ) in anhydrous THF (10 mL) was added NaH (12 mg, 0.49 mmol). The reaction mixture was stirred at 70 °C overnight. The completion was monitored by TLC. The reaction was quenched with water (10 mL) and the aqueous solution was extracted with DCM/MeOH (10/1, 2 x 20mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The residue was purified by preparative TLC purification to provide 4-morpholino-6- (pyridin-4-yl)-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (Compound 42, 31.2 mg, 0.049 mmol) as a yellow solid. LC-MS (ESI+): m/z 439 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.80-8.78 (m, 2H), 8.71 (s, 1H), 8.08 (s, 1H), 7.68 (d, J = 5.7 Hz, 2H), 7.42 (d, J = 7.5 Hz, 2H), 7.34-7.31 (m, 2H), 7.11 (d, J = 3.9 Hz, 1H), 4.22-4.16 (m, 4H), 3.98-3.91 (m, 4H), 2.41 (s, 3H). [0356] EXAMPLE 11: Compound 43 using General Synthetic Route 11:

1.1) Synthesis of 5-phenylisoxazol-3-amine

[0357] A solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) in EtOH/H₂O (1/1, 20 mL) was added hydroxylamine hydrochloride (785 mg, 11.3 mmol) and sodium hydroxide (450 mg, 11.3 mmol). The reaction mixture was heated to 80 °C overnight. To the above solution was added conc. HCl aq. (1.3 mL). The resulting mixture was stirred at 80 °C for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NaHCO3 solution and the pH was adjusted to 10. The aqueous solution was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 15% EtOAc/hex to 35% EtOAc/hex to provide 5- phenylisoxazol-3-amine (0.68 g, 1.25 mmol) as a yellow solid. LC-MS (ESI+): m/z 161 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 7.72-7.68 (m, 2H), 7.47-7.35 (m, 3H), 6.08 (s, 1H), 4.08 (brs, 2H). 1.2) Synthesis of Compound 43, 4-morpholino-N-(5-phenylisoxazol-3-yl)-6-(pyridin-4-yl) furo[3,2-d]pyrimidin-2-amine

[0358] A suspension of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (50 mg, 0.14 mmol), 5-phenylisoxazol-3-amine (35 mg, 0.21 mmol), Cs2CO3 (91 mg, 0.28 mmol), PdCl₂(PPh₃)₂ (10 mg, 0.014 mmol) and Xantphos (24 mg, 0.042 mmol) in 1,4-dioxane (4 mL) was heated to 90 °C for 30 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 4-morpholino-N-(5-phenylisoxazol-3-yl)-6- (pyridin-4-yl)furo[3,2-d]pyrimidin-2-amine (Compound 43, 15 mg, 0.034 mmol) as a white solid. LC-MS (ESI+): m/z 441 (MH⁺). ¹HNMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.74 (d, J = 6.0 Hz, 2H), 7.93 (d, J = 6.0 Hz, 2H), 7.83-7.81 (m, 2H), 7.69 (s, 1H), 7.56-7.53 (m, 3H), 7.40 (s, 1H), 4.08-4.02 (m, 4H), 3.85-3.79 (m, 4H). [0359] EXAMPLE 12: Compound 44 using General Synthetic Route 12:

1.1) Synthesis of Compound 44, 4-morpholino-N-(3-phenylisoxazol-5-yl)-6-(pyridin-4-yl) furo[3,2-d]pyrimidin-2-amine H

[0360] A suspension of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (76 mg, 0.21 mmol), 3-phenylisoxazol-5-amine (40 mg, 0.25 mmol), Cs2CO3 (158 mg, 0.48 mmol), Pd(OAc)₂ (5 mg, 0.021 mmol) and Xantphos (12 mg, 0.021 mmol) in DMF/1,4-dioxane (1/7, 8 mL) was heated to 80 °C for 25 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 4-morpholino-N-(3-phenylisoxazol-5-yl)-6- (pyridin-4-yl)furo[3,2-d]pyrimidin-2-amine (Compound 44, 61 mg, 0.14 mmol) as a yellow solid. LC-MS (ESI+): m/z 441 (MH⁺). ¹HNMR (300 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.75 (d, J = 4.5 Hz, 2H), 7.93 (d, J = 5.7 Hz, 2H), 7.84-7.81 (m, 2H), 7.75 (s, 1H), 7.53-7.51 (m, 3H), 6.70 (s, 1H), 4.08-4.03 (m, 4H), 3.87-3.82 (m, 4H). [0361] EXAMPLE 13: Compound 50 using General Synthetic Route 13:

1.1) Synthesis of 3-amino-N,N-dimethyl-1H-indazole-1-sulfonamide

[0362] To a solution of 1H-indazol-3-amine (1 g, 7.5 mmol) in THF (30 mL) at 0 °C was added NaH (541 mg, 13.53 mmol). After stirred at 0 °C for 1 h, to the solution was added dimethylsulfamoyl chloride (1.61 g, 11.28 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with a saturated NH4Cl solution. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 3-amino-N,N-dimethyl-1H-indazole -1- sulfonamide (600 mg, 2.5 mmol) as a yellow solid. LC-MS: m/z 241 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.55-7.48 (m, 2H), 7.29-7.24 (m, 1H), 4.46 (brs, 2H), 2.92 (s, 6H). 1.2) Synthesis of N,N-dimethyl-3-((4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidin-2-yl) amino)-1H-indazole-1-sulfonamide

[0363] A suspension of 2-bromo-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (60 mg, 0.17 mmol), 3-amino-N,N-dimethyl-1H-indazole-1-sulfonamide (48 mg, 0.20 mmol), Cs2CO3 (125 mg, 0.38 mmol), Pd(OAc)₂ (4 mg, 0.017 mmol) and Xantphos (10 mg, 0.017 mmol) in DMF/1,4-dioxane (1/7, 4 mL) was heated to 90 °C for 25 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N,N-dimethyl-3-((4- morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidin-2-yl)amino)-1H-indazole-1-sulfonamide (50 mg, 0.096 mmol) as a white solid. LC-MS (ESI+): m/z 521 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.74 (d, J = 6.0 Hz, 2H), 8.04 (d, J = 8.7 Hz, 1H), 7.9 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 6.0 Hz, 2H), 7.60-7.48 (m, 2H), 7.16 (s, 1H), 4.02-3.97 (m,4H), 3.83-3.80 (m, 4H), 2.99 (s, 6H). 1.3) Synthesis of Compound 50, N-(1H-indazol-3-yl)-4-morpholino-6-(pyridin-4-yl)furo[3,2-d] pyrimidin-2-amine hydrochloride

[0364] To a solution of N,N-dimethyl-3-((4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidin- 2-yl)amino) -1H-indazole-1-sulfonamide (50 mg, 0.096 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), N-(1H-indazol-3-yl)-4-morpholino-6- (pyridin-4-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride (Compound 50, 33.8 mg, 0.06 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 414 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 8.94 (d, J = 6.6 Hz, 2H), 8.48 (d, J = 5.7 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H), 7.58-7.48 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 4.44-4.15 (m, 4H), 3.96-3.87 (m, 4H). [0365] EXAMPLE 14: Compound 52 using General Synthetic Route 14:

1.1) Synthesis of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid

[0366] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (2.4 g, 10 mmol) in anhydrous THF (4 mL) at -78 °C under N₂ was added n-BuLi ( 5.2 mL, 2.5 M, 13 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the solution was added dry ice (4.4 g, 100 mmol) in one portion. The resulting reaction mixture was stirred at that temperature for 3 h. The completion of the reaction was monitored by TLC. The reaction was quenched with water and the pH was adjusted to 5. The aqueous solution was extracted with DCM (3 x 80 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was slurry in Et₂O to provide 2- chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid ( 2.92 g, 10.3 mmol) as a yellow solid. LC-MS (ESI+): m/z 284/286 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 4.04-3.95 (m, 4H), 3.81-3.76 (m, 4H). 1.2) Synthesis of 2-chloro-N-(2,4-dimethoxybenzyl)-4-morpholinofuro[3,2-d]pyrimidine -6- carboxamide

[0367] A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (112 mg, 0.41 mmol), (2,4-dimethoxyphenyl)methanamine (68 mg, 0.41 mmol), HBOT (137 mg, 1.02 mmol) and EDCl (195 mg, 1.02 mmol) in DMF was stirred at room temperature overnight. The completion of the reaction was monitored by TLC. The solution was diluted with water (10 mL) and extracted with DCM/MeOH (10/1, 3 x 30mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to provide crude 2-chloro- N- (2,4-dimethoxybenzyl)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (140 mg, 0.32 mmol) as a yellow oil. LC-MS (ESI+): m/z 433/435 (MH⁺). 1.3) Synthesis of N-(2,4-dimethoxybenzyl)-2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol - 5-yl)amino)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide [0368] A suspens

ion of 2-chloro-N-(2,4-dimethoxybenzyl)-4-morpholinofuro[3,2- d]pyrimidine-6- carboxamide (2 x 50 mg, 0.12 mmol), 5-amino-N,N-dimethyl-3-phenyl-1H- pyrazole-1- sulfonamide (37 mg, 0.14 mmol), Cs2CO3 (90 mg, 0.27 mmol), Pd(OAc)2 (3 mg, 0.012 mmol) and Xantphos (6.5 mg, 0.012 mmol) in DMF/1,4-dioxane (1/7, 4 mL) was heated to 90 °C for 30 min under microwave conditions. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N-(2,4-dimethoxybenzyl)-2-((1-(N,N-dimethylsulfamoyl)-3- phenyl-1H- pyrazol-5-yl)amino)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (43 mg, 0.065 mmol) as a yellow solid. LC-MS (ESI+): m/z 663 (MH⁺). 1.4) Synthesis of Compound 52, 4-morpholino-2-((3-phenyl-1H-pyrazol-5-yl)amino)furo[3,2-d] pyrimidine-6-carboxamide

[0369] To a solution of N-(2,4-dimethoxybenzyl)-2-((1-(N,N-dimethylsulfamoyl)-3-phenyl- 1H- pyrazol-5-yl)amino)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (43 mg, 0.065 mmol) in DCM (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature overnight. The completion was monitored by LC-MS. The reaction mixture was quenched with a saturated NaHCO3 solution and the pH was adjusted to 10. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated. After concentration and slurry in MeOH, the impure azetidin-1-yl(4-morpholino-2-((3-phenyl-1H-pyrazol-5-yl)amino)furo[3,2- d]pyrimidin-6-yl)methanone (Compound 52, 21 mg, 0.048 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 406 (MH⁺). 1.5) Synthesis of Compound 52, 4-morpholino-2-((3-phenyl-1H-pyrazol-5-yl)amino)furo[3,2-d] pyrimidine-6-carboxamide hydrochloride

[0370] To a solution of impure azetidin-1-yl(4-morpholino-2-((3-phenyl-1H-pyrazol-5- yl)amino)furo [3,2-d]pyrimidin-6-yl)methanone (21 mg, 0.048 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 4-morpholino-2-((3-phenyl-1H-pyrazol-5- yl)amino)furo[3,2-d]pyrimidine-6- carboxamide hydrochloride (Compound 52, 17.1 mg, 0.039 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 406 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 7.74 (d, J = 9.9 Hz, 2H), 7.70 (s, 1H), 7.60-7.42 (m, 3H), 6.42 (s, 1H), 4.48-4.14 (m, 4H), 3.91-3.85 (m, 4H). [0371] EXAMPLE 15: Compound 53 using General Synthetic Route 15:

1.1) Synthesis of azetidin-1-yl(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methanone

[0372] A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (200 mg, 0.71 mmol) in DCM was added oxalyl dichloride (182 mg, 1.4 mmol) and one drop of DMF. The mixture was stirred at room temperature for 6 h. The solution was concentrated, and the resulting residue was dissolved in DCM (15 mL). To the solution was added azetidine (60 mg, 1.06 mmol) and followed by triethylamine (107 mg, 1.06 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide azetidin-1-yl(2-chloro- 4-morpholinofuro [3,2-d]pyrimidin-6-yl)methanone (75.8 mg, 0.25 mmol) as a yellow solid. LC-MS (ESI+): m/z 323/325 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 7.19 (s, 1H), 4.58-4.52 (m, 2H), 4.35-4.27 (m, 2H), 4.07-4.04 (m, 4H), 3.86-3.83 (m, 4H), 2.52- 2.45 (m, 2H). 1.2) Synthesis of 5-((6-(azetidine-1-carbonyl)-4-morpholinofuro[3,2-d]pyrimidin-2-yl)amino) - N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide

[0373] A suspension of azetidin-1-yl(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6- yl)methanone (3 x 50 mg, 0.47 mmol), 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1- sulfonamide (148 mg, 0.56 mmol), Cs₂CO₃ (344 mg, 1.06 mmol), Pd(OAc)₂ (10 mg, 0.047 mmol) and Xantphos (25 mg, 0.047 mmol) in DMF/1,4-dioxane (7/1, 4 mL) was heated to 50 °C for 50 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 5-((6-(azetidine-1-carbonyl)-4-morpholinofuro[3,2-d]pyrimidin-2- yl)amino)-N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide (143 mg, 0.26 mmol) as a yellow solid. LC-MS (ESI+): m/z 553 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 8.70 (s, 1H), 7.91 (d, J = 6.9 Hz, 2H), 7.46-7.36 (m, 4H), 7.22 (s, 1H), 4.07-4.04 (m, 4H), 3.87-3.76 (m, 6H), 3.73-3.67 (m, 2H), 3.06 (s, 6H), 2.11-1.96 (m, 2H). 1.3) Synthesis of Compound 53, azetidin-1-yl(4-morpholino-2-((3-phenyl-1H-pyrazol-5- yl)amino) furo[3,2-d]pyrimidin-6-yl)methanone hydrochloride

[0374] To a solution of 5-((6-(azetidine-1-carbonyl)-4-morpholinofuro[3,2-d]pyrimidin-2- yl)amino)- N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide (65 mg, 0.11 mmol) in DCM (4 mL) was added HCl/Et2O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), azetidin-1-yl(4-morpholino-2-((3- phenyl-1H-pyrazol-5-yl) amino)furo[3,2-d] pyrimidin-6-yl)methanone hydrochloride (Compound 53, 30.1 mg, 0.06 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 446 (MH⁺).¹HNMR (300 MHz, CD3OD) δ 7.71 (d, J = 7.2 Hz, 2H), 7.64 -7.40 (m, 4H), 6.42 (s, 1H), 4.87-4.65 (m, 2H), 4.38-4.13 (m, 6H), 3.91-3.83 (m, 4H), 2.54-2.43 (m, 2H).

[0375] EXAMPLE 16: Compound 55 using General Synthetic Route 16:

1.1) Synthesis of (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)(piperidin-1-yl)methanone

[0376] A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (200 mg, 0.71 mmol), piperidine (61 mg, 0.71 mmol), HOBT (245 mg, 1.76 mmol), EDCl (340 mg, 1.76 mmol) in DMF (12 mL) was stirred at room temperature overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)(piperidin-1-yl)methanone (171 mg, 0.49 mmol) as a white solid. LC-MS (ESI+): m/z 351/353 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 6.99 (s, 1H), 4.08-4.03 (m, 4H), 3.85-3.79 (m, 4H), 3.75-3.58 (m, 4H), 1.78-1.66 (m, 6H). 1.2) Synthesis of N,N-dimethyl-5-((4-morpholino-6-(piperidine-1-carbonyl)furo[3,2- d]pyrimidin- 2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide

[0377] A suspension of (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)(piperidin-1- yl)methanone (100 mg, 0.29 mmol), 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1- sulfonamide (91 mg, 0.34mmol), Cs₂CO₃ (214 mg, 0.66 mmol), Pd(OAc)₂ (6.4 mg, 0.029 mmol) and Xantphos (16.5 mg, 0.029 mmol) in DMF/1,4-dioxane (7/1, 4 mL) was heated to 90 °C for 45 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N,N-dimethyl-5-((4-morpholino-6-(piperidine-1-carbonyl)furo[3,2- d]pyrimidin-2-yl) amino)-3-phenyl-1H-pyrazole-1-sulfonamide (53 mg, 0.09 mmol) as a colorless oil. LC-MS (ESI+): m/z 581 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.70 (s, 1H), 7.90 (d, J = 6.9 Hz, 2H), 7.45-7.34 (m, 4H), 7.02 (s, 1H), 4.04-4.02 (m, 4H), 3.87-3.85 (m, 4H), 3.79- 3.70 (m, 4H), 3.06 (s, 6H), 1.76-1.68 (m, 6H). 1.3) Synthesis of Compound 55, (4-morpholino-2-((3-phenyl-1H-pyrazol-5-yl)amino)furo[3,2-d] pyrimidin-6-yl)(piperidin-1-yl)methanone hydrochloride [0378] To a solution of

N,N-dimethyl-5-((4-morpholino-6-(piperidine-1-carbonyl)furo[3,2-d] pyrimidin-2-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide (53 mg, 0.09 mmol) in DCM (4 mL) was added HCl/Et2O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), (4-morpholino-2-((3-phenyl-1H- pyrazol-5-yl)amino)furo [3,2-d]pyrimidin-6-yl)(piperidin-1-yl)methanone hydrochloride (Compound 55, 17.6 mg, 0.35 mmol) was obtained as a white solid. LC-MS (ESI+): m/z 474 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 7.78 (d, J = 7.5 Hz, 2H), 7.59-7.45 (m, 2H), 7.40-7.36 (m, 1H), 7.29 (s, 1H), 6.61 (s, 1H), 4.19-4.03 (m, 4H), 3.88-3.79 (m, 4H), 3.59-3.47 (m, 4H), 1.76-1.47 (m, 6H). [0379] EXAMPLE 17: Compound 64 using General Synthetic Route 17:

1.1) Synthesis of methyl 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylate

[0380] A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (1.0 g, 3.5 mmol) in DCM was added oxalyl dichloride (912.0 mg, 7.0 mmol) and one drop of DMF. The mixture was stirred at room temperature for 6 h. The solution was concentrated directly and the residue was dissolved in DCM (15 mL). To the solution was added methanol (80 mL) and followed by triethylamine (1.07 g, 10.5 mmol). The completion of the reaction was monitored by TLC. The reaction was quenched with water (10 ml) and a large amount of yellow solid was precipitated. After filtration, 800 mg of methyl 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6- carboxylate was obtained. LC-MS (ESI+): m/z 298/300 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 7.40 (s, 1H), 4.09-4.01 (m, 4H), 3.99 (s, 3H), 3.87-3.84 (m, 4H). 1.2) Synthesis of methyl 2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5-yl)amino)-4- morpholinofuro[3,2-d]pyrimidine-6-carboxylate

[0381] A suspension of methyl 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylate (400 mg, 1.35 mmol), 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide (430 mg, 1.620 mmol), Cs2CO3 (1.1 g, 3.38 mmol), Pd(OAc)2 (30 mg, 0.135 mmol) and Xantphos (80 mg, 0.135 mmol) in DMF/1,4-dioxane (1/7, 40 mL) was heated to 80 °C for 2 h. The reaction mixture was diluted with water and extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 50% EtOAc/PE to DCM to provide 2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5- yl)amino) -4-morpholinofuro[3,2-d]pyrimidine-6-carboxylate (250 mg, 0.47 mmol) as a yellow solid. LC-MS (ESI+): m/z 528 (MH⁺). 1.3) Synthesis of 2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5-yl)amino)-4- morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid

[0382] To a solution of 2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5-yl)amino)-4- morpholinofuro[3,2-d]pyrimidine-6-carboxylate (250 mg, 0.47 mmol) in MeOH/DCM (1/2, 30 mL) was added NaOH aqueous solution (2M, 0.3 mL). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with HCl aqueous solution and adjusted the pH to 5. The aqueous phase was extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The residue was purified by slurry using Et2O to provide 2-((1-(N,N- dimethylsulfamoyl)-3-phenyl- 1H-pyrazol-5-yl)amino)-4-morpholinofuro[3,2-d]pyrimidine-6- carboxylic acid (200 mg, 0.39 mmol) as a yellow solid. LC-MS (ESI+): m/z 514 (MH⁺). 1.4) Synthesis of (R)-N-(1-cyclopropylethyl)-2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H- pyrazol-5-yl)amino)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide

[0383] A solution of 2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5-yl)amino)-4- morpholinofuro [3,2-d]pyrimidine-6-carboxylic acid (150 mg, 0.29 mmol), (R)-1- cyclopropylethanamine (30 mg, 0.35 mmol), HOBT (99 mg, 0.73 mmol) and EDCl (140 mg, 0.73 mmol) in DMF (3 mL) was stirred at room temperature overnight. The completion of the reaction was monitored by TLC. The reaction was quenched with water (10 ml) and extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide (R)-N-(1-cyclopropylethyl)-2- ((1-(N,N-dimethylsulfamoyl)-5-phenyl-1H-pyrazol-3- yl)amino)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (80 mg, 0.14 mmol). LC-MS (ESI+): m/z 581 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 7.90 (d, J = 6.6 Hz, 2H), 7.47-7.39 (m, 3H), 7.35 (s, 1H), 6.24 (d, J = 8.1 Hz, 1H), 4.10-4.04 (m, 4H), 3.89-3.84 (m, 4H), 3.59-3.56 (m, 1H), 3.07 (s, 6H), 1.36 (d, J = 6.6 Hz, 3H), 0.97-0.95 (m, 1H), 0.60-0.52 (m, 2H), 0.47-0.32 (m, 2H). 1.5) Synthesis of Compound 64, (R)-N-(1-cyclopropylethyl)-4-morpholino-2-((5-phenyl- 1H- pyrazol-3-yl)amino)furo[3,2-d]pyrimidine-6-carboxamide hydrochloride [0384] To a solut

ion of (R)-N-(1-cyclopropylethyl)-2-((1-(N,N-dimethylsulfamoyl)-5-phenyl- 1H- pyrazol-3-yl)amino)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (80 mg, 0.14 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), (R)-N-(1- cyclopropylethyl)-4-morpholino -2-((5-phenyl-1H-pyrazol-3-yl)amino)furo[3,2-d]pyrimidine-6- carboxamide hydrochloride (Compound 64, 30 mg, 0.06 mmol) was obtained as a white solid. LC-MS (ESI+): m/z 474 (MH⁺).¹HNMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H), 8.93 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.5 Hz, 2H), 7.59 (s, 1H), 7.54-7.42 (m, 2H), 7.39-7.37 (m, 1H), 6.61(s, 1H), 4.16-4.05 (m, 4H), 3.86-3.79 (m, 4H), 3.40-3.30 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.11- 1.04 (m, 1H), 0.49-0.40 (m, 2H), 0.39-0.25 (m, 2H). [0385] EXAMPLE 18: Compound 65 using General Synthetic Route 18:

1.1) Synthesis of 2-chloro-N-(methylsulfonyl)-4-morpholinofuro[3,2-d]pyrimidine-6- carboxamide

[0386] A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (200 mg, 0.71 mmol), methanesulfonamide (134 mg, 1.42 mmol), 2-chloro-1-methylpyridin-1-ium iodide (216 mg, 0.85 mmol), Et₃N (214 mg, 2.12 mmol) and DMAP (4.3 mg, 0.035 mmol) in DCM (25 mL) was stirred at room temperature overnight. The completion of the reaction was monitored by TLC. The reaction was quenched with water (10 ml) and adjusted the pH to 4 using 1 N HCl aqueous solution. The aqueous phase was extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-chloro-N-(methylsulfonyl)-4- morpholinofuro [3,2-d]pyrimidine-6-carboxamide (244 mg, 0.68 mmol) as a yellow solid. LC- MS (ESI+): m/z 361/363 (MH⁺). 1.2) Synthesis of 2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5-yl)amino)-N- (methylsulfonyl)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide [0387] A suspension of 2-chlo

ro-N-(methylsulfonyl)-4-morpholinofuro[3,2-d]pyrimidine-6- carboxamide (60 mg x3, 0.17 mmol), 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1- sulfonamide (53 mg, 0.2 mmol), Cs2CO3 (127 mg, 0.39 mmol), Pd(OAc)2 (3.8 mg, 0.017 mmol) and Xantphos (9.6 mg, 0.017 mmol) in DMF/1,4-dioxane (7/1, 8 mL) was heated to 100 °C for 40 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 10% MeOH/DCM to provide 2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5-yl)amino)-N- (methylsulfonyl)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (30 mg, 0.051 mmol) as a white solid. LC-MS (ESI+): m/z 591 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 7.86 (d, J = 6.9 Hz, 2H), 7.48-7.40 (m, 3H), 7.28 (s, 1H), 7.21 (s, 1H), 4.13-4.07 (m, 4H), 3.89-3.84 (m, 4H), 3.15 (s, 3H), 3.03 (s, 6H). 1.3) Synthesis of Compound 65, N-(methylsulfonyl)-4-morpholino-2-((3-phenyl-1H-pyrazol-5-yl) amino)furo[3,2-d]pyrimidine-6-carboxamide hydrochloride [0388] To a solution of

2-((1-(N,N-dimethylsulfamoyl)-3-phenyl-1H-pyrazol-5-yl)amino)-N- (methylsulfonyl)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (30 mg, 0.05 mmol) in DCM (4 mL) was added HCl/Et2O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et₂O (1/20, 2 mL), N- (methylsulfonyl)-4-morpholino-2- ((3-phenyl-1H-pyrazol-5-yl)amino)furo[3,2-d]pyrimidine-6- carboxamide hydrochloride (Compound 65, 23.3 mg, 0.082 mmol) was obtained as a white solid. LC-MS (ESI+): m/z 484 (MH⁺). ¹HNMR (300 MHz, CD3OD) δ 7.75 (s, 1H), 7.72 (d, J = 6.9 Hz, 2H), 7.52-7.40 (m, 3H), 6.43(s, 1H), 4.36-4.18 (m, 4H), 3.91-3.86 (m, 4H), 3.39 (s, 3H). [0389] EXAMPLE 19: Compound 66 using General Synthetic Route 19:

1.1) Synthesis of 2-chloro-N-(cyclopropylmethyl)-N-methyl-4-morpholinofuro[3,2-d] pyrimidine-6-carboxamide

[0390] A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (270 mg, 0.95 mmol), 1-cyclopropyl-N-methylmethanamine (80 mg, 0.95 mmol), DMAP (292 mg, 2.4 mmol) and EDCl (460 mg, 2.4 mmol) in DCM (20 mL) was stirred at room temperature overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 2-chloro-N-(cyclopropylmethyl)-N-methyl- 4-morpholinofuro[3,2-d] pyrimidine-6-carboxamide (272mg, 0.78 mmol) as a white solid. LC- MS (ESI+): m/z 351/353 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 7.09 (s, 1H), 4.09-4.04 (m, 4H), 3.88-3.82 (m, 4H), 3.48-3.37 (m, 2H), 3.29 (s, 1.5H), 3.20 (s, 1.5H), 1.11-0.98 (m, 1H), 0.65- 0.60 (m, 2H), 0.34-0.21 (m, 2H). 1.2) Synthesis of Compound 66, N-(cyclopropylmethyl)-N-methyl-4-morpholino-2-(4-phenyl - 1H-pyrazol-1-yl)furo[3,2-d]pyrimidine-6-carboxamide

[0391] A suspension of 2-chloro-N-(cyclopropylmethyl)-N-methyl-4-morpholinofuro[3,2- d]pyrimidine- 6-carboxamide (100 mg, 0.29 mmol), 4-phenyl-1H-pyrazole (41 mg, 0.29 mmol), CuI (11 mg, 0.06 mmol) and Cs2CO3 (186 mg, 0.57 mmol) in DMF (10 mL) was stirred at 100 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with DCM/MeOH (15/1, 3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide N-(cyclopropylmethyl)-N-methyl-4- morpholino-2- (4-phenyl-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine-6-carboxamide (Compound 66, 27 mg, 0.059 mmol) as a white solid. LC-MS (ESI+): m/z 459 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.35 (s, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.44-7.39 (m, 3H), 7.30-7.28 (m, 1H), 4.12-4.06 (m, 4H), 3.85-3.78 (m, 4H), 3.39-3.30 (m, 2H), 3.30 (s, 1.5H), 3.10 (s, 1.5H), 1.10-1.01 (m, 1H), 0.53-0.51 (m, 2H), 0.34-0.15 (m, 2H). [0392] EXAMPLE 20: Compound 69 using General Synthetic Route 20:

1.1) Synthesis of 4-cyclopropyl-3-oxobutanenitrile

[0393] To a solution of acetonitrile (1.08 g, 26.3 mmol) and methyl 2-cyclopropylacetate (2.0 g, 17.5 mmol) in anhydrous THF (40 mL) at 0 °C under N₂ was added NaHDMS (13.2 mL, 26.3 mmol) dropwise. After addition, the solution was stirred at room temperature for 2 h. The completion of the reaction was monitored by TLC. The reaction was quenched with NH₄Cl aqueous solution (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 33% EtOAc/PE to provide 4-cyclopropyl-3-oxobutanenitrile (1.6 g, 13.1 mmol) as yellow oil. ¹HNMR (300 MHz, CDCl3) δ 3.34 (s, 2H), 2.29 (d, J = 6.9 Hz, 2H), 1.89- 1.84 (m, 1H), 0.85-0.79 (m, 2H), 0.06-0.01 (m, 2H). 1.2) Synthesis of 3-(cyclopropylmethyl)-1H-pyrazol-5-amine

[0394] To a solution of 4-cyclopropyl-3-oxobutanenitrile (1.15 g, 7.2 mmol) in EtOH (40 mL) was added NH₂NH₂.H₂O (0.98 g, 19.5 mmol). The reaction mixture was heated to reflux overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 3-(cyclopropylmethyl)-1H-pyrazol-5-amine (1.64 g, 0.012 mmol) as a yellow oil. LC-MS (ESI+): m/z 138 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 5.51 (m, 1H), 4.41 (brs, 2H), 2.47 (d, J = 6.9 Hz, 2H), 1.02-0.90 (m, 1H), 0.59-0.56 (m, 2H), 0.22-0.17 (m, 2H). 1.3) Synthesis of 5-amino-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide

[0395] To a solution of 3-(cyclopropylmethyl)-1H-pyrazol-5-amine (1.0 g, 7.25 mmol) in THF (30 mL) at 0 °C was added NaH (521 mg, 8.7 mmol). After stirred at 0 °C for 1 h, to the solution was added dimethylsulfamoyl chloride (1.14 g, 7.97 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 33% EtOAc/PE to provide 5-amino-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide (540 mg, 2.2 mmol). LC-MS: m/z 245 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 5.79 (s, 1H), 3.83 (brs, 2H), 2.94 (s, 6H), 2.71 (d, J = 6.9 Hz, 2H), 1.08-1.01 (m, 1H), 0.60-0.54 (m, 2H), 0.23-0.19 (m, 2H). 1.4) Synthesis of 3-(cyclopropylmethyl)-N,N-dimethyl-5-((4-morpholino-6-(pyridin-4-yl) furo[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazole-1-sulfonamide [0396] A suspension of 2-brom

o-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (200 mg, 0.56 mmol), 5-amino-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide (162 mg, 0.67 mmol), Cs2CO3 (365 mg, 1.12 mmol), Pd(OAc)2 (12 mg, 0.056 mmol) and Xantphos (32 mg, 0.056 mmol) in DMF/1,4-dioxane (7/1, 8 mL) was heated to 85 °C for 40 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 3-(cyclopropylmethyl)-N,N-dimethyl-5-((4-morpholino-6-(pyridin-4- yl)furo[3,2-d] pyrimidin-2-yl)amino)-1H-pyrazole-1-sulfonamide (47 mg, 0.09 mmol) as a white solid. LC-MS (ESI+): m/z 525 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 8.74 (d, J = 5.7 Hz, 1H), 8.69 (s, 1H), 7.64 (d, J = 6.0 Hz, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 4.12-4.07 (m, 4H), 3.92-3.88 (m, 4H), 2.99 (s, 6H), 2.54 (d, J = 7.2 Hz, 2H), 1.11-1.02 (m, 1H), 0.57-0.53 (m, 2H), 0.28-0.23 (m, 2H). 1.5) Synthesis of Compound 69, N-(3-(cyclopropylmethyl)-1H-pyrazol-5-yl)-4-morpholino- 6- (pyridin-4-yl)furo[3,2-d]pyrimidin-2-amine hydrochloride

[0397] To a solution of 3-(cyclopropylmethyl)-N,N-dimethyl-5-((4-morpholino-6-(pyridin-4- yl) furo[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazole-1-sulfonamide (47 mg, 0.09 mmol) in DCM (4 mL) was added HCl/Et₂O (2 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et₂O (1/20, 2 mL), N-(3-(cyclopropylmethyl)-1H- pyrazol-5-yl)- 4-morpholino-6-(pyridin-4-yl)furo[3,2-d] pyrimidin-2-amine hydrochloride (Compound 69, 32.5 mg, 0.072 mmol) was obtained as a yellow solid. LC-MS (ESI+): m/z 418 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 8.98 (d, J = 6.9 Hz, 2H), 8.58 (d, J = 6.9 Hz, 2H), 8.06 (s, 1H), 6.00 (s, 1H), 4.37-4.27 (m, 4H), 3.94-3.90 (m, 4H), 2.61 (d, J = 6.9 Hz, 2H), 1.09-1.02 (m, 1H), 0.62-0.54 (m, 2H), 0.29-0.24 (m, 2H). [0398] EXAMPLE 21: Compound 78 using General Synthetic Route 21:

1.1) Synthesis of 5-amino-3-cyclopropyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide H N

[0399] To a solution of 3-cyclopropyl-1H-pyrazol-5-amine (500 mg, 4.06 mmol) in THF (30 mL) at 0 °C was added NaH (243 mg, 6.1 mmol). After stirred at 0 °C for 1 h, to the solution was added dimethylsulfamoyl chloride (755 mg, 5.28 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 25% EtOAc/PE to provide 5- amino-3-cyclopropyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide (372 mg, 1.6 mmol). LC-MS: m/z 231 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 5.05 (s, 1H), 4.71 (brs, 2H), 2.96 (s, 6H), 1.84- 1.80 (m, 1H), 0.93-0.86 (m, 2H), 0.72-0.67 (m, 2H). 1.2) Synthesis of 2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide [0400] A solution of 2-chloro-4-m

orpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (400 mg, 1.4 mmol), methanamine hydrochloride (113 mg, 1.70 mmol), EDCl (678 mg, 3.5 mmol) and DMAP (431 mg, 3.5 mmol) in DCM (3 mL) was stirred at room temperature overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 ml) and extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-chloro-N-methyl-4-morpholinofuro[3,2- d]pyrimidine-6-carboxamide (230 mg, 0.78 mmol). LC-MS (ESI+): m/z 297/299 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 7.35 (s, 1H), 6.34 (brs, 1H), 4.08-4.03 (m, 4H), 3.88-3.83 (m, 4H), 3.07 (d, J = 5.1 Hz, 3H). 1.3) Synthesis of 2-bromo-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide

[0401] A solution of 2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (230 mg, 0.78 mmol) in HBr/AcOH (33 wt.% in Acetic acid, 3 mL) was heated to reflux for 3.5 h. The completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with a saturated NaHCO3 aqueous solution and the pH was adjusted to 8. The aqueous solution was extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure to provide 245 mg of crude 2-bromo-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide as a brown solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 341/343 (MH⁺). 1.4) Synthesis of 2-((3-cyclopropyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazol-5-yl)amino) -N- methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide

[0402] A solution of 2-bromo-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (50 mg x3, 0.15 mmol), 5-amino-3-cyclopropyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide (40 mg, 0.18 mmol), Cs₂CO₃ (110 mg, 0.35 mmol), Pd(OAc)₂ (3.5 mg, 0.015 mmol) and Xantphos (8.5 mg, 0.015 mmol) in DMF/1,4-dioxane (7/1, 4 mL) was heated to 80 °C for 20 min under microwave condition. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-((3-cyclopropyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazol-5-yl)amino)-N-methyl-4- morpholinofuro[3,2-d]pyrimidine-6-carboxamide (62 mg, 0.13 mmol) as a white solid. LC-MS (ESI+): m/z 491 (MH⁺).¹HNMR (300 MHz, CDCl3) δ8.67 (s, 1H), 7.32 (s, 1H), 6.55 (s, 1H), 6.33 (d, J = 5.1 Hz, 1H), 4.03-3.95 (m, 4H), 3.88-3.84 (m, 4H), 3.05 (d, J = 5.1 Hz, 3H), 2.89 (s, 6H), 1.95-1.92 (m, 1H), 0.99-0.93 (m, 2H), 0.87-0.84 (m, 2H). 1.5) Synthesis of Compound 78, 2-((3-cyclopropyl-1H-pyrazol-5-yl)amino)-N-methyl-4- morpholinofuro[3,2-d]pyrimidine-6-carboxamide hydrochloride

[0403] To a solution of 2-((3-cyclopropyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazol-5- yl)amino)-N-methyl- 4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (62 mg, 0.13 mmol) in DCM (4 mL) was added HCl/Et₂O (3 mL). The reaction mixture was stirred at room temperature for 2 h. After concentration and slurry in MeOH/Et2O (1/20, 2 mL), 2-((3- cyclopropyl-1H-pyrazol-5-yl)amino)-N-methyl- 4-morpholinofuro[3,2-d]pyrimidine-6- carboxamide hydrochloride (Compound 78, 32.8 mg, 0.078 mmol) was obtained as a white solid. LC-MS (ESI+): m/z 384 (MH⁺). ¹HNMR (300 MHz, CD3OD) δ 7.51 (s, 1H), 5.73 (s, 1H), 4.30-4.15 (m, 4H), 3.92-3.86 (m, 4H), 2.96 (s, 3H), 1.99-1.91 (m, 1H), 1.19-1.15 (m, 2H), 0.89- 0.67 (m, 2H). [0404] The compounds in Table 2 were prepared using methods analogous to those described in the referenced General Synthetic Routes. Table 2

[0405] EXAMPLE 22: Compound 89 using General Synthetic Route 22:

1.1) Synthesis of (Z)-methyl 2-((2-cyano-1-(pyridin-4-yl)vinyl)oxy)acetate

[0406] To a solution of triphenylphosphine (3.5 g, 13.4 mmol) in dry tetrahydrofuran (THF) was added Diethyl azodicarboxylate (DEAD) (2.3 g, 13.4 mmol), 3-oxo-3-(pyridin-4- yl)propanenitrile (1.5 g, 10.3 mmol) and methyl 2-hydroxyacetate (1.2 g, 13.4 mmol) under N2. The reaction was stirred at room temperature overnight. Upon the completion of the reaction as monitored by thin layer chromatography (TLC), the reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 4.4 g of impure (Z)-methyl2-((2-cyano-1-(pyridin-4- yl)vinyl)oxy)acetate containing triphenylphosphine oxide as a yellow solid. LC-MS (ESI+): m/z 219 (MH⁺). 1.2) Synthesis of methyl 3-amino-5-(pyridin-4-yl)furan-2-carboxylate NH

[0407] To a solution of impure (Z)-methyl2-((2-cyano-1-(pyridin-4-yl)vinyl)oxy)acetate (4.6 g, 21.1 mmol) in dry THF at 0°C was added NaH (1.5 g, 31.6 mmol). The reaction was warmed to room temperature and stirred at room temperature for 2 h. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with a saturated NH4Cl solution and the pH was adjusted to 3 using 2 N HCl aqueous solutions. The aqueous solution was washed with ethyl acetate (3 x 50 mL) to remove some impurities. To the aqueous solution was added a saturated Na2CO3 solution to adjust the pH to 11 and extracted with DCM/MeOH (10/1, 3 x 60 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated to provide 1.35 g of crude methyl 3-amino-5-(pyridin-4-yl)furan-2- carboxylate as an oil. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 219 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.66 (dd, J = 4.5, 1.5 Hz, 2H), 7.58 (dd, J = 4.8, 1.2 Hz, 2H), 6.58 (s, 1H), 4.67 (brs, 2H), 3.93 (s, 3H). 1.3) Synthesis of methyl 5-(pyridin-4-yl)-3-ureidofuran-2-carboxylate

[0408] To a solution of methyl 3-amino-5-(pyridin-4-yl)furan-2-carboxylate (1.94 g, 8.9 mmol) in DCM (40 mL) at -78 °C under N2 was added sulfurisocyanatidic chloride (3.79 g, 26.7 mmol) dropwise. After addition, the reaction was warmed to room temperature and stirred at room temperature for 1 h. The organic solvent was removed by evaporation in vacuo. To the resulting residue was added 6 N HCl (10 mL) aqueous solutions. The mixture was heated to reflux for 30 min. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature and the pH was adjusted to 9 using a saturated NaHCO₃ solution. A large amount of solid was precipitated. After filtration, the filter cake was washed with water and dried to provide 2.7 g of crude methyl5-(pyridin-4-yl)-3-ureidofuran-2-carboxylate as a yellow solid. LC-MS (ESI+): m/z 262 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 8.61 (dd, J = 4.8, 1.5 Hz, 2H), 7.89 (s, 1H), 7.78 (dd, J = 5.1, 1.5 Hz, 2H), 3.95 (s, 3H). 1.4) Synthesis of 6-(pyridin-4-yl)furo[3,2-d]pyrimidine-2,4-diol [0409] To a solution of crude

methyl 5-(pyridin-4-yl)-3-ureidofuran-2-carboxylate (2.7 g, 10.3 mmol) in MeOH (40 mL) was added 1.5 N NaOH (15 mL). The reaction was heated to reflux for 1.5 h. Upon the completion of the reaction as monitored by TLC, the solvent MeOH was removed by evaporation in vacuo. To the resulting residue were added 6 N HCl solutions until the pH to 2. A large amount of solid was precipitated. After filtration, the filter cake was washed with water and dried to provide crude 2.1 g of 6-(pyridin-4-yl)furo[3,2-d]pyrimidine-2,4-diol as a yellow solid. LC-MS (ESI+): m/z 230 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 11.61 (s, 1H), 11.37 (s, 1H), 8.89 (d, J = 6.6 Hz, 2H), 8.24 (d, J = 6.3 Hz, 2H), 7.63 (s, 1H). 1.5) Synthesis of 2,4-dichloro-6-(pyridin-4-yl)furo[3,2-d]pyrimidine

[0410] To a solution of 6-(pyridin-4-yl)furo[3,2-d]pyrimidine-2,4-diol (1.5 g, 6.54 mmol) in phenylphosphonic dichloride (30 mL) was added DIPEA (8.43 g, 65.4 mmol). The reaction mixture was heated to 120 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, a saturated NaHCO3 solution was added to adjust the pH to 8. The aqueous solution was extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 50% EtOAc/PE to 75% EtOAc/PE to provide 2,4-dichloro-6-(pyridin-4-yl) furo[3,2-d]pyrimidine (1.6 g, 6.9 mmol) as a yellow solid. LC-MS (ESI+): m/z 266/268 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.85 (dd, J = 4.8, 1.5 Hz, 2H), 7.82 (dd, J = 4.5, 1.5 Hz, 2H), 7.38 (s, 1H). 1.6) Synthesis of 2-chloro-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine

[0411] To a solution of 2,4-dichloro-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (1.6 g, 6.9 mmol) in DCM/EtOH (1/3, 120 mL) was added morpholine (0.91 g, 10.5 mmol) and K2CO3 (1.91 g, 14 mmol). The reaction was stirred at room temperature for 2 h. Upon the completion of the reaction as monitored by TLC, the reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 3% MeOH/DCM to provide 2-chloro-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (770 mg, 2.43 mmol) as a yellow solid. LC-MS (ESI+): m/z 317/319 (MH⁺).¹HNMR (300 MHz, DMSO- d₆) δ 8.76 (d, J = 6.0 Hz, 2H), 7.97 (d, J = 6.0 Hz, 2H), 7.82 (s, 1H), 4.06-3.97 (m, 4H), 3.82- 3.75 (m, 4H). 1.7) Synthesis of 4-morpholino-6-(pyridin-4-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo [3,2- d]pyrimidine

[0412] To a solution of 2-chloro-4-morpholino-6-(pyridin-4-yl)furo[3,2-d]pyrimidine (100 mg, 0.32 mmol) in DMF (10 mL) was added 3-(m-tolyl)-1H-pyrazole (55 mg, 0.35 mmol), Cs₂CO₃ (210 mg, 0.64 mmol) and CuI (12 mg, 0.064 mmol). The reaction mixture was stirred at 110 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 4% MeOH/DCM to provide 4-morpholino-6- (pyridin-4-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo [3,2-d]pyrimidine (28 mg, 0.064 mmol) as a white solid. LC-MS (ESI+): m/z 439 (MH⁺).¹HNMR (300 MHz, DMSO-d₆) δ 8.78 (brs, 2H), 8.72 (s, 1H), 8.05-8.01 (m, 2H), 7.91 (s, 1H), 7.81 (s, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.03 (s, 1H), 4.18-4.12 (m, 4H), 3.90-3.84 (m, 4H), 2.40 (s, 3H).

[0413] EXAMPLE 23: Compound 90 using General Synthetic Route 23:

1.1) Synthesis of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine

[0414] To a solution of 2,4-dichlorofuro[3,2-d]pyrimidine (6.46 g, 34.2 mmol mmol) in 1,4- dioxane (100 mL) was added morpholine (5.95 g, 68.4 mmol). The reaction was stirred at room temperature for 30 min. Upon the completion of the reaction as monitored by TLC, the reaction mixture was concentrated directly and the resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 20% EtOAc/PE to provide 2- chloro-4-morpholinofuro[3,2-d]pyrimidine (7.5 g, 40.1 mmol) as a white solid. LC-MS (ESI+): m/z 240/242 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.74 (d, J = 1.8 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.05-4.02 (m, 4H), 3.85-3.82 (m, 4H). 1.2) Synthesis of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine

[0415] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (2.0 g, 0.83 mmol) in anhydrous THF (30 mL) at -78 °C under N₂ was added LDA (1.33 mL, 2M, 2.66 mmol). After stirred at -78 °C for 1 h, to the solution was added a solution of NIS (2.25 g, 1.0 mmol) in anhydrous THF (10 mL). Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 10% EtOAc/PE to provide 2-chloro-6-iodo-4- morpholinofuro[3,2-d]pyrimidine (1.6 g, 4.4 mmol) as yellow solid. LC-MS (ESI+): m/z 366/368 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 6.97 (s, 1H), 4.01-3.98 (m, 4H), 3.85-3.82 (m, 4H). 1.3) Synthesis of 2-chloro-4-morpholino-6-(pyridin-3-yl)furo[3,2-d]pyrimidine

[0416] To a solution of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (500 mg, 1.37 mmol) in 1,4-dioxane/H₂O (2/1, 30 mL) was added pyridin-3-ylboronic acid (168 mg, 1.37 mmol), K₂CO₃ (567 mg, 4.1 mmol) and Pd(PPh₃)₄ (158 mg, 0.13 mmol). The reaction was stirred at 90 °C for 5 h. Upon the completion of the reaction as monitored by TLC, the reaction solution was concentrated directly and the resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 2- chloro-4-morpholino-6-(pyridin-3-yl)furo[3,2-d] pyrimidine (410 mg, 1.29 mmol) as a light yellow solid. LC-MS (ESI+): m/z 317/319 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 9.07 (d, J = 1.5 Hz, 1H), 8.69-8.68 (m, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.46-7.42 (m, 1H), 7.08 (s, 1H), 4.11-4.08 (m, 4H), 3.90-3.87 (m, 4H). 1.4) Synthesis of 4-morpholino-6-(pyridin-3-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl) furo[3,2- d]pyrimidine

[0417] To a solution of 2-chloro-4-morpholino-6-(pyridin-3-yl)furo[3,2-d]pyrimidine (100 mg, 0.32 mmol) in DMF (10 mL) was added 3-(m-tolyl)-1H-pyrazole (60 mg, 0.38 mmol) and NaH (25 mg, 0.63 mmol). The reaction was stirred at 90 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 4-morpholino-6-(pyridin-3-yl)-2-(3-(m-tolyl) -1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (80 mg, 0.18 mmol) as an off-white solid. LC-MS (ESI+): m/z 439 (MH⁺).¹HNMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.71-8.69 (m, 2H), 8.43 (d, J = 7.5 Hz, 1H), 7.81-7.74 (m, 3H), 7.63- 7.60 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 2.7 Hz, 1H), 4.15- 4.11 (m, 4H), 3.90-3.82 (m, 4H), 2.41 (s, 3H). [0418] EXAMPLE 24: Compound 91 using General Synthetic Route 24:

1.1) Synthesis of 2-chloro-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine

[0419] A solution of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (1 g, 2.7 mmol), 2- (tributylstannyl)pyridine (1.2 g, 3.3 mmol) and Pd(PPh3)4 (155 mg, 0.14 mmol) in toluene (5 mL) was heated to 90 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, diluted with water and extracted with DCM/MeOH (15/1, 3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-chloro-4-morpholino-6-(pyridin-2-yl)furo[3,2-d] pyrimidine (352 mg, 1.11 mmol) as a yellow solid. LC-MS (ESI+): m/z 317/319 (MH⁺).¹HNMR (300 MHz, DMSO- d₆) δ 8.74-8.70 (m, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.63-7.49 (m, 2H), 4.05-3.97 (m, 4H), 3.82-3.76 (m, 4H). 1.2) Synthesis of 4-morpholino-6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl) furo[3,2- d]pyrimidine

[0420] To a solution of 2-chloro-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (80 mg, 0.25 mmol) in DMF (10 mL) was added 3-(m-tolyl)-1H-pyrazole (48 mg, 0.30 mmol), Cs2CO3 (165 mg, 0.51 mmol) and Cu2O (3.6 mg, 0.025 mmol). The reaction was stirred at 110 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, quenched with water (10 mL) and extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to provide 4- morpholino-6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-d]pyrimidine (39 mg, 0.089 mmol) as a white solid. LC-MS (ESI+): m/z 439 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 8.76-8.71 (m, 2H), 8.12 (d, J = 7.5 Hz, 1H), 8.01 (t, J = 7.5 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.68 (s, 1H), 7.62-7.49 (m, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.02 (s, 1H), 4.18-4.12 (m, 4H), 3.90-3.84 (m, 4H), 2.40 (s, 3H). [0421] EXAMPLE 25: Compound 92 using General Synthetic Route 25:

1.1) Synthesis of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid

[0422] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (2.4 g, 10 mmol) in anhydrous THF (40 mL) at -78 °C under N2 was added n-BuLi ( 5.2 mL, 2.5 M, 13 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the solution was added excessive amount of dry ice in one portion. The resulting reaction mixture was stirred at that temperature for 3 h. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water and the pH was adjusted to 5 using 1 N HCl aqueous solution. The aqueous solution was extracted with DCM (3 x 80 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was slurry in Et2O to provide 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid ( 2.92 g, 10.3 mmol) as a yellow solid. LC-MS (ESI+): m/z 284/286 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 4.04-3.95 (m, 4H), 3.78-3.76 (m, 4H). 1.2) Synthesis of 2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide

[0423] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (100 mg, 0.36 mmol) in DCM (10 mL) was added methanamine hydrochloride (13.5 mg, 0.2 mmol), EDCl (86 mg, 0.45 mmol) and DMAP (55 mg, 0.45 mmol). The reaction was stirred at room temperature overnight. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 2-chloro-N-methyl-4-morpholinofuro[3,2- d]pyrimidine-6- carboxamide (67 mg, 0.22 mmol) as white solid. LC-MS (ESI+): m/z 297/299 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.61 (s, 1H), 6.35 (brs, 1H), 4.06-4.03 (m, 4H), 3.88-3.85 (m, 4H), 3.06 (d, J = 5.1 Hz, 3H). 1.3) Synthesis of N-methyl-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d] pyrimidine- 6-carboxamide

[0424] To a solution of 2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6- carboxamide (60 mg, 0.19 mmol) in DMF (4 mL) was added 3-(m-tolyl)-1H-pyrazole (35 mg, 0.23 mmol), Cs₂CO₃ (123 mg, 0.38 mmol) and CuI (8 mg, 0.038 mmol). The reaction was stirred at 110 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was then cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to provide N-methyl-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl) furo[3,2-d]pyrimidine-6- carboxamide (15 mg, 0.036 mmol) as a white solid. LC-MS (ESI+): m/z 419 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 8.85-8.82 (m, 1H), 8.70 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.12-4.08 (m, 4H), 3.86-3.82 (m, 4H), 2.86 (d, J = 4.5 Hz, 3H), 2.39 (s, 3H).

[0425] EXAMPLE 26: Compound 98 using General Synthetic Route 26:

1.1) Synthesis of 4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine [0426] To a solution of 2-

chloro-4-morpholinofuro[3,2-d]pyrimidine (300 mg, 1.25 mmol) in DMF (4 mL) was added 3-(m-tolyl)-1H-pyrazole (237 mg, 0.35 mmol), Cs₂CO₃ (815 mg, 2.5 mmol) and CuI (24 mg, 0.125 mmol). The reaction was stirred at 110 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was then cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 4-morpholino-2-(3- (m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (269 mg, 0.75 mmol) as a white solid. LC-MS (ESI+): m/z 362 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.7 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 2.7 Hz, 1H), 4.12-4.06 (m, 4H), 3.92-3.86 (m, 4H), 2.40 (s, 3H). 1.2) Synthesis of 4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine -6- carboxylic acid

[0427] To a solution of 4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (493 mg, 1.36 mmol) in anhydrous THF (20 mL) at -78 °C under N2 was added n-BuLi ( 0.8 mL, 2.5 M, 2.0 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the solution was added excessive amount of dry ice in one portion. The resulting reaction mixture was stirred at that temperature for 3 h. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water and the pH was adjusted to 5 using 1 N HCl aqueous solution. The aqueous solution was extracted with DCM/MeOH (15/1, 2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was slurry in Et₂O to provide 4-morpholino-2-(3-(m- tolyl)-1H-pyrazol-1-yl)furo [3,2-d]pyrimidine-6-carboxylic acid (361 mg, 0.89 mmol) as a yellow solid. LC-MS (ESI+): m/z 406 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 14.18 (s,1H), 8.72 (d, J = 2.7 Hz, 1H), 7.79-7.71 (m, 3H), 7.35 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 4.11-4.05 (m, 4H), 3.88-3.82 (m, 4H), 2.39 (s, 3H). 1.3) Synthesis of N-(methylsulfonyl)-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- d]pyrimidine-6-carboxamide

[0428] To a solution of 4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine - 6-carboxylic acid (60 mg, 0.15 mmol) in DCM (10 mL) was added methanesulfonamide (28 mg, 0.30 mmol), 2-chloro-1-methylpyridinium iodide (45 mg, 0.18 mmol) and DMAP (1 mg, 0.007 mmol). The reaction was stirred at room temperature overnight. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to provide N-(methylsulfonyl)-4-morpholino -2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- d]pyrimidine-6-carboxamide (14.2 mg, 0.03 mmol) as a yellow solid. LC-MS (ESI+): m/z 483 (MH⁺).¹HNMR (300 MHz, CD₃OD) δ 8.61 (s, 1H), 7.79-7.69 (m, 2H), 7.61-7.59 (m, 1H), 7.50- 7.18 (m, 2H), 6.84-6.80 (m, 1H), 4.25-4.14 (m, 4H), 3.91-3.85 (m, 4H), 3.16 (s, 3H), 2.37 (s, 3H). [0429] EXAMPLE 27: Compound 127 using General Synthetic Route 27:

1.1) Synthesis of 2-chloro-7-iodo-4-morpholinofuro[3,2-d]pyrimidine

[0430] To a solution of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (5.0 g, 13.7 mmol) in anhydrous THF (30 mL) at -78 °C under N2 was added LDA (14 mL, 2 M, 27.4 mmol). The reaction mixture was stirred at -78 °C for 1 h. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with H₂O (100 mL) and extracted with DCM (3 x 200 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2- chloro-7-iodo-4-morpholinofuro[3,2-d]pyrimidine (2.5 g, 6.85 mmol) as a white solid. LC-MS (ESI+): m/z 366/368 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 4.04-3.97 (m, 4H), 3.85- 3.81 (m, 4H). 1.2) Synthesis of 2-chloro-7-methyl-4-morpholinofuro[3,2-d]pyrimidine

[0431] To a solution of 2-chloro-7-iodo-4-morpholinofuro[3,2-d]pyrimidine (50 mg, 0.14 mmol) in DME/H₂O (2/1, 3 mL) was added methylboronic acid (25 mg, 0.42 mmol), K3PO4 (44 mg, 0.21 mmol) and Pd(PPh3)4 (15 mg, 0.014 mmol). The reaction was stirred at 120 °C for 30 min under Microwave condition. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2- chloro-7-methyl-4-morpholinofuro[3,2-d]pyrimidine (35 mg, 0.14 mmol) as a white solid. LC- MS (ESI+): m/z 254/256 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 7.53 (s, 1H), 4.04-3.98 (m, 4H), 3.86-3.82 (m, 4H), 2.22 (s, 3H). 1.3) Synthesis of 2-chloro-7-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid

[0432] To a solution of 2-chloro-6-iodo-7-methyl-4-morpholinofuro[3,2-d]pyrimidine (90 mg, 0.24 mmol) in anhydrous THF (100 mL) at -78 °C under N2 was added n-BuLi (0.15 mL, 2.5 M, 0.36 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the solution was added excessive amount of dry ice in one portion. The resulting reaction mixture was stirred at that temperature for 1 h. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water and the pH was adjusted to 5 using 1 N HCl aqueous solution. The aqueous solution was extracted with DCM (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was slurry in Et₂O to provide 2-chloro-7-methyl-4- morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (60 mg, 0.20 mmol) as a yellow solid. LC- MS (ESI+): m/z 298/300 (MH⁺). 1.4) Synthesis of 2-chloro-N-cyclopropyl-7-methyl-4-morpholinofuro[3,2-d]pyrimidine-6- carboxamide

[0433] To a solution of 2-chloro-7-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (60 mg, 0.20 mmol) in DCM (40 mL) was added oxalyl dichloride (52 mg, 0.4 mmol) and DMF (10 mg, 0.13 mmol). The reaction was stirred at room temperature for 2 h. Upon the completion of the reaction as monitored by TLC, the reaction solution was concentrated directly and the resulting residue was dissolved in DCM (20 mL). To the solution was added cyclopropanamine (23 mg, 0.4 mmol), followed by Et₃N (40 mg, 0.4 mmol) dropwise. The completion of the reaction was monitored by TLC. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 2-chloro-N-cyclopropyl-7- methyl-4-morpholinofuro[3,2-d]pyrimidine-6- carboxamide (54 mg, 0.16mmol) as a white solid. LC-MS (ESI+): m/z 337/339 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 6.37 (s, 1H), 4.03-3.99 (m, 4H), 3.87-3.84 (m, 4H), 2.88-2.83 (m, 1H), 2.55 (s, 3H), 0.98-0.92 (m, 2H), 0.71-0.65 (m, 2H). 1.5) Synthesis of N-cyclopropyl-7-methyl-4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine-6-carboxamide

[0434] To a solution of 2-chloro-N-cyclopropyl-7-methyl-4-morpholinofuro[3,2- d]pyrimidine-6- carboxamide (54 mg, 0.16mmol) in DMF (3.0 mL) was added 4-(m-tolyl)-1H- pyrazole (50 mg, 0.32 mmol), Cs₂CO₃ (105 mg, 0.32 mmol) and Cu₂O (2.2 mg, 0.016 mmol). The reaction was stirred at 110 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (10 mL) and a large amount of solid was precipitated. After filtration, the filtrate was concentrated directly and purified by flash silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide N-cyclopropyl-7-methyl-4-morpholino-2-(4-(m-tolyl)-1H -pyrazol-1-yl)furo[3,2-d]pyrimidine-6-carboxamide (25 mg, 0.054 mmol) as white solid. LC- MS (ESI+): m/z 459 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 8.08 (s, 1H), 7.43-7.40 (m, 2H), 7.30-7.27 (m, 1H), 7.10 (d, J = 6.9 Hz, 1H), 6.45 (s, 1H), 4.13-4.08 (m, 4H), 3.92-3.89 (m, 4H), 2.95-2.86 (m, 1H), 2.65 (s, 3H), 2.55 (s, 3H), 0.97-0.93 (m, 2H), 0.77-0.70 (m, 2H). [0435] EXAMPLE 28: Compound 122 using General Synthetic Route 28:

1.1) Synthesis of 2-chloro-6-iodo-7-met

hyl-4-morpholinofuro[3,2-d]pyrimidine

[0436] To a solution of 2-chloro-7-methyl-4-morpholinofuro[3,2-d]pyrimidine (350 mg, 1.38 mmol) in anhydrous THF (30 mL) at -78 °C under N2 was added LDA (1.4 mL, 2 M, 2.76 mmol). After stirred at -78 °C for 1 h, to the solution was added a solution of NIS (374 mg, 1.66 mmol) in anhydrous THF (5 mL). Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-6-iodo-7-methyl-4- morpholinofuro[3,2-d]pyrimidine (280 mg, 2.55 mmol) as yellow solid. LC-MS (ESI+): m/z 380/382 (MH⁺). 1.2) Synthesis of 2-chloro-7-methyl-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine

[0437] A solution of 2-chloro-6-iodo-7-methyl-4-morpholinofuro[3,2-d]pyrimidine (200 mg, 0.53 mmol), 2-(tributylstannyl)pyridine (389 mg, 1.06 mmol) and Pd(PPh3)4 (61 mg, 0.053 mmol) in toluene (5 mL) was heated to 90 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction mixture was diluted with water and extracted with DCM/MeOH (15/1, 3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide 2- chloro-7-methyl-4-morpholino-6-(pyridin-2-yl) furo[3,2-d]pyrimidine (70 mg, 0.21 mmol) as a white solid. LC-MS (ESI+): m/z 331/333 (MH⁺). 1.3) Synthesis of 7-methyl-4-morpholino-6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H- pyrazol-1- yl)furo[3,2-d]pyrimidine

[0438] To a solution of 2-chloro-7-methyl-4-morpholino-6-(pyridin-2-yl)furo[3,2- d]pyrimidine (80 mg, 0.24 mmol) in CH3CN (10 mL) was added 3-(m-tolyl)-1H-pyrazole (77 mg, 0.32 mmol) and Cs₂CO₃ (158 mg, 0.48 mmol). The reaction was stirred at 160 °C in a sealed tube overnight. The reaction mixture was then cooled to room temperature, diluted with water (10 mL) and extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide 7-methyl-4-morpholino-6- (pyridin-2-yl)-2-(3-(m- tolyl)-1H-pyrazol-1-yl)furo [3,2-d]pyrimidine (9.2 mg, 0.02 mmol) as white solid. LC-MS (ESI+): m/z 453 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.75 (d, J = 4.2 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.90 (s, 1H), 7.85-7.77 (m, 3H), 7.43-7.27 (m, 2H), 7.16 (d, J = 7.5 Hz, 1H), 6.78 (s, 1H), 4.23-4.17 (m, 4H), 3.96-3.87 (m, 4H), 2.77 (s, 3H), 2.43 (s, 3H). [0439] EXAMPLE 29: Compound 112 using General Synthetic Route 29:

1.1) Synthesis of 2-chloro-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine F C

[0440] A solid mixture of 2-chloro-7-iodo-4-morpholinofuro[3,2-d]pyrimidine (300 mg, 0.82 mmol), KF (144 mg, 2.47 mmol), CuI (30 mg, 0.16 mmol) and 1,10-phenanthroline (30 mg, 0.16 mmol) in three neck flask was heated to 100 °C under reduced pressure using oil pump for 1 h. After being cooled to room temperature, to the mixture was added anhydrous DMSO (6.0 mL) to form a brown solution. To the solution was added B(OMe)3 (252 mg, 2.47 mmol) and TMSCF₃ (348 mg, 2.47 mmol) dropwise. The reaction mixture was then heated to 55 °C. After stirred at that temperature for 1 h, an additional TMSCF₃ (348 mg, 2.47 mmol) was added dropwise. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-4-morpholino -7-(trifluoromethyl)furo[3,2- d]pyrimidine (98 mg, 0.32 mmol) as a yellow solid. LC-MS (ESI+): m/z 308/310 (MH⁺). 1.2) Synthesis of 2-chloro-6-iodo-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine

[0441] To a solution of 2-chloro-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine (160 mg, 0.52 mmol) in anhydrous THF (10 mL) at -78 °C under N₂ was added LDA (0.39 mL, 2 M, 0.78 mmol). After stirred at -78 °C for 1 h, to the solution was added a solution of NIS (141 mg, 0.63 mmol) in THF (10 mL). Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (25 mL) and extracted with DCM (3 x 15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-6-iodo-4-morpholino- 7-(trifluoromethyl)furo[3,2-d] pyrimidine (148 mg, 0.34 mmol) as a white solid. LC-MS (ESI+): m/z 434/436 (MH⁺). 1.3) Synthesis of 2-chloro-4-morpholino-6-(pyridin-2-yl)-7-(trifluoromethyl)furo[3,2- d]pyrimidine [0442] A solution of 2-chloro

-6-iodo-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine (100 mg, 0.23 mmol), 2-(tributylstannyl)pyridine (170 mg, 0.46 mmol) and Pd(PPh3)4 (13 mg, 0.023 mmol) in toluene (5 mL) was heated to 90 °C overnight. Upon the completion of the reaction as monitored by TLC, the reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 40% EtOAc/PE to provide 2- chloro-4-morpholino-6-(pyridin-2-yl)-7- (trifluoromethyl)furo[3,2-d]pyrimidine (55 mg, 0.14 mmol) as a yellow solid. LC-MS (ESI+): m/z 385/387 (MH⁺). 1.4) Synthesis of 4-morpholino-6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)-7- (trifluoromethyl)furo[3,2-d]pyrimidine

[0443] To a solution of 2-chloro-4-morpholino-6-(pyridin-2-yl)-7-(trifluoromethyl) furo[3,2- d]pyrimidine (55 mg, 0.14 mmol) in DMF (6 mL) was added 3-(m-tolyl)- 1H-pyrazole (45 mg, 0.29 mmol), Cs₂CO₃ (92 mg, 0.29 mmol) and Cu₂O (2 mg, 0.014 mmol). The reaction was stirred at 110 °C overnight. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 4-morpholino-6- (pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)-7- (trifluoromethyl)furo[3,2-d]pyrimidine (9.3 mg, 0.018 mmol) as a yellow solid. LC-MS (ESI+): m/z 507 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 9.04 (d, J = 4.2 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.28-8.25 (m, 1H), 8.13-8.08 (m, 1H), 7.86-7.78 (m, 3H), 7.36-7.31 (m, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.82 (s,1H), 4.40-4.31 (m, 4H), 4.02-3.92 (m, 4H), 2.43 (s, 3H). [0444] EXAMPLE 30: Compound 134 using General Synthetic Route 30:

1.1) Synthesis of 2,4-dichlorofuro[3,2-d]pyrimidine-6-carboxylic acid

[0445] To a solution of 2,4-dichlorofuro[3,2-d]pyrimidine (1 g, 5.29 mmol) in anhydrous THF (100 mL) at -78 °C under N2 was added LDA ( 5.3 mL, 2 M, 10.6 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the solution was added excessive amount of dry ice in one portion. The resulting reaction mixture was stirred at that temperature for 1 h. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water and the pH was adjusted to 5 using 1 N HCl aqueous solution. The aqueous solution was extracted with DCM (2 x 40 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was slurried in Et2O to provide 2,4-dichlorofuro[3,2-d] pyrimidine-6-carboxylic acid (650 mg, 2.8 mmol) as a yellow solid. LC-MS (ESI+): m/z 233/235 (MH⁺). 1.2) Synthesis of 2,4-dichloro-N-ethylfuro[3,2-d]pyrimidine-6-carboxamide

[0446] To a solution of 2,4-dichlorofuro[3,2-d]pyrimidine-6-carboxylic acid (519 mg, 2.23 mmol) in DCM (40 mL) was added oxalyl dichloride (566 mg, 4.45 mmol) and DMF (20 mg, 0.27 mmol). The reaction was stirred at room temperature for 2 h. The completion of the reaction was monitored by TLC. The solution was concentrated directly without work-up. The resulting residue was dissolved in DCM (20 mL). To the solution was added ethanamine hydrochloride (218 mg, 2.67 mmol) and followed by Et3N (450 mg, 4.45 mmol) dropwise. Upon the completion of the reaction as monitored by TLC, the reaction solution was concentrated directly and purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2,4-dichloro-N- ethylfuro[3,2-d]pyrimidine-6- carboxamide (160 mg, 0.62 mmol) as a yellow solid. LC-MS (ESI+): m/z 260/262 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 7.59 (s, 1H), 6.76 (brs, 1H), 3.61-3.54 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H). 1.3) Synthesis of 2-chloro-N-ethyl-4-(2,2,6,6-tetrafluoromorpholino)furo[3,2-d] pyrimidine-6- carboxamide

[0447] To a solution of 2,4-dichloro-N-ethylfuro[3,2-d]pyrimidine-6-carboxamide (200 mg, 0.77 mmol) in 1,4-dioxane/H₂O (2/1, 10 mL) under N₂ was added 2,2,6,6-tetrafluoromorpholine (110 mg, 0.69 mmol), Cs2CO3 (276 mg, 0.85 mmol), Pd(OAc)2 (17 mg, 0.077 mmol) and Xantphos (45 mg, 0.077 mmol). The reaction mixture was stirred at 80 °C for 1 h. Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-N-ethyl-4-(2,2,6,6-tetrafluoromorpholino)furo[3,2-d]pyrimidine-6- carboxamide (83 mg, 0.22 mmol) as a brown solid. LC-MS (ESI+): m/z 383/385 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 7.61 (s, 1H), 6.36 (brs, 1H), 4.53-4.48 (m, 4H), 3.61-3.52 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H). 1.4) Synthesis of N-ethyl-4-(2,2,6,6-tetrafluoromorpholino)-2-(4-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine-6-carboxamide

[0448] To a solution of 2-chloro-6-(pyridin-3-yl)-4-(2,2,6,6-tetrafluoromorpholino)furo [3,2- d]pyrimidine (59 mg, 0.15 mmol) in DMF (1 mL) was added 4-(m-tolyl)-1H- pyrazole (29 mg, 0.19 mmol), Cs₂CO₃ (102 mg, 0.31 mmol) and Cu₂O (2 mg, 0.015 mmol). The reaction was stirred at 110 °C for 1 h. The solution was then cooled to room temperature and concentrated directly. The resulting residue was purified by preparative TLC to provide N-ethyl-4-(2,2,6,6- tetrafluoromorpholino)-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine-6-carboxamide (11 mg, 0.022 mmol) as a brown solid. LC-MS (ESI+): m/z 505 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 8.10 (s, 1H), 7.51 (s, 1H), 7.44-7.41 (m, 2H), 7.34-7.29 (m, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.40-6.38 (m, 1H), 4.63-4.58 (m, 4H), 3.63-3.54 (m, 2H), 2.42 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). [0449] EXAMPLE 31: Compound 133 using General Synthetic Route 31:

1.1) Synthesis of 2,4-dichloro-6-iodofuro[3,2-d]pyrimidine

[0450] To a solution of 2,4-dichlorofuro[3,2-d]pyrimidine (1.0 g, 5.32 mmol) in anhydrous THF (30 mL) at -78 °C under N₂ was added n-BuLi (5.33 mL, 2.5M, 13.3 mmol). After stirred at -78 °C for 1 h, to the solution was added a solution of NIS (1.44 g, 6.38 mmol) in anhydrous THF (10 mL). Upon the completion of the reaction as monitored by TLC, the reaction was quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 10% EtOAc/PE to provide 2,4-dichloro-6-iodofuro[3,2-d]pyrimidine (800 mg, 2.55 mmol) as yellow solid. LC-MS (ESI+): m/z 315/317 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 7.21 (s, 1H). 1.2) Synthesis of 2,4-dichloro-6-(pyridin-3-yl)furo[3,2-d]pyrimidine

[0451] To a solution of 2,4-dichloro-6-iodofuro[3,2-d]pyrimidine (500 mg, 1.59 mmol) in 1,4- dioxane/H₂O (2/1, 30 mL) was added pyridin-3-ylboronic acid (156 mg, 1.27 mmol), K2CO3 (567 mg, 4.1 mmol) and PdCl₂(dppf) (117 mg, 0.16 mmol). The reaction was stirred at 100 °C for 1 h. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (4 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2,4-dichloro-6-(pyridin-3- yl)furo[3,2-d]pyrimidine (295 mg, 1.11 mmol) as a brown solid. LC-MS (ESI+): m/z 266/268 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 9.21 (s, 1H), 8.78 (d, J = 3.3 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.74-7.71 (m, 1H), 7.21 (s, 1H). 1.3) Synthesis of 2-chloro-6-(pyridin-3-yl)-4-(2,2,6,6-tetrafluoromorpholino)furo [3,2- d]pyrimidine

[0452] To a solution of 2,4-dichloro-6-(pyridin-3-yl)furo[3,2-d]pyrimidine (117 mg, 0.43 mmol) in 1,4-dioxane/H₂O (2/1, 10 mL) under N₂ was added 2,2,6,6-tetrafluoromorpholine (63 mg, 0.39 mmol), Cs₂CO₃ (154 mg, 0.47 mmol), Pd(OAc)₂ (9 mg, 0.04 mmol) and Xantphos (27 mg, 0.04 mmol). The reaction was stirred at 80 °C for 1 h. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, quenched with water (30 mL) and extracted with DCM (4 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-6-(pyridin-3-yl)- 4-(2,2,6,6-tetrafluoromorpholino)furo[3,2- d]pyrimidine (97 mg, 0.25 mmol) as a brown solid. LC-MS (ESI+): m/z 389/391 (MH⁺). ¹HNMR (300 MHz, CDCl3) δ 9.11 (s, 1H), 8.74 (d, J = 3.9 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.51-7.47 (m, 1H), 7.16 (s, 1H), 4.58-4.53 (m, 4H). 1.4) Synthesis of 6-(pyridin-3-yl)-4-(2,2,6,6-tetrafluoromorpholino)-2-(4-(m-tolyl)-1H -pyrazol- 1-yl)furo[3,2-d]pyrimidine

[0453] To a solution of 2-chloro-6-(pyridin-3-yl)-4-(2,2,6,6-tetrafluoromorpholino) furo[3,2- d]pyrimidine (87 mg, 0.22 mmol) in DMF (1 mL) was added 4-(m-tolyl)- 1H-pyrazole (43 mg, 0.27 mmol), Cs2CO3 (147 mg, 0.45 mmol) and Cu2O (4 mg, 0.02 mmol). The reaction was stirred at 110 °C for 5 h. Upon the completion of the reaction as monitored by TLC, the reaction was cooled to room temperature, quenched with water (10 mL) and extracted with DCM/MeOH (15/1, 3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to provide 6-(pyridin-3-yl)-4-(2,2,6,6- tetrafluoromorpholino)-2-(4-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine (7.5 mg, 0.014 mmol) as a white solid. LC-MS (ESI+): m/z 511 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.74-8.71 (m, 2H), 8.13-8.11 (m, 2H), 7.52- 7.42 (m, 3H), 7.34-7.32 (m, 2H), 7.13 (d, J = 7.5 Hz, 1H), 4.67-4.62 (m, 4H), 2.42 (s, 3H). [0454] Compounds 89 to 142 in Table 3 are made according to the procedures above. Table 3

[0455] EXAMPLE 32: Compound 143 using General synthetic route 32: N N N Cl Sn N Cl I O N N N O N N P_d(PPh3)4 ^{/CuCl/LiCl/THF} N O O 1 2 N HN N N N N N O N Cu₂O/Cs₂CO₃/DMF N O Compound 143 1) Synthesis of 2-chloro-4-morpholino-6-(pyrimidin-4-yl)furo[3,2-d]pyrimidine N Cl N N O N N O [0456] A suspension of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (80 mg, 0.22 mmol), 4-(tributylstannyl)pyrimidine (128 mg, 0.34 mmol), LiCl (1 mg, 0.022 mmol) and Pd(PPh₃)₄ (25 mg, 0.022 mmol) in DMF (5 mL) under N₂ was heated to 90 °C for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 2-chloro-4-morpholino-6-(pyrimidin- 4-yl)furo[3,2-d] pyrimidine (87 mg, 0.27 mmol) as a yellow solid. LC-MS (ESI+): m/z 318/320 (MH⁺). 2) Synthesis of 4-morpholino-6-(pyrimidin-4-yl)-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- d]pyrimidine

[0457] To a solution of 2-chloro-4-morpholino-6-(pyrimidin-4-yl)furo[3,2-d]pyrimidine (73 mg, 0.23 mmol) in DMF (10 mL) was added 4-(m-tolyl)-1H-pyrazole (44 mg, 0.28 mmol), Cs₂CO₃ (151 mg, 0.46 mmol) and Cu₂O (4 mg, 0.023 mmol). The reaction mixture was stirred at 110 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 10% MeOH/DCM to provide 4- morpholino-6-(pyrimidin-4-yl)-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (Compound 143, 28 mg, 0.064 mmol) as a white solid. LC-MS (ESI+): m/z 440 (MH⁺).¹HNMR (300 MHz, DMSO-d₆) δ 9.34 (s, 1H), 9.05 (d, J = 4.2 Hz, 2H), 8.31-8.14 (m, 2H), 7.87-7.82 (m, 1H), 7.62-7.57 (m, 2H), 7.32-7.27 (m, 1H), 7.10-7.05 (m, 1H), 4.27-4.14 (m, 4H), 3.95-3.85 (m, 4H), 2.36 (s, 3H).

EXAMPLE 33: Compound 156 using General synthetic route 33:

1) Synthesis of 2-chloro-4-morpholino-6-(pyridin-3-yl)furo[3,2-d]pyrimidine [0458] To a solution of 2-chloro

-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (500 mg, 1.37 mmol) in 1,4-dioxane/H₂O (2/1, 30 mL) was added pyridin-3-ylboronic acid (185 mg, 1.51 mmol), K₂CO₃ (378 mg, 2.74 mmol) and PdCl₂(PPh₃)₂ (48 mg, 0.068 mmol) under N₂. The reaction mixture was stirred at 90 °C for 5 h. The completion of the reaction was monitored by TLC. The solution was concentrated directly and the resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 2-chloro-4-morpholino-6-(pyridin-3-yl)furo[3,2-d]pyrimidine (410 mg, 1.29 mmol) as a light yellow solid. LC-MS (ESI+): m/z 317/319 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.69 (d, J = 6.9 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.71-7.40 (m, 1H), 7.08 (s, 1H), 4.15- 4.08 (m, 4H), 3.92-3.86 (m, 4H). 2) Synthesis of 4-morpholino-2-(3-phenyl-1H-pyrazol-1-yl)-6-(pyridin-3-yl)furo[3,2- d]pyrimidine

[0459] To a solution of 2-chloro-4-morpholino-6-(pyridin-3-yl)furo[3,2-d]pyrimidine (120 mg, 0.38 mmol) in DMF (10 mL) was added 3-phenyl-1H-pyrazole (60 mg, 0.42 mmol), Cs₂CO₃ (248 mg, 0.76 mmol) and Cu₂O (6 mg, 0.038 mmol). The reaction was stirred at 110 °C overnight. The completion was monitored by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with DCM (3 x 30 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 4-morpholino-2-(3-phenyl- 1H-pyrazol-1-yl)-6- (pyridin-3-yl)furo[3,2-d]pyrimidine (114 mg, 0.27 mmol) as an off-white solid. LC-MS (ESI+): m/z 425 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 9.11 (s, 1H), 8.69 (d, J = 3.9 Hz, 1H), 8.57 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 6.9 Hz, 2H), 7.45- 7.32 (m, 4H), 7.30-7.26 (m, 1H), 6.79 (d, J = 2.7 Hz, 1H), 4.20-4.14 (m, 4H), 3.97-3.92 (m, 4H). EXAMPLE 34: Compounds 145 and 146 using General synthetic route 34: H I

1) Synthesis of tert-butyl 5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-3-methyl-1H- pyrazole-1-carboxylate N

[0460] A suspension of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (5.72 g, 15.67 mmol), (1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-5-yl)boronic acid (3.90 g, 17.24 mmol), Pd(PPh)2Cl2 (2.20 g, 3.13 mmol) and CsF (7.15 g, 47.01 mmol) in 1,4-dioxane/H₂O (4/1, 330 mL) under N2 was heated to 80 °C for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and the resulting residue was purified by silica gel column chromatography with a gradient elution of 25% EtOAc/Hex to EtOAc to provide tert-butyl 5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-3-methyl-1H-pyrazole-1- carboxylate (10.32 g, 24.57 mmol) as a light yellow solid. LC-MS (ESI+): m/z 420/422 (MH⁺). ¹HNMR (300 MHz, DMSO-d₆) δ 7.31 (s, 1H), 6.94 (s, 1H), 4.01-3.90 (m, 4H), 3.78-3.70 (m, 4H), 2.21 (s, 3H), 1.44 (s, 9H). 2) Synthesis of 2-chloro-6-(3-methyl-1H-pyrazol-5-yl)-4-morpholinofuro[3,2-d]pyrimidine

[0461] To a solution of tert-butyl 5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)- 3- methyl-1H-pyrazole-1-carboxylate (10.32 g, 24.63 mmol) in DCM (300 mL) was added TFA (30 mL). The mixture was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO3 solution until the pH = 8. A large amount of solid was precipitated. After filtration, the filter cake was washed with ether twice to provide crude 4-(5-(benzyloxy)-2-(5-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a] pyrimidin-7-yl)morpholine (7.96 g, 24.95 mmol) as a light yellow solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 320/322 (MH⁺). 3) Synthesis of 2-(5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-3-methyl-1H- pyrazol-1-yl)-N,N-dimethylethan-1-amine (to Compound 146) and 2-(3-(2-chloro-4- morpholinofuro[3,2-d]pyrimidin-6-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethan-1- amine (to Compound 145)

[0462] To a solution of crude 4-(5-(benzyloxy)-2-(5-methyl-1H-pyrazol-3-yl)pyrazolo [1,5- a]pyrimidin-7-yl)morpholine (170 mg, 0.53 mmol) in DMF was added K₂CO₃ (220 mg, 1.60 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (115 mg, 0.80 mmol). The mixture was stirred at 50 °C for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The residue was purified by preparative TLC with an elution of 10% MeOH/DCM to provide 2-(3- (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-5-methyl-1H- pyrazol-1-yl)-N,N- dimethylethanamine (lower spot, 90 mg, 0.23 mmol) and 2-(5-(2-chloro-4-morpholinofuro[3,2- d]pyrimidin-6-yl)-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine (upper spot, 60 mg, 0.15 mmol). [0463] 2-(3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-5-methyl-1H-pyrazol-1-yl)- N,N-dimethylethanamine (lower spot): LC-MS (ESI+): m/z 391/393 (MH⁺) ¹HNMR (300 MHz, DMSO-d6) δ 7.06 (s, 1H), 6.65 (s, 1H), 4.23 (t, J = 6.3 Hz, 2H), 3.96-3.88 (m, 4H), 3.82-3.75 (m, 4H), 2.71 (t, J = 6.0 Hz, 2H), 2.35 (s, 3H), 2.24 (s, 6H). 2-(5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-3-methyl-1H-pyrazol-1-yl)-N,N- dimethylethanamine (upper spot): LC-MS (ESI+): m/z 391/393 (MH⁺) ¹HNMR (300 MHz, DMSO-d6) δ 7.32 (s, 1H), 6.73 (s, 1H), 4.43 (t, J = 6.9 Hz, 2H), 3.97-3.88 (m, 4H), 3.82-3.73 (m, 4H), 2.68 (t, J = 6.9 Hz, 2H), 2.21 (s, 3H), 2.18 (s, 6H). 4) Synthesis of N,N-dimethyl-2-(5-methyl-3-(4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethanamine (Compound 146)

[0464] A suspension of 2-(3-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-5-methyl-1H- pyrazol-1-yl)-N,N-dimethylethanamine (50 mg, 0.13 mmol), 4-(m-tolyl)-1H-pyrazole (24 mg, 0.15 mmol), Cs2CO3 (83 mg, 0.26 mmol) and Cu2O (1.8 mg, 0.01 mmol) in DMF (5 mL) was heated to 110 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 5% MeOH/DCM to 10% MeOH/DCM to provide N,N-dimethyl-2-(5- methyl-3-(4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin-6-yl)-1H-pyrazol- 1-yl)ethanamine (20 mg, 0.04 mmol) as a white solid. LC-MS (ESI+): m/z 513 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.07 (s, 1H), 7.61-7.40 (m, 2H), 7.35-7.27 (m, 1H), 7.11-7.06 (m, 2H), 6.44 (s, 1H), 4.40-4.37 (m, 2H), 4.16-4.10 (m, 4H), 3.93-3.88 (m, 4H), 3.10-2.98 (m, 2H), 2.45 (m, 3H), 2.41 (s, 9H). 5) Synthesis of N,N-dimethyl-2-[3-methyl-5-[4-morpholino-2-[4-(m-tolyl)pyrazol-1- yl]furo[3,2-d]pyrimidin-6-yl]pyrazol-1-yl]ethanamine (Compound 145)

[0465] Compound 145 was prepared by the same method used for Compound 146. [0466] EXAMPLE 35: Compound 148 using General synthetic route 35:

1) Synthesis of 2,4-dichloro-6-(pyridin-2-yl)furo[3,2-d]pyrimidine

[0467] To a solution of 2,4-dichloro-6-iodofuro[3,2-d]pyrimidine (2.3 g, 7.3 mmol) in DMF (60 mL) under N2 was added 2-(tributylstannyl)pyridine (2.7 g, 7.3 mmol), CuI (416 mg, 2.2 mmol) and PdCl₂(dppf) (534 mg, 0.73 mmol). The reaction was stirred at 100 °C for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL) and extracted with DCM (4 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2,4-dichloro-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (1.2 g, 4.53 mmol) as a yellow solid. LC-MS (ESI+): m/z 266/268 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 8.78 (d, J = 4.2 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.47- 7.41 (m, 1H). 2) Synthesis of 2-chloro-4-methoxy-6-(pyridin-2-yl)furo[3,2-d]pyrimidine

[0468] To a solution of 2,4-dichloro-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (500 mg, 1.89 mmol) in DMF/MeOH (1:1, 30 mL) at 0 °C was added sodium methanolate (204 mg, 3.78 mmol). The reaction was stirred at 0 °C for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL) and a large amount of solid was precipitated. After filtration, the filter cake was washed with Et2O to provide 2-chloro-4- methoxy-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (450 mg, 1.72 mmol) as a brown solid. LC-MS (ESI+): m/z 262/264 (MH⁺).¹HNMR (300 MHz, CDCl₃) ¹HNMR (300 MHz, CDCl₃) δ 8.78 (d, J = 4.2 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.39-7.35 (m, 1H), 4.23 (s, 3H). 3) Synthesis of 2-bromo-6-(pyridin-2-yl)furo[3,2-d]pyrimidin-4-ol [0469] A solution of 2-chloro-4

-methoxy-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (200 mg, 0.76 mmol) in HBr/AcOH (33 wt.% in Acetic acid, 10 mL) was heated to refluxed for 2 h. The completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with water (30 mL) and a large amount of solid was precipitated. After filtration, the filter cake was washed with Et2O to provide 292 mg of crude 2-bromo-6-(pyridin-2-yl)furo[3,2-d]pyrimidin-4- ol as a yellow solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 292/294 (MH⁺). 4) Synthesis of 6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin-4-ol

[0470] A suspension of crude 2-bromo-6-(pyridin-2-yl)furo[3,2-d]pyrimidin-4-ol (200 mg, 0.68 mmol), 3-(m-tolyl)-1H-pyrazole (108 mg, 0.68 mmol), Cs2CO3 (447 mg, 1.37 mmol) and Cu2O (10 mg, 0.068 mmol) in DMF (10 mL) was heated to 110 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 5% MeOH/DCM to 10% MeOH/DCM to provide 6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin- 4-ol (100 mg, 0.27 mmol) as a green solid. LC-MS (ESI+): m/z 370 (MH⁺). 5) Synthesis of 4-chloro-6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- d]pyrimidine

[0471] A solution of 6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin-4- ol (114 mg, 0.31 mmol) in phenylphosphonic dichloride (5 mL) was heated to 120 °C for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and a large amount of yellow solid was precipitated. After filtration, the filter cake was washed with Et2O to provide 80 mg of crude 4-chloro-6-(pyridin-2-yl)-2-(3-(m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-d]pyrimidine as a yellow solid. The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 388/390 (MH⁺). 6) Synthesis of 4-(6-(pyridin-2-yl)-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin-4- yl)morpholin-3-one N

[0472] A suspension of 4-chloro-6-(pyridin-2-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- d]pyrimidine (40 mg, 0.1 mmol), morpholin-3-one (12.5 mg, 0.12 mmol), Pd(PPh)2Cl2 (7.2 mg, 0.01 mmol), Cs2CO3 (78 mg, 0.2 mmol) and Xantphos (12 mg, 0.02 mmol) in 1,4-dioxane (10 mL) under N2 was heated to 90 °C for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduced pressure. The resulting residue was purified by preparative TLC with a elution of 10% MeOH/DCM to provide 4-(6-(pyridin-2-yl)-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d] pyrimidin-4-yl)morpholin-3-one (5 mg, 0.011mmol) as a white solid. LC-MS (ESI+): m/z 453 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.75 (d, J = 3.9 Hz, 1H), 8.62 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.96-7.89 (m, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.67 (s, 1H), 7.48-7.31 (m, 2H), 7.20-7.15 (m, 1H), 6.82 (s, 1H), 4.53 (s, 2H), 4.32-4.24 (m, 2H), 4.19-4.10 (m, 2H), 2.43 (s, 3H). [0473] EXAMPLE 36: Compound 150 using General synthetic route 36:

1) Synthesis of (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methanol

[0474] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (1 g, 3.53 mmol) in THF (10 mL) at 0 °C was added BH₃/THF (1 mol/L, 14 mL) dropwise. The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction was quenched with 1N HCl. The mixture was heated under reflux for 2h. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide (2-chloro-4- morpholinofuro[3,2-d]pyrimidin-6-yl)methanol (165 mg, 0.61 mmol) as a white solid. LC-MS (ESI+): m/z 270 (MH⁺). 2) Synthesis of (4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin-6- yl)methanol

[0475] To a solution of (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methanol (250 mg, 0.93 mmol) in 1,4-dioxane (20 mL) was added 4-(m-tolyl)-1H-pyrazole (176 mg, 0.42 mmol), Pd₂(dba)₃ (85 mg, 0.093 mmol), t-Buxphos and K₃PO₄ (900 mg, 3.72 mmol). The reaction mixture was stirred at 90 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with DCM (3 x 30 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 3% MeOH/DCM to 8% MeOH/DCM to provide (4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin-6-yl)methanol (120 mg, 0.31 mmol) as an off-white solid. LC-MS (ESI+): m/z 392 (MH⁺). 3) Synthesis of 4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine-6- carbaldehyde N

[0476] To a solution of (4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidin- 6-yl) methanol (60 mg, 0.15 mmol) in DCM at rt (10 mL) was added Dess-Martin periodinane (DMP) (120 mg, 0.28 mmol). The reaction was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction was quenched with saturated NaHCO₃ solution. The aqueous solution was extracted with MeOH/DCM (1/10, 3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine-6- carbaldehyde (32 mg, 0.08 mmol) as a light yellow solid. LC-MS (ESI+): m/z 390 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 9.94 (s, 1H), 8.69 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 7.48-7.40 (m, 2H), 7.35-7.26 (m, 2H), 7.11 (d, J = 7.8 Hz, 1H), 4.25-4.15 (m, 4H), 3.95-3.85 (m, 4H), 2.41 (s, 3H). 4) Synthesis of 4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine-6- carboxylic acid

[0477] To a solution of 4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine- 6-carbaldehyde (32 mg, 0.08 mmol) in i-PrOH/H₂O (4:1, 5 mL) at 0 °C was added NaH₂PO4.H₂O (64.2 mg, 0.41 mmol) and NaClO2 (37 mg, 0.41 mmol) in portions. The reaction was stirred at rt for 1 h. The completion of the reaction was monitored by TLC. The reaction was quenched with a 1N HCl solution. The aqueous solution was extracted with MeOH/DCM (1/10, 3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated to provide crude 4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d] pyrimidine-6-carboxylic acid (38 mg, 0.09 mmol) as a white solid. LC-MS (ESI+): m/z 406 (MH⁺) 5) Synthesis of N-(2-(methylsulfonyl)ethyl)-4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine-6-carboxamide N

[0478] A solution of 4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine-6- carboxylic acid (38 mg, 0.09 mmol), 2-(methylsulfonyl)ethanamine (16 mg, 0.10 mmol), EDCl (37.8 mg, 0.20 mmol) and HOBT (26 mg, 0.20 mmol) in DCM was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 5% MeOH/DCM to provide N-(2-(methylsulfonyl)ethyl)-4-morpholino-2-(4- (m-tolyl)-1H-pyrazol-1-yl) furo[3,2-d]pyrimidine-6-carboxamide (14 mg, 0.027 mmol) as a white solid. LC-MS (ESI+): m/z 511 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 8.70 (s, 1H), 8.07 (s, 1H), 7.67-7.62 (m, 1H), 7.53 (s, 1H), 7.48-7.40 (m, 2H), 7.35-7.26 (m, 1H), 7.12-7.09 (m, 1H), 4.15-4.05 (m, 6H), 3.92-3.85 (m, 4H), 3.34-3.07 (m, 2H), 3.04 (s, 3H), 2.42 (s, 3H). [0479] EXAMPLE 37: Compound 192 using General synthetic route 37:

1)Synthesis of tert-butyl 4-(3-chlorophenyl)-1H-pyrazole-1-carboxylate

[0480] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole -1-carboxylate (1 g, 4.20 mmol) in 1,4-dioxane/H₂O (10/1, 20 mL) was added 1-chloro-3- iodobenzene (1.24 g, 1.51 mmol), CsF (958 mg, 6.30 mmol) and PdCl₂(PPh₃)₂ (295 mg, 0.42 mmol) under N2. The reaction was stirred at 80 °C for 2 h. The completion of the reaction was monitored by TLC. The reaction was quenched with water. The aqueous solution was extracted with DCM (3 x 80 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide tert- butyl 4-(3-chlorophenyl)-1H-pyrazole-1-carboxylate (650 mg, 2.34 mmol) as a light yellow oil. LC-MS (ESI+): m/z 279/281 (MH⁺). 2) Synthesis of 4-(3-chlorophenyl)-1H-pyrazole

[0481] To a solution of tert-butyl 4-(3-chlorophenyl)-1H-pyrazole-1-carboxylate (650 mg, 2.34 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO₃ solution until the pH = 8. The aqueous solution was extracted with DCM (3 x 80 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 4-(3- chlorophenyl)-1H-pyrazole (130 mg, 0.73 mmol) as a light yellow solid. LC-MS (ESI+): m/z 179/181 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.87 (brs, 2H), 7.46 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.30-7.28 (m, 1H), 7.23-7.20 (m, 1H). 3) Synthesis of 2-(4-(3-chlorophenyl)-1H-pyrazol-1-yl)-6-(1-methyl-1H-pyrazol-3-yl)-4- morpholinofuro[3,2-d]pyrimidine

[0482] To a solution of 2-chloro-6-(1-methyl-1H-pyrazol-3-yl)-4-morpholinofuro[3,2- d]pyrimidine (60 mg, 0.19 mmol) in DMF (10 mL) was added 4-(3-chlorophenyl)-1H-pyrazole (40 mg, 0.19 mmol), Cs₂CO₃ (221 mg, 0.68 mmol) and Cu₂O (5 mg, 0.04 mmol). The reaction was stirred at 110 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with DCM (3 x 30 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 2- (4-(3-chlorophenyl)-1H-pyrazol-1-yl)-6-(1-methyl-1H-pyrazol-3-yl)-4-morpholinofuro[3,2- d]pyrimidine (22 mg, 0.048 mmol) as an off-white solid. LC-MS (ESI+): m/z 462/464 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.50-7.40 (m, 2H), 7.26- 7.20 (m, 2H), 7.11 (s, 1H), 6.66 (d, J = 2.4 Hz, 1H), 4.21-4.15 (m, 4H), 4.02 (s, 3H), 3.95-3.89 (m, 4H). [0483] EXAMPLE 38: Compound 157 using General synthetic route 38:

1)Synthesis of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid

[0484] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (2.4 g, 10 mmol) in anhydrous THF (40 mL) at -78 °C under N2 was added n-BuLi (5.2 mL, 2.5 M, 13 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the above solution was added dry ice (4.4 g, 100 mmol) in one potion. The resulting reaction mixture was stirred at that temperature for 3 h. The completion of the reaction was monitored by TLC. The reaction was quenched with water and the pH was adjusted to 5 using 1 N HCl solution. The aqueous solution was extracted with DCM (3 x 80 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was slurry in Et₂O to provide 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid ( 2.92 g, 10.3 mmol) as a yellow solid. LC-MS (ESI+): m/z 284/286 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 4.04-3.95 (m, 4H), 3.78-3.76 (m, 4H). 2) Synthesis of 2-chloro-N-(1-methylpiperidin-4-yl)-4-morpholinofuro[3,2-d]pyrimidine-6- carboxamide

[0485] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (400 mg, 1.42 mmol) in DCM was added oxalyl dichloride (360 mg, 2.84 mmol) and one drop of DMF. The mixture was stirred at rt for 2 h. The solution was concentrated and the resulting residue was dissolved in DCM (15 mL). To the solution was added 1-methylpiperidin-4-amine (178 mg, 1.56 mmol) and followed by DIEA (107 mg, 2.84 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 5% MeOH/DCM to 10% MeOH/DCM to provide 2- chloro-N-(1-methylpiperidin-4-yl)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide (320 mg, 0.84 mmol) as a yellow solid. LC-MS (ESI+): m/z 380/382 (MH⁺). 3) Synthesis of N-(1-methylpiperidin-4-yl)-4-morpholino-2-(4-phenyl-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine-6-carboxamide N

[0486] To a solution of 2-chloro-N-(1-methylpiperidin-4-yl)-4-morpholinofuro[3,2- d]pyrimidine- 6-carboxamide (100 mg, 0.26 mmol) in DMF (4 mL) was added 4-phenyl-1H- pyrazole (42 mg, 0.29 mmol), Cs₂CO₃ (172 mg, 0.53 mmol) and Cu₂O (4 mg, 0.026 mmol). The reaction was stirred at 110 °C overnight. The reaction mixture was quenched with water (10 mL). The aqueous solution was extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated. The resulting residue was purified by preparative HPLC to provide N-(1-methylpiperidin-4-yl)-4-morpholino-2-(4-phenyl-1H- pyrazol-1-yl)furo[3,2-d]pyrimidine-6-carboxamide (32 mg, 0.065 mmol) as a white solid. LC- MS (ESI+): m/z 488 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.08 (s, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.44 (s, 1H), 7.38-7.26 (m, 3H), 6.33 (d, J = 7.8 Hz, 1H), 4.21-4.03 (m, 5H), 3.94-3.88 (m, 4H), 2.99-2.88 (m, 2H), 2.40 (s, 3H), 2.33-2.22 (m, 2H), 2.19-2.05 (m, 2H), 1.87- 1.75 (m, 2H). [0487] EXAMPLE 39: Compound 179 using General synthetic route 39:

1)Synthesis of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine

[0488] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (2.0 g, 0.83 mmol) in THF (30 mL) at -78 °C under N₂ was added LDA (1.33 mL, 2M, 2.66 mmol). After stirred at - 78 °C for 1 h, to the solution was added a solution of NIS (2.25 g, 1.0 mmol) in THF (10 mL). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with DCM (3 x 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 10% EtOAc/PE to provide 2-chloro-6-iodo-4- morpholinofuro[3,2-d]pyrimidine (1.6 g, 4.4 mmol) as a yellow solid. LC-MS (ESI+): m/z 366/368 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 6.97 (s, 1H), 4.01-3.98 (m, 4H), 3.85-3.82 (m, 4H). 2) Synthesis of 2-chloro-7-iodo-4-morpholinofuro[3,2-d]pyrimidine

[0489] To a solution of 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (5.0 g, 13.7 mmol) in THF (30 mL) at -78 °C under N2 was added LDA (14 mL, 2M, 27.4 mmol). After addition, the reaction mixture was stirred at -78 °C for 1 h. The completion of the reaction was mornitored by TLC. The reaction mixture was quenched with H₂O (100 mL). The aqueous solution was extracted with DCM (3 x 200 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-7-iodo-4-morpholinofuro[3,2-d]pyrimidine (2.5 g, 6.85 mmol) as a white solid. LC-MS (ESI+): m/z 366/368 (MH⁺).¹HNMR (300 MHz, CDCl₃) δ 7.77 (s, 1H), 4.04-3.94 (m, 4H), 3.85-3.81 (m, 4H). 3) Synthesis of 2-chloro-7-methyl-4-morpholinofuro[3,2-d]pyrimidine [0490] To a solution of 2-chloro-7-i

odo-4-morpholinofuro[3,2-d]pyrimidine (500 mg, 0.14 mmol) in DME/H₂O (2/1, 30 mL) was added methylboronic acid (250 mg, 4.2 mmol), K3PO4 (440 mg, 2.1 mmol) and Pd(PPh3)4 (150 mg, 0.14 mmol). The reaction was stirred at 120 °C for overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with EtOAc (2 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-7-methyl-4-morpholinofuro[3,2- d]pyrimidine (350 mg, 1.4 mmol) as a white solid. LC-MS (ESI+): m/z 254/256 (MH⁺). 4) Synthesis of 2-chloro-6-iodo-7-methyl-4-morpholinofuro[3,2-d]pyrimidine

[0491] To a solution of 2-chloro-7-methyl-4-morpholinofuro[3,2-d]pyrimidine (350 mg, 1.38 mmol) in THF (30 mL) at -78 °C under N2 was added LDA (1.4 mL, 2 M, 2.76 mmol). After stirred at -78 °C for 1 h, to the solution was added a solution of NIS (374 mg, 1.66 mmol) in THF (5 mL). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-6-iodo-7-methyl-4- morpholinofuro[3,2-d]pyrimidine (280 mg, 2.55 mmol) as yellow solid. LC-MS (ESI+): m/z 380/382 (MH⁺). 5) Synthesis of 2-chloro-7-methyl-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine

[0492] A solution of 2-chloro-6-iodo-7-methyl-4-morpholinofuro[3,2-d]pyrimidine (200 mg, 0.53 mmol), 2-(tributylstannyl)pyridine (389 mg, 1.06 mmol) and Pd(PPh3)4 (61 mg, 0.053 mmol) in toluene (5 mL) was heated to 90 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with DCM/MeOH (15/1, 3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide 2-chloro-7-methyl-4-morpholino-6-(pyridin-2-yl)furo[3,2-d]pyrimidine (70 mg, 0.21 mmol) as a white solid. LC-MS (ESI+): m/z 331/333 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.67 (d, J = 4.8 Hz, 1H), 7.78-7.67 (m, 2H), 7.31-7.25 (m, 1H), 4.06-4.01 (m, 4H), 3.82-3.79 (m, 4H), 2.59 (s, 3H). 6) Synthesis of 7-methyl-4-morpholino-2-(3-phenyl-1H-pyrazol-1-yl)-6-(pyridin-2- yl)furo[3,2-d]pyrimidine

[0493] To a solution of 2-chloro-7-methyl-4-morpholino-6-(pyridin-2-yl)furo[3,2- d]pyrimidine (80 mg, 0.24 mmol) in DMF (10 mL) was added 3-phenyl-1H-pyrazole (42 mg, 0.29 mmol) and Cs2CO3 (160 mg, 0.49 mmol). The reaction was stirred at 100 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL). The aqueous solution was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 5% MeOH/DCM to provide 7-methyl-4-morpholino-2-(3-phenyl-1H-pyrazol-1- yl)-6-(pyridin-2-yl) furo[3,2-d]pyrimidine (28.6 mg, 0.065 mmol) as white solid. LC-MS (ESI+): m/z 439 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.76 (d, J = 1.5 Hz, 1H), 8.62 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.83-7.81 (m, 2H), 7.46-7.41 (m, 2H), 7.37-7.27 (m, 2H), 6.79 (d, J = 2.7 Hz, 1H), 4.21-4.15 (m, 4H), 3.96-3.90 (m, 4H), 2.77 (s, 3H). [0494] EXAMPLE 40: Compound 147 using General synthetic route 40:

1)Synthesis of 2-chloro-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine

[0495] To a solution of 2-chloro-7-iodo-4-morpholinofuro[3,2-d]pyrimidine (300 mg, 0.82 mmol) in anhydrous DMSO (6 mL) was added KF (144 mg, 2.47 mmol), CuI (30 mg, 0.16 mmol), 1,10-phenanthroline (30 mg, 0.16 mmol), B(OMe)₃ (252 mg, 2.47 mmol) and TMSCF₃ (348 mg, 2.47 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with water (10 mL). The aqueous solution was extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-4-morpholino-7- (trifluoromethyl)furo[3,2-d]pyrimidine (98 mg, 0.32 mmol) as a yellow solid. LC-MS (ESI+): m/z 308/310 (MH⁺). 2) Synthesis of 2-chloro-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine-6- carboxylic acid F

[0496] To a solution of 2-chloro-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine (490 mg, 1.60 mmol) in anhydrous THF (100 mL) at -78 °C under N₂ was added n-BuLi (0.96 mL, 2.5 M, 2.4 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the above solution was added dry ice (705 mg, 16 mmol) in one potion. The resulting reaction mixture was stirred at that temperature for 1 h. The completion of the reaction was monitored by TLC. The reaction was quenched with water and the pH was adjusted to 5 using 1 N HCl solution. The aqueous solution was extracted with DCM (2 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was slurry in Et₂O to provide 2-chloro-4-morpholino-7- (trifluoromethyl)furo[3,2-d]pyrimidine-6-carboxylic acid (270 mg, 0.77 mmol) as a brown solid. LC-MS (ESI+): m/z 352/354 (MH⁺). 3) Synthesis of 2-chloro-N-cyclopropyl-4-morpholino-7-(trifluoromethyl)furo[3,2- d]pyrimidine-6-carboxamide

[0497] To a solution of 2-chloro-4-morpholino-7-(trifluoromethyl)furo[3,2-d]pyrimidine-6- carboxylic acid (270 mg, 0.77 mmol) in DCM (10 mL) was added cyclopropanamine (43 mg, 0.77 mmol), EDCl (175 mg, 0.92 mmol) and DMAP (112 mg, 0.92 mmol). The reaction was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 2-chloro-N-cyclopropyl-4-morpholino-7- (trifluoromethyl)furo[3,2-d]pyrimidine-6-carboxamide (60 mg, 0.15 mmol) as white solid. LC- MS (ESI+): m/z 391/393 (MH+). 4) Synthesis of N-cyclopropyl-4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)-7- (trifluoromethyl)furo[3,2-d]pyrimidine-6-carboxamide

[0498] To a solution of 2-chloro-N-cyclopropyl-4-morpholino-7-(trifluoromethyl)furo[3,2- d]pyrimidine -6-carboxamide (60 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added 4-(m-tolyl)- 1H-pyrazole (30 mg, 0.18 mmol), Pd2(dba)3 (15 mg, 0.015 mmol), t-Buxphos (15 mg, 0.015 mmol) and K3PO4 (50 mg, 0.63 mmol). The reaction was stirred at 80 °C under microwave for 30 min. The reaction mixture was diluted with water and extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide N-cyclopropyl-4- morpholino-2-(4-(m-tolyl)-1H-pyrazol-1-yl)-7-(trifluoromethyl)furo[3,2-d]pyrimidine-6- carboxamide (13 mg, 0.025 mmol) as a yellow solid. LC-MS (ESI+): m/z 513 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.08 (s, 1H), 7.61-7.42 (m, 2H), 7.35-7.27 (m, 1H), 7.11-7.09 (m, 1H), 6.48 (s, 1H), 4.17-4.12 (m, 4H), 3.92-3.88 (m, 4H), 2.95-2.90 (m, 1H), 2.41 (s, 3H), 0.98-0.93 (m, 2H), 0.75-0.69 (m, 2H). [0499] EXAMPLE 41: Compound 204 using General synthetic route 41:

1) Synthesis of 4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine

[0500] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (300 mg, 1.25 mmol) in DMF (4 mL) was added 3-(m-tolyl)-1H-pyrazole (237 mg, 0.35 mmol), Cs₂CO₃ (815 mg, 2.5 mmol) and CuI (24 mg, 0.125 mmol). The reaction mixture was stirred at 110 °C overnight. The reaction mixture was quenched with water (10 mL). The aqueous solution was extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 4- morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (269 mg, 0.75 mmol) as a white solid. LC-MS (ESI+): m/z 362 (MH⁺).¹HNMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.7 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.39-7.34 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 2.7 Hz, 1H), 4.08-4.07 (m, 4H), 3.82- 3.81 (m, 4H), 2.35 (s, 3H). 2) Synthesis of 6-iodo-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine

[0501] To a solution of 4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (180 mg, 0.5 mmol) in anhydrous THF (40 mL) at -78 °C under N2 was added n-BuLi (0.24 mL, 2.5 M, 0.6 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the solution was added a solution of NIS (135 mg, 0.6 mmol) in THF (3 mL) dropwise. The resulting reaction mixture was stirred at that temperature for 2 h. The completion of the reaction was monitored by TLC. The reaction was quenched with water. The aqueous solution was extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 6-iodo-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (70 mg, 0.14 mmol) as a white solid. LC-MS (ESI+): m/z 488 (MH⁺). 3) Synthesis of 6-(3-methylisoxazol-5-yl)-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine

[0502] A suspension of 6-iodo-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- d]pyrimidine (70 mg, 0.14 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole (36 mg, 0.172 mmol), K₂CO₃ (60 mg, 0.43 mmol) and Pd(dppf)Cl₂ (11 mg, 0.014 mmol) in 1,4-dioxane/H₂O (8/1, 10 mL) was heated to 90 °C for 2 h under N₂. The completion of the reaction was monitored by TLC. The reaction was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 6% MeOH/DCM to provide 6-(3-methylisoxazol-5-yl)-4-morpholino-2-(3-(m- tolyl)-1H- pyrazol-1-yl)furo[3,2-d]pyrimidine (22 mg, 0.05 mmol) as a light yellow solid. LC- MS (ESI+): m/z 443 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 8.54 (d, J = 2.7 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.39-7.26 (m, 2H), 7.17 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.58 (s, 1H), 4.17-4.13 (m, 4H), 3.95-3.91 (m, 4H), 2.42 (s, 6H). [0503] EXAMPLE 42: Compound 212 using General synthetic route 42:

1) Synthesis of (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)boronic acid

[0504] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (200 mg, 0.84 mmol) in THF (30 mL) at -78 °C under N₂ was added n-BuLi (0.4 mL, 2.5 M, 1.00 mmol). After stirred at -78 °C for 1 h, to the solution was added a solution of triisopropyl borate (190 mg, 1.00 mmol) in THF (2 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water (0.1 mL) and a large amount of white solid was precipitated. After filtration, the filter cake was washed with 4 mL THF and dried in vacuum to provide (2-chloro- 4-morpholinofuro[3,2-d]pyrimidin-6-yl)boronic acid (150 mg, 0.53 mmol) as white solid. LC- MS (ESI+): m/z 284/286 (MH⁺).¹HNMR (300 MHz, CD3OD) δ 6.58 (s, 1H), 4.12-4.05 (m, 4H), 3.84-3.78 (m, 4H). 2) Synthesis of 4-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-N,N,2-trimethyl-1H- imidazole-1-sulfonamide

[0505] A suspension of 4-iodo-N,N,2-trimethyl-1H-imidazole-1-sulfonamide (367 mg, 1.17 mmol), (2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)boronic acid (300 mg, 1.06 mmol), K2CO3 (439 mg, 3.18 mmol) and Pd(dppf)Cl2 (78 mg, 0.106 mmol) in 1,4-dioxane/H₂O (8/1, 20 mL) was heated to 90 °C for 1 h under N₂. The completion of the reaction was monitored by TLC. The reaction was concentrated directly under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 4-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-N,N,2-trimethyl- 1H-imidazole-1-sulfonamide (340 mg, 0.80 mmol) as a yellow solid. LC-MS (ESI+): m/z 427/429 (MH⁺).¹HNMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.02 (s, 1H), 4.09-4.03 (m, 4H), 3.91-3.84 (m, 4H), 3.04 (s, 6H), 2.69 (s, 3H). 3) Synthesis of N,N,2-trimethyl-4-(4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- d]pyrimidin-6-yl)-1H-imidazole-1-sulfonamide

[0506] A suspension of 4-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-N,N,2-trimethyl- 1H- imidazole-1-sulfonamide (110 mg, 0.26 mmol), 3-(m-tolyl)-1H-pyrazole (49 mg, 0.31 mmol), t-BuONa (0.52 mL, 1M, 0.52 mmol), Pd2(dba)3 (14.8 mg, 0.066 mmol) and t-BuXphos (80 mg, 0.18 mmol) in toluene (10 mL) under N2 was heated to 100 °C for 1 h. The completion of the reaction was monitored by TLC. The reaction was concentrated directly. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide to provide 50 mg of impure product. After further slurry in MeOH to provide N,N,2-trimethyl-4-(4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-d] pyrimidin- 6-yl)-1H-imidazole-1-sulfonamide (35 mg, 0.064 mmol) as a white solid. LC-MS (EMS+): m/z 549 (MH⁺). 4) Synthesis of 6-(2-methyl-1H-imidazol-5-yl)-4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine

[0507] To a solution of N,N,2-trimethyl-4-(4-morpholino-2-(3-(m-tolyl)-1H-pyrazol-1-yl) furo[3,2-d]pyrimidin-6-yl)-1H-imidazole-1-sulfonamide (35 mg, 0.064 mmol) in 1,4-dioxane (4 mL) was added conc. HCl (0.3 mL). The reaction mixture was stirred at 80 °C for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO₃ solution to pH = 8. A large amount of solid was precipitated. After filtration, the filter cake was slurry in Et₂O to provide N,N,2-trimethyl-4-(4-morpholino-2-(3-(m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-d]pyrimidin-6-yl)-1H-imidazole-1-sulfonamide (20 mg, 0.045 mmol) as a light yellow solid. LC-MS (ESI+): m/z 442 (MH⁺). ¹HNMR (300 MHz, CDCl3) δ 8.53 (d, J = 2.7 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.31-7.26 (m, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 6.76 (d, J = 2.7 Hz, 1H), 4.15-4.11 (m, 4H), 3.95-3.91 (m, 4H), 2.51 (s, 3H), 2.41 (s, 3H). [0508] EXAMPLE 43: Compound 144 using General synthetic route 43: l

1) Synthesis of 2-chloro-6-(3-methyl-1H-pyrazol-5-yl)-4-morpholinofuro[3,2-d]pyrimidine [0509] A suspension of 2-chloro-6

-iodo-4-morpholinofuro[3,2-d]pyrimidine (400 mg, 1.08 mmol), (3-methyl-1H-pyrazol-5-yl)boronic acid (154 mg, 1.1 mmol), Na2CO3 (232 mg, 2.16 mmol) and Pd(PPh₃)₄ (12 mg, 0.01 mmol) in 1,4-dioxane/H₂O (8 mL, 4:1) under N₂ was heated to 50 °C for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 33% EtOAc/PE to 50% EtOAc/PE to provide 2- chloro-6-(3-methyl-1H-pyrazol-5-yl)-4-morpholinofuro[3,2-d]pyrimidine (180 mg, 0.57 mmol) as a yellow solid. LC-MS (ESI+): m/z 320/322 (MH⁺). 2) Synthesis of 5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-N,N,3-trimethyl-1H- pyrazole-1-sulfonamide

[0510] To a solution of 2-chloro-6-(3-methyl-1H-pyrazol-5-yl)-4-morpholinofuro[3,2- d]pyrimidine (180 mg, 0.57 mmol) in THF at 0 °C was added NaH (27 mg, 0.67 mmol). The mixture was stirred at 0 °C for 0.5 h. To the above mixture at 0 °C was added Dimethylsulfamoyl chloride (104 mg, 0.73 mmol) dropwise. After addition, the reaction mixture was stirred at rt for 3.5 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL). The aqueous solution was extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residual was slurry in Et₂O to provide crude 5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-N,N,3-trimethyl-1H-pyrazole-1- sulfonamide (270 mg, 0.63 mmol) as a yellow solid. LC-MS (ESI+): m/z 427/429 (MH⁺). ¹HNMR (300 MHz, CDCl₃) δ 7.06 (s, 1H), 6.49 (s, 1H), 4.13-4.04 (m, 4H), 3.87-3.81 (m, 4H), 3.10 (s, 6H), 2.58 (s, 3H). 3) Synthesis of 6-(3-methyl-1H-pyrazol-5-yl)-4-morpholino-2-(4-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-d]pyrimidine

[0511] To a solution of 5-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-N,N,3-trimethyl- 1H-pyrazole-1-sulfonamide (90 mg, 0.21mmol) in CH₃CN (5 mL) was added 4-(m-tolyl)-1H- pyrazole (40 mg, 0.25 mmol) and Cs2CO3 (138 mg, 0.42 mmol). The reaction mixture was stirred at 160 °C in a sealed tube overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by preparative TLC with a elution of 10% MeOH/DCM to provide 6-(3-methyl-1H-pyrazol-5-yl)-4-morpholino-2-(4-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-d]pyrimidine (18 mg, 0.041 mmol) as a yellow solid. LC-MS (ESI+): m/z 442 (MH⁺).¹HNMR (300 MHz, DMSO-d₆) δ 13.52 (s, 1H), 9.00 (s, 1H), 8.22 (s, 1H), 7.61 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.65 (s, 1H), 4.15-4.06 (m, 4H), 3.90-3.80 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). [0512] Compounds 143 to 225 in Table 4 are made according to the procedures above. Table 4

[0513] Compounds 226-257 in Table 5 are prepared using methods analogous to those described herein. Table 5

Biological Example 1: Inhibition of PIKfyve [0514] Full length human recombinant PIKFYVE expressed in baculovirus expression system as N-terminal GST-fusion protein (265 kDa) was obtained from Carna Biosciences (Kobe, Japan). The kinase substrate was prepared by mixing and sonicating fluorescently-labeled phosphatidylinositol 3-phosphate (PI3P) with phospho-L-serine (PS) at a 1:10 ratio in 50 mM HEPES buffer pH 7.5. [0515] The kinase reactions were assembled in 384-well plates (Greiner) in a total volume of 20 mL as follows. Kinase protein was pre-diluted in an assay buffer comprising 25 mM HEPES, pH 7.5, 1 mM DTT, 2.5 mM MgCl2, and 2.5 mM MnCl2, and 0.005% Triton X-100, and dispensed into a 384-well plate (10 µL per well). Test compounds were serially pre-diluted in DMSO and added to the protein samples by acoustic dispensing (Labcyte Echo). The concentration of DMSO was equalized to 1% in all samples. All test compounds were tested at 12 concentrations. Apilimod was used as a reference compound and was tested in identical manner in each assay plate. Control samples (0%-inhibition, in the absence of inhibitor, DMSO only) and 100%-inhibition (in the absence of enzyme) were assembled in replicates of four and were used to calculate %-inhibition in the presence of compounds. The reactions were initiated by addition of 10 µL of 2x PI3P/PS substrate supplemented with ATP. The final concentration of enzyme was 2 nM, the final concentration of ATP was 10 mM, and the final concentration of PI3P/PS substrate was 1 µM (PI3P). The kinase reactions were allowed to proceed for 3 h at room temperature. Following incubation, the reactions were quenched by addition of 50 mL of termination buffer (100 mM HEPES, pH 7.5, 0.01% Triton X-100, 20 mM EDTA). Terminated plates were analyzed on a microfluidic electrophoresis instrument (Caliper LabChip® 3000, Caliper Life Sciences/Perkin Elmer). The change in the relative fluorescence intensity of the PI(3)P substrate and PI(3,5)P product peaks was measured. The activity in each test sample was determined as the product to sum ratio (PSR): P/(S+P), where P is the peak height of the product, and S is the peak height of the substrate. Percent inhibition (Pinh) was determined using the following equation: P_inh = (PSR_0%inh - PSR_compound)/(PSR_0%inh - PSR_100%inh)*100 in which PSR_compound is the product/sum ratio in the presence of compound, PSR0_%inh is the product/sum ratio in the absence of compound, and the PSR100%inh is the product/sum ratio in the absence of the enzyme. To determine the IC₅₀ of test compounds (50%-inhibition) the %-inh cdata (P_inh versus compound concentration) were fitted by a four-parameter sigmoid dose- response model using XLfit software (IDBS).

[0516] The IC50 values for certain compounds of the disclosure are provided in Table 6 below. Table 6

Biological Example 2: Antiviral effects of PIKfyve inhibitors in a Vero-E6 SARS-CoV-2 cytopathic assay [0517] Materials and Methods [0518] An in vitro antiviral assay to test compounds acting against SARS-CoV-2 was designed and run based on cytopathic effect (CPE) in Vero (African green monkey kidney epithelial) cells essentially according to the methods of Ivens et al. (2005) Journal of Virological Methods 129, 56-63. [0519] VeroE6-EGFP cells (provided by Lab of Virology & Chemotherapy, Rega Institute, KU Leuven, Leuven, Belgium) (sometimes referred to herein as VeroE6, Vero-E6, or Vero-E6- GFP) were propagated in growth medium which was prepared by supplementing DMEM (Gibco 41965-039) with 10% v/v heat-inactivated FCS and 5 mL sodium bicarbonate 7.5% (Gibco 25080-060). Cells were cultured in T150 bottles and split 1/4 twice a week. Pen-strep was added directly to the T150 bottle at a 1/100 dilution. [0520] Assay medium was prepared by supplementing DMEM (Gibco 41965-039) with 2% v/v heat-inactivated FCS and 5 mL sodium bicarbonate 7.5% (Gibco 25080-060). [0521] Serial dilutions of compounds were prepared in 96-well plates to which cells were added (25,000 cells/well) after which plates were incubated overnight (37°C; 5% CO₂). The next day virus inoculum (SARS-CoV-2 clinical isolate, Belgian strain: BetaCov/Belgium/GHB- 03021/2020) was added and plates were incubated for 4 days (37°C; 5% CO2) until a maximal cytopathic effect (CPE) could be observed in the untreated, infected (virus control) conditions. On day 4, GFP signal was determined using high-content imaging. [0522] Antiviral activity is expressed as the EC50 or concentration required to rescue 50% of the GFP signal from the virus-induced cytopathogenicy. The signal is provided as the logarithm of the surface of the well that is covered with fluorescent pixels which correlates with living cells. [0523] In parallel, and to avoid false positives, cytotoxicity was assessed by growing uninfected cells in the presence of the test compound at the concentrations tested. After a 4 day incubation, cell viability was measured using a commercial kit. [0524] Antiviral readout was performed using high-content imagers. Using a 5x objective, almost the entire well of a 384-well plate is captured at once (for an 96-well plate, the well is covered by 4 field of views). A GFP marker located in both the cell cytoplasm as well as the nucleus allowed for the calculation of the surface of the well that is (still) covered by cells (SpotTotalAreaCh2). The data are exported to .csv files and dose-response curves are processed in Dotmatics. [0525] Results and Discussion Compound 101 was tested to determine activity against SARS-CoV2. All tests were run in duplicate, with a top concentration of 10 µM (8 concentrations; dilution step 1/3). Figure 1 shows antiviral effect and cell toxicity data for Compound 101, which has an EC50 of about 0.1- 0.5 µM, CC50 > 100 µM, and Safety index (i.e., the ratio of CC50 to EC50) > 200. Compound 101 demonstrated reproducible and robust anti-viral activity in Vero-E6 cells with a therapeutically acceptable safety index. Biological Example 3: Antiviral effects of PIKfyve inhibitors in an A549-ACE2 cell assay [0526] Materials and Methods [0527] PIKfyve inhibitors were assessed for anti-viral activity against SARS-COV-2 using A549-ACE2 cells (adenocarcinomic human alveolar basal epithelial cells) transduced to express the human Angiotensin-converting enzyme 2 (ACE2), provided by Institut Pasteur, Paris, France. A549-ACE2 cells were grown in 96-well plates, and ten concentrations of each tested PIKfyve inhibitor was tested in triplicate. Concentrations of compounds tested included: 0.001 – 1uM (0, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10). The DMSO concentration in the final assay was < 1% (dilution of stock made in serial dilutions of media). [0528] Cells were pretreated for 2 hours before infection with SARS-CoV-2 virus (isolate BetaCoV/France/IDF0372/2020 C2). After virus infection, cells were incubated for 1 hour at 37°C. All cells were washed after a 48-hour incubation. [0529] Viral replication was measured by quantitative RT-PCR in the presence and absence of the tested compounds. [0530] In parallel, and to avoid false positives, cytotoxicity was assessed by growing uninfected cells in the presence of the three tested compounds at the concentrations tested. After 48 hours of incubation, cell viability was measured using a commercial kit. [0531] The test compound was provided in 10 mM solutions in 100 uL DMSO. [0532] Results [0533] Exemplary results are shown in Figure 2. The tested compound showed potent antiviral effects with minimal toxicity. Figure 2 shows results for Compound 97 where the viral titer is shown as Log₁₀ of plaque forming units per mL (PFU/mL) on the left axis (data represented by white circles). Percent cell viability is shown on the right axis (data represented by black circles). Compound 97 has IC50 = 0.069 µM. Compounds 171 and 163 were also tested. Compound 171 has EC₅₀ of 55.85 µM; Compound 163 has EC₅₀ of 4.228 µM. Both compounds 163 and 171 have CC₅₀ of >10000 nM. Biological Example 4: Reduction of virus-induced cytopathic effect (primary CPE assay) [0534] Materials and Methods [0535] Confluent or near-confluent cell culture monolayers of Vero 76 (African green monkey kidney epithelial cells, are provided by Institute for Antiviral Research, Utah State University, Utah, USA) cells and are prepared in 96-well disposable microplates the day before testing. Cells are maintained in MEM supplemented with 5% FBS. For antiviral assays, the same medium is used but with FBS reduced to 2% and supplemented with 50-µg/ml gentamicin. Compounds are dissolved in DMSO. The test compounds are prepared at four serial log10 concentrations, 0.1, 1.0, 10, and 100 µg/ml or µM. Five microwells are used per dilution: three for infected cultures and two for uninfected toxicity cultures. Controls for the experiment consisted of six microwells that are infected and not treated (virus controls) and six that are untreated and uninfected (cell controls) on every plate. A known active drug, the protease inhibitor M128533, is tested in parallel as a positive control drug using the same method as is applied for test compounds. [0536] Growth media is removed from the cells and the test compound is applied in 0.1 ml volume to wells at 2X concentration. The SARS-CoV-2, USA_WA1/2020 strain, normally at ~60 CCID50 (50% cell culture infectious dose) in 0.1 ml volume, is added to the wells designated for virus infection. Medium devoid of virus is placed in toxicity control wells and cell control wells. Plates are incubated at 37°C with 5% CO₂ until marked CPE (>80% CPE for most virus strains) is observed in virus control wells. The plates are then stained with 0.011% neutral red for approximately two hours at 37°C in a 5% CO2 incubator. The neutral red medium is removed by complete aspiration, and the cells are optionally rinsed 1X with phosphate buffered solution (PBS) to remove residual dye. The PBS is completely removed, and the incorporated neutral red is eluted with 50% Sorensen’s citrate buffer/50% ethanol for at least 30 minutes. Neutral red dye penetrates into living cells, thus, the more intense the red color, the larger the number of viable cells present in the wells. The dye content in each well is quantified using a spectrophotometer at 540 nm wavelength. The dye content in each set of wells is converted to a percentage of dye present in untreated control wells using a Microsoft Excel computer-based spreadsheet and normalized based on the virus control. The 50% effective (EC50, virus-inhibitory) concentrations and 50% cytotoxic (CC50, cell-inhibitory) concentrations are then calculated by regression analysis. The quotient of CC50 divided by EC50 gives the selectivity index (SI) value. Compounds showing SI values >10 are considered active. Biological Example 5: Anti-viral Activity Against Human Alphacoronavirus Strain 229E (HCoV 229E) and Human Betacoronavirus Strain OC43 (HCoV OC43) [0537] Materials and Methods [0538] Representative compounds were tested for virustatic or virucidal properties against HCoV 229E and HCoV OC43. Stock solutions for each compound were prepared at a stock concentration of 10 mM for immediate use. [0539] EC₅₀ (half maximal efficacious concentration) – Using appropriate concentrations of virus, this study assessed the virustatic or virucidal properties of tested Compounds. Cells were seeded into 96-well plates. The tested compounds were serially diluted (8-point, 3-fold dose titration) and added prophylactically for an hour, to cells. Cells were then infected with virus for one hour, at a single infective dose (100x median tissue culture infectious dose; TCID50). Additional media was added to the wells, with equivalent concentrations of compound, for the duration of the study. Vehicle and positive control wells were set up to control for any influence on cell viability. Cells were visually inspected daily for the appearance of any cytophathic/cytopathogenic effect (CPE). A colorimetric mammalian cell viability assay (Thiazolyl Blue Tetrazolium Bromide (MTT) assay; Sigma Catalog # M5655-1G; Lot # MKCL1832) was performed once CPE was complete. Percentage viral inhibition was calculated as follows: % Inhibition = [(A−B)/ (C−B)]×100, where: A: mean optical density of test, B: mean optical density of virus controls, C: mean optical density of cell controls. [0540] Values above 100% inhibition occur when A>C, due either to natural variation or compound effects. [0541] Values below 0% inhibition occur when A<B, due either to natural variation or compound toxicity. [0542] EC50 values were calculated using non-linear regression (log(agonist) vs. response – Variable slope (four parameters)) using log(concentration). [0543] CC₅₀ (half maximal cytotoxic concentration) – The CC₅₀ was determined in the manner described above for EC50. Plates were developed to show any cytotoxic effect of the compounds on cells in the absence of viral infection. The MTT assay was performed once CPE was complete. Percentage cell viability was calculated as follows: % viability = (A/B)×100, where: A: mean optical density of test, B: mean optical density of cell controls. Values above 100% inhibition occur when A>B, due either to natural variation or compound effects. [0544] CC50 values were calculated used non-linear regression as above for EC50. [0545] Experimental conditions and readouts – The virus strains/serotypes used were human alphacoronavirus 229E (HCoV 229E; ATCC^® CVR-740™) and betacoronavirus 1 OC-4 (HCoV OC43; ATCC^® VR-1558™). HCoV 229E was tested with human bronchial epithelial (16BHE) cells. HCoV OC43 was tested with human lung mucoepidermoid (H₂92) cells. Remdesivir was used as the control compound. [0546] Results [0547] Efficacy against HCoV 229E in 16BHE cells – Compound 91 showed efficacy against HCoV 229E, with percentage viral inhibition reaching 35% at approximately 0.32 µM (Figure 3A). Due to cytotoxicity observed above 0.32 µM, an EC₅₀ value was not calculated. The CC50 was 0.21 µM. [0548] Compound 121 showed efficacy against HCoV 229E, with percentage viral inhibition reaching 33% at approximately 3.2 µM (Figure 3B). Cytotoxicity was observed between 10 µM and 3.2 µM. For Compound 121 the EC50 ≥ 3.16 µM and the CC50 was caculated to be 4.97 µM. [0549] Compound 114 was also tested and had EC50 ≥ 10 µM and CC50 of 1.02. Data not shown. [0550] Efficacy against HCoV OC43 in H292 cells – Compound 91 showed efficacy against HCoV OC43, with an EC50 of 0.08 µM (Figure 4A) and CC50 ≥ 10 µM. Compound 91 increased cell viability to levels that were higher than the uninfected cells, leading to percentages above 100%. The viability in infected cells was reduced to below 0% at 10 µM, 3.16 µM, and 1 µM. In order to calculate a more representative EC50, these data points were excluded from the calculation. [0551] Compound 114 showed efficacy against HCoV OC43, with an EC₅₀ of 0.31 µM (Figure 4B). Compound 114 increased cell viability to levels that were higher than the uninfected cells, leading to percentages above 100%. The viability in infected cells was reduced to below 0% at 10 µM and 3.16 µM. In order to calculate a more representative EC₅₀, these data points were excluded from the calculation. The compound had a CC50 ≥ 10 µM. [0552] Compound 121 showed efficacy against HCoV OC43, with an EC50 of 0.99 µM (Figure 4C). Compound 121 increased cell viability to levels that were higher than the uninfected cells, leading to percentages above 100%. No reduction in viability in infected cells was seen at the tested concentrations. The compound had a CC50 ≥ 10 µM. Biological Example 6: PIKfyve inhibition of SARS CoV2–induced cytopathic effect (CPE) in Vero E6 cells [0553] Materials and Methods [0554] Five PIKfyve inhibitors were assessed for anti-viral activity against SARS-CoV-2, strain USA_WA1/2020, using Vero E6 and Vero 6 cells according to the methods of Severson et al. (2007) Journal of Biomolecular Screening 33-40. [0555] Results [0556] A summary of the results is shown in Table 7. The tested compounds showed potent antiviral effects with minimal toxicity. Table 7.

Biological Example 7: Drug Drug Interaction Study with Cytochrome P450 Enzymes [0557] Preparation of stock solutions [0558] The stock solutions of test compound were prepared in dimethyl sulfoxide (DMSO) at 10 mM concentration, then diluted to 2 mM with DMSO. The final concentration of test compound was 10 μM. [0559] Preparation of positive inhibitors [0560] The concentration of positive inhibitor was listed in Table 8. For the stock solution preparation, if the positive control could not be well dissolved in the mixture of DMSO and acetonitrile (1:4) at the highest concentration, another mixture of acetonitrile and DMSO, the mixture of acetonitrile and H₂O or DMSO was used to dissolve the compound. Table 8.

[0561] Preparation of substrate stock solution [0562] Preparation details of these substrates are given in Table 9. The substrate solution, which is stored at -20°C, was warmed to room temperature prior to use. Table 9.

[0563] Preparation of phosphate buffer (100 mM, pH 7.4) [0564] Solution A was prepared by adding 7.098 g of disodium hydrogen phosphate into 500 mL of pure water, followed by sonication. Solution B was prepared by adding 3.400 g of potassium dihydrogen phosphate to 250 mL of pure water, followed by sonication. Solution A was placed on a stirrer and Solution B was added slowly into Solution A until the pH reached 7.4. [0565] 10 mM NADPH solution was prepared, fresh prior to use, by dissolving nicotinamide adenine dinucleotide phosphate (NADPH) at 8.334 mg/mL in phosphate buffer. [0566] Preparation of master solution [0567] The master solution was prepared according to Table 10. The incubation was carried out in 96 deep well plates. The following volumes were dispensed into each well of the incubation plate, 179 μL of the substrate and human liver microsomes (HLM) mixture in phosphate buffer, 1 μL of the compound working solution, or vehicle (mixture of DMSO and acetonitrile (1:4)). The incubation plate was placed into the water bath and pre-warmed at 37°C for 15 minutes before the reactions were started by the addition of 20 μL of 10 mM NADPH solution in phosphate buffer. After the addition of NADPH, the incubation plate was incubated at 37°C for the corresponding time. The assay was performed in duplicate. Table 10.

[0568] The reaction was quenched by the addition of 1.5 volumes (300 μL) of cold acetonitrile containing 3% formic acid and internal standards (200 nM Labetalol, 200 nM Alprazolam and 200 nM tolbutamide). The plate was centrifuged at 3,220 g for 40 minutes, the 100 μL of the supernatant was transferred to a new plate. The supernatant was diluted with 100 μL pure water if appropriate. After mixing, the samples were analyzed using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS). [0569] Data Analysis [0570] The automatic peak integration areas were checked for all of the samples. The Analyte Peak Area and Internal Standard Peak Area were exported into excel spreadsheet. The inhibition of each P450 enzyme in human liver microsomes was measured as the percentage decrease in the activity of marker metabolite formation compared to non-inhibited controls (= 100% activity). [0571] The percentage of remaining activity was calculated as follows: Area Ratio = Peak Area Analyte/ Peak Area Internal Standard Remaining Activity (%) = Area Ratio test compound/ Area Ratio vehicle*100% Inhibition% = 100-Remaining Activity (%) Table 11.

Biological Example 8: Permeability Study [0572] Preparation of MDCK-MDR1 Cells [0573] 50 μL and 25 mL of cell culture medium were added to each well of the Transwell^® insert and reservoir, respectively. The HTS Transwell^® plates were incubated at 37 °C, 5% CO₂ for 1 hour before cell seeding. [0574] MDCK-MDR1 cells were diluted to 1.56х10⁶ cells/mL with culture medium and 50 μL of cell suspension were dispensed into the filter well of the 96-well HTS Transwell plate. Cells were cultivated for 4-8 days in a cell culture incubator at 37 °C, 5% CO₂, and 95% relative humidity. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating. [0575] Preparation of Stock Solutions [0576] Stock solutions of the test compounds and of the positive controls were prepared in dimethyl sulfoxide (DMSO) at the concentration of 10 mM. Metoprolol and Digoxin were used as the control compounds. [0577] Assessment of Cell Monolayer Integrity [0578] Medium was removed from the reservoir and each Transwell insert and replaced with prewarmed fresh culture medium. Transepithelial electrical resistance (TEER) across the monolayer was measured using Millicell® Epithelial Volt-Ohm measuring system (Millipore®, USA). The Plate was returned to the incubator once the measurement was complete and the TEER value was calculated according to the following equation: [0579] TEER measurement (ohms) x Area of membrane (cm²) = TEER value (ohm•cm²) [0580] TEER value should be greater than 42 ohm•cm², which indicates the well-qualified MDCK-MDR1 monolayer. [0581] Assay Procedures [0582] The MDCK-MDR1 plate was removed from the incubator and washed twice with pre- warmed Hanks' Balanced Salt solution (HBSS) (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of control compounds were diluted in DMSO to get 200 μM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 1 μM working solutions. The test compounds were diluted in DMSO to get 200 μM solutions and then diluted with HBSS (10 mM HEPES with 4% BSA, pH 7.4) to get 1 μM working solutions. The final concentration of DMSO in the incubation system was 0.5%. [0583] To determine the rate of drug transport in the apical to basolateral direction 125 μL of the working solution was added to the Transwell insert (apical compartment), and 50 μL of sample was transferred immediately from the apical compartment to 200 μL of acetonitrile (ACN) containing internal standard (IS) (100 nM alprazolam, 200 nM Caffeine and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (A-B). After vortexing at 1000 rpm for 10 minutes, the wells in the receiver plate (basolateral compartment) were filled with 235 μL of transport buffer. [0584] To determine the rate of drug transport in the basolateral to apical direction.285 μL of the working solution were added to the receiver plate wells (basolateral compartment), and 50 μL of sample were transferred immediately from the basolateral compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM Caffeine and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (B-A). After vortexing at 1000 rpm for 10 minutes, the Transwell insert (apical compartment) was filled with 75 μL of transport buffer, with the apical to basolateral direction and the basolateral to apical direction measured at the same time. [0585] Following incubation of the plates at 37 °C for 2 hours, 50 μL samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap) were transferred to wells of a new 96-well plate, followed by the addition of 4 volumes of acetonitrile containing IS (100 nM alprazolam, 200 nM Caffeine and 100 nM tolbutamide). Samples were vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 µL of the supernatant was mixed with an appropriate volume of ultra-pure water before LC-MS/MS analysis. [0586] To determine the Lucifer Yellow leakage after 2-hour transport period, stock solution of Lucifer yellow was prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 μM.100 μL of the Lucifer yellow solution was added to each Transwell insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates were Incubated at 37 °C for 30 mins.80 μL samples were removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal was measured in a fluorescence plate reader at 480 nM excitation and 530 nM emission. [0587] Data Analysis [0588] The apparent permeability coefficient (Papp), in units of centimeter per second, was calculated for the MDCK-MDR1 drug transport assays using the following equation: Papp = (VA × [drug]acceptor) / (Area × Time × [drug]initial,donor) [0589] where VA is the volume (in mL) in the acceptor well, Area is the surface area of the membrane (0.143 cm² for Transwell-96 Well Permeable Supports), and time is the total transport time in seconds. [0590] The leakage of Lucifer Yellow, in unit of percentage (%), can be calculated using the following equation: %LY leakage = 100×[LY]acceptor/([LY]donor+[LY]acceptor) LY leakage of <1% is acceptable to indicate the well-qualified MDCK-MDR1 monolayer. [0591] Results for this Example are shown in Table 15. Biological Example 9: Hepatocyte Drug Metabolism Study [0592] Preparation of Working Solutions [0593] 10 mM stock solutions of test compound and positive controls were prepared in DMSO. In separate conical tubes, 10 mM test compound and the positive control were diluted to 100 μM by combining 198 μL of 50% acetonitrile / 50% water and 2 μL of 10 mM stock. [0594] Preparation of Hepatocytes [0595] Incubation medium (William’s E Medium supplemented with GlutaMAX^TM) and hepatocyte thawing medium were placed in a 37 °C water bath, and allowed to warm for at least 15 minutes prior to use. [0596] A vial of cryopreserved hepatocytes was transferred from storage, ensuring that vials remain at cryogenic temperatures until thawing process ensued. The cells were thawed by placing the vial in a 37°C water bath and gently shaking the vials for 2 minutes. After thawing was completed, the vial was sprayed with 70% ethanol, and transferred to a biosafety cabinet. [0597] The hepatocytes were transferred into 50 mL conical tube containing thawing medium. The 50 mL conical tube was placed into a centrifuge and spun at 100 g for 10 minutes. Upon completion of spin, the thawing medium was aspirated and the hepatocytes resuspended in enough incubation medium to yield ~1.5 × 106 cells/mL. [0598] AO/PI Staining was used to count cells and determine the viable cell density, after which, the cells were diluted with incubation medium to a working cell density of 0.5 × 106 viable cells/mL. [0599] Procedure for Stability Determination [0600] 198 μL of hepatocytes were pipetted into each wells of a 96-well non-coated plate, which was then placed in the incubator to warm the hepatocytes for 10 minutes.2 μL of the 100 μM test compound or positive control were pipetted into respective wells of the 96-well non- coated plate to start the reaction, and the plate was returned to the incubator for the designed time points. [0601] The well contents were transferred in 25 μL aliquots at time points of 0, 15, 30, 60, 90 and 120 minutes, then mixed with 6 volumes (150 μL) of acetonitrile containing internal standard, IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide) to terminate the reaction. After 5 minutes of vortexing, the samples were centrifuged for 45 minutes at 3,220 g. Aliquots of 100 µL of the supernatant were diluted by 100 µL ultra-pure water, and the mixture was used for liquid chromatography (LC) tandem mass spectrometry (MS) (LC/MS/MS) analysis. All incubations were performed in duplicate. [0602] Data Analysis [0603] All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The in vitro half-life (t1/2) of parent compound were determined by regression analysis of the percent parent disappearance vs. time curve. [0604] The in vitro half-life (in vitro t_1/2) was determined from the slope value: in vitro t_1/2 = 0.693 / k [0605] Conversion of the in vitro t1/2 (in min) into the in vitro intrinsic clearance (in vitro CLint, in µL/min/1×106 cells) was done using the following equation (mean of duplicate determinations): in vitro CLint = kV/N where V = incubation volume (0.2 mL); and N = number of hepatocytes per well (0.1 × 106 cells). [0606] The calculations of Scaled-up CLint (mL/min/kg), Predicted CLH (mL/min/kg) and EH were done using the following equation: Scaled-up CLint = (0.693/T1/2) × (1/(hepatocytes concentration (0.5 × 106 cells/mL))) × Scaling Factors (See Table 9); Predicted CLH = (QH × Scaled-up CLint × f_ub) / (QH + Scaled-up CLint × f_ub); and EH = Predicted CLH/QH where QH is the hepatic blood flow (mL/min/kg) (Table 9), f_ub is the fraction of unbound drug in plasma which is assumed to be 1. Table 12 shows scaling factors for intrinsic clearance prediction in human, monkey, dog, rat and mouse hepatocytes. Table 12.

[0607] The rules for data processing are shown in Table 13. Table 13.

[0608] Results for this example are shown in Table 14. Table 14.

Biological Example 10: Antiviral effects of PIKfyve inhibitors in a Vero-E6 SARS-CoV-2 cytopathic assay [0609] Materials and Methods [0610] To determine the half maximal inhibitory concentration (IC₅₀) of the compounds against SARS-CoV-2, anti-viral screening was performed against two (2) SARS-CoV-2 strains, Wildtype (WT) and Delta (D). [0611] Adherent Vero-E6 cells were seeded in multi-well plates. Cell cultures were inoculated with a standardized amount of virus, in the absence and presence of serial compound dilutions, followed by 18-24 hours of incubation and an appropriate virus detection method (e.g., Immunostaining). Eight 3.16-fold dilutions of the compounds (lowest concentration 1 nM) were added to the assay cells for 1h before infection with each SARS-CoV-2 strain respectively. Virus signals detected in the presence of each compound concentration were used to determine the IC50. After infection, cells were fixed and immunostained for a viral antigen, and the percentage of infected cells quantified relative to an infected, untreated control using high content imaging. In parallel, the cytotoxicity of the same concentrations of each compound were tested in the absence of viral infection by MTT assay. As positive control, remdesivir was included. [0612] Results and Discussion [0613] Representative PYKfyve inhibitors were tested to determine their activity against two SARS-CoV2 strains: Wildtype (WT) and Delta (D). A summary of the results is shown in Table 15. Figures 5A, 5B and 5C show this data graphically. Table 15

[0614] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

What is claimed is: 1. A method of blocking alpha-coronavirus, beta-coronavirus lineage B, and beta- coronavirus lineage A entry into a host cell and preventing an infection caused by alpha- coronavirus, beta-coronavirus lineage B, and beta-coronavirus lineage A, comprising administering to a subject in need thereof a compound of (i) Formula (I)

wherein X and Y are independently N or CR^a; wherein R^a is H or C1-4alkyl; and R^b is phenyl, monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three R^d substituents; or R^1a is H or C1-4alkyl; and R^1b is a heteroaryl optionally substituted with R^c; wherein R^c is C_1-4alkyl, phenyl, -C_1-4alkyl-phenyl, monocyclic cycloalkyl, -C_1-4alkyl-(monocyclic cycloalkyl), monocyclic heterocyclyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, or -C1-4alkyl-(monocyclic heteroaryl), wherein each alkyl, phenyl, cycloalkyl, heterocyclyl, heterocycloalkyl or heteroaryl is optionally substituted with one, two, or three R^d substituents; wherein each R^d substituent is independently C1-4alkyl, C1-4alkenyl, C1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)_1-2R^h, -NR^gS(=O)1-2NR^gR^h, =NSO2R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)2R^g, -OS(=O)1-2R^g, -S(=O)_1-2OR^g, or -S(=O)_1-2NR^gR^h; wherein R^g and R^h are each independently H or C_1-4alkyl; each of R² and R³ is independently chosen from H, C_1-4alkyl, cycloalkyl, C_1-4alkylcycloalkyl, heterocyclyl, heterocycloalkyl, and heteroaryl optionally substituted with one, two, or three R^j substituents; or R² and R³ taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one, two, three, or four R^j substituents, or further wherein any of the hydrogens bonded to carbon atoms are optionally replaced by deuterium; wherein each R^j substituent is independently C1-4alkyl, -OH, oxo, -NR^kR^l, halo, C_1-4haloalkyl, -O-C_1-4alkyl, or -O-C_1-4-haloalkyl; where R^k and R^l are each independently H or C1-4alkyl; R⁴ is H, halo, -C(O)OH, C1-4alkylNR^xR^y, or -C(O)NR^xR^y, or is a cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl, wherein each cycloalkyl, heterocyclyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one, two, or three R^z substituents; wherein R^x is H or C_1-4alkyl and R^y is H, C_1-4alkyl, -O-C_1-4alkyl, -SO₂-R^r, C_1-4alkyl-SO₂-R^r, monocyclic cycloalkyl, -C_1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; or R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C1-4alkyl or -OC1-4alkyl; and each R^z substituent is independently C1-4alkyl, halo, -NR^pR^q, -C(O)NR^pR^q, -OH, or -OC_1-4alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ; wherein R^m and Rⁿ are each independently H, C1-4alkyl, C(O)C1-2alkyl, C(O)C1-2haloalkyl, C(O)C1-2alkenyl, or R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl, optionally substituted with one or two R^o substituents; wherein each R^o substituent is independently C1-4alkyl, -OH, -OC1-4alkyl, halo, cyano, methylsulfonyl, -NR^pR^q, or -C(O)NR^pR^q; wherein R^p and R^q are each independently H, C_1-4alkyl, C_1-4alkylNH₂, C_1-4alkylNH(C_1- 4alkyl), or C1-4alkylN(C1-4alkyl)2; wherein each R^r is independently C1-4alkyl or NR^pR^q; and R⁵ is H, C_1-4alkyl, halo, -OH, or -OC_1-4alkyl; or a pharmaceutically acceptable salt or prodrug or prodrug thereof; or (ii) Formula (II) wherein

R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C1-4alkylNR^xR^y or C(O)NR^xR^y; or is phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof; or (iii) Formula (III): wherein

R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C1-4alkylNR^xR^y or -C(O)NR^xR^y; or is phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof; or (iv) Formula (IV): wherein

R^c1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C1-4alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; and R^4a is C_1-4alkylNR^xR^y or -C(O)NR^xR^y; or is phenyl, pyrazolyl, or pyridyl, each optionally substituted with one or two R^z groups; or a pharmaceutically acceptable salt or prodrug thereof. 2. The method of claim 1, wherein a. the alpha-coronavirus is HCoV 229E; b. the beta-coronavirus lineage B is SARS-CoV2; and c. the beta-coronavirus lineage A is HCoV OC43. 3. The method of claim 1, wherein the infection caused by SARS-CoV-2 is COVID-19. 4. The method of any one of claims 1 - 3, wherein R^1a and R^1b are taken together with the nitrogen to which they are attached to form

5. The method of any one of claims 1 - 3, wherein R^1a and R^1b are taken together with the nitrogen to which they are attached to form

. 6. The method of any one of claims 1 - 5, wherein X is N and Y is CR^a. 7. The method of any one of claims 1 - 5, wherein X is CR^a and Y is N. 8. The method of any one of claims 1 - 5, wherein X is N and Y is N. 9. The method of any one of claims 1 - 8, wherein R^a is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. 10. The method of any one of claims 1 - 8, wherein R^a is H or methyl. 11. The method of any one of claims 1 - 8, wherein R^a is H. 12. The method of any one of claims 1 - 11, wherein R^b is optionally substituted phenyl. 13. The method of any one of claims 1 - 11, wherein R^b is tolyl. 14. The method of any one of claims 1 - 11, wherein R^b is phenyl. 15. The method of any one of claims 1 - 11, wherein R^b is optionally substituted pyridinyl or pyrimidinyl. 16. The method of any one of claims 1 - 11, wherein R^b is optionally substituted pyridinyl. 17. The method of any one of claims 1 - 11, wherein R^b is substituted with one or two R^d substituents. 18. The method of any one of claims 1 - 11, wherein R^b is methylpryridinyl, phenyl, m-tolyl, chlorophenyl, bromophenyl, methoxyphenyl. 19. The method of any one of claims 1 - 18, wherein R^1a is H or C_1-4alkyl; and R^1b is a 5- membered N-containing heteroaryl optionally substituted with R^c. 20. The method of any one of claims 1 - 18, wherein R^1a is H.

21. The method of any one of claims 1 - 18, wherein R^1a is C_1-4alkyl. 22. The method of any one of claims 1 - 18, wherein R^1a is methyl. 23. The method of any one of claims 1 - 22, wherein R^1b is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazolopyridinyl, or indazolyl, each optionally substituted with R^c. 24. The method of any one of claims 1 - 22, wherein R^1b is pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl or isoxazolyl, each optionally substituted with R^c. 25. The method of any one of claims 1 - 22, wherein R^1b is pyrazolyl, optionally substituted with R^c. 26. The method of any one of claims 1 - 22, wherein R^1b is

_{27. The method of any one of claims 1 - 22, wherein R} ^1b _is

. 28. The method of any one of claims 1 - 27, wherein R^c is optionally substituted C_1-4alkyl. 29. The method of any one of claims 1 - 27, wherein R^c is methyl, ethyl, isopropyl, or trifluoromethyl. 30. The method of any one of claims 1 - 27, wherein R^c is optionally substituted phenyl. 31. The method of any one of claims 1 - 27, wherein R^c is phenyl or o-, m-, p-tolyl, fluorophenyl, methoxyphenyl, or trifluoromethoxyphenyl. 32. The method of any one of claims 1 - 27, wherein R^c is phenyl. 33. The method of any one of claims 1 - 27, wherein R^c is optionally substituted monocyclic cycloalkyl. 34. The method of any one of claims 1 - 27, wherein R^c is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 35. The method of any one of claims 1 - 27, wherein R^c is optionally substituted cyclopropyl. 36. The method of any one of claims 1 - 27, wherein R^c is optionally substituted monocyclic heterocycloalkyl. 37. The method of any one of claims 1 - 27, wherein R^c is optionally substituted cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

38. The method of any one of claims 1 - 27, wherein R^c is optionally substituted monocyclic heterocyclyl. 39. The method of any one of claims 1 - 27, wherein R^c is optionally substituted pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, or piperazinyl. 40. The method of any one of claims 1 - 27, wherein R^c is optionally substituted monocyclic heteroaryl. 41. The method of any one of claims 1 - 27, wherein R^c is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 42. The method of any one of claims 1 - 27, wherein R^c is optionally substituted pyrazole, thiophenyl, imidazolyl, pyridinyl, or pyrimidinyl. 43. The method of any one of claims 1 - 27, wherein R^c is optionally substituted pyrazolyl. 44. The method of any one of claims 1 - 27, wherein R^c is optionally substituted pyridinyl. 45. The method of any one of claims 1 - 27, wherein R^c is methylpyridinyl. 46. The method of any one of claims 1 - 27, wherein R^c is optionally substituted -C_1-4alkyl- phenyl, -C1-4alkyl-(monocyclic cycloalkyl), monocyclic heterocycloalkyl, or -C1-4alkyl- (monocyclic heteroaryl). 47. The method of any one of claims 1 - 27, wherein R^c is optionally substituted with one or two R^d substituents and each R^d substituent is independently C1-4alkyl, C1-4alkenyl, C1-4alkynyl, -O-C1-4alkyl, halo, cyano, nitro, azido, C1-4haloalkyl, -O-C1-4-haloalkyl, -NR^gR^h, -NR^gC(=O)R^h, -NR^gC(=O)NR^gR^h, -NR^gC(=O)OR^h, =NOR^g, -NR^gS(=O)_1-2R^h, -NR^gS(=O)1-2NR^gR^h, =NSO2R^g, -C(=O)R^g, -C(=O)OR^g, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^gR^h, -OR^g, -SR^g, -S(=O)R^g, -S(=O)2R^g, -OS(=O)1-2R^g, -S(=O)1-2OR^g, or -S(=O)_1-2NR^gR^h. 48. The method of any one of claims 1 - 47, wherein each R^d substituent is independently C_1- 4alkyl, -O-C1-4alkyl, C1-4haloalkyl, or halo. 49. The method of any one of claims 1 - 47, wherein each R^d substituent is independently methyl, ethyl, isopropyl, -CF₃, -OCH₃, -OCF₃, or fluoro. 50. The method of any one of claims 1 - 49, wherein R^g and R^h are each independently H or methyl. 51. The method of any one of claims 1 - 50, wherein each of R² and R³ are independently selected from H, pyrrolidinyl, piperidinyl, and piperazinyl, wherein each pyrrolidinyl, piperidinyl, and piperazinyl is optionally substituted with one R^j substituent.

52. The method of any one of claims 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each optionally substituted with one, two, three, or four R^j substituents. 53. The method of any one of claims 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form morpholino or piperazinyl, optionally substituted with one, two, three, or four R^j substituents. 54. The method of any one of claims 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form 2,2,6,6-tetrafluoro-morpholino, morpholino-2-one, morpholino-3-one, piperazinyl-2-one, piperazinyl-3-one, thiomorpholino-1,1-dioxide. 55. The method of any one of claims 1 - 50, wherein each R^j substituent is independently methyl, oxo, hydroxy, NH₂, -OCH₃, halo, -CF₃, or -OCF₃. 56. The method of any one of claims 1 - 50, wherein R² and R³ taken together with the nitrogen to which they are attached form morpholino in which 1 to 8 hydrogens are replaced with deuterium. 57. The method of any one of claims 1 - 56, wherein R^k and R^l are each independently H or methyl. 58. The method of any one of claims 1 - 57, wherein R⁴ is H. 59. The method of any one of claims 1 - 57, wherein R⁴ is chloro. 60. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted phenyl. 61. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted heteroaryl. 62. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted monocyclic heteroaryl. 63. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 64. The method of any one of claims 1 - 57, wherein R⁴ is

, , , , , , , or each optionally

substituted with 1 or 2 R^z groups.

65. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted pyridinyl or pyrimidinyl. 66. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted pyridinyl. 67. The method of any one of claims 1 - 57, wherein R⁴ is pyridinyl. 68. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted pyrazolyl. 69. The method of any one of claims 1 - 57, wherein R⁴ is optionally substituted with one or two R^z substituents. 70. The method of any one of claims 1 - 57, wherein R⁴ is pyrazolyl optionally substituted with one or two R^z substituents. 71. The method of any one of claims 1 - 57, wherein R⁴ is phenyl or pyridyl, each optionally substituted with one or two substituents selected from C_1-4alkyl, -CF₃, fluoro, chloro, -OCH₃, and -OCF3. 72. The method of any one of claims 1 - 57, wherein R⁴ is heterocyclyl, optionally substituted with one or two R^z substituents. 73. The method of any one of claims 1 - 57, wherein R⁴ is pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, optionally substituted with one or two R^z substituents. 74. The method of any one of claims 1 - 57, wherein R⁴ is heterocycloalkyl, optionally substituted with one or two R^z substituents. 75. The method of any one of claims 1 - 57, wherein R⁴ is pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinomethyl, or thiomorpholinomethyl, optionally substituted with one or two R^z substituents. 76. The method of any one of claims 1 - 57, wherein R⁴ is 3-methyl-1H-pyrazol-5-yl, 3- methylisothiazol-5-yl, 2-methyl-1H-imidazol-5-yl, 1-methyl-pyrazol-4-yl, 1-methylpyrazol-3-yl, 1-((1-acetamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1-chloromethylamido)-eth-2-yl)-5- methyl-pyrazol-3-yl, 1-((1-acrylamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, thiazol-2-yl, pyrazol-4- yl, pyrazol-1-yl, oxazol-2-yl, 3-(1-N,N-dimethyl-eth-2-yl)-4-methyl-pyrazol-1-yl, or pyridinyl. 77. The method of any one of claims 1 - 57, wherein R⁴ is C1-4alkylNR^xR^y. 78. The method of any one of claims 1 - 57, wherein R⁴ is CH₂NR^xR^y _. 79. The method of any one of claims 1 - 57, wherein R⁴ is -C(O)NR^xR^y. 80. The method of any one of claims 1 - 79, wherein R^x is H. 81. The method of any one of claims 1 - 79, wherein R^x is methyl or ethyl, optionally substituted with one, two, or three R^o substituents. 82. The method of any one of claims 1 - 79, wherein R^x is methyl. 83. The method of any one of claims 1 - 82, wherein R^y is H. 84. The method of any one of claims 1 - 82, wherein R^y is C_1-4alkyl, optionally substituted with one, two, or three R^o substituents. 85. The method of any one of claims 1 - 82, wherein R^y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R^o substituents. 86. The method of any one of claims 1 - 82, wherein R^y is H, methyl, ethyl, methyoxy, or methoxyethyl. 87. The method of any one of claims 1 - 82, wherein R^y is methyl. 88. The method of any one of claims 1 - 82, wherein R^y is -SO₂-R^r or C_1-4alkyl-SO₂-R^r. 89. The method of any one of claims 1 - 82, wherein R^y is -SO2-R^r, C1-4alkyl-SO2-R^r; and R^r is CH3 or NH₂, NHCH3, or N(CH3)2. 90. The method of any one of claims 1 - 82, wherein R^y is -SO₂-methyl, C_2-4alkyl-SO₂- N(CH3)2. 91. The method of any one of claims 1 - 82, wherein R^y is monocyclic cycloalkyl or -C1- ₂alkyl(monocyclic cycloalkyl), each optionally substituted with one, two, or three R^o substituents. 92. The method of any one of claims 1 - 82, wherein R^y is monocyclic cycloalkyl, optionally substituted with one, two, or three R^o substituents. 93. The method of any one of claims 1 - 82, wherein R^y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one, two, or three R^o substituents. 94. The method of any one of claims 1 - 82, wherein R^y is cyclopropyl. 95. The method of any one of claims 1 - 82, wherein R^y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl.

96. The method of any one of claims 1 - 82, wherein R^y is monocyclic heterocyclyl, optionally substituted with one, two, or three R^o substituents. 97. The method of any one of claims 1 - 82, wherein R^y is optionally substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, azocanyl, tetrahydrofuranyl, or tetrahydropyranyl, optionally substituted with methyl. 98. The method of any one of claims 1 - 82, wherein R^y is monocyclic heterocycloalkyl, optionally substituted with one, two, or three R^o substituents. 99. The method of any one of claims 1 - 82, wherein R^y is optionally substituted azetidinylmethyl, oxetanylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, or piperazinylmethyl, optionally substituted with methyl. 100. The method of any one of claims 1 - 79, wherein one of R^x and R^y is H and the other is - CH₃. 101. The method of any one of claims 1 - 79, wherein both of R^x and R^y is H. 102. The method of any one of claims 1 - 79, wherein both of R^x and R^y is -CH₃. 103. The method of any one of claims 1 - 79, wherein R^x and R^y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with C1-4alkyl. 104. The method of any one of claims 1 - 79, wherein R^x and R^y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally substituted with methyl. 105. The method of any one of claims 1 - 104, wherein each R^z is independently C_1-4alkyl, halo, -OH, or -OC1-4alkyl, wherein each alkyl is optionally substituted with -NR^mRⁿ. 106. The method of any one of claims 1 - 104, wherein each R^z is independently -CH3, -OH, halo, or -OCH₃. 107. The method of any one of claims 1 - 104, wherein R^z is C_2-4alkyl substituted with -NR^mRⁿ or OCH3. 108. The method of any one of claims 1 - 104, wherein each R^z substituent is independently -NR^pR^q, -C(O)NR^pR^q. 109. The method of any one of claims 1 - 104, wherein each R^z substituent is methyl, ethyl, isopropyl, -CF3, fluoro, chloro, -OCH3, -OCF3, methylamino, ethylamino, propylamino, butylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, - C(O)methylamino, -C(O)ethylamino, -C(O)propylamino, -C(O)butylamino, - C(O)dimethylamino, -C(O)dimethylaminomethyl, -C(O)dimethylaminoethyl, - C(O)dimethylaminopropyl, or -C(O)dimethylaminobutyl. 110. The method of any one of claims 1 - 109, wherein R^m and Rⁿ are each independently H, C_1-4alkyl, C(O)CH₃, C(O)CH₂Cl, or C(O)CH₂CH₂. 111. The method of any one of claims 1 - 109, wherein R^m and Rⁿ are each H. 112. The method of any one of claims 1 - 109, wherein R^m and Rⁿ are each methyl. 113. The method of any one of claims 1 - 109, wherein R^m and Rⁿ taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with one or two R^o substituents. 114. The method of any one of claims 1 - 109, wherein R^m and Rⁿ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, or thiomorpholino-1,1-dioxide, each optionally substituted with one or two R^o substituents. 115. The method of any one of claims 1 - 109, wherein R^m and Rⁿ taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or morpholino, each optionally substituted with methyl. 116. The method of any one of claims 1 - 115, wherein each R^o substituent is C1-4alkyl, or -NR^pR^q. 117. The method of any one of claims 1 - 116, wherein R^p and R^q are each independently H, methyl, C1-4alkylNH₂, C1-4alkylNHCH3, or C1-4alkylN(CH3)2. 118. The method of any one of claims 1 - 116, wherein R^p and R^q are each independently H or methyl. 119. The method of any one of claims 1 - 118, wherein R⁵ is H, methyl, ethyl, chloro, bromo, fluoro, -OH, or -OCH₃. 120. The method of any one of claims 1 - 118, wherein R⁵ is H. 121. The method of any one of claims 1 - 3, wherein R^c1 is phenyl or pyridyl, each optionally substituted with methyl, -CF₃, Cl, Br, or OCH₃. 122. The method of any one of claims 1 - 3, wherein R^c1 is phenyl. 123. The method of any one of claims 1 - 3, wherein R^c1 is tolyl. 124. The method of any one of claims 1 - 3, wherein R^c1 is pyridyl optionally substituted with methyl or -CF₃. 125. The method of any one of claims 1 - 3 or 121-124, wherein R^4a is pyridyl, optionally substituted with one or two R^z groups. 126. The method of any one of claims 1 - 3 or 121-124, wherein R^4a is pyridyl.

127. The method of any one of claims 1 - 3 or 121-124, wherein R^4a is pyrazolyl optionally substituted with one or two R^z groups. 128. The method of any one of claims 1 - 3 or 121-124, wherein R^4a is 3-methyl-1H-pyrazol- 5-yl, 3-methylisothiazol-5-yl, 2-methyl-1H-imidazol-5-yl, 1-methyl-pyrazol-4-yl, 1- methylpyrazol-3-yl, 1-((1-acetamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1- chloromethylamido)-eth-2-yl)-5-methyl-pyrazol-3-yl, 1-((1-acrylamido)-eth-2-yl)-5-methyl- pyrazol-3-yl, thiazol-2-yl, pyrazol-4-yl, pyrazol-1-yl, oxazol-2-yl, or 3-(1-N,N-dimethyl-eth-2- yl)-4-methyl-pyrazol-1-yl. 129. The method of any one of claims 1 - 3 or 121-124, wherein R^4a is -C(O)NR^xR^y wherein R^x is H or C1-4alkyl and R^y is H, C1-4alkyl, -O-C1-4alkyl, -SO2-R^r, C1-4alkyl-SO2-R^r monocyclic cycloalkyl, -C_1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, or monocyclic heterocycloalkyl, each optionally substituted with one, two, or three R^o substituents; and R^r and R^o are as defined herein. 130. The method of any one of claims 1 - 3 or 121-124, wherein R^4a is -C(O)NR^xR^y wherein R^x is H or methyl; and R^y is H, methyl, ethyl, butyl, isopropyl, methoxy, -SO₂-methyl, C2-4alkyl-SO2-methyl, C2-4alkyl-SO2-N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted azetidinylmethyl, oxetanylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, or piperazinylmethyl, each optionally substituted with one, two, or three methyl, methoxy, fluoro or amino groups. 131. The method of any one of claims 1 to 130, wherein the compound is selected from a compound of Table 1 or a pharmaceutically acceptable salt thereof. 132. The method of any one of claims 1 to 131, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms. 133. The method of any one of claims 1 to 132, wherein the compound and/or the pharmaceutically acceptable salt is in a pharmaceutical composition. 134. The method of claim 133, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.