Inhibitors of cyclic gmp-amp synthase and uses thereof

Abstract

The present disclosure relates to compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R2, Ring B, R3A, R4, p, and m are described herein, methods of preparation, methods of treatment, and pharmaceutical compositions comprising same. The present disclosure further relates to the use of the compounds of Formula (I), and pharmaceutically acceptable salts thereof, in the treatment of cGAS-related diseases and disorders.

Description

[0001] INHIBITORS OF CYCLIC GMP-AMP SYNTHASE AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003]

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S.S.N. 63 / 501,251, filed May 10, 2023, the entire contents of which is incorporated herein by reference.

[0004] BACKGROUND

[0005]

[0002] Aberrant accumulation of cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also induce autoimmunity. This DNA signaling pathway requires the stimulator of interferon genes (STING) adapter protein and the transcription factors NF- KB and IRF3, but the mechanism of DNA sensing was unclear until recently. It is now understood that mammalian cytosolic extracts synthesize cyclic GMP-AMP (cGAMP) in vitro from ATP and GTP in the presence of DNA rather than RNA (WO 2014 / 099824). DNA transfection or DNA virus infection of mammalian cells also trigger the production of cGAMP. cGAMP binds to STING, leading to IRF3 activation and induction of interferon-(3 (IFN(3). Thus, cGAMP is the first cyclic dinucleotide in metazoans, and cGAMP functions as an endogenous secondary messenger that induces interferon production in response to cytosolic DNA.

[0006]

[0003] cGAMP synthase (cGAS) is an enzyme that intervenes in the synthesis of cyclic GMP-AMP and belongs to the nucleotidyltransferase family. Overexpression of cGAS activates the transcription factor IRF3 and induces IFN(3 in a STING-dependent manner. Knockdown of cGAS inhibits IRF3 activation and IFN(3 induction by DNA transfection or DNA virus infection. cGAS binds to DNA in the cytoplasm and catalyzes cGAMP synthesis. These findings indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.

[0007]

[0004] The critical role of cGAS in cytosolic DNA sensing has been established in different pathogenic bacteria, viruses, and retroviruses (US 2021 / 0155625). Additionally, cGAS is essential in various other biological processes, such as cellular senescence and recognition of ruptured micronuclei in the surveillance of potential cancer cells.

[0008]

[0005] There is a need for therapeutic agents that target cGAS. Small molecule inhibitors that are specific for cGAS would be of great value in treating diseases that arise from inappropriate cGAS activity and the resulting undesired type I interferon activity. This present disclosure is intended to fill this unmet need associated with current cGAS inhibition therapy. SUMMARY

[0009]

[0006] Provided herein are cGAS inhibitors of Formula (I): and pharmaceutically acceptable salts thereof, wherein Ring A, R1, R2, Ring B, R3A, R4, p, and m are as described herein.

[0010]

[0007] Further provided are methods of preparation, methods of treatment, and pharmaceutical compositions comprising same.

[0011] DEFINITIONS

[0012]

[0008] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March s ’ Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0013]

[0009] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). Compounds described herein can additionally encompasses individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0014]

[0010] Unless otherwise stated, compounds described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0015] [Oil] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, Ci^, C1-3, C1-2, C2-6, C2-5, C2 4. C2-3, C3-6, C3-5, C3 4. C4-6, C4-5, and C5-6 alkyl.

[0016]

[0012] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C ,()alkyl groups include methyl (Ci), ethyl (C2), w-propyl (C3), isopropyl (C3), w-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), w-pcntyl (C5), 3- pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and w-hcxyl (Ce). Additional examples of alkyl groups include w-hcptyl (C7), w-octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents. In some embodiments, the alkyl group is an unsubstituted C1-10 alkyl (e.g., -CH3). In some embodiments, the alkyl group is a substituted C1-10 alkyl.

[0017]

[0013] “Haloalkyl” refers to a substituted alkyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-s haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“Ci^ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CF3, -CF2CF3, - CF2CF2CF3, -CCh, -CFCI2, -CF2CI, and the like.

[0018]

[0014] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (”€’2 4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C2 4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C 4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In some embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In some embodiments, the alkenyl group is a substituted C2-10 alkenyl.

[0019]

[0015] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2- 10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (”€’2 ■, alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (”€’2 4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl). Examples of C 4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C 4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In some embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In some embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0020]

[0016] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms (“C3-9 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C>), cyclononenyl (C>), cyclodecyl (Cw), cyclodecenyl (Cw), octahydro- 1H- indenyl (C>), decahydronaphthalenyl (Cw), spiro[4.5]decanyl (Cw), and the like. As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons designate the number of carbons in the polycyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0021]

[0017] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-W cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0022]

[0018] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). It is understood that the ring sulfur or ring nitrogen may exist in an oxygenated state, such as an N-oxide (N-O), sulfonyl (S(=O)2) or sulfinyl (S=O) ring heteroatom. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carboncarbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes (i) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused (e.g., spiro-fused or ring fused) or bridged with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or (ii) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the polycyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0023]

[0019] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0024]

[0020] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetra- hydropyrano [3,4-b]pyrrolyl, 5 ,6-dihydro-4H-furo[3 ,2-b]pyrrolyl, 6,7-dihydro-5H-furo [3 ,2- b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3- dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydro- furo [3 ,2-c]pyridinyl, 4,5 ,6,7-tetrahydrothieno [3 ,2-b]pyridinyl, 1 ,2,3 ,4-tetrahydro- 1,6- naphthyridinyl, and the like.

[0025]

[0021] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Cearyl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2- naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cwaryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms designate the number of carbon atoms in the polycyclic ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is an unsubstituted Ce i4 aryl. In some embodiments, the aryl group is a substituted Ce i4 aryl.

[0026]

[0022] “Heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes polycyclic ring systems wherein the heteroaryl ring, as defined above, (i) is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, or (ii) is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the fused polycyclic ring system. Polycyclic heteroaryl groups wherein one ring does not contain a ring heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., eitherthe ring bearing a ring heteroatom (e.g., 2-indolyl) or the ring that does not contain a ring heteroatom (e.g., 5-indolyl).

[0027]

[0023] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0028]

[0024] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0025] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, - Br), or iodine (iodo, -I) radicals.

[0029]

[0026] “Saturated” refers to a ring moiety that does not contain a double or triple bond, z.e., the ring contains all single bonds.

[0030]

[0027] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, haloalkylene is the divalent moiety of haloalkyl alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. By way of example, alkylene may be a Ci-6 alkylene, which may be linear or branched. An alkylene may further be a Ci-4 alkylene. Exemplary C1.4 alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, - CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0031]

[0028] “Salt” refers to any and all salts, including pharmaceutically acceptable salts.

[0029] “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid salts, or salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Cj ^alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0030] A “free base” refers to a neutral non-ionized form of a compound which is not a salt or pharmaceutically acceptable salt.

[0032]

[0031] A “leaving group” is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March A dvanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and sulfonyl substituted hydroxyl groups (e.g., -O-tosyl, -O-mesyl, and -O-besyl).

[0033]

[0032] A “patient” or “subject” is used interchangeably herein, and refers to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. In certain embodiments, the patient or subject is a human.

[0034]

[0033] “Effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of the compound sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition in a subject in need thereof. An effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. The effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0035]

[0034] “Disease”, “disorder”, “condition”, or “state” are used interchangeably herein.

[0036]

[0035] “Treating” or “treat” or “treatment” describes the management and care of a subject in need thereof, for the purpose of combating a disease, condition, or disorder in the subject, and includes the administration of a compound, or a pharmaceutically acceptable salt thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition, and therefore includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e. , causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0037]

[0036] “Modulate”, “modulating” and the like, refer to the ability of a compound to change the activity of a particular biological process (e.g., cGAS activity) in a cell relative to a control.

[0037] “Inhibition”, “inhibiting”, “inhibit” and “inhibitor”, and the like, refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological process (e.g., cGAS activity) in a cell relative to a control.

[0038]

[0038] The phrase “at least one” refers to one instance or more than one instance.

[0039]

[0039] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e. , to at least one) of the grammatical object of the article.

[0040]

[0040] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0041] DETAILED DESCRIPTION i. Compounds

[0042]

[0041] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein:

[0043] Ring A is a 5-membered monocyclic heteroaryl;

[0044] R1is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -Ls- Cs-Ce carbocyclyl), or -L3-(4- to 10- membered heterocyclyl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently halogen, -OR1B, -N(R1B)2, -SR1B, -C(=O)OR1B, -C(=O)N(R1C)2, -(C1-C3 alkylene)-OR1B, or -(C1-C3 alkylene)-SR1B; or two instances of R1Aare taken together to form =0; each R1Bis independently hydrogen, C1-C4 alkyl, or Ci-C4haloalkyl, wherein the alkyl and haloalkyl are independently substituted with 0, 1, 2, 3, or 4 R1D; each R1Cis independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR1F; each R1Dis independently halogen, -OR1F, or -N(R1F)2; and each R1Fis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0045] L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is independently substituted with 0, 1, 2, 3, or 4 R1E; and each R1Eis independently -(C1-C3 alkylene)-OR1Bor -OR1B, or two instances of R1Eare taken together to form =0;

[0046] R2is hydrogen or Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R2A; each R2Ais independently halogen, -OR2B, or -N(R2B)2; and each R2Bis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; or R1and R2are joined, with the atoms to which they are attached, to form a 6- or 7- membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A;

[0047] Ring B is a Ce-Cio aryl or 5- to 10-membered heteroaryl; each R3Ais independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, -Li-CN, -Li- SOR3C, -LI-SO2R3C, -LI-SR3B, -LI-PO(R3C)2, -LI-OR3B, -LI-N(R3B)2, -LI-C(=O)N(R3B)2, -LI- C(=O)OR3B, -Li-(C3-Ce carbocyclyl), -Li-(4- to 6-membered heterocyclyl), -Li-(Ce-io aryl), or -Li-(5- to 10-membered heteroaryl), or two R3Agroups are joined, with the atoms to which they are attached, to form Ce aryl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen, C1-C3 alkyl, Cs-C,, carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Cis independently C1-C3 alkyl or C1-C3 haloalkyl; each R3Dis independently halogen, -OR3E, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; each R3Eis independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; each R4is independently halogen, -CN, -L2-OR4A, -L2-N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R4Aand R4Bis independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -C(=O)R4C, wherein R4Cis Ci-Ce alkyl or Ci-Ce haloalkyl; each Li and L2 is independently a bond, C1-C3 alkylene, or C1-C3 haloalkylene; p is 0, 1, 2, 3, or 4; and m is 0, 1 or 2.

[0048]

[0042] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0049] R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently -OR1B, -C(=O)OR1B, or -C(=O)N(R1C)2; each R1Bis independently hydrogen or C1-C3 alkyl; and each R1Cis independently hydrogen, C1-C3 alkyl, or -OR1B;

[0050] R2is hydrogen or R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A; each R3Ais independently C1-C3 alkyl, halogen, -Li-CN, or -LI-OR3B, and wherein the alkyl is independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D; each R3Cis independently C1-C3 alkyl; each R3Dis independently halogen, -CN, or -OR3E;

[0051] R3Eis hydrogen or C1-C3 alkyl; each R4is independently halogen, -CN, -L2-OR4A, or -L2-N(R4B)2; and each R4Aand R4Bare independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each Li and L2 is independently a bond or C1-C3 alkylene; p is 0, 1, or 2; and m is 1 or 2.

[0052]

[0043] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0053] R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently -OR1Bor -C(=O)N(R1C)2; each R1Bis independently hydrogen or C1-C3 alkyl; and each R1Cis independently hydrogen, C1-C3 alkyl, or -OR1B;

[0054] R2is hydrogen; each R3Ais independently C1-C3 alkyl, halogen, -CN, or -OR3B, wherein the alkyl is substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D; each R3Dis independently halogen, -CN, or -OR3E;

[0055] R3Eis hydrogen or C1-C3 alkyl; each R4is independently halogen, -CN, -N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R4Bis independently hydrogen or C1-C3 alkyl; p is 0, 1, or 2; and m is 1 or 2.

[0056]

[0044] In some additional embodiments of Formula (I), the compound is of Formula (I'): or a pharmaceutically acceptable salt thereof, wherein a nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety.

[0057]

[0045] Applicants have found that compounds of Formula (I), comprising the combination of an -OR1group at the C3 position of the pyrone ring, an amino moiety at the C4 position of the pyrone ring, and a 5-membered monocyclic heteroaryl Ring A, show improvement in one or more desirable drug-like properties, such as improvement in unbound clearance, permeability, bioavailability, hcGAS potency, and / or solubility. Applicants have additionally found incorporating at least one halo (e.g., -Cl) R4substituent on Ring A and / or at least one -Li-CN R3Asubstituent on Ring B shows improvement in cGAS potency. Compare, for example, the improvement in cGAS potency (hcGAS kinase-glo IC50 (uM) and hcGAS LCMS IC50 (uM), as provided in Table D of the Examples) moving from a 5-methyl-lH-pyrazol-l-yl Ring Ato a 3-chloro-l -methyl- lH-pyrrol-2-yl Ring A: from Compound 28 (C and B) to Compound 19 (B and A); from Compound 68 (C and B) to Compound 17 (A and A); and from Compound 22 (B and B) to Compound 39 (A and A). Further compare the improvement in cGAS potency moving from a 4-(pyrimidin-2-ylamino) or 4-(pyridin-3-ylamino) Ring B group to a 4-((4-cyanopyridin-3-yl)amino) Ring B group: from Compound 28 (C and B) and Compound 68 (C and B) to Compound 22 (B and B).

[0058]

[0046] Additional embodiments are further described below and herein.

[0059] (a) R1, R1A, R1B, R1C, R1D, R1E, R1F, R2, R2A, R2B, X, Ring B, p, R3A, R3B, R3C, R3D, R3E, Lltand L3

[0047] As generally described herein, R1is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L3-(C3-Ce carbocyclyl), or -L3-(4- to 10-membered heterocyclyl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently halogen, -OR1B, -N(R1B)2, -SR1B, -C(=O)OR1B, -C(=O)N(Rlc)2, -(C1-C3 alkylene)-OR1B, or -(C1-C3 alkylene)-SR1B; or two instances of R1Aare taken together to form =0; each R1Bis independently hydrogen, C1-C4 alkyl, or Ci-C4haloalkyl, wherein the alkyl and haloalkyl are independently substituted with 0, 1, 2, 3, or 4 R1D; each R1Cis independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR1F; each R1Dis independently halogen, -OR1F, or -N(R1F)2; and each R1Fis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0060] L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is independently substituted with 0, 1, 2, 3, or 4 R1E; and each R1Eis independently -(C1-C3 alkylene)-OR1Bor -OR1B, or two instances of R1Eare taken together to form =0.

[0061]

[0048] In some embodiments, R1is Ci-Ce alkyl, C2-Ce alkenyl, or C2-Ce alkynyl, wherein the alkyl, alkenyl, and alkynyl are independently substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently halogen, -OR1B, -N(R1B)2, -C(=O)OR1B, or -C(=0)N(Rlc)2; each R1Bis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; and each R1Cis independently hydrogen, C1-C3 alkyl, Ci- C3 haloalkyl, or -OR1B.

[0062]

[0049] In some embodiments, R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is C1-C4 alkyl substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is Ci- C3 alkyl substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is Ci-C2alkyl substituted with 0, 1, 2, 3, or 4 R1A.

[0063]

[0050] In some embodiments, R1is C2-Ce alkenyl substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -C4 alkenyl substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is C2-C3alkenyl substituted with 0, 1, 2, 3, or 4 R1A.

[0064]

[0051] In some embodiments, R1is C2-Ce alkynyl substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -C4 alkynyl substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is C2-C3alkynyl substituted with 0, 1, 2, or 3 R1A.

[0065]

[0052] In some embodiments, R1is Ci-Ce alkyl substituted with 0 R1A.

[0066]

[0053] In some embodiments, R1is Ci-Ce alkyl substituted with 1 R1A; R1Ais halogen, -OR1B, or -N(R1B)2; and each R1Bis independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0067]

[0054] In some embodiments, R1is Ci-Ce alkyl substituted with 1 R1A; R1Ais -OR1B; and R1Bis hydrogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0068]

[0055] In some embodiments, R1is Ci-Ce alkyl substituted with 1 R1A; R1Ais -OR1B; and R1Bis hydrogen.

[0069]

[0056] In some embodiments, R1is Ci-Ce alkyl substituted with 1 R1A; R1Ais -OR1B; and R1Bis C1-C3 alkyl.

[0057] In some embodiments, R1is Ci-Ce alkyl substituted with 1 R1A; R1Ais -C(=O)N(Rlc)2; and each R1Cis independently hydrogen or -OR1B.

[0070]

[0058] In some embodiments, R1is Ci-Ce alkyl substituted with 1 R1A; R1Ais -C(=O)N(Rlc)2; and one instance of R1Cis hydrogen, and the other is -OR1B.

[0071]

[0059] In some embodiments, R1is -Ls-lC’s-C,, carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -L3-(C3-C4 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -L3-(C3 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R1A.

[0072]

[0060] In some embodiments, R1is -L3-(C3-Ce carbocyclyl), wherein the carbocyclyl is substituted with 1 R1A; and R1Ais -OR1B. In some embodiments, R1is -L3-(C3-C4 carbocyclyl), wherein the carbocyclyl is substituted with 1 R1A; and R1Ais -OR1B. In some embodiments, R1is -L3-(C3 carbocyclyl), wherein the carbocyclyl is substituted with 1 R1A; and R1Ais -OR1B.

[0073]

[0061] In some embodiments, R1is -L3-(C3-Ce carbocyclyl), wherein the carbocyclyl is substituted with 1 R1A; L3 is C1-C3 alkylene; and R1Ais -OR1B. In some embodiments, R1is -L3-(C3-C4 carbocyclyl), wherein the carbocyclyl is substituted with 1 R1A; L3 is C1-C3 alkylene; and R1Ais -OR1B. In some embodiments, R1is -L3-(C3 carbocyclyl), wherein the carbocyclyl is substituted with 1 R1A; L3is C1-C3 alkylene; and R1Ais -OR1B

[0074]

[0062] In some embodiments, when R1is -L3-(C3-6 carbocyclyl), the carbocyclyl ring is:

[0075]

[0063] In some embodiments, R1is -Ls-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -Ls-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -L3-(5- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -L3-(6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R1A. In some embodiments, R1is -L3-(5 -membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R1A.

[0076]

[0064] In some embodiments, R1is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R1A; and L3is C1-C3 alkylene, wherein the alkylene is substituted with 0 R1E. In some embodiments, R1is -Ls-(5- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R1A; and L3 is C1-C3 alkylene, wherein the alkylene is substituted with 0 R1E. In some embodiments, R1is -L3-(6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R1A; and L3 is C1-C3 alkylene, wherein the alkylene is substituted with 0 R1E.

[0077]

[0065] In some embodiments, R1is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R1A; and L3 is a bond. In some embodiments, R1is -Ls-(5- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R1A; and L3 is a bond. In some embodiments, R1is -L3-(5-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R1A; and L3is a bond.

[0078]

[0066] In some embodiments, when R1is -L3-(4- to 10-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R1is -L3-(4- to 10-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S.

[0079]

[0067] In some embodiments, when R1is -L3-(7- to 10-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R1is -L3-(7- to 10-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S.

[0080]

[0068] In some embodiments, when R1is -L3-(4- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R1is -L3-(4- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S.

[0081]

[0069] In some embodiments, when R1is -L3-(5- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R1is -L3-(5- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S.

[0082]

[0070] In some embodiments, when R1is -L3-(6-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R1is -L3-(6-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S.

[0083]

[0071] In some embodiments, when R1is -L3-(5 -membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R1is -L3-(5 -membered heterocyclyl), the heterocyclyl ring comprises 1 ring O atom.

[0084]

[0072] In some embodiments, when R1is -L3-(4- to 10-membered heterocyclyl), the heterocyclyl ring is selected from:

[0085]

[0073] As generally described herein, L3is a bond, Ci-C3alkylene, or -(Ci-C3alkylene)-O-, wherein the alkylene is independently substituted with 0, 1, 2, 3, or 4 R1E.

[0086]

[0074] In some embodiments, L3is a bond.

[0087]

[0075] In some embodiments, L3is Ci-C3alkylene independently substituted with 0, 1, 2, 3, or 4 R1E.

[0088] In some embodiments, L3is C1-C2 alkylene independently substituted with 0, 1, 2, 3, or 4 R1E. In some embodiments, L3is Ci alkylene independently substituted with 0, 1, or 2 R1E.

[0089]

[0076] In some embodiments, L3is C1-C3 alkylene independently substituted with 0 R1E. In some embodiments, L3is C1-C2 alkylene independently substituted with 0 R1E. In some embodiments, L3is Ci alkylene substituted with 0 R1E.

[0090]

[0077] In some embodiments, at least one R1Ais independently halogen, -OR1B, or -N(R1B)2.

[0091]

[0078] In some embodiments, at least one R1Ais independently halogen.

[0092]

[0079] In some embodiments, at least one R1Ais independently -OR1Bor -N(R1B)2.

[0093]

[0080] In some embodiments, at least one R1Ais independently -OR1B.

[0094]

[0081] In some embodiments, at least one R1Ais independently -OH. In some embodiments, at least one R1Ais independently -O(Ci-C3 alkyl).

[0095]

[0082] In some embodiments, at least one R1Ais independently -N(R1B)2.

[0096]

[0083] In some embodiments, at least one instance of R1Ais -C(=O)OR1B.

[0097]

[0084] In some embodiments, at least one instance of R1Ais -C(=O)N(Rlc)2.

[0098]

[0085] In some embodiments, at least one R1Bis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0099]

[0086] In some embodiments, at least one R1Bis independently hydrogen.

[0100]

[0087] In some embodiments, at least one R1Bis independently C1-C3 alkyl or C1-C3 haloalkyl.

[0101]

[0088] In some embodiments, at least one R1Bis independently C1-C3 alkyl.

[0102]

[0089] In some embodiments, at least one R1Bis independently C1-C3 haloalkyl.

[0103]

[0090] In some embodiments, at least one R1Cis independently hydrogen.

[0104]

[0091] In some embodiments, at least one R1Cis independently C1-C3 alkyl.

[0105]

[0092] In some embodiments, at least one R1Cis independently C1-C3 haloalkyl.

[0106]

[0093] In some embodiments, at least one R1Cis independently -OR1B. In some embodiments, at least one R1Cis independently -OCH3.

[0107]

[0094] In some embodiments, R1is -CH3, -CH2-C(CH3)2-CH2OCH3, -CH2CH2OH, or -CH2CH2OCH3.

[0095] In some embodiments, R1is -CH3, -CH2CH2OH, -CH2CH2OCH3, or -CH2C(=O)N(H)OCH3.

[0108]

[0096] In some embodiments, R1is -CH3. In some embodiments, R1is -CH2-C(CH3)2-CH2OCH3. In some embodiments, R1is -CH2CH2OH. In some embodiments, R1is -CH2CH2OCH3. In some embodiments, R1is -CH2C(=O)N(H)OCH3.

[0109]

[0097] In some embodiments, R1is selected from:

[0110]

[0099] As generally defined herein, R2is hydrogen or Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R2A; each R2Ais independently halogen, -OR2B, or -N(R2B)2; and each R2Bis independently hydrogen, Ci- C3alkyl, or C1-C3 haloalkyl.

[0111]

[0100] In some embodiments, R2is hydrogen or Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R2A.

[0112]

[0101] In some embodiments, R2is hydrogen. In some embodiments, R2is Ci-Ce alkyl substituted with O, 1, 2, 3, or 4 R2A.

[0113]

[0102] In some embodiments, R2is Ci-Ce alkyl substituted with 0 R2A.

[0114]

[0103] In some embodiments, R2is Ci-Ce alkyl substituted with 1 R2A.

[0115]

[0104] In some embodiments, R2is Ci-Ce alkyl substituted with 2 R2A. In some embodiments, R2is

[0116] Ci-Ce alkyl substituted with 3 R2A. In some embodiments, R2is Ci-Ce alkyl substituted with 4 R2A.

[0117]

[0105] In some embodiments, at least one R2Ais independently halogen, -OR2B, or -N(R2B)2.

[0118]

[0106] In some embodiments, at least one R2Ais independently halogen.

[0119]

[0107] In some embodiments, at least one R2Ais independently -OR2B.

[0120]

[0108] In some embodiments, at least one R2Ais independently -OH.

[0121]

[0109] In some embodiments, at least one R2Ais independently -O(Ci-C alkyl).

[0122]

[0110] In some embodiments, at least one R2Ais independently -O(CHs).

[0123]

[0111] In some embodiments, at least one R2Ais independently -N(R2B)2.

[0124]

[0112] In some embodiments, at least one R2Bis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0125]

[0113] In some embodiments, at least one R2Bis independently hydrogen.

[0126]

[0114] In some embodiments, at least one R2Bis independently C1-C3 alkyl or C1-C3 haloalkyl.

[0127]

[0115] In some embodiments, at least one R2Bis independently C1-C3 alkyl.

[0128]

[0116] In some embodiments, at least one R2Bis independently methyl. In some embodiments, at least one R2Bis independently ethyl. In some embodiments, at least one R2Bis independently propyl.

[0129]

[0117] In some embodiments, at least one R2Bis independently C1-C3 haloalkyl.

[0130]

[0118] In some embodiments, R2is hydrogen or -CH3. In some embodiments, R2is -CH3.

[0131]

[0119] In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form a 6- or 7-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A.

[0132]

[0120] In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A.

[0133]

[0121] In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 0 R1A. In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 1 R1A. In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form a 6- membered heterocyclyl substituted with 2 R1A. In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 3 R1A. In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 4 R1A.

[0134]

[0122] In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form: , wherein x is 0, 1, 2, 3, or 4. In some embodiments, R1and R2are joined, with the atoms to which they are attached, to form:

[0135]

[0123] As generally defined herein, x is 0, 1, 2, 3, or 4. In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0136]

[0124] As generally defined herein, Ring B is a Ce-Cio aryl or 5- to 10-membered heteroaryl.

[0137]

[0125] In some embodiments, Ring B is a monocyclic Ce aryl (phenyl). In some embodiments, Ring B is phenyl, and p is 0. In some embodiments, Ring B is phenyl, and p is 1. In some embodiments, Ring B is phenyl, and p is 2. In some embodiments, Ring B is phenyl, and p is 3. In some embodiments, Ring B is phenyl, and p is 4.

[0138]

[0126] In some embodiments, Ring B is of the formula (i-c): (i-c). In some embodiments, Ring B is of one of the following formulae:

[0127] In some embodiments, Ring B is a monocyclic 5- or 6-membered heteroaryl.

[0139]

[0128] In some embodiments, Ring B is 6-membered heteroaryl. In some embodiments, Ring B is 6- membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N and O. In some embodiments, Ring B is 6-membered heteroaryl, wherein the heteroaryl has 1 or 2 ring heteroatoms independently selected from N and O. In some embodiments, Ring B is 6- membered heteroaryl, wherein the heteroaryl has 1 ring heteroatom selected from N and O. In some embodiments, Ring B is 6-membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring N atoms. In some embodiments, Ring B is 6-membered heteroaryl, wherein the heteroaryl has 1 or 2 ring N atoms. In some embodiments, Ring B is 6-membered heteroaryl, wherein the heteroaryl has 1 ring N atom.

[0140]

[0129] In some embodiments, ring B is a pyridine ring. In some embodiments, Ring B is of the formula (ii-c): (ii-c). In some embodiments, Ring B is of the formula (ii-c), and p is 0. In some embodiments, Ring B is of the formula (ii-c), and p is 1. In some embodiments, Ring B is of the formula (ii-c), and p is 2. In some embodiments, Ring B is of the formula (ii-c), and p is 3. In some embodiments, Ring B is of the formula (ii-c), and p is 4.

[0141]

[0130] In some embodiments, Ring B is of one of the following formulae:

[0142]

[0131] In some embodiments, Ring B is of the formula (iii-c): (iii-c). In some embodiments, Ring B is of the formula (iii-c), and p is 0. In some embodiments, Ring B is of the formula (iii-c), and p is 1. In some embodiments, Ring B is of the formula (iii-c), and p is 2. In some embodiments, Ring B is of the formula (iii-c), and p is 3. In some embodiments, Ring B is of the formula (iii-c), and p is 4.

[0133] In some embodiments, Ring B is of the formula (iv-c): (iv-c). In some embodiments, Ring B is of the formula (iv-c), and p is 0. In some embodiments, Ring B is of the formula (ii-c), and p is 1. In some embodiments, Ring B is of the formula (iv-c), and p is 2. In some embodiments, Ring B is of the formula (iv-c), and p is 3. In some embodiments, Ring B is of the formula (iv-c), and p is 4.

[0143]

[0134] In some embodiments, Ring B is of one of the following formulae:

[0144]

[0135] In some embodiments, ring B is a pyrimidine ring. In some embodiments, Ring B is of the formula (v-c): (v-c). In some embodiments, Ring B is of the formula (v-c), and p is 0. In some embodiments, Ring B is of the formula (v-c), and p is 1. In some embodiments, Ring B is of the formula (ii-c), and p is 2. In some embodiments, Ring B is of the formula (v-c), and p is 3.

[0145]

[0136] In some embodiments, Ring B is of one of the following formulae:

[0146]

[0137] In some embodiments, Ring B is 5-membered heteroaryl. In some embodiments, Ring B is 5- membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is 5 -membered heteroaryl, wherein the heteroaryl has 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is 5 -membered heteroaryl, wherein the heteroaryl has 1 ring heteroatom selected from N, O, and S. In some embodiments, Ring B is 5 -membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N and O. In some embodiments, Ring B is 5 -membered heteroaryl, wherein the heteroaryl has 1 or 2 ring heteroatoms independently selected from N and O. In some embodiments, Ring B is 5 -membered heteroaryl, wherein the heteroaryl has 1 ring heteroatom selected from N and O.

[0147]

[0138] In some embodiments, Ring B is an oxadiazole ring (e.g., a 1,2,4-oxodiazole ring, 1,3,4- oxadiazole ring, or 1,2, 3 -oxadiazole ring). In some embodiments, Ring B is of the formula (vi-c):

[0148] N" N (vi-c). In some embodiments, Ring B is of the formula (vi-c), and p is 0. In some embodiments, Ring B is of the formula (vi-c), and p is 1.

[0149]

[0139] In some embodiments, Ring B is of the formula: N—NorN—N

[0150]

[0140] In some embodiments, Ring B is an oxazole ring. In some embodiments, Ring B is an isoxazole ring. In some embodiments, Ring B is of the formula (vii-c): (vii-c). In some embodiments, Ring B is of the formula (vii-c), and p is 0. In some embodiments, Ring B is of the formula (vii-c), and p is 1. In some embodiments, Ring B is of the formula (vii-c), and p is 2.

[0151]

[0141] In some embodiments, Ring B is of the formula: . In some embodiments, Ring

[0152]

[0142] In some embodiments, Ring B is selected from:

[0153]

[0143] In some embodiments, compounds of Formula (I) comprise at least one R3Asubstituent -Li- CN, and Ring B is substituted with 0, 1, 2, or 3 additional R3Asubstituents.

[0154]

[0144] For example, in some embodiments, the group of the formula: Formula (I) is of the formula: , wherein p is 0, 1, 2, or 3.

[0155]

[0145] For example, in some embodiments, the amino moiety the C4 position of

[0156] Formula (I) may be a group of formula (ii-a) : wherein p is 0, 1, 2, or 3.

[0157]

[0146] In some embodiments, the amino moiety selected from:

[0158]

[0159]

[0147] As generally defined herein, each R3Ais independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, -Li-CN, -LI-SOR3C, -LI-SO2R3C, -LI-SR3B, -LI-PO(R3C)2, -LI-OR3B, -LI-N(R3B)2, -LI-C(=O)N(R3B)2, -LI-C(=O)OR3B, -Li-(C3-Ce carbocyclyl), -Li-(4- to 6-membered heterocyclyl), -Li-(Ce-ioaryl), or -Li-(5- to 10-membered heteroaryl), or two R3Agroups are joined, with the atoms to which they are attached, to form Ce aryl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R3D.

[0160]

[0148] In some embodiments, each R3Ais independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, -Li-CN, -Li-SOR3C, -LI-SO2R3C, -Li-SR3B, -Li-OR3B, -LI-N(R3B)2, -LI-(C3-C6carbocyclyl), -Li-(4- to 6-membered heterocyclyl), -Li-(Ce-ioaryl), or -Li-(5- to 10-membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R3D.

[0161]

[0149] In some embodiments, each R3Ais independently C1-C3 alkyl, halogen, -Li-CN, -Li-SChR30, - LI-OR3B, -LI-N(R3B)2, -Li-(C3-Ce carbocyclyl), -Li-(4- to 6-membered heterocyclyl), -Li-(Ce-ioaryl), or -Li-(5- to 10-membered heteroaryl), wherein the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R3D.

[0162]

[0150] In some embodiments, at least one R3Ais independently C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D

[0163]

[0151] In some embodiments, at least one R3Ais independently C1-C3 alkyl.

[0164]

[0152] In some embodiments, at least one R3Ais independently C1-C3 alkyl substituted with 1 R3D.

[0165]

[0153] In some embodiments, at least one R3Ais independently C1-C3 alkyl substituted with 2 R3D. In some embodiments, at least one R3Ais independently C1-C3 alkyl substituted with 3 R3D.

[0166]

[0154] In some embodiments, at least one R3Ais independently C1-C3 alkyl substituted with 4 R3D.

[0167]

[0155] In some embodiments, at least one R3Ais independently halogen.

[0168]

[0156] In some embodiments, at least one R3Ais independently F or Cl.

[0169]

[0157] In some embodiments, at least one R3Ais independently F. In some embodiments, at least one R3Ais independently Cl.

[0170]

[0158] In some embodiments, at least one R3Ais independently -Li-CN, -Li-SChR30, -LI-OR3B, or -LI-N(R3B)2.

[0171]

[0159] In some embodiments, at least one R3Ais independently -Li-CN.

[0172]

[0160] In some embodiments, at least one R3Ais independently -CN.

[0173]

[0161] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-CN.

[0174]

[0162] In some embodiments, at least one R3Ais independently -L1-SO2R .

[0175]

[0163] In some embodiments, at least one R3Ais independently -SO2R \

[0176]

[0164] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-SC>2R3C.

[0177]

[0165] In some embodiments, at least one R3Ais independently -LI-PO(R3C)2.

[0178]

[0166] In some embodiments, at least one R3Ais independently -PO(R3C)2.

[0179]

[0167] In some embodiments, at least one R3Ais independently -Li-OR3B.

[0180]

[0168] In some embodiments, at least one R3Ais independently -OR3B.

[0181]

[0169] In some embodiments, at least one R3Ais independently -LI-C(=O)N(R3B)2 or -LI-C(=O)OR3B.

[0182]

[0170] In some embodiments, at least one R3Ais independently -C(=O)N(R3B)2 or -C(=O)OR3B.

[0183]

[0171] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-OR3B.

[0184]

[0172] In some embodiments, at least one R3Ais independently -Li-(C3-Ce carbocyclyl), -Li-(4- to 6- membered heterocyclyl), -Li-(C6-ioaryl), or -Li-(5- to 10-membered heteroaryl), wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R3D.

[0185]

[0173] In some embodiments, at least one R3Ais independently -Li-(C3-Ce carbocyclyl) substituted with O, 1, 2, 3, or 4 R3D.

[0186]

[0174] In some embodiments, at least one R3Ais independently -Li-(C3-Ce carbocyclyl).

[0187]

[0175] In some embodiments, at least one R3Ais independently -Li-(C3-Ce carbocyclyl) substituted with 1 R3D.

[0188]

[0176] In some embodiments, at least one R3Ais independently -Li-(C3-Ce carbocyclyl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -Li-(C3-Ce carbocyclyl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -Li-(C3-Ce carbocyclyl) substituted with 4 R3D.

[0177] In some embodiments, at least one R3Ais independently -(Cs-Ce carbocyclyl) substituted with 0, 1, 2, 3, or 4 R3D.

[0189]

[0178] In some embodiments, at least one R3Ais independently -(Cs-Ce carbocyclyl).

[0190]

[0179] In some embodiments, at least one R3Ais independently -(Cs-Ce carbocyclyl) substituted with

[0191] 1 R3D

[0192]

[0180] In some embodiments, at least one R3Ais independently -(Cs-Ce carbocyclyl) substituted with

[0193] 2 R3D. In some embodiments, at least one R3Ais independently -(Cs-Ce carbocyclyl) substituted with

[0194] 3 R3D. In some embodiments, at least one R3Ais independently -(Cs-Ce carbocyclyl) substituted with 4 R3D

[0195]

[0181] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(C3-Ce carbocyclyl) substituted with 0, 1, 2, 3, or 4 R3D.

[0196]

[0182] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(C3-Ce carbocyclyl).

[0197]

[0183] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(C3-Ce carbocyclyl) substituted with 1 R3D.

[0198]

[0184] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(C3-Ce carbocyclyl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)- (C3-C6 carbocyclyl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently - (C1-C3 alkylene) -(C3-C6 carbocyclyl) substituted with 4 R3D.

[0199]

[0185] In some embodiments, at least one R3Ais independently -Li-(4- to 6-membered heterocyclyl) substituted with 0, 1, 2, 3, or 4 R3D.

[0200]

[0186] In some embodiments, at least one R3Ais independently -Li-(4- to 6-membered heterocyclyl).

[0201]

[0187] In some embodiments, at least one R3Ais independently -Li-(4- to 6-membered heterocyclyl) substituted with 1 R3D.

[0202]

[0188] In some embodiments, at least one R3Ais independently -Li-(4- to 6-membered heterocyclyl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -Li-(4- to 6- membered heterocyclyl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -Li-(4- to 6-membered heterocyclyl) substituted with 4 R3D.

[0203]

[0189] In some embodiments, at least one R3Ais independently -(4- to 6-membered heterocyclyl) substituted with 0, 1, 2, 3, or 4 R3D.

[0204]

[0190] In some embodiments, at least one R3Ais independently -(4- to 6-membered heterocyclyl).

[0205]

[0191] In some embodiments, at least one R3Ais independently -(4- to 6-membered heterocyclyl) substituted with 1 R3D.

[0206]

[0192] In some embodiments, at least one R3Ais independently -(4- to 6-membered heterocyclyl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -(4- to 6-membered heterocyclyl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -(4- to 6-membered heterocyclyl) substituted with 4 R3D.

[0207]

[0193] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 0, 1, 2, 3, or 4 R3D.

[0208]

[0194] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl).

[0209]

[0195] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 1 R3D.

[0210]

[0196] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 4 R3D.

[0211]

[0197] In some embodiments, at least one R3Ais independently -Li-(C6-ioaryl) substituted with 0, 1, 2, 3, or 4 R3D

[0212]

[0198] In some embodiments, at least one R3Ais independently -Li-(Ce aryl) substituted with 0, 1, 2,

[0213] 3, or 4 R3D

[0214]

[0199] In some embodiments, at least one R3Ais independently -Li-(Ce aryl).

[0215]

[0200] In some embodiments, at least one R3Ais independently -Li-(Ce aryl) substituted with 1 R3D.

[0216]

[0201] In some embodiments, at least one R3Ais independently -Li-(Ce aryl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -Li-(Ce aryl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -Li-(Ce aryl) substituted with 4 R3D.

[0217]

[0202] In some embodiments, at least one R3Ais independently -(Ce aryl) substituted with 0, 1, 2, 3, or 4 R3D.

[0218]

[0203] In some embodiments, at least one R3Ais independently -(Ce aryl).

[0219]

[0204] In some embodiments, at least one R3Ais independently -(Ce aryl) substituted with 1 R3D.

[0220]

[0205] In some embodiments, at least one R3Ais independently -(Ce aryl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -(Ce aryl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -(Ce aryl) substituted with 4 R3D.

[0221]

[0206] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(Ce aryl) substituted with O, 1, 2, 3, or 4 R3D.

[0222]

[0207] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(Ce aryl).

[0223]

[0208] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(Ce aryl) substituted with 1 R3D.

[0224]

[0209] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(Ce aryl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(Ce aryl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(Ce aryl) substituted with 4 R3D.

[0225]

[0210] In some embodiments, at least one R3Ais independently -Li-(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R3D.

[0226]

[0211] In some embodiments, at least one R3Ais independently -Li-(5- to 10-membered heteroaryl).

[0212] In some embodiments, at least one R3Ais independently -Li-(5- to 10-membered heteroaryl) substituted with 1 R3D.

[0227]

[0213] In some embodiments, at least one R3Ais independently -Li-(5- to 10-membered heteroaryl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -Li-(5- to 10- membered heteroaryl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -Li-(5- to 10-membered heteroaryl) substituted with 4 R3D.

[0228]

[0214] In some embodiments, at least one R3Ais independently -(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R3D.

[0229]

[0215] In some embodiments, at least one R3Ais independently -(5- to 10-membered heteroaryl).

[0230]

[0216] In some embodiments, at least one R3Ais independently -(5- to 10-membered heteroaryl) substituted with 1 R3D.

[0231]

[0217] In some embodiments, at least one R3Ais independently -(5- to 10-membered heteroaryl) substituted with 2 R3D. In some embodiments, each R3Ais independently -(5- to 10-membered heteroaryl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -(5- to 10-membered heteroaryl) substituted with 4 R3D.

[0232]

[0218] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R3D.

[0233]

[0219] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl).

[0234]

[0220] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 1 R3D.

[0235]

[0221] In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 2 R3D. In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 3 R3D. In some embodiments, at least one R3Ais independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 4 R3D.

[0236]

[0222] In some embodiments, two R3Agroups are joined, with the atoms to which they are attached, to form Ce aryl, 5- to 6-membered heteroaryl, Cs-Ce carbocyclyl, or 4- to 6-membered heterocyclyl.

[0237]

[0223] In some embodiments, two R3Agroups are joined, with the atoms to which they are attached, to form Ce aryl.

[0238]

[0224] In some embodiments, two R3Agroups are joined, with the atoms to which they are attached, to form 5- to 6-membered heteroaryl.

[0239]

[0225] In some embodiments, two R3Agroups are joined, with the atoms to which they are attached, to form Cs-Ce carbocyclyl.

[0240]

[0226] In some embodiments, two R3Agroups are joined, with the atoms to which they are attached, to form 4- to 6-membered heterocyclyl.

[0241]

[0227] As generally defined herein, each R3Bis independently hydrogen, C1-C3 alkyl, G-C, carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R3D.

[0242]

[0228] In some embodiments, at least one R3Bis independently hydrogen.

[0243]

[0229] In some embodiments, each R3Bis independently C1-C3 alkyl, C;-C„ carbocyclyl, or 4- to 6- membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R3D.

[0244]

[0230] In some embodiments, each R3Bis independently C1-C3 alkyl, Cs-Ce carbocyclyl, or 4- to 6- membered heterocyclyl.

[0245]

[0231] In some embodiments, at least one R3Bis independently C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D.

[0246]

[0232] In some embodiments, at least one R3Bis independently C1-C3 alkyl.

[0247]

[0233] In some embodiments, at least one R3Bis independently C1-C3 alkyl substituted with 1 R3D.

[0248]

[0234] In some embodiments, at least one R3Bis independently C1-C3 alkyl substituted with 2 R3D.

[0249]

[0235] In some embodiments, at least one R3Bis independently C1-C3 alkyl substituted with 3 R3D.

[0250]

[0236] In some embodiments, at least one R3Bis independently C1-C3 alkyl substituted with 4 R3D.

[0251]

[0237] In some embodiments, at least one R3Bis independently Cs-Ce carbocyclyl substituted with 0, 1, 2, 3, or 4 R3D.

[0252]

[0238] In some embodiments, at least one R3Bis independently G-C, carbocyclyl.

[0253]

[0239] In some embodiments, at least one R3Bis independently G-C, carbocyclyl substituted with 1 R3D.

[0254]

[0240] In some embodiments, at least one R3Bis independently G-G, carbocyclyl substituted with 2 R3D.

[0255]

[0241] In some embodiments, at least one R3Bis independently G-G, carbocyclyl substituted with 3 R3D.

[0256]

[0242] In some embodiments, at least one R3Bis independently G-G, carbocyclyl substituted with 4 R3D.

[0257]

[0243] In some embodiments, at least one R3Bis independently 4- to 6-membered heterocyclyl substituted with 0, 1, 2, 3, or 4 R3D.

[0258]

[0244] In some embodiments, at least one R3Bis independently 4- to 6-membered heterocyclyl.

[0259]

[0245] In some embodiments, at least one R3Bis independently 4- to 6-membered heterocyclyl substituted with 1 R3D.

[0260]

[0246] In some embodiments, at least one R3Bis independently 4- to 6-membered heterocyclyl substituted with 2 R3D.

[0261]

[0247] In some embodiments, at least one R3Bis independently 4- to 6-membered heterocyclyl substituted with 3 R3D.

[0262]

[0248] In some embodiments, at least one R3Bis independently 4- to 6-membered heterocyclyl substituted with 4 R3D.

[0263]

[0249] As generally defined herein, each R3Cis independently C1-C3 alkyl or C1-C3 haloalkyl.

[0250] In some embodiments, at least one R3Cis independently C1-C3 alkyl.

[0264]

[0251] In some embodiments, at least one R3Cis independently C1-C3 haloalkyl.

[0265]

[0252] As generally defined herein, each R3Dis independently halogen, -OR3E, -CN, C1-C3 alkyl, or C1-C3 haloalkyl.

[0266]

[0253] In some embodiments, each R3Dis independently halogen or -OC1-C3 alkyl.

[0267]

[0254] In some embodiments, at least one R3Dis independently halogen.

[0268]

[0255] In some embodiments, at least one R3Dis independently F or Cl.

[0269]

[0256] In some embodiments, at least one R3Dis independently F. In some embodiments, at least one R3Dis independently Cl.

[0270]

[0257] In some embodiments, at least one R3Dis independently -OR3E.

[0271]

[0258] In some embodiments, at least one R3Dis independently -OC1-C3 alkyl.

[0272]

[0259] In some embodiments, at least one R3Dis independently -CN.

[0273]

[0260] As generally defined herein, each R3Eis independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

[0274]

[0261] In some embodiments, at least one R3Eis independently hydrogen.

[0275]

[0262] In some embodiments, at least one R3Eis independently C1-C3 alkyl.

[0276]

[0263] In some embodiments, at least one R3Eis independently C1-C3 haloalkyl.

[0277]

[0264] As generally defined herein, each Li is independently a bond, C1-C3 alkylene, or C1-C3 haloalky lene.

[0278]

[0265] In some embodiments, each Li is independently a bond or C1-C3 alkylene.

[0279]

[0266] In some embodiments, at least one Li is independently a bond.

[0280]

[0267] In some embodiments, at least one Li is independently C1-C3 alkylene.

[0281]

[0268] In some embodiments, at least one Li is independently branched C1-C3 alkylene.

[0282]

[0269] In some embodiments, at least one Li is independently Ci alkylene. In some embodiments, at least one Li is independently C2 alkylene. In some embodiments, at least one Li is independently C3 alkylene.

[0283]

[0270] In some embodiments, at least one R3Ais independently -CH2OCH3, -CH2OH, -OCH3, -OH, - OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2CN, -CN, or F. In some embodiments, at least one R3Ais independently -CH2OCH3. In some embodiments, at least one R3Ais independently -CH2OH. In some embodiments, at least one R3Ais independently -OCH3. In some embodiments, at least one R3Ais independently -OH. In some embodiments, at least one R3Ais independently -OCH2CH2OCH3. In some embodiments, at least one R3Ais independently -OCH2CH2OH. In some embodiments, at least one R3Ais independently -OCH2CH2CN. In some embodiments, at least one R3Ais independently -CN. In some embodiments, at least one R3Ais independently F.

[0284] (b) Ring A, R4, L2, and m

[0285]

[0271] As generally defined herein, Ring A is a 5-membered monocyclic heteroaryl.

[0272] In some embodiments, Ring A is a 5 -membered monocyclic heteroaryl comprising 1 nitrogen atom.

[0286]

[0273] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 2 nitrogen atoms.

[0287]

[0274] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 oxygen atom.

[0288]

[0275] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 nitrogen atom and 1 oxygen atom.

[0289]

[0276] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 sulfur atom.

[0290]

[0277] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 nitrogen atom and 1 sulfur atom.

[0291]

[0278] In some embodiments, Ring A is a pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, or thiazole ring.

[0292]

[0279] In some embodiments, Ring A is:

[0293]

[0280] In some embodiments, Ring A is:

[0294]

[0281] In some embodiments, Ring A is: (ii-b). In some embodiments, Ring A is:

[0295] S N (vii-b). In some embodiments, Ring A is: some embodiments, Ring A is: (xiv-b).

[0296]

[0282] In some embodiments, Ring A is a 5 -membered monocyclic heteroaryl directly linked to the thiadiazole via an N atom, as provided in formula (xvii-b): (xvii-b).

[0297]

[0283] Exemplary Ring A ring systems that fall within the scope of formula (xvii-b) include, but are not limited to:

[0298]

[0284] As generally defined herein, each R4is independently halogen, -CN, -L2-OR4A, -L2-N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl, wherein R4Aand R4Bare each independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, or -C(=O)R4C, wherein R4Cis Ci-Ce alkyl or Ci-Ce haloalkyl; each L2is a bond, C1-C3 alkylene, or C1-C3 haloalkylene; and m is 0, 1 or 2.

[0299]

[0285] In some embodiments, each R4is independently halogen, -CN, -L2-OR4. -L2-N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0300]

[0286] In some embodiments, at least one R4is independently halogen.

[0301]

[0287] In some embodiments, at least one R4is independently -F or -Cl.

[0302]

[0288] In some embodiments, at least one R4is independently -F. In some embodiments, at least one R4is independently -Cl.

[0303]

[0289] In some embodiments, at least one R4is independently -CN.

[0304]

[0290] In some embodiments, at least one R4is independently -L2-OR4A.

[0305]

[0291] In some embodiments, at least one R4is independently -OR4A.

[0306]

[0292] In some embodiments, at least one R4is independently -(C1-C3 alkylene) -OR4A.

[0307]

[0293] In some embodiments, at least one R4is independently -(Ci alkylene)-OR4A.

[0308]

[0294] In some embodiments, at least one R4is independently -(C2 alkylene)-OR4A.

[0309]

[0295] In some embodiments, at least one R4is independently -(C3 alkylene)-OR4A.

[0310]

[0296] In some embodiments, at least one R4is independently -OH.

[0311]

[0297] In some embodiments, at least one R4is independently -(C1-C3 alkylene)-OH.

[0312]

[0298] In some embodiments, at least one R4is independently -(Ci alkylene)-OH.

[0313]

[0299] In some embodiments, at least one R4is independently -(C2alkylene)-OH.

[0314]

[0300] In some embodiments, at least one R4is independently -(C3 alkylene)-OH.

[0315]

[0301] In some embodiments, at least one R4is independently -O(Ci-C3 alkyl).

[0316]

[0302] In some embodiments, at least one R4is independently -(C1-C3 alkylene)-O(Ci-C3 alkyl).

[0317]

[0303] In some embodiments, at least one R4is independently -(Ci alkylene)-O(Ci-C3 alkyl).

[0318]

[0304] In some embodiments, at least one R4is independently -(C2 alkylene)-O(Ci-C3 alkyl).

[0319]

[0305] In some embodiments, at least one R4is independently -(C3 alkylene)-O(Ci-C3 alkyl).

[0320]

[0306] In some embodiments, at least one R4is independently -N(R4B)2.

[0321]

[0307] In some embodiments, at least one R4is independently -L2-N(R4B)2.

[0322]

[0308] In some embodiments, at least one R4is independently -(C1-C3 alkylene)-N(R4B)2.

[0323]

[0309] In some embodiments, at least one R4is independently -NH2.

[0324]

[0310] In some embodiments, at least one R4is independently -L2-NH2.

[0325]

[0311] In some embodiments, at least one R4is independently -(C1-C3 alkylene)-NH2.

[0326]

[0312] In some embodiments, at least one R4is independently -NH(R4B).

[0327]

[0313] In some embodiments, at least one R4is independently -L2-NH(R4B).

[0328]

[0314] In some embodiments, at least one R4is independently -(C1-C3 alkylene)-NH(R4B).

[0329]

[0315] In some embodiments, at least one R4is independently -N(CI-C3 alkyl)2.

[0330]

[0316] In some embodiments, at least one R4is independently -L2-N(CI-C3 alkyl)2.

[0317] In some embodiments, at least one R4is independently -(C1-C3 alkylene)-N(Ci-C3 alkyl)2.

[0331]

[0318] In some embodiments, at least one R4is independently Ci-Ce alkyl.

[0332]

[0319] In some embodiments, at least one R4is independently methyl. In some embodiments, at least one R4is independently ethyl. In some embodiments, at least one R4is independently propyl. In some embodiments, at least one R4is independently isopropyl. In some embodiments, at least one R4is independently butyl. In some embodiments, at least one R4is independently isobutyl. In some embodiments, at least one R4is independently tert-butyl.

[0333]

[0320] In some embodiments, at least one R4is independently Ci-Ce haloalkyl.

[0334]

[0321] In some embodiments, at least one R4is independently halomethyl. In some embodiments, at least one R4is independently haloethyl. In some embodiments, at least one R4is independently halopropyl. In some embodiments, at least one R4is independently halo-isopropyl. In some embodiments, at least one R4is independently halobutyl. In some embodiments, at least one R4is independently halo-isobutyl. In some embodiments, at least one R4is independently halo-tert-butyl.

[0335]

[0322] In some embodiments, each instance of R4is independently selected from the group consisting of -CH3, -CH2CH3, -CHF2, -CF3, -Cl, -CN, -NH2, and -CH2OH.

[0336]

[0323] In some embodiments, at least one instance of R4is independently -CH3 or -CH2CH3.

[0337]

[0324] In some embodiments, at least one instance of R4is independently -CHF2or -CF3.

[0338]

[0325] In some embodiments, Ring A is selected from:

[0339]

[0326] In some embodiments, Ring A ring systems of formula (xvii-b) are selected from:

[0327] In some embodiments, Ring A is selected from:

[0340]

[0328] As generally defined herein, each L2is independently a bond, Ci-C3alkylene, or Ci-C3haloalky lene.

[0341]

[0329] In some embodiments, each L2is independently a bond or Ci-C3alkylene.

[0342]

[0330] In some embodiments, at least one L2is independently a bond.

[0343]

[0331] In some embodiments, at least one L2is independently Ci-C3alkylene.

[0344]

[0332] In some embodiments, at least one L2is independently Ci alkylene. In some embodiments, at least one L2is independently C2alkylene. In some embodiments, at least one L2is independently C3alkylene.

[0345]

[0333] As generally defined herein, m is 0, 1, or 2.

[0346]

[0334] In some embodiments, m is 0.

[0347]

[0335] In some embodiments, m is 1 or 2.

[0348]

[0336] In some embodiments, m is 1. In some embodiments, m is 2.

[0349] (c) Subgenera

[0350]

[0337] It is understood that, for a compound of the present disclosure, variables Ring A, R1, R1A, R1B, R1C, R1D, R1E, R1F, R2, R2A, R2B, Ring B, R3A, R3B, R3C, R3D, R3E, R4, R4A, R4B, LbL2, L3, x, p, and m can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables Ring A, R1, R1A, R1B, R1C, R1D, R1E, R1F, R2, R2A, R2B, Ring B, R3A, R3B, R3C, R3D, R3E, R4, R4A, R4B, LI, L2, L3, X, p, and m can be combined, where applicable, with any group described herein for one or more of the remainder of variables Ring A, R1, R1A, R1B, R1C, R1D, R1E, R1F, R2, R2A, R2B, Ring B, R3A, R3B, R3C, R3D, R3E, R4, R4A, R4B, LI, L2, L3, X, p, and m. Additional exemplary combinations of the above described embodiments are further contemplated herein.

[0351]

[0338] For example, in some embodiments, wherein Ring A is a group of formula (ii-b), the compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at the C4 position is a group of formula (ii-a). In certain embodiments, R1is -CH3or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Ci.3alkyl (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0352]

[0339] In some embodiments, wherein Ring A is a group of formula (iv-b), the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at the C4 position is a group of formula (ii-a). In certain embodiments, R1is -CH3or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Ci.salkyl (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0353]

[0340] In some embodiments, wherein Ring A is a group of formula (xiii-b), the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at the C4 position is a group of formula (ii-a). In certain embodiments, R1is -CH3or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, the R4group attached to the N atom is -CH3, each other instance of R4is independently halo (e.g., -Cl), Chalky I (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0354]

[0341] In some embodiments, wherein Ring B is of the formula (i-c), the compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt thereof. In certain embodiments, R1is -CH3 or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Ci-salkyl (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0355]

[0342] In some embodiments, wherein Ring B is a group of the formula (ii-c), (iii-c), or (iv-c), the compound of Formula (I) is of Formula (I-e-1), (I-e-2), or (I-e-3), respectively: or a pharmaceutically acceptable salt thereof. In certain embodiments, R1is -CH3 or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Chalky I (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0356]

[0343] In some embodiments, wherein Ring B is of the formula (v-c), the compound of Formula (I) is of Formula (I-f): or a pharmaceutically acceptable salt thereof. In certain embodiments, R1is -CH3or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Chalky I (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0357]

[0344] In some embodiments, wherein Ring B is of the formula (vi-c), the compound of Formula (I) is of Formula (I-g): or a pharmaceutically acceptable salt thereof. In certain embodiments, R1is -CH3 or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Chalky I (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0 or 1.

[0358]

[0345] In some embodiments, wherein Ring B is of the formula (vii-c), the compound of Formula (I) is of Formula (I-h): or a pharmaceutically acceptable salt thereof. In certain embodiments, R1is -CH3 or -CH2CH2OH. In certain embodiments, R2is hydrogen. In certain embodiments, R1and R2are joined to form an unsubstituted 6-membered heterocyclyl. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Ci-salkyl (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0359]

[0346] In some embodiments, wherein R1and R2are joined to form a 6-membered heterocyclyl ring, provided is a compound of Formula (I-BC-a) or (I-BC-b): or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4. In certain embodiments, each instance of R4is independently halo (e.g., -Cl), Ci-salkyl (e.g, -CH3) or -NH2. In certain embodiments, each instance of R3Ais independently halo (e.g., -F), -Li-CN, or -LI-OR3B. In certain embodiments, m is 1 or 2. In certain embodiments, p is 0, 1, or 2.

[0360]

[0347] In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0361]

[0348] In some embodiments, the compound of Formula (I) is selected from a pharmaceutically acceptable salt of any one of the compounds of Table 1.

[0362]

[0349] In some embodiments, the compound of Formula (I) is a free base selected from any one of the compounds of Table 1.

[0363]

[0350] The below Table 1 also provides the location of the Compound (#) in the Examples (Ex) by

[0364] Example Number or as provided in Table A (TA) of the Examples. Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I)

[0365] Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1. Compounds of Formula (I)

[0366]

[0351] In certain embodiments, the compound is Compound 14, Compound 24, Compound 25, Compound 27, Compound 28, Compound 36, Compound 39, Compound 48, Compound 50, Compound 51, Compound 65, or Compound 70, or a pharmaceutically acceptable salt of any of the foregoing. ii. Pharmaceutical Compositions

[0367]

[0352] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Exemplary pharmaceutical acceptable carriers include excipients, diluents, and surfactants.

[0368]

[0353] In some embodiments, the compounds of the present disclosure, or pharmaceutical compositions comprising same, can be administered in an amount effective to treat a disorder in a subject.

[0369]

[0354] Administration can be accomplished via any mode of administration. Exemplary modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration modes.

[0370]

[0355] Depending on the intended mode of administration, the disclosed compounds and compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.

[0371]

[0356] Likewise, the disclosed compounds and compositions can also be administered by intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular in a form suitable for these types of administration. For example, parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0357] Illustrative pharmaceutical compositions may be tablets or gelatin capsules comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, or PEG200. iii. Methods of Treatment

[0372]

[0358] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0373]

[0359] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0374]

[0360] In some aspects, the present disclosure provides a method of modulating cGAS activity in a cell (e.g., in vitro or in vivo), comprising contacting the cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0375]

[0361] In some aspects, the present disclosure provides a method of modulating cGAS activity in a cell (e.g., in vitro or in vivo), comprising contacting the cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0376]

[0362] In some embodiments, the disease or disorder is associated with increased cGAS activity. In some embodiments, the disease or disorder is a disease or disorder in which cGAS activity is implicated.

[0363] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in modulating cGAS activity (e.g., in vitro or in vivo).

[0377]

[0364] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0378]

[0365] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating cGAS activity (e.g., in vitro or in vivo).

[0379]

[0366] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0380]

[0367] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0381]

[0368] The present disclosure provides compounds that function as modulators of cGAS activity.

[0382]

[0369] In some embodiments, modulation is inhibition.

[0383]

[0370] In some embodiments, the disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an cGAS-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in cGAS.

[0384]

[0371] In some aspects, the disease or disorder is cancer. In some embodiments, the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, or prostate cancer.

[0385]

[0372] In some aspects, the disease or disorder is a central nervous system disorder. In certain embodiments, the central nervous system disorder is Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis (ALS), multiple sclerosis, ataxia telangiectasia, or age-related macular degeneration.

[0386]

[0373] In some aspects, the disease or disorder is kidney disease. In certain embodiments, the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease. In certain embodiments, the chronic kidney disease is diabetic nephropathy.

[0387]

[0374] In some aspects, the disease or disorder is a skin disease. In certain embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0375] In some aspects, the disease or disorder is a rheumatic disease. In certain embodiments, the rheumatic disease is dermatomyositis, Still’s disease, or juvenile idiopathic arthritis.

[0388]

[0376] In some aspects, the disease or disorder is a liver disease. In certain embodiments, the liver disease is nonalcoholic steatohepatitis (NASH).

[0389]

[0377] In some aspects, the disease or disorder is a cardiovascular disease. In certain embodiments, the cardiovascular disease is cardiomyopathy, atherosclerosis, or peripheral artery disease (PAD).

[0390]

[0378] In some embodiments, the disease or disorder is a metabolic disease. In certain embodiments, the metabolic disease is obesity-induced insulin-resistance.

[0391]

[0379] In some aspects, the disease or disorder is a cGAS-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in cGAS.

[0392]

[0380] In some embodiments, the disease or disorder is an inflammatory, allergic or autoimmune disease such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), Chilblain lupus, psoriasis, insulin-dependent diabetes mellitus (IDDM), scleroderma, Aicardi Goutieres syndrome, dermatomyositis, systemic sclerosis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, or Sjogren’s syndrome (SS).

[0393]

[0381] In some embodiments, the disease or disorder is inflammation of any tissue or organ of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation.

[0394]

[0382] In some embodiments, musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons. Examples of musculoskeletal inflammation include arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic). Ocular inflammation refers to inflammation of any structure of the eye, including the eye lids. Examples of ocular inflammation include blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis. Examples of inflammation of the nervous system include encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, and schizophrenia.

[0395]

[0383] Examples of inflammation of the vasculature or lymphatic system include arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[0396]

[0384] Examples of inflammatory conditions of the digestive system include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), ileitis, and proctitis.

[0397]

[0385] Examples of inflammatory conditions of the reproductive system include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo- ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[0398]

[0386] In some embodiments, the disease or disorder is an autoimmune conditions having an inflammatory component. Such conditions include systemic lupus erythematosus, cutaneous lupus erythematosus, acute disseminated alopecia universalise, Bechet’s disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, Goodpasture's syndrome. Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord’s thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, Aicardi Goutieres syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0399]

[0387] In some embodiments, the disease or disorder is a T-cell mediated hypersensitivity diseases having an inflammatory component. Such conditions include contact hypersensitivity, contact dermatitis (including that due to poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (Celiac disease).

[0400]

[0388] In some embodiments, other inflammatory conditions include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, prostatitis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xenografts, serum sickness, and graft vs host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome. Sezary’s syndrome, congenital adrenal hyperplasis, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and oiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) haemolytic anemia, leukemia and lymphomas in adults, acute leukemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, and sepsis. iv. Methods of Preparation

[0401]

[0389] Compounds of Formula (I) may be synthesized following General Schemes 1-10, as provided below. The Examples further described non-limiting examples of the general syntheses.

[0402]

[0390] For example, as depicted in General Scheme 7, 3-hydroxy-2-oxo-2H-pyran-6-carboxylic acid of Formula (A), or salt thereof, may be protected as the alkyl ester of Formula (B), or salt thereof, wherein Rais Ci-6 alkyl or Ci-6 haloalkyl, followed by halogenation at the C4 position to provide a compound of Formula (C), or salt thereof, wherein X is Cl, Br, or I. Hydroxyl protection with group R1, as defined herein, may provide a compound of Formula (D), or salt thereof. Deprotection of the alkyl ester of Formula (D), or salt thereof, may provide a carboxylic acid compound of Formula (D), or salt thereof, wherein Rais hydrogen.

[0403] General Scheme 1.

[0404]

[0391] As depicted in General Scheme 2. reacting a hydrazine carbothioamide of Formula (G), or salt thereof, with a carboxylic acid containing compound of Formula (F-l), or nitrile containing compound of Formula (F-2), or salts thereof, wherein R4and m are as defined herein, may provide a l,3,4-thiadiazol-2-amine of Formula (H-l), or salt thereof. Alternatively, as depicted in General Scheme 3. amine compounds of Formula (H-2), wherein the nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety and wherein R4and m are as defined herein, may be prepared by coupling a 5-halo-l,3,4-thiadiazol-2-amine of Formula (M), or salt thereof, wherein Y is Cl, Br, or I, with an amine of Formula (L), or salt thereof.

[0405] General Scheme 2.

[0406] General Scheme 3.

[0407] (L) (H-2)

[0408]

[0392] As depicted in General Scheme 4. cross-coupling of an amine of Formula (K), or salt thereof, with an alkyl ester of Formula (D), or salt thereof, wherein Rais Ci-6 alkyl or Ci-6 haloalkyl, may provide an amine compound of Formula (N), or salt thereof. The amine compound of Formula (N), or salt thereof, may then be deprotected to provide an amine compound of Formula (N), or salt thereof, wherein Rais hydrogen.

[0409] General Scheme 4.

[0410]

[0393] The above-described compounds of Formula (D) and (N), or salts thereof, wherein Rais hydrogen, Ci-6 alkyl or Ci-6 haloalkyl, and amine compounds of Formula (H-l) or (H-2), or salts thereof, each may be used as intermediates in preparing compounds of Formula (I), or salts thereof.

[0411]

[0394] For example, as depicted in Scheme 5, peptide coupling the amine of Formula (H-l), or salt thereof, with the compound of Formula (D), or salt thereof, wherein Rais hydrogen, Ci-6 alkyl or Ci-6 haloalkyl, may provide an amide compound of Formula (J-l), or salt thereof. The amide compound of Formula (J-l), or salt thereof, (also referred to herein as a “halo-pyrone reagent”) may then be cross-coupled with an amine of Formula (K), or salt thereof, (also referred to herein as an “amine reagent”) to provide a compound of Formula (I), or salt thereof.

[0412] General Scheme 5.

[0413]

[0395] Alternatively, as depicted in General Scheme 6. peptide coupling of the amine of Formula (H- 2), or salt thereof, with the compound of Formula (D), or salt thereof, wherein Rais hydrogen, Ci-6 alkyl or Ci-6 haloalkyl, may provide an amide compound of Formula (J-2), or salt thereof (also referred to herein as a “halo-pyrone reagent”). The amide compound of Formula (J-2), or salt thereof, may then be cross-coupled with an amine of Formula (K), or salt thereof, (also referred to herein as an “amine reagent”) to provide a compound of Formula (I '), or salt thereof, wherein the nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety.

[0414] General Scheme 6.

[0415]

[0396] In other embodiments, such as depicted in General Scheme 7, peptide coupling of the amine of Formula (H-l), or salt thereof, (also referred to herein as an “ADT amine reagent”) with a compound of Formula (N), or salt thereof, (also referred to herein as an “amino-pyrone reagent”) wherein Rais hydrogen, Ci-6 alkyl or Ci-6 haloalkyl, may provide a compound of Formula (I), or salt thereof.

[0416] General Scheme 7.

[0417]

[0397] In yet other embodiments, such as depicted in General Scheme 8. peptide coupling of the amine of Formula (H-2), or salt thereof, (also referred to herein as an “ADT amine reagent”) with a compound of Formula (N), or salt thereof, (also referred to herein as an “amino-pyrone reagent”) wherein Rais hydrogen, Ci-6 alkyl or Ci-6 haloalkyl, may provide a compound of Formula (I"), or salt thereof, wherein the nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety.

[0418] General Scheme 8.

[0419]

[0398] In still yet other embodiments, such as depicted in General Schemes 9 and 10. wherein R1is the group -CH2CH2-OH and R2is hydrogen, a bicyclic compound of Formula (I-BC-a) and (I-BC-b) may be formed from conversion of the terminal -OH of R1to a leaving group (LG), as defined herein, followed by cyclization. In certain embodiments, the leaving group is a sulfonyl substituted hydroxyl group, such as -O-tosyl, -O-mesyl, or O-besyl.

[0420] General Scheme 9. General Scheme 10. v. Biological Assays

[0421]

[0399] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the compounds described herein can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0422]

[0400] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the compounds described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0423]

[0401] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, as well as assays for determining hcGAS potency and inhibitory activity, unbound clearance, solubility, and permeability.

[0424]

[0402] In some embodiments, the compounds of the instant disclosure may be tested for their human- cGAS (h-cGAS) inhibitory activity using known procedures, such as the methodology reported in Lama etal., Nature Communications (2019) 10:2261 (2019). See also Examples, Assay Methods.

[0425]

[0403] In some embodiments, the compounds of the instant disclosure may be tested for unbound clearance (Clu) following known procedures, such as described in Miller et al., J. Med. Chem. (2020) 63: 12156-12170. For example, unbound clearance (Clu) may be calculated by dividing total clearance (‘CL’ in mL / min / kg) as measured in blood or plasma by the unbound fraction in plasma (fu).

[0426]

[0404] In some embodiments, the solubility of compounds of the instant disclosure may be determined following known procedures, such as described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567, and Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, the kinetic solubility in physiologically relevant media may be measured using serial dilution and two hour incubation period, followed by filtration, and reported in uM by LC-MS / MS. Thermodynamic solubility in physiologically relevant media may be measured by LC-MS / MS, after a twenty-four hour incubation, followed by filtration, and reported in mg / mL.

[0427]

[0405] In some embodiments, the permeability of compounds of the instant disclosure may be determined following known procedures, such as described in Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, permeability across cell membranes may be measured using either Caco-2 or MDCK-MDR1 cell lines in Transwell plates, after measuring the compound in both apical and basolateral chambers, and reported as an apparent permeability Papp A-B in 10'6cm / s. vi. Additional Embodiments

[0428]

[0406] Additional embodiments are provided according to the following numbered Embodiments:

[0429]

[0407] Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0430] Ring A is a 5-membered monocyclic heteroaryl;

[0431] R1is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -Ls-IC’s-C,, carbocyclyl), or -L3-(4- to 10- membered heterocyclyl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently halogen, -OR1B, -N(R1B)2, -SR1B, -C(=O)OR1B, -C(=O)N(R1C)2, -(C1-C3 alkylene)-OR1B, or -(C1-C3 alkylene)-SR1B; or two instances of R1Aare taken together to form =0; each R1Bis independently hydrogen, C1-C4 alkyl, or Ci-C4haloalkyl, wherein the alkyl and haloalkyl are independently substituted with 0, 1, 2, 3, or 4 R1D; each R1Cis independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR1F; each R1Dis independently halogen, -OR1F, or -N(R1F)2; and each R1Fis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0432] L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is independently substituted with 0, 1, 2, 3, or 4 R1E; and each R1Eis independently -(C1-C3 alkylene)-OR1Bor -OR1B, or two instances of R1Eare taken together to form =0;

[0433] R2is hydrogen or Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R2A; each R2Ais independently halogen, -OR2B, or -N(R2B)2; and each R2Bis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; or R1and R2are joined, with the atoms to which they are attached, to form a 6- or 7- membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A;

[0434] Ring B is a Ce-Cio aryl or 5- to 10-membered heteroaryl; each R3Ais independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, -Li-CN, -Li- SOR3C, -LI-SO2R3C, -LI-SR3B, -LI-PO(R3C)2, -LI-OR3B, -LI-N(R3B)2, -LI-C(=O)N(R3B)2or -Li- C(=O)OR3B, -Li-(C3-Ce carbocyclyl), -Li-(4- to 6-membered heterocyclyl), -Li-(Ce-io aryl), or -Li-(5- to 10-membered heteroaryl), or two R3Agroups are joined, with the atoms to which they are attached, to form Ce aryl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen, C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Cis independently C1-C3 alkyl or C1-C3 haloalkyl; each R3Dis independently halogen, -OR3E, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; each R3Eis independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; each R4is independently halogen, -CN, -L2-OR4A, -L2-N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R4Aand R4Bis independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -C(=O)R4C, wherein R4Cis Ci-Ce alkyl or Ci-Ce haloalkyl; each Li and L2 is independently a bond, C1-C3 alkylene, or C1-C3 haloalkylene; p is 0, 1, 2, 3, or 4; and m is 0, 1 or 2.

[0435]

[0408] Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl substituted with 0, 1, 2, 3, or 4 R3A.

[0436]

[0409] Embodiment 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 6-membered heteroaryl, wherein the heteroaryl has 1 or 2 ring N atoms.

[0437]

[0410] Embodiment 4. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N and O.

[0438]

[0411] Embodiment 5. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one R3Asubstituent is -Li-CN, in order to provide a Ring B of formula: wherein Ring B is Ce aryl or 5- or 6-membered heteroaryl, and p is 0, 1, 2, or 3.

[0439]

[0412] Embodiment 6. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from one of the following formulae:

[0440]

[0413] Embodiment 7. The compound of any one of Embodiments 1-5, wherein the compound is of

[0441] Formula (I-d): or a pharmaceutically acceptable salt thereof.

[0442]

[0414] Embodiment 8. The compound of any one of Embodiments 1-5, wherein the compound is of

[0443] Formula (I-e-1), (I-e-2), (I-e-3), or (I-f):

[0444] or a pharmaceutically acceptable salt thereof.

[0445]

[0415] Embodiment 9. The compound of any one of Embodiments 1-5, wherein the compound is of Formula (I-g): or a pharmaceutically acceptable salt thereof.

[0416] Embodiment 10. The compound of any one of Embodiments 1-5, wherein the compound is of Formula (I-h): or a pharmaceutically acceptable salt thereof.

[0446]

[0417] Embodiment 11. The compound of any one of Embodiments 1-5, wherein the compound is of

[0447] Formula (I'), (I"), (I'"), (I-BC-a), or (I-BC-b): or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4.

[0448]

[0418] Embodiment 12. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently halogen, -CN, -OR3B, or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D.

[0449]

[0419] Embodiment 13. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently -CH2OCH3, -CH2OH, -OCH3, -OH, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2CN, -CN, or F.

[0450]

[0420] Embodiment 14. The compound of any one of Embodiments 1-6 or 11-13, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:

[0451]

[0421] Embodiment 15. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A

[0452]

[0422] Embodiment 16. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein R1is -CH3, , ,

[0453]

[0423] Embodiment 17. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

[0454]

[0424] Embodiment 18. The compound of any one of the preceding Embodiments, or pharmaceutically acceptable salt thereof, wherein Ring A is of one of the following formulae:

[0455]

[0425] Embodiment 19. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is of one of the following formulae:

[0456]

[0426] Embodiment 20. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein each R4is independently halogen, -CN, -L2-OR4A,

[0457] -L2-N(R4B)2, CI-C6alkyl, or Ci-C6haloalkyl.

[0458]

[0427] Embodiment 21. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -CH;. -CHF2, Cl, -CN, or

[0459] -NH2.

[0460]

[0428] Embodiment 22. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

[0461]

[0429] Embodiment 23. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

[0462]

[0430] Embodiment 24. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0463]

[0431] Embodiment 25. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0464]

[0432] Embodiment 26. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0465]

[0433] Embodiment 27. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0466]

[0434] Embodiment 28. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 2.

[0467]

[0435] Embodiment 29. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein:

[0468] R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently -OR1B, -C(=O)OR1B, or -C(=O)N(R1C)2; each R1Bis independently hydrogen or C1-C3 alkyl; and each R1Cis independently hydrogen, C1-C3 alkyl, or -OR1B;

[0469] R2is hydrogen or R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A; each R3Ais independently C1-C3 alkyl, halogen, -Li-CN, or -LI-OR3B, and wherein the alkyl is independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D; each R3Cis independently C1-C3 alkyl; each R3Dis independently halogen, -CN, or -OR3E;

[0470] R3Eis hydrogen or C1-C3 alkyl; each R4is independently halogen, -CN, -L2-OR4A, or -L2-N(R4B)2; and each R4Aand R4Bare independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each Li and L2is independently a bond or C1-C3 alkylene; p is 0, 1, or 2; and m is 1 or 2.

[0471]

[0436] Embodiment 30. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein:

[0472] R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently -OR1Bor -C(=O)N(R1C)2; each R1Bis independently hydrogen or C1-C3 alkyl; and each R1Cis independently hydrogen, C1-C3 alkyl, or -OR1B; R2is hydrogen; each R3Ais independently C1-C3 alkyl, halogen, -CN, or -OR3B, wherein the alkyl is substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D; each R3Dis independently halogen, -CN, or -OR3E;

[0473] R3Eis hydrogen or C1-C3 alkyl; each R4is independently halogen, -CN, -N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R4Bis independently hydrogen or C1-C3 alkyl; p is 0, 1, or 2; and m is 1 or 2.

[0474]

[0437] Embodiment 31. The compound of Embodiment 1, wherein the compound is selected from those in Table 1, and pharmaceutically acceptable salts thereof.

[0475]

[0438] Embodiment 32. A pharmaceutical composition comprising the compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0476]

[0439] Embodiment 33. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 32.

[0477]

[0440] Embodiment 34. A method of modulating cGAS activity in a cell comprising contacting a cell with a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 32.

[0478]

[0441] Embodiment 35. A method of preparing a compound of Formula (I): or a salt thereof, wherein Ring A, Ring B, R1, R2, R3A, R4, p and m are defined in Embodiment 1, the method comprising peptide coupling of a compound of Formula (H-l), or salt thereof, with a compound of Formula (N), or salt thereof: wherein Rais hydrogen, Ci-e alkyl or Ci-e haloalkyl, to provide a compound of Formula (I), or salt thereof.

[0479]

[0442] Embodiment 36. The method of Embodiment 35, wherein the compound of Formula (H-l), or salt thereof, is of Formula (H-2): salt thereof, and wherein the method provides a compound of Formula (I'): (I'), or salt thereof.

[0480]

[0443] Embodiment 37. The method of Embodiment 35 or 36, further comprising cross-coupling a compound of Formula (K), or salt thereof, with a compound of Formula (D), or salt thereof, wherein Rais Ci-e alkyl or Ci-e haloalkyl, R3is Ring B, and X is Cl, Br, or I, to provide a compound of Formula (N), or salt thereof.

[0481]

[0444] Embodiment 38. A method of preparing a compound of Formula (I): or a salt thereof, wherein Ring A, Ring B, R1, R2, R3A, R4, p and m are defined in Embodiment 1, the method comprising cross-coupling of the amine of Formula (K), or salt thereof, with a compound of

[0482] Formula ( J-l ), or salt thereof: wherein R3is Ring B and X is Cl, Br, or I, to provide a compound of Formula (I), or salt thereof.

[0445] Embodiment 39. The method of Embodiment 38, wherein the compound of Formula (J-l), or salt thereof, is of Formula (J-2): (J-2), or salt thereof, and wherein the method provides a compound of Formula (I'): (I'), or salt thereof.

[0483]

[0446] Embodiment 40. The method of Embodiment 38, further comprising peptide coupling of a compound of Formula (H-l), or salt thereof, with a compound of Formula (D), or salt thereof: to provide a compound of Formula (J-l), or salt thereof.

[0484]

[0447] Embodiment 41. The method of Embodiment 39, further comprising peptide coupling of a compound of Formula (H-2), or salt thereof, with a compound of Formula (D), or salt thereof: to provide a compound of Formula (J-2), or salt thereof.

[0485]

[0448] Embodiment 42. The method of Embodiment 35 or 40, further comprising reacting a hydrazine carbothioamide of Formula (G), or salt thereof, with a carboxylic acid containing compound of Formula (F-l), or salt thereof, or nitrile containing compound of Formula (F-2), or salt thereof: to provide a compound of Formula (H-l), or salt thereof.

[0486]

[0449] Embodiment 43. The method of Embodiment 36 or 41, further comprising coupling a compound

[0487] Formula (M), or salt thereof, wherein Y is Cl, Br, or I, with an amine of Formula (L), or salt thereof: to provide a compound of Formula (H-2), or salt thereof.

[0488]

[0450] Embodiment 44. The method of any one of Embodiments 37, 40, and 41, further comprising:

[0489] (a) Protecting a compound of Formula (A), or salt thereof, to provide an alkyl ester of Formula (B): or salt thereof, wherein Rais Ci-6 alkyl or Ci-6 haloalkyl;

[0490] (b) Halogenating the compound of Formula (B), or salt thereof, to provide a compound of Formula (C): or salt thereof, wherein X is Cl, Br, or I;

[0491] (c) Protecting the hydroxyl group of the compound of Formula (C), or salt thereof, to provide a compound of Formula (D): or salt thereof, wherein R1is as defined in Embodiment 1 ; and

[0492] (d) optionally, deprotecting the compound of Formula (D), or salt thereof, to provide a carboxylic acid of Formula (D), wherein Rais hydrogen.

[0493]

[0451] Embodiment 45. A method of preparing a compound of Formula (I-BC-a): r salt thereof; wherein Ring A, R3A, R4, p and m are defined in Embodiment 1, the method comprising cyclizing a compound of Formula (L-l): r salt thereof, wherein LG is a leaving group.

[0494]

[0452] Embodiment 46. The method of Embodiment 45, wherein the compound of Formula (I-BC-a), or salt thereof, is of Formula (I-BC-b): (I-BC-b), or salt thereof; and the compound of Formula (L-l), or salt thereof, is of Formula (L-2): or salt thereof.

[0495]

[0453] Embodiment 47. The method of Embodiment 45 or 46, wherein the compound of Formula (L-l), or salt thereof, or compound of Formula (L-2), or salt thereof, is prepared by conversion of the terminal -OH of Formula (I") or of Formula (I'"): r salt thereof, (I ' ' '), or salt thereof, to a leaving group.

[0496] EXEMPLIFICATION

[0497]

[0454] In order that this disclosure may be more fully understood, the following Examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

[0498] Analytical Methods

[0499]

[0455] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (5) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16 or 32 scans. Typical NMR solvents include deuterated dimethylsulfoxide (DMSO-d6) and deuterated methanol (CD3OD).

[0500]

[0456] Liquid Chromatography - Mass Spectrometry (LCMS) chromatograms and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7 - 8.0 pl and the flow rates were typically 0.8 or 1.2 mL / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100 - 1000 Da.

[0501] Mobile phases of water and / or acetonitrile (MeCN) may contain a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid (TFA), formic acid (FA), or ammonium carbonate (NH4HCO3). ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (minutes).

[0502]

[0457] Purification / Separation Methods. The synthetic methods describe purification and / or separation chromatographic methods which have been employed in the purification and / or isolation of the exemplified compounds. Rf = retention factor; RT = retention time (minutes); Prep-HPLC = Preparative High-performance Liquid Chromatography.

[0503] Synthetic Methods

[0504]

[0458] Future tense (“may be” prepared / synthesized) language signify examples to be conducted. Example 1 : 3-methoxy-4-((2-methoxypyridin-3-yl)amino)-JV-(5-(5-methyl-LH-pyrazol-l-yl)- l,3,4-thiadiazol-2-yl)-2-oxo-2 / f-pyran-6-carboxamide (Compound 8)

[0505] Scheme 1A.

[0506] Scheme 1C.

[0507]

[0508] 3-methoxy-4-((2-methoxypyridin-3- yl)amino)-A / -(5-(5-methyl-1 / -pyrazol-1- yl)-1 ,3,4-thiadiazol-2-yl)-2-oxo-2H- pyran-6-carboxamide

[0509] Example 1, Part A: Preparation of 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid

[0510]

[0459] Step 1: Into a solution of 5-hydroxy-6-oxopyran-2-carboxylic acid (180 g, 1153 mmol, 1 equiv) in methanol (MeOH) (2000 mL) was added H2SO4 (10 mL, 56 mmol) at room temperature. Then the resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (EtOAc) (1000 mL) and the organic phase was washed water (3 x 300 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to provide methyl 5-hydroxy-6-oxopyran-2- carboxylate (85 g, 43% yield). LCMS (ES, m / z) = 171 [M+l]+.

[0511]

[0460] Step 2: To a stirred solution of methyl 5-hydroxy-6-oxopyran-2-carboxylate (1.0 g, 5.9 mmol, 1 equiv) in acetic acid (AcOH) (25 mL, 323 mmol) was added N-bromosuccinimide (NBS) (1.25 g, 7.02 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C then diluted with water (70 mL). The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 70 mL). The combined organic layers were washed with brine (2 x 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (3:7) to afford methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate(also referred to herein as methyl 4-bromo-3-hydroxy-2-oxo-2H-pyran-6-carboxylate) (800 mg, 55% yield). LCMS (ES, z) = 247 [M-l]-.

[0512]

[0461] Step 3: To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (4.0 g, 16 mmol, 1 equiv) in dichloromethane (DCM) (50 mL) was added diisopropylethylamine (DIEA) (11.0 g, 85.1 mmol, 5 equiv) and methyl trifluoromethanesulfonate (TfOMe) (13.0 g, 79.2 mmol, 5 equiv) dropwise at room temperature. The resulting mixture was stirred for 4 h at room temperature. The mixture was then diluted with water (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (2 x 30 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (3:2) to afford methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (also referred to herein as methyl 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylate) (3.0 g, 71% yield). LCMS (ES, m / z) = 263 [M+l]+.

[0513]

[0462] Step 4: To methyl 4-bromo-5-methoxy-6-oxopyran-2 -carboxylate (10.0 g, 38.02 mmol, 1 equiv) was added HC1 (6M) (200 mb, 65.8 mmol). The mixture was stirred for 4 h at 80 °C then concentrated under reduced pressure to provide 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (also referred to herein as 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid) (9.5 g) which was used directly without further purification. LCMS (ES, m / z) = 249 [M+l]+.

[0514] Example 1, Part B: Preparation of 5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-amine

[0515]

[0463] Step 5: A mixture of 5-bromo-l,3,4-thiadiazol-2-amine (200 g, 1110 mmol, 1 equiv), diisopropylethylamine (DIEA) (431 g, 3333 mmol, 3 equiv) and pyrazole (90.76 g, 1333 mmol, 1.2 equiv) in 1,4-dioxane was stirred for 3 h at 80 °C. The resulting mixture was concentrated under vacuum and the residue was dissolved in tetrahydrofuran (THF). The mixture was filtered, and the filter cake was washed with tetrahydrofuran (THF). The filtrate was concentrated under reduced pressure to afford 5-(pyrazol-l-yl)-l,3,4-thiadiazol-2-amine (100 g, 54% yield), which was used directly in the next step without further purification.

[0516]

[0464] Step 6: A mixture of 5-(pyrazol-l-yl)-l,3,4-thiadiazol-2-amine (100 g, 598 mmol, 1 equiv), tosic acid (TsOH) (20.60 g, 119.6 mmol, 0.2 equiv) and 2,5 -hexanedione (102 g, 897 mmol, 1.5 equiv) in toluene was stirred for 2 h at 110 °C. The resulting mixture was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (9: 1) to afford 2-(2,5-dimethylpyrrol-l-yl)-5-(pyrazol-l- yl)-l,3,4-thiadiazole (90.3 g, 61 % yield). LCMS (ES, m / z) = 246.1 [M+l]+.

[0517]

[0465] Step 7: A solution of 2-(2,5-dimethylpyrrol-l-yl)-5-(pyrazol-l-yl)-l,3,4-thiadiazole (50.0 g, 204 mmol, 1 equiv) in THF was treated with n-butyl lithium (n-BuLi) (97.8 mb, 245 mmol, 1.2 equiv) for 1 h at -78 °C under N2 (nitrogen gas) followed by the addition of methyl iodide (CH3I) (34.7 g, 245 mmol, 1.2 equiv) dropwise at -78 °C. The resulting mixture was stirred for 2 h at room temperature under N2. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (9: 1) to afford 2-(2,5-dimethylpyrrol-l-yl)-5-(5-methylpyrazol-l-yl)-l,3,4- thiadiazole (40 g, 76% yield). LCMS (ES, m / z) = 260.0 [M+l]+.

[0518]

[0466] Step 8: To a solution of 2-(2, 5 -dimethylpyrrol- l-yl)-5 -(5 -methylpyrazol-l-yl)- 1,3,4- thiadiazole (7.0 g, 27 mmol, 1.0 equiv) in tetrahydrofiiran (THF) (14 mb) and H2O (28 mL) at room temperature was added trifluoroacetic acid (TFA) (28 mL). The resulting mixture was stirred for 2 h at 50 °C then concentrated under reduced pressure. The residue was purified by Cl 8 reverse phase flash chromatography (acetonitrile (MeCN) in water, 10% to 20% gradient in 10 min; Wave Length: 254 nm) to afford 5-(5-methylpyrazol-l-yl)-l,3,4-thiadiazol-2-amine (also referred to herein as 5-(5- methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-amine) (3 g, 58% yield). LCMS (ES, m / z) = 181.95 [M+l]+.

[0519] Example 1, Part C: Preparation of 3-methoxy-4-((2-methoxypyridin-3-yl)amino)-N-(5-(5-methyl- lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 8)

[0520]

[0467] Step 9: To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (12.0 g, 48.2 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (150 m ) was added hydroxybenzotriazole (HOBt) (13.02 g, 96.38 mmol, 2 equiv), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (27.81 g, 145.05 mmol, 3 equiv) and 5-(5-methylpyrazol-l-yl)-l,3,4-thiadiazol-2-amine (9.00 g, 49.7 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature then quenched by the addition of water (70 mb). The precipitated solids were collected by fdtration and washed with acetonitrile (MeCN) (5 x 3 mb) to provide 4-bromo-3-methoxy-N-(5-(5-methyl- lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (11 g, 55% yield). ECMS (ES, m / z) = 412 [M+l]+.

[0521]

[0468] Step 10: To a stirred solution of 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (100 mg, 0.243 mmol, 1 equiv) (“halo-pyrone reagent”) in N,N-dimethylformamide (DMF) (10 mb) was added 2-methoxypyridin-3 -amine (“amine reagent”) (34 mg, 0.27 mmol, 1.1 equiv), 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos) (10 mg, 0.02 mmol, 0.1 equiv), (2-dicyclohexylphosphino-2',6'- diisopropoxy- 1 , 1 '-biphenyl) [2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II) methane sulfonate (RuPhos Palladacycle Gen3) (35 mg, 0.04 mmol, 0.18 equiv) and CS2CO3 (237 mg, 0.73 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at 120 °C under N2 (nitrogen gas). The resulting mixture was diluted with water and extracted with ethyl acetate (EtOAc) (3 x 50 mb). The combined organic extracts were dried over MgSCE. After filtration, the filtrate was concentrated under reduced pressure and purified by prep-HPEC (XBridge Prep Phenyl OBD Column, 19* 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile (MeCN); Flow rate: 60 mb / min; Gradient: 15% B to 28% B in 8 min, 28% B; Wave Eength: 254 nm) to provide 3- methoxy-4-((2-methoxypyridin-3-yl)amino)-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2- yl)-2-oxo-2H-pyran-6-carboxamide (Compound 8) (25 mg, 22% yield). ECMS (ESI, m / z): 456.1 [M+H]+. ’H NMR (400 MHz, DMSO-6) 5 8.55 (s, 1H), 8.13 - 8.12 (m, 1H), 7.70 (d, J= 1.6 Hz, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.11-7.09 (m, 1H), 6.80 (s, 1H), 6.37 (d, J= 1.6 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 2.62 (s, 3H). Example 2: 2V-(5-(3-chloro-l-methyl-LH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-4-((4- cyanopyrimidin-2-yl)amino)-3-methoxy-2-oxo-2 / 7-pyran-6-carboxamide (Compound 1)

[0522]

[0469] Step 1: Into a 250mL round-bottom flask were added methyl 3 -chloro- lH-pyrrole-2- carboxylate (2.40 g, 15.0 mmol, 1 equiv) and tetrahydrofuran (THF) (20 mL, 247 mmol, 16 equiv) at room temperature. To the above mixture was added NaH (1.44 g, 60.0 mmol, 4 equiv) in portions at 0 °C. The resulting mixture was stirred for an additional 1 h at 0 °C. To the above mixture was then added methyl iodide (Mel) (6.48 g, 45.6 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was then stirred overnight at room temperature. The reaction was then quenched by the addition of HC1 (IN) (40 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 40 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1: 1) to afford methyl 3-chloro-l -methyl- lH-pyrrole-2-carboxylate (1.7 g, 71% yield). LCMS (ESI, m / z) = 173.85 [M +l]+.

[0523]

[0470] Step 2: Into a 40 mL vial was added methyl 3 -chloro- 1 -methyl- lH-pyrrole-2 -carboxylate (750 mg, 4.32 mmol, 1 equiv) and methanol (MeOH) (4.0 mL, 99 mmol, 23 equiv) at room temperature. To the above mixture was added NaOH (330 mg, 8.25 mmol, 2 equiv) in H2O (4.0 mL) at room temperature. The resulting mixture was stirred for an additional 2 h at 50 °C. The mixture was then acidified to pH 6 with HC1 (3 M). The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-chloro-l- methylpyrrole-2 -carboxylic acid (580 mg, 80% yield). LCMS (ESI, m / z) = 160.00 [M +1]+.

[0524]

[0471] Step 3: Into a 40 mL vial was added 3 -chloro- l-methylpyrrole-2 -carboxylic acid (2.20 g, 13.8 mmol, 1 equiv), N,N-dimethylformamide (DMF) (20 mL), l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (15.7 g, 41.4 mmol, 3 equiv), diisopropylethylamine (DIEA) (5.42 g, 41.9 mmol, 3 equiv) and NH4CI (2.97 g, 55.6 mmol, 4 equiv) at room temperature. The resulting mixture was stirred for 3 h at 80 °C. The reaction was then quenched with water at room temperature and the aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) then concentrated under reduced pressure. The resulting residue was purified by Cl 8 reverse phase flash chromatography (acetonitrile (MeCN) in water, 20% to 50% gradient in 10 min; detector, UV 254 nm) to afford 3 -chloro- l-methylpyrrole-2-carboxamide (1.47 g, 60% yield). LCMS (ESI, m / z) = 159.05 [M +l]+.

[0525]

[0472] Step 4: Into a 40 mL vial was added 3 -chloro- l-methylpyrrole-2 -carboxamide (1.40 g, 8.83 mmol, 1 equiv), dichloroethane (DCE) (20 mL) and methyl A-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (6.29 g, 26.4 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at 50 °C. The reaction was then quenched with water at room temperature and extracted with dichloromethane (DCM) (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (70:30), to afford 3 -chloro- l-methylpyrrole-2- carbonitrile (940 mg, 68% yield).

[0526]

[0473] Step 5: A mixture of 3 -chloro- l-methylpyrrole-2 -carbonitrile (100 mg, 0.71 mmol, 1 equiv) and thiosemicarbazide (200 mg, 2.19 mmol, 3 equiv) in trifluoroacetic acid (TFA) (5 mL) was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by Cl 8 reverse phase flash chromatography (acetonitrile (MeCN) in water, 30% to 40% gradient in 10 min; detector, UV 254 nm) to afford 5-(3-chloro-l-methylpyrrol-2-yl)-l,3,4- thiadiazol-2 -amine (also referred to herein as 5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol- 2-amine) (45 mg, 26% yield). LCMS (ESI, m / z) = 215.00 [M +1]+.

[0527]

[0474] Step 6: Into a solution of 4-bromo-5-methoxy-6-oxopyran-2 -carboxylic acid (product of Example 1, Step 4) (770 mg, 3.09 mmol, 1 equiv) in acetonitrile (MeCN) (20 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (960 mg, 3.42 mmol, 1.11 equiv), N-methylimidazole (NMI) (900 mg, 11.0 mmol, 3.5 equiv) and 5 -(3 -chloro- 1- methylpyrrol-2-yl)-l,3,4-thiadiazol-2-amine (616 mg, 2.87 mmol, 0.9 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 10 mL) to afford 4-bromo-A'-|5-(3-chloro- 1 - methylpyrrol-2-yl)-l, 3, 4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2 -carboxamide (also referred to herein as 4-bromo-N-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2- oxo-2H-pyran-6-carboxamide) (910 mg, 65 % yield).

[0528]

[0475] Step 7: JV-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-4-((4-cyanopyrimidin- 2-yl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 1) was prepared according to Example 1, Step 10 using 4-bromo-JV-[5-(3-chloro-l-methylpyrrol-2-yl)-l,3,4-thiadiazol-2-yl]-5- methoxy-6-oxopyran-2 -carboxamide as the “halo-pyrone reagent” and 2-aminopyrimidine-4- carbonitrile as the “amine reagent”. LCMS (ES, m / z)-. 484.95 [M+H]+. 'H NMR (400 MHz, DMSO- d6) 59.75 (s, 1H), 8.96 (d, J = 4.8 Hz, 1H), 8.10 (s, 1H), 7.67 (d, J = 4.8 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.20 (d, J = 2.8 Hz, 1H), 3.90(s, 3H), 3.86 (s, 3H).

[0529] Example 3: 4-((2-fluoro-6-methoxyphenyl)amino)-3-(2-methoxyethoxy)-2V-(5-(5-methyl-lH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 2)

[0530]

[0476] Step 1: To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Example 1, Step 2) (5.0 g, 20 mmol, 1 equiv) and 2-methoxyethanol (2.0 g, 26 mmol, 1.3 equiv) in tetrahydrofuran (THF) was added triphenyl phosphine (PPhs) (8.0 g, 30 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirred for 10 min at 0 °C. To this was then added di-tert-butyl azodicarboxylate (DBAD) (7.0 g, 30 mmol, 1.5 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was then diluted with ethyl acetate (EtOAc) (600 mb), washed with water (3 x 200 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1:3), to afford methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2 -carboxylate (also referred to as methyl 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylate) (3.7 g, 60% yield). LCMS (ESI, m / z) = 307,309 [M+l]+.

[0531]

[0477] Step 2 : A solution of methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2 -carboxylate (1700 mg, 5.54 mmol, 1 equiv) in HC1 (6M) (30 mL) was stirred for 3 h at 80 °C. The resulting mixture was then concentrated under reduced pressure and diluted with ethyl acetate (EtOAc) (200 mL), washed with brine (3 x 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2- carboxylic acid, which was used directly in the next step without further purification. LCMS (ESI, m / z) = 293.0 [M+l]+.

[0532]

[0478] Step 3: To a stirred solution of 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2 -carboxylic acid (1200 mg, 4.09 mmol, 1 equiv) and 5-(5-methylpyrazol-I-yl)-I,3,4-thiadiazol-2-amine (product of Example 1, step 8) (820 mg, 4.52 mmol, 1.1 equiv) in N,N-dimethylformamide (DMF) (21 mL) was added hydroxybenzotriazole (HOBT) (1110 mg, 8.22 mmol, 2 equiv) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (2355 mg, 12.3 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature before being diluted with water (40 mL). The precipitated solids were collected by filtration to afford 4-bromo-3-(2-methoxyethoxy)-N- (5-(5-methyl-lH-pyrazol-I-yl)-I,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (1.3 g, 70% yield). LCMS (ESI, m / z) = 458.05 [M+l]+.

[0533]

[0479] Step 4: 4-((2-fluoro-6-methoxyphenyl)amino)-3-(2-methoxyethoxy)-A-(5 -(5 -methyl- 1H- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 2) was prepared according to Example 1, Step 10 using 4-bromo-3-(2-methoxyethoxy)-N-(5-(5-methyl-lH-pyrazol- I-yl)-I,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide as the “halo-pyrone reagent” and 2- fluoro-6-methoxyaniline as the “amine reagent”. LCMS (ES, m / z)-. 517.05 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 7.60 (d, J = 1.6 Hz, 1H), 7.43-7.34 (m, 1H), 7.13 - 6.92 (m, 2H), 6.51 (s, 1H), 6.29 (d, J = 1.6 Hz, 1H), 4.17 - 3.98 (m, 2H), 3.85 (s, 3H), 3.69 - 3.51 (m, 2H), 3.30 (s, 3H), 2.57 (s, 3H).

[0534] Example 4: 4-((3-fluoropyridin-2-yl)amino)-3-methoxy-A-(5-(5-methyl-LH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 4)

[0535] Compound 4

[0536] 4-( ( 3-fluoropyndin-2-yl)amino)-3- methoxy- / V-(5-(5-methyr-1 / - / -pyrazol-1- yl )- 1 , 3, 4-th i adi azol -2-yl )-2-oxo-2H- pyran-6-carboxami de

[0537]

[0480] Into a 20 mL vial was added 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 9, Example 1; “halo-pyrone reagent”) (100 mg, 0.243 mmol, 1 equiv), N,N-dimethylformamide (DMF) (1.5 mL), 3- fluoropyridin-2-amine (“amine reagent”) (33 mg, 0.294 mmol, 1.2 equiv), [(2-di-tert- butylphosphino-2',4',6'-triisopropyl-l,T-biphenyl)-2-(2'-amino-l,T-biphenyl)] palladium(II) methanesulfonate (tBuXPhos Pd Gs) (39 mg, 0.049 mmol, 0.2 equiv), 2-di-fert-butylphosphino- 2',4',6'-triisopropylbiphenyl (tBuXPhos) (31 mg, 0.073 mmol, 0.3 equiv) and CS2CO3 (230 mg, 0.706 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere then purified directly by Prep-HPLC (Xselect CSH Cl 8 OBD Column 30* 150mm; Mobile Phase A: acetonitrile, Mobile Phase B: water (0.05% TFA); Flow rate: 60 mL / min; Gradient: 41% B to 51% B in 10 min, 51% B; Wave Length: 254 / 220 nm) to afford 4-((3- fluoropyridin-2-yl)amino)-3-methoxy-A-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2- oxo-2H-pyran-6-carboxamide (Compound 4) (10.4 mg, 9.6% yield). LCMS (ES, m / z)'. 444.10 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 13.50 (br, 1H), 8.90 (s, 1H), 8.25 (d, J= 4.0 Hz, 1H), 8.09 (s, 1H), 7.89 - 7.76 (m, 2H), 7.25 (dd, J= 8.4, 4.4 Hz, 1H), 6.44 (d, J= 1.2 Hz, 1H), 3.86 (s, 3H), 2.67 (s, 3H).

[0538] Example 5: 4-((2-fluorophenyl)amino)-3-methoxy-A-(5-(5-methyl-l / 7-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 5)

[0539] Compound 5

[0540] 4-( ( 2-f I uorophenyl )amino)-3-methoxy-

[0541] / V-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- tni adi azol-2-yl )-2-oxo-2 / -pyran-6- carboxamide

[0542]

[0481] To a stirred solution of 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol- 2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 9, Example 1; “halo-pyrone reagent”) (130 mg, 0.315 mmol, 1 equiv) in dioxane (3.5 m ) was added 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene

[0543] (XantPhos) (30 mg, 0.052 mmol, 0.16 equiv), chloro[(4,5-bis(diphenylphosphino)-9,9- dimethylxanthene)-2-(2'-amino-l,l'-biphenyl)]palladium(II) (XantPhos-Pd-G2) (42 mg, 0.047 mmol, 0.15 equiv), 2-fluoroaniline (“amine reagent”) (55 mg, 0.495 mmol, 1.6 equiv) and CS2CO3 (208 mg, 0.638 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere. The mixture was then cooled to rt and diluted with water (30 mb). The mixture was then extracted with ethyl acetate (EtOAc) (3 x 70 mL), and the combined EtOAc extracts were washed with brine (10 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure, and the crude residue was purified by Cl 8 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) followed by additional purification by prep-HPLC (XBridge Shield RP18 OBD Column, 30* 150 mm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (20% MeCN up to 35% in 8 min); Detector, UV 254nm) to afford 4-((2- fhrorophenyl)amino)-3 -methoxy-JV-(5 -(5 -methyl- IH-pyrazol- 1 -yl)- 1 ,3 ,4-thiadiazol-2-yl)-2-oxo-2H- pyran-6-carboxamide (Compound 5) (3.6 mg, 2.6% yield). LCMS (ES, m / z)'. 443.13 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.84 (br, 1H), 7.68 (d, J= 1.6 Hz 1H), 7.44 -7.35 (m, 3H), 7.31 (d, J = 6.4 Hz, 1H), 6.80 (br, 1H), 6.44 (d, J= 1.6 Hz, 1H), 3.76 (s, 3H), 2.62 (s, 3H).

[0544] Example 6: 3-methoxy-4-((3-methoxypyridin-2-yl)amino)-2V-(5-(5-methyl-lH-pyrazol-l-yl)- l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 6)

[0545] Compound 6

[0546] 3-methoxy-4-((3-methoxypyridin-2- yl)amino)-A / -(5-(5-methyl-1r / -pyrazol-1- yl)-1 ,3,4-fhiadiazol-2-yl)-2-oxo-27-pyran- 6-carboxamide

[0547]

[0482] To a stirred solution of 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol- 2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 9, Example 1; “halo-pyrone reagent”) (100 mg, 0.243 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (5 m ) was added 3-methoxypyridin-2- amine (“amine reagent”) (80 mg, 0.64 mmol, 3 equiv), [3,6-dimethoxy-2',4',6'-tris(l-methylethyl) [1,1 '-biphenyl] -2 -yl]bis(l,l-dimethylethyl)phosphine (t-BuBrettPhos) (40 mg, 0.083 mmol, 0.3 equiv), CS2CO3 (240 mg, 0.737 mmol, 3 equiv) and [(2-di-fert-butylphosphino-3,6-dimethoxy- 2',4',6'-triisopropyl-l,r-biphenyl)-2-(2'-amino-l,r-biphenyl)]palladium(II) methane sulfonate (t- BuBrettPhos Pd G3) (40 mg, 0.047 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was cooled to rt and diluted with water (30 mL) and extracted with ethyl acetate (EtOAc) (3 x 30 mL). The combined organic layers were washed with brine (10 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure and the resulting crude residue was purified by C18 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide a residue that was then triturated with DMSO (0.3 mL) and acetonitrile (2 mL). The resulting residue obtained from the trituration were collected by filtration and washed with acetonitrile (3 x 1 mL) to afford 3-methoxy-4-((3-methoxypyridin-2-yl)amino)-A-(5-(5- methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 6) (18.6 mg, 17% yield). LCMS (ES, m / z): 456.10 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 58.78 (s, 1H), 8.14 (d, J= 2.4 Hz, 1H), 7.96 (d, J= 5.2 Hz, 1H), 7.79 (d, J= 1.6 Hz, 1H), 7.50 (d, J= 8.0, 1.6 Hz, 1H), 7.14-7.11 (m, 1H), 6.45 (d, J= 1.6 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.67 (s, 3H).

[0548] Example 7: 2V-(5-(3-chloro-l-methyl-LH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-

[0549] (pyridin-3-ylamino)-2 / / -pyran-6-carboxamide (Compound 17)

[0550] Compound 17

[0551] / V-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)- 1 ,3,4-tniadiazol-2-yl)-3-methoxy-2-oxo-4- (pyridin-3-ylamino)-2 / - / -pyran-6- carboxamide

[0552]

[0483] To a solution of 4-bromo-N-[5-(3-chloro-l-methylpyrrol-2-yl)-l,3,4-thiadiazol-2-yl]-5- methoxy-6-oxopyran-2 -carboxamide (product of step 6, Example 2; “halo-pyrone reagent”) (200 mg, 0.449 mmol, 1 equiv) in dioxane (8 mL) was added [(2-di-cyclohexylphosphino-3,6-dimethoxy- 2', 4', 6'- triisopropyl- l,l'-biphenyl)-2-(2'-amino- 1,1' -biphenyl)]palladium(II) methane sulfonate (BrettPhos Pd G3) (81 mg, 0.09 mmol, 0.2 equiv), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'- triisopropyl-l,T-biphenyl (BrettPhos) (48 mg, 0.09 mmol, 0.2 equiv), CS2CO3 (439 mg, 1.35 mmol, 3 equiv) and 3 -aminopyridine (“amine reagent”) (127 mg, 1.35 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 4 h at 100 °C under nitrogen atmosphere. The reaction was then cooled to rt and diluted with water. The resulting mixture was extracted with ethyl acetate (EtOAc) (4 x 20 mL) and then the aqueous layer was concentrated under reduced pressure and the resulting residue was purified by Cl 8 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide a residue, which was further purified by Prep-HPLC (Xselect CSH C18 OBD Column 30* 150mm 5um, mobile phase, MeCN and water (0.05%TFA) (23% water (0.05%TFA) up to 33% in 10 min); Detector, UV 254nm) to afford A'-(5-(3-chloro- l-mcthyl- l / / -pyrrol-2-yl)- 1.3.4-thiadiazol-2-yl)-3- methoxy-2-oxo-4-(pyridin-3-ylamino)-2H-pyran-6-carboxamide (Compound 17) (11.1 mg, 5.4%) LCMS (ES, m / z): 459.05 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 13.61 (s, 1H), 9.29 (s, 1H), 8.58 - 8.52 (m, 1H), 8.44 (d, J= 4.4 Hz, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.25 (d, J= 2.0 Hz, 1H), 7.16 (d, J= 2.8 Hz, 1H), 6.33 (d, J= 2.8 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H).

[0553] Example 8: 2V-(5-(5-(difluoromethyl)-LH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4- (pyridin-3-ylamino)-2 / 7-pyran-6-carboxamide (Compound 18)

[0554] S5

[0555] Compound 18

[0556] A / -(5-(5-(difluoromethyl)-1 H- pyrazol-'i-yl)-1,3,4-thiadiazol-2-yl)- 3-methoxy-2-oxo-4-(pyridin-3- ylamino)-2 H-pyran-6-carboxamide

[0557]

[0484] Step 1: Into a solution of 2-(2,5-dimethylpyrrol-l-yl)-5-(pyrazol-l-yl)-l,3,4-thiadiazole

[0558] (product of Example 1, Step 6) (5 g, 20 mmol, 1 equiv) in tetrahydrofuran (THF) (100 mL) was added n-butyl lithium (n-BuLi) (8.97 mL, 22.4 mmol, 1.1 equiv) dropwise over 5 min at -78 °C. The resulting mixture was stirred for 1 h at -78 °C. To the mixture was then added ethyl formate (4.53 g, 61.1 mmol, 3equiv) dropwise over 5 min at -78 °C. The mixture was stirred for an additional 1 h at - 78 °C then quenched with sat. NH4C1 (aq.) at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 100 mL). The resulting mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (8: 1), to afford 2-[5-(2,5-dimethylpyrrol-l-yl)-l,3,4-thiadiazol-2- yl]pyrazole-3-carbaldehyde (3.5 g, 56% yield). LCMS (ESI, m / z) = 274.2 [M+l]+.

[0559]

[0485] Step 2: To a stirred solution of 2-[5-(2,5-dimethylpyrrol-l-yl)-l,3,4-thiadiazol-2-yl]pyrazole- 3-carbaldehyde (700 mg, 2.56 mmol, 1 equiv) in dichloromethane (DCM) (5 mL) was added diethylaminosulfur trifluoride (DAST) (826 mg, 5.12 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The reaction was then quenched by the addition of water (2 mL) at room temperature and extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (5: 1), to afford 2-[5-(difluoromethyl)pyrazol-l-yl]-5-(2,5-dimethylpyrrol-l-yl)-l,3,4-thiadiazole (300 mg, 40% yield).

[0560]

[0486] Step 3: Into a solution of 2- [5 -(difluoromethyl)pyrazol-l-yl] -5 -(2,5 -dimethylpyrrol- 1-yl)- 1,3,4-thiadiazole (300 mg, 1.02 mmol, 1 equiv) in tetrahydrofuran (THF) (1 mL) and H2O (0.5 mL) was added trifluoroacetic acid (TFA) (0.5 mL) at 0 °C. The resulting mixture was stirred for 2 h at 60 °C under air atmosphere. The mixture was then concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (5: 1), to afford 5-[5-(difluoromethyl)pyrazol-l-yl]-l,3,4-thiadiazol-2-amine (also referred to as 4-bromo-N-(5-(5-(difluoromethyl)-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy- 2-oxo-2H-pyran-6-carboxamide) (190 mg, 86% yield). LCMS (ESI, m / z) = 218.0 [M+l]+.

[0561]

[0487] Step 4: To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Step 4) (218 mg, 0.87 mmol, 1 equiv) in acetonitrile (MeCN) (1 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (294 mg, 1.05 mmol, 1.2 equiv), N-methylimidazole (NMI) (215 mg, 2.62 mmol, 3 equiv) and 5-[5-(difluoromethyl)pyrazol- l-yl]-l,3,4-thiadiazol-2-amine (190 mg, 0.875 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for an additional 50 min at room temperature. The resulting solids were collected by filtration and washed with acetonitrile (MeCN) (3 x 10 mL) to provide 4-bromo-A-{5-[5- (difluoromethyl)pyrazol-l-yl]-l,3,4-thiadiazol-2-yl}-5-methoxy-6-oxopyran-2-carboxamide (220 mg, 56% yield). LCMS (ESI, m / z) = 447.9 [M+l]+.

[0562]

[0488] Step 5 : N-(5 -(5 -(difluoromethyl)- IH-pyrazol-l-yl)- 1,3, 4-thiadiazol-2-yl)-3-methoxy-2 -oxo-4- (pyridin-3-ylamino)-2H-pyran-6-carboxamide (Compound 18) was prepared according to Example 1, Step lO using 4-bromo-A-{5-[5-(difluoromethyl)pyrazol-l-yl]-l,3,4-thiadiazol-2-yl}-5-methoxy- 6-oxopyran-2 -carboxamide as the “halo-pyrone reagent” and pyridin-3 -amine as the “amine reagent”. LCMS (ES, m / z)-. 462.05 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 9.04 (s, 1H), 8.51 (d, J= 2.4 Hz, 1H), 8.41-8.40 (m, 1H), 7.78 - 7.57 (m, 3H), 7.48-7.45 (m, 1H), 7.02 (s, 1H), 6.92 (s, 1H), 3.76 (s, 3H).

[0563] Example 9: 2V-(5-(5-amino-LH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2- yl)amino)-3-methoxy-2-oxo-2 / 7-pyran-6-carboxamide (Compound 31) and N-(5-(5-acetamido- lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2-yl)amino)-3-methoxy-2-oxo-2H- pyran-6-carboxamide (Compound 31-Ac) -

[0564] / V-(5-(5-acetamido-1 / - / -pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-4-((3-

[0565] 1,3,4-thiadiazol-2-yl)-4-((3- fluoropyridin-2-yl)amino)-3-methoxy- fluoropyridin-2-yl)amino)-3-methoxy- 2-oxo-2 / 7-pyran-6-carboxamide 2-oxo-2 / 7-pyran-6-carboxamide

[0566]

[0489] Step 1: To a stirred solution of 2-(2,5-dimethylpyrrol-l-yl)-5-(pyrazol-l-yl)-l,3,4-thiadiazole (product of Example 1, Step 6) (6 g, 24.46 mmol, 1 equiv) in tetrahydrofuran (THF) (70 mL) was added w-BuLi (11.74 mL, 29.35 mmol, 1.20 equiv, 2.5 M) in portions at -78 °C under N2 (nitrogen gas). The resulting mixture was stirred for 1 h at -78 °C under N2. And then to the above mixture was added I2 (18.62 g, 73.38 mmol, 3 equiv) in THF (20 mL) in portions over 30 min at -78 °C under N2. The resulting mixture was stirred for an additional 40 min at -78 °C and then the resulting mixture was stirred for 2 h at room temperature under N2. The reaction was then quenched with sat. NH4C1 (aq.) at room temperature. The mixture was extracted with ethyl acetate (EtOAc) (3 x lOOmL), washed with sat. Na2S20s (2 x 100 mL), then with brine (2 x 100 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (15: 1), to afford 2-(2,5-dimethylpyrrol-l-yl)-5-(5-iodopyrazol-l-yl)-l,3,4-thiadiazole (6.8 g, 75% yield). LCMS (ES, m / z) = 372 [M+l]+.

[0567]

[0490] Step 2 : A mixture of 2-(2,5-dimethylpyrrol-l-yl)-5-(5-iodopyrazol-l-yl)-l,3,4-thiadiazole (2 g, 5.39 mmol, 1 equiv), tris(dibenzylidenaceton)dipalladinm(0) (Pd2(dba)s) (494 mg, 0.539 mmol, 0.1 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (XantPhos) (624 mg, 1.078 mmol, 0.2 equiv), CS2CO3 (3.53 g, 10.8 mmol, 2 equiv) and acetamide (962 mg, 16.3 mmol, 3 equiv) in dioxane (25 mL) was stirred for 1 h at 120 °C under N2 then concentrated under vacuum. The resulting residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EtOAc) (8: 1), to afford A-{2-[5-(2,5-dimethylpyrrol-l-yl)-l,3,4-thiadiazol- 2-yl]pyrazol-3-yl}acetamide (1.1 g, 67% yield). LCMS (ES, m / z) = 303 [M+l]+.

[0568]

[0491] Step 3: To a stirred solution ofX-{2-[5-(2,5-dimethylpyrrol-l-yl)-l,3,4-thiadiazol-2- yl]pyrazol-3-yl} acetamide (1. 10 g, 3.64 mmol, 1 equiv) in tetrahydrofuran (THF) (4 mL) and H2O (4 mL) was slowly added trifluoroacetic acid (TFA) (8 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature then volatiles removed under a stream of N2. The residue was then diluted with dichloromethane (DCM) (3 mL). The precipitated solids were collected by filtration and washed with DCM (2 x 1 mL) to afford N-[2-(5-amino-l,3,4-thiadiazol-2-yl)pyrazol-3- yl] acetamide (400 mg, 49% yield). LCMS (ES, m / z) = 225 [M+l]+.

[0569]

[0492] Step 4: To a solution of 4-bromo-5-methoxy-6-oxopyran-2 -carboxylic acid (product of Example 1, Step 4) (220 mg, 0.883 mmol, 1.00 equiv) in acetonitrile (MeCN) (3 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (506 mg, 1.80 mmol, 2 equiv) and N-methylimidazole (NMI) (375 mg, 4.57 mmol, 5 equiv) and the mixture was stirred for 5 min at room temperature. To the above mixture was added N-[2-(5-amino-l,3,4-thiadiazol-2- yl)pyrazol-3-yl] acetamide (198 mg, 0.883 mmol, 1 equiv). The resulting mixture was stirred for 1 h at room temperature then diluted with water (4 mL) at room temperature. The precipitated solids were collected by filtration to afford 4-bromo- / V-[5-(5-acetamidopyrazol-l-yl)-l,3,4-thiadiazol-2-yl]- 5-methoxy-6-oxopyran-2 -carboxamide (140 mg, 35% yield). LCMS (ES, m / z) = 455, 457 [M+l]+.

[0570]

[0493] Step 5: N-(5-(5-acetamido-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2- yl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 31-Ac) was prepared according to Example 1 Step 10 using 4-bromo- / V-[5-(5-acetamidopyrazol-l-yl)-l,3,4-thiadiazol-2-yl]-5- methoxy-6-oxopyran-2 -carboxamide as the “halo-pyrone reagent” and 3-fluoropyridin-2-amine as the “amine reagent”. LCMS (ES, m / z) = 487.15 [M+l]+.

[0571]

[0494] Step 6: To a solution of N-(5-(5-acetamido-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3- fluoropyridin-2-yl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (90 mg, 0.185 mmol, 1 equiv) in ethanol (EtOH) (3.6 mL) was added hydrochloric acid (0.9 mb, 6 M). The solution was stirred for 1 h at 60 °C. The resulting mixture was filtered, and the filter cake was washed with acetonitrile (MeCN) (3 x 4 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by Cl 8 reverse phase flash chromatography (mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide a residue which was further purified by Prep-HPLC (YMC-Actus Triart C18 ExRS, 30* 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 11% B to 25% B in 10 min, 25% B; Wave Length: 254 nm) to afford A'-(5-(5-amino- l / / -pyrazol- 1 -yl)- 1.3.4-thiadiazol-2-yl)-4- ((3-fluoropyridin-2-yl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 31) (2.3 mg, 2.7% yield). LCMS (ES, m / z): 444.95 [M+l]+; ’H NMR (400 MHz, DMSO-d6) 5 8.64 (s, 1H), 8.29 - 8.24 (m, 1H), 7.92 (s, 1H), 7.86 - 7.78 (m, 1H), 7.36 (s, 1H), 7.27 - 7.19 (m, 1H), 6.62 (s, 2H), 5.39 (s, 1H), 3.82 (s, 3H).

[0572] Example 10: A-(5-(3-chloro-l-methyl-LH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-

[0573] 2-yl)amino)-3-(2-methoxyethoxy)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 36)

[0574]

[0495] JV-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2- yl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 36) was prepared according to Example 3, Steps 3-4 by: (1) coupling 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2- carboxylic acid (product of Example 3, Step 2) with 5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4- thiadiazol-2 -amine (product of Example 2, Step 5) instead of 5-(5-methyl-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-amine to provide 4-bromo-N-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2- yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (“halo-pyrone reagent”), and (2) coupling 4-bromo-N-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (“halo-pyrone reagent”) with 3-fluoropyridin-2- amine (“amine reagent”). LCMS (ESI, m / z) = 521.1 [M+l]+. ’HNMR (400 MHz, DMSO-d6) 5 13.65 (s, 1H), 8.55 (s, 1H), 8.51-8.49 (m, 1H), 8.23 (d, J = 2.8 Hz, 1H), 7.85-7.82 (m, 1H), 7.20- 7.16 (m, 1H), 7.11 (s, 1H), 6.30 (d, J = 2.8 Hz, 1H), 4.26-4.23 (m, 2H), 3.93 (s, 3H), 3.60 - 3.56 (m, 2H), 3.32 (s, 3H).

[0575] Example 11: JV-(5-(3-chloro-l-methyl-LH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-3-(2- methoxyethoxy)-2-oxo-4-(pyridin-3-ylamino)-2 / / -pyran-6-carboxamide (Compound 37)

[0576]

[0496] To a stirred solution of 4-bromo-N-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2- yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Example 10 “halo-pyrone reagent”) (100 mg, 0.204 mmol, 1 equiv), [(2-di-fert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l,T- biphenyl)-2-(2'-amino-l,T-biphenyl)]palladium(II) methane sulfonate (t-BuBrettPhos Pd G3) (35 mg, 0.041 mmol, 0.2 equiv), [3,6-dimethoxy-2',4',6'-tris(l-methylethyl) [1, 1 '-biphenyl] -2 -yl]bis(l, 1- dimethylethyl)phosphine (t-BuBrettPhos) (20 mg, 0.041 mmol, 0.2 equiv) and CS2CO3 (200 mg, 0.614 mmol, 3 equiv) in dioxane (1.5 mL) was added 3 -aminopyridine (“amine reagent”) (29 mg, 0.31 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. The resulting solution was stirred for 1 h at 100 °C under nitrogen atmosphere then concentrated under vacuum. The crude mixture was purified directly by Cl 8 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) followed by additional purification by Prep-HPLC (XBridge Shield RP18 OBD Column, 30* 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 20% B to 30% B in 10 min, 30% B; Wave Length: 254 nm; RT(min): 8.5) to afford JV-(5-(3-chloro-l-methyl- lH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-4-(pyridin-3-ylamino)-2H-pyran- 6-carboxamide (Compound 37) (8.8 mg, 8.4% yield). LCMS (ES, m / z) = 503.0 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.83 (s, 1H), 8.52 (d, J= 2.8 Hz, 1H), 8.45 (dd, J= 4.4, 1.2 Hz, 1H), 7.70- 7.67 (m, 1H), 7.46- (dd, J= 8.0, 4.8 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J= 2.8 Hz, 1H), 6.28 (d, J= 2.8 Hz, 1H), 4.15 (t, J = 4.0 Hz, 2H), 3.91 (s, 3H), 3.62 (t, J= 4.0 Hz, 2H), 3.31 (s, 3H).

[0577] Example 12: JV-(5-(5-amino-LH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4- (pyrimidin-2-ylamino)-2 / / -pyran-6-carboxamide (Compound 48) and N-(5-(5-acetamido-lH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-6- carboxamide (Compound 48-Ac)

[0578] M-(5-(5-acetamido-1 H-pyrazol- 1-yl)-1 ,3,4-thiadiazol-2-yl)-3- oxo-4-(pyrimidin-2-ylamino)-2 imethoxy-2-oxo-4-(pyrimidin-2- py ran-6 -carboxamide ylamino)-2 H-pyran-6- carboxamide

[0579]

[0497] Step 1: To a stirred solution of methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (product of Example 1, Step 3) (2 g, 7.60 mmol, 1 equiv) in dioxane (45 mL) was added 2- aminopyrimidine (1.4 g, 14.75 mmol, 1.94 equiv), tris(dibenzylideneacetone)dipalladiuin(0) (Pd2(dba)s) (1.39 g, 1.52 mmol, 0.2 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (792 mg, 1.37 mmol, 0.2 equiv) and CS2CO3 (7.4 g, 22.7 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2.5 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and was concentrated under vacuum. The crude residue was then purified by silica gel column chromatography, eluting with CH2Q2 / methanol (MeOH) (3: 1), to afford methyl 5-methoxy-6-oxo-4-(pyrimidin-2-ylamino)pyran-2- carboxylate (1.3 g, 57% yield). LCMS (ES, m / z) = 278 [M+H]+.

[0580]

[0498] Step 2: To a stirred solution of methyl 5-methoxy-6-oxo-4-(pyrimidin-2-ylamino)pyran-2- carboxylate (2 g, 7.21 mmol, 1 equiv) was added hydrochloric acid (20 mL, 6 M) at room temperature. The resulting mixture was stirred overnight at 50 °C then cooled down to room temperature. The precipitated solids were collected by filtration and washed with acetonitrile (MeCN) (1 mL) to provide 5-methoxy-6-oxo-4-(pyrimidin-2-ylamino)pyran-2-carboxylic acid (800 mg, 38% yield). LCMS (ES, m / z) = 264 [M+H]+.

[0581]

[0499] Step 3: To a stirred solution of 5-methoxy-6-oxo-4-(pyrimidin-2-ylamino)pyran-2-carboxylic acid (“amino-pyrone reagent”) (109 mg, 0.41 mmol, 1 equiv) in acetonitrile (2.8 mL) was added chloro-N.N.N'.N'-tctramcthylfomiamidinium hexafluorophosphate (TCFH) (175 mg, 0.62 mmol, 1.51 equiv) and N-methylimidazole (NMI) (102 mg, 1.24 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 30 min at room temperature. To the above mixture was then added N-[2-(5-amino-l,3,4-thiadiazol-2-yl)pyrazol-3-yl] acetamide (product of Example 9, Step 3; “ADT amine reagent”) (107 mg, 0.48 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The precipitated solids were then collected by filtration and washed with acetonitrile (MeCN) (3 x 3 m ) to provide N-(5-(5-acetamido-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-3-methoxy-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-6-carboxamide (Compound 48-Ac) (80 mg, 13% yield). LCMS (ES, m / z) = 470 [M+H]+.

[0582]

[0500] Step 4: To a stirred solution ofN-(5-(5-acetamido-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3- methoxy-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-6-carboxamide (Compound 48-Ac) (80 mg, 0.17 mmol, 1 equiv) in tetrahydrofuran (THF) (1.6 mL) was added water (1.6 m ) and 2,2,2- trifluoroacetic acid (TFA) (4.8 mL) at room temperature. The resulting mixture was stirred for 1.5 h at 80 °C then cooled down to room temperature and concentrated under reduced pressure. The resulting crude residue was purified directly by C18 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) followed by additional purification by Prep-HPLC (XBridge Prep Phenyl OBD Column, 19* 150 mm; Mobile Phase A: water (lOmmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 15% B to 15% B in 8 min, 15% B; Wave Length: 254 nm) to afford / V-(5-(5-amino- IH-pyrazol- l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(pyrimidin-2-ylamino)- 2H-pyran-6-carboxamide (Compound 48) (5.6 mg, 7.6% yield). LCMS (ES, m / z) = 428.05 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 8.99 (s, 1H), 8.69 (d, J= 4.8 Hz, 2H), 8.42 (s, 1H), 7.35 (d, J= 1.6 Hz, 1H), 7.15-7.13 (m, 1H), 6.64-6.61 (m, 2H), 5.39 (d, J= 1.6 Hz, 1H), 3.85 (s, 3H).

[0583] Example 13: JV-(5-(3-chlorothiophen-2-yl)-l,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-4- (pyrimidin-2-ylamino)-2 / 7-pyran-6-carboxamide (Compound 49)

[0584] Scheme 13 A. Scheme 13B.

[0585] Compound 49

[0586] A / -(5-(3-chlorothiophen-2-yl)-1 ,3,4- thiadiazol-2-yl)-3-(2-methoxyethoxy)-2- ox o-4-(py ri mi i n-2-y lami no)-2 / 7-py ran-6- carbox amide

[0587]

[0501] Step 1: To a stirred solution of methyl 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxylate (product of Example 3, Step 1) (500 mg, 1.63 mmol, 1 equiv) and pyrimidin-2-amine (235 mg, 2.47 mmol, 1.52 equiv) in AA'-dimcthylformamidc (DMF) (3.0 m ) were added 3rd Generation RuPhos Pd precatalyst (275 mg, 0.329 mmol, 0.200 equiv), Ruphos (310 mg, 0.664 mmol, 0.410 equiv) and CS2CO3 (800 mg, 2.46 mmol, 1.51 equiv) at room temperature. The resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was poured into water and extracted with EtOAc (3 x 100 m ). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 100 mb), dried over anhydrous Na2SO4and fdtered under vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether (PE) / ethyl acetate (EA) (55:45) to afford methyl 3-(2-methoxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-6-carboxylate (310 mg, 59 % yield) as a light brown solid.-LCMS (ES, m / z) = 322 [M+H]+.

[0588]

[0502] Step 2: Into a 20 mL vial was added methyl 3-(2-methoxyethoxy)-2-oxo-4-(pyrimidin-2- ylamino)-2H-pyran-6-carboxylate (280 mg, 0.87 mmol, 1 equiv) and hydrochloric acid (3 mL, 6M) at room temperature. The resulting mixture was stirred for 1 h at 80 °C then cooled to rt and concentrated under reduced pressure. The crude residue was then directly purified by Cl 8 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient in 10 min (H2O:MeCN=7:3); detector, UV 254 nm) to afford 3-(2-methoxyethoxy)-2-oxo-4-(pyrimidin-2- ylamino)-2H-pyran-6-carboxylic acid (91 mg, 34% yield). LCMS (ES, m / z) = 307 [M+H]+.

[0589]

[0503] Step 3: A solution of 3-chlorothiophene-2-carboxylic acid (4.00 g, 24.6 mmol, 1 equiv) and thiosemicarbazide (4.50 g, 49.4 mmol, 2 equiv) in sulfuric acid (60 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (400 mL) and the pH adjusted to 9 with aqueous saturated NaHCOs. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 400 mL). The combined organic layers were washed with water (200 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1: 1)) to afford 5-(3-chlorothiophen-2-yl)-l,3,4- thiadiazol-2 -amine (413 mg, 7.2% yield). LCMS (ES, m / z) = 507.05 [M+H]+ %). LCMS (ES, m / z) = 217.7 [M+H]+.

[0590]

[0504] Step 4: To a stirred solution of 3-(2-methoxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H- pyran-6-carboxylic acid (“amino-pyrone reagent”) (65 mg, 0.21 mmol, 1 equiv) and 5-(3- chlorothiophen-2-yl)-l,3,4-thiadiazol-2-amine (“ADT amine reagent”) (55 mg, 0.25 mmol, 1.2 equiv) in N,N-dimethylformamide (DMF) (2 mL) was added l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (97 mg, 0.25 mmol, 1.2 equiv) and diisopropylethylamine (DIEA) (40 mg, 0.31 mmol, 1.46 equiv) at room temperature. The resulting mixture was stirred for 1 h at 50 °C. The precipitated solids were then collected by fdtration and washed with water (3 x 1 mL) and acetonitrile (MeCN) (3 x 3 mL) to afford A-(5-(3- chlorothiophen-2-yl)-l,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)- 2H-pyran-6-carboxamide (27 mg, 25% yield). LCMS (ES, m / z) = 507.05 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 13.69 (s, 1H), 9.14 (s, 1H), 8.82 (s, 1H), 8.70 (d, J= 4.8 Hz, 2H), 7.93 (d, J = 5.4 Hz, 1H), 7.32 (d, J= 5.4 Hz, 1H), 7.18 (dd, J= 4.8, 2.4 Hz, 1H), 4.28 - 4.22 (m, 2H), 3.66 - 3.60 (m, 2H), 3.40 (s, 3H).

[0591] Example 14: 2V-(5-(3-chlorothiophen-2-yl)-l,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-4- (phenylamino)-2 / 7-pyran-6-carboxamide (Compound 51)

[0592]

[0505] Step 1: To a stirred solution of methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2- carboxylate (product of Example 3, Step 1) (500 mg, 1.63 mmol, 1.00 equiv) in N.N- dimethylformamide (DMF) (4 m ) was added aniline (152 mg, 1.63 mmol, 1.00 equiv), Ruphos (153 mg, 0.328 mmol, 0.20 equiv), 3rd Generation RuPhos Pd precatalyst (273 mg, 0.326 mmol, 0.200 equiv) and CS2CO3 (1.3 mg, 0.0040 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was poured into water and extracted with EtOAc (3 x 50 m ). The aqueous layer was acidified to pH 3 with HC1 (aq. 1 M). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4 and filtered under vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, acetonitrile (MeCN) in Water , 10% to 100% gradient in 10 min; detector, UV 254 nm (ACN:H2O=13:87). This resulted in 5-(2-methoxyethoxy)-6-oxo-4-(phenylamino)pyran-2- carboxylic acid (190 mg, 38% yield) as a yellow oil. LCMS (ES, m / z) = 306 [M+H]+.

[0593]

[0506] Step 2: To a stirred solution of 5-(3-chlorothiophen-2-yl)-l,3,4-thiadiazol-2-amine (product of Example 13, Step 3; “ADT amine reagent”) (50 mg, 0.230 mmol, 0.8 equiv) in N,N- dimethylformamide (DMF) (2.5 mL) was added hydroxybenzotriazole (HoBt) (60 mg, 0.444 mmol, 1.5 equiv), l-ethyl-3-(3-dimethylammopropyl)carbodiimide (EDCI) (130 mg, 0.678 mmol, 2.3 equiv), 4-dimethylaminopyridine (DMAP) (80 mg, 0.655 mmol, 2.2 equiv) and 3-(2- methoxyethoxy)-2-oxo-4-(phenylamino)-2H-pyran-6-carboxylic acid (“amino-pyrone reagent”) (90 mg, 0.295 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature then purified directly by Cl 8 reverse phase chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) followed by additional purification by Prep-HPLC (Xselect CSH C18 OBD Column 30* 150mm; Mobile Phase A: MeCN, Mobile Phase B: water (0.05% TFA); Flow rate: 60 mL / min; Gradient: 50% B to 60% B in 10 min, 60% B; Wave Length: 254 / 220 nm) to afford / V-(5-(3-chlorothiophen-2-yl)-l,3,4-thiadiazol-2-yl)-3- (2-methoxyethoxy)-2-oxo-4-(phenylamino)-2H-pyran-6-carboxamide (Compound 51) (7.3 mg, 4.9% yield). LCMS (ES, m / z) = 505.05 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 8.77 (s, 1H), 7.92 (d, J= 5.4 Hz, 1H), 7.46 (d, J= 8.0 Hz, 2H), 7.34 - 7.22 (m, 5H), 4.18-4.16 (m, 2H), 3.70-3.65 (m, 2H), 3.31 (s, 3H). Example 15: 2V-(5-(5-amino-LH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo- 4-(phenylamino)-2 / / -pyran-6-carboxamide (Compound 52) and N-(5-(5-acetamido-lH-pyrazol- l-yl)-l,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-4-(phenylamino)-2H-pyran-6- carboxamide (Compound 52-Ac)

[0594] Compound 52-Ac

[0595] N-( 5-(5-acetami do- 1 H-pyrazol- 1 -yl)- l,3,4-thiadiazol-2-yl)-3-(2- methoxyethoxy)-2-oxo-4- (phenylamino)-2H-pyran-6- carboxamide

[0596]

[0507] Step 1: To a stirred solution of 3-(2-methoxyethoxy)-2-oxo-4-(phenylamino)-2H-pyran-6- carboxylic acid (product of Step 1, Example 14; “amino-pyrone reagent”) (100 mg, 0.328 mmol, 1 equiv) in acetonitrile (MeCN) (1.5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (281 mg, 1.00 mmol, 3 equiv), N-methylimidazole (NMI) (280 mg, 3.41 mmol, 10 equiv) and N-[2-(5-amino-l,3,4-thiadiazol-2-yl)pyrazol-3-yl] acetamide (product of Example 9, Step 3; “ADT amine reagent”) (141 mg, 0.629 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The precipitated solids were then collected by filtration and washed with MeCN (3 x 5 mL) to provide N-(5-(5-acetamido-lH-pyrazol- l-yl)-l,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-4-(phenylamino)-2H-pyran-6-carboxamide (Compound 52-Ac) (60 mg, 36% yield). LCMS (ES, m / z) = 512 [M+l]+.

[0597]

[0508] Step 2: Into a solution ofN-(5-(5-acetamido-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-(2- methoxyethoxy)-2-oxo-4-(phenylamino)-2H-pyran-6-carboxamide (Compound 52-Ac) (50 mg, 0.098 mmol, 1 equiv) in ethanol (EtOH) (1.2 mL) was added cone. HC1 (0.2 mL) at room temperature. The resulting mixture was stirred for 3 h at 60 °C then concentrated under reduced pressure. The crude product was then purified by Prep-HPLC (XBridge Prep Phenyl OBD Column, 19*250 mm; Mobile Phase A: water (0.1% TFA), Mobile Phase B: acetonitrile (MeCN); Flow rate: 20 mL / min; Gradient: 45% B to 55% B in 10 min, 55% B; Wave Length: 254 nm) to afford N-(5-(5- amino- 1 H-pyrazol- 1 -yl)- 1 ,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-4-(phenylamino)-2H- pyran-6-carboxamide (Compound 52) (2.2 mg, 4.6% yield). LCMS (ES, m / z) = 470.05 [M+l]+; 'H NMR (400 MHz, DMSO-d6) 5 13.38 (s, 1H), 8.79 (s, 1H), 7.52-7.39 (m, 3H), 7.33-7.15 (m, 4H), 6.64 (s, 2H), 5.44 (d, J= 2.0 Hz, 1H), 4.21-4.11 (m, 2H), 3.69-3.61 (m, 2H), 3.31 (s, 3H).

[0598] Example 16: 3-methoxy-2V-(5-(l-methyl-LH-imidazol-2-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-4-

[0599] (pyrimidin-2-ylamino)-2 / 7-pyran-6-carboxamide (Compound 53) S2

[0600]

[0509] Step 1: To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Step 4) (180 mg, 0.72 mmol, 1 equiv) in acetonitrile (MeCN) (6 m ) was added chloro-

[0601] N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (306 mg, 1.09 mmol, 1.5 equiv) and N-methylimidazole (NMI) (179 mg, 2.18 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was then added commercially available 5-(l-methylimidazol-2-yl)-l,3,4-thiadiazol-2-amine (130 mg, 0.717 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for an additional 3 h at room temperature. The precipitated solids were then collected by filtration and washed with MeCN (2 x 1 m ) to provide 4- bromo-5-methoxy-N-[5-(l-methylimidazol-2-yl)-l,3,4-thiadiazol-2-yl]-6-oxopyran-2 -carboxamide (165 mg, 54% yield). LCMS (ES, m / z) = 412 [M+H]+.

[0602]

[0510] Step 2: To a stirred solution of 4-bromo-5-methoxy-N-[5-(l-methylimidazol-2-yl)-l,3,4- thiadiazol-2-yl]-6-oxopyran-2 -carboxamide (“halo-pyrone reagent”) (155 mg, 0.38 mmol, 1 equiv) in dimethylformamide (DMF) (3.5 mb) was added 2-aminopyrimidine (“amine reagent”) (72 mg,

[0603] O.76 mmol, 2.0 equiv), (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (63 mg, 0.075 mmol, 0.2 equiv), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (35 mg, 0.075 mmol, 0.2 equiv) and CS2CO3 (368 mg, 1.13 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The mixture was then cooled to room temperature and filtered and the filter cake was washed with N,N-dimethylformamide (DMF) (2 x 1 mL). The filtrate was then purified by Prep-HPLC (conditions: column, XB ridge Prep OBD C18 Column, 30* 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile (MeCN); Flow rate: 60 mL / min; Gradient: 14% B to 22% B in 8 min, 22% B; Wave Length: 254 nm) to afford 3-methoxy-JV-(5-( 1 -methyl- lH-imidazol-2-yl)- 1 ,3,4-thiadiazol-2-yl)-2-oxo-4- (pyrimidin-2-ylamino)-2H-pyran-6-carboxamide (Compound 53) (28 mg, 18% yield). LCMS (ES, m / z) = 427 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 9.15 (s, 1H), 8.70 (d, J= 4.8 Hz, 2H), 8.52 (d, J= 2.0 Hz, 1H), 7.37 (s, 1H), 7.16 (dd, J= 4.8, 2.4Hz, 1H), 7.06 (d, J= 2.0 Hz 1H), 4.05 (s, 3H), 3.87 (s, 3H).

[0604] Example 17: 3-methoxy-4-((5-(2-methoxyethoxy)pyrimidin-2-yl)amino)-JV-(5-(5-methyl-LH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 55)

[0605]

[0511] Step 1: To a stirred mixture of 2-chloropyrimidin-5-ol (500 mg, 3.83 mmol, 1 equiv) in tetrahydrofuran (THF) (7 mL) was added 2-methoxyethanol (351 mg, 4.61 mmol, 1.2 equiv), triphenylphosphine (1.51 g, 5.76 mmol, 1.5 equiv) and di-fert-butyl azodidicarboxylate (DBAD) (1.33 g, 5.77 mmol, 1.51 equiv) at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was then diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (50 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1: 1)) to afford 2-chloro-5-(2-methoxyethoxy)pyrimidine (400 mg, 50% yield). LCMS (ES, m / z) = 189 [M+H]+.

[0606]

[0512] Step 2: To a stirred mixture of 2-chloro-5-(2-methoxyethoxy)pyrimidine (220 mg, 1.17 mmol, 1.00 equiv) in dioxane (8.2 mL) was added tris(dibenzylidenaceton)dipalladium(0) (Pd2(dba)3) (214 mg, 0.234 mmol, 0.2 equiv), di-tert-butyl([3,6-dimethoxy-2-[2,4,6-tris(propan-2- yl)phenyl]phenyl])phosphane (tBuBrettPhos) (227 mg, 0.468 mmol, 0.4 equiv), sodium tert- butoxide (157 mg, 1.63 mmol, 1.4 equiv) and ammonia in dioxane (8.2 mL, 0.4 M) at room temperature. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere then cooled to room temperature and concentrated under reduced pressure. The crude residue was then purified by silica gel column chromatography (eluting with CH2Q2 / methanol (MeOH) (9: 1)) to afford 5-(2-methoxyethoxy)pyrimidin-2-amine (160 mg, 78% yield). LCMS (ES, m / z) = 170 [M+H]+.

[0607]

[0513] Step 3: 3-methoxy-4-((5-(2-methoxyethoxy)pyrimidin-2-yl)amino)- / V-(5-(5-methyl-lH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared according to Example 1 Step 10 using 5 -(2 -methoxyethoxy )pyrimidin-2 -amine as the “amine reagent” and 4- bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6- carboxamide (product of step 9, Example 1) as the “halo-pyrone reagent”. LCMS (ES, m / z) = 501.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 9.15 (s, 1H), 8.70 (d, J= 4.8 Hz, 2H), 8.52 (d, J= 2.0 Hz, 1H), 7.37 (s, 1H), 7.16 (dd, J= 4.8, 2.4Hz, 1H), 7.06 (d, J= 2.0 Hz 1H), 4.05 (s, 3H), 3.87 (s, 3H).

[0608] Example 18: 4-((5-(2-hydroxyethoxy)pyrimidin-2-yl)amino)-3-methoxy-JV-(5-(5-methyl-LH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 56)

[0609]

[0514] Step 1: To a stirred solution of 2-chloropyrimidin-5-ol (378 mg, 2.90 mmol, 1 equiv) in N,N- dimethylformamide (DMF) (15 mL) was added tert-butyl (2-iodoethoxy)dimethylsilane (1 g, 3.49 mmol, 1.2 equiv) and K2CO3 (1.00 g, 7.26 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred for 1 h at 20 °C. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with water (3 x 5 mL), then brine (10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (2: 1)) to afford 5-{2-[(tert- butyldimethylsilyl)oxy]ethoxy}-2-chloropyrimidine (610 mg, 73% yield). LCMS (ES, m / z) = 289 [M+H]+.

[0610]

[0515] Step 2: To a stirred solution of 5-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-2-chloropyrimidine (400 mg, 1.38 mmol, 1 equiv) in dioxane (8 mL) was added tris(dibenzylidenaceton)dipalladium(0) (Pd2(dba)s) (120 mg, 0.13 mmol, 0.1 equiv), [3,6-dimethoxy-2',4',6'-tris(l-methylethyl) [1,1'- biphenyl]-2-yl]bis(l,l-dimethylethyl)phosphine (t-BuBrettPhos) (120 mg, 0.25 mmol, 0.2 equiv), t- BuONa (200 mg, 2.08 mmol, 1.5 equiv) and ammonia in dioxane (20 mL, 0.4 M) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with brine (10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (2: 1)) to afford 5-{2-[(tert-butyldimethylsilyl)oxy]ethoxy} pyrimidin-2 -amine (93 mg, 25% yield). LCMS (ES, m / z) = 270 [M+H]+.

[0611]

[0516] Step 3: To a stirred solution of 5-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}pyrimidin-2 -amine (“amine reagent”) (500 mg, 1.86 mmol, 1 equiv) in N,N -dimethylformamide (DML) (15 mL) was added 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran- 6-carboxamide (product of step 9, Example 1; “halo-pyrone reagent”) (500 mg, 1.21 mmol, 0.7 equiv), 2-dicyclohexylphosphino-2',6'-bis(AA-dimethylamino)biphenyl (Cphos) (200 mg, 0.46 mmol, 0.3 equiv), [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino) -l,l'-biphenyl)-2-(2'- amino-l,l'-biphenyl)] palladium(II) methane sulfonate (Cphos Pd G3) (200 mg, 0.24 mmol, 0.1 equiv) and CS2CO3 (750 mg, 2.30 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The mixture was then allowed to cool down to room temperature and directly purified by Cl 8 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide 4- [(5-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}pyrimidin-2-yl)amino]-5-methoxy-A-[5-(5- methylpyrazol-l-yl)-l, 3, 4-thiadiazol-2-yl]-6-oxopyran-2 -carboxamide (320 mg, 29% yield). LCMS (ES, m / z) = 601 [M+H]+.

[0612]

[0517] Step 4: To a stirred solution of 4-[(5-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}pyrimidin-2- yl)amino]-5-methoxy-6-oxo-N-[5-(pyrazol-l-yl)-l,3,4-thiadiazol-2-yl]pyran-2 -carboxamide (40 mg, 0.068 mmol, 1 equiv) in dichloromethane (DCM) (0.80 mL) was added HC1 (4 M in 1,4-dioxane, 0.8 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature then concentrated under reduced pressure. The crude product was then purified by Prep-HPLC (Xselect CSH C18 OBD Column 30* 150mm 5um; mobile phase, water (0.05% TFA) and acetonitrile (MeCN) (29% MeCN up to 39% in 10 min); Detector, UV 254) to provide 4-((5-(2- hydroxyethoxy)pyrimidin-2-yl)amino)-3 -methoxy-A-(5 -(5-methyl- IH-pyrazol- 1 -yl)- 1 ,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 56) (5.1 mg, 15% yield). LCMS (ES, m / z) = 487 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 13.49 (br, 1H), 9.24 (s, 1H), 8.56 (s, 1H), 8.51 (s, 2H), 7.78 (d, J= 1.6 Hz, 1H), 6.44 (d, J= 1.6 Hz, 1H), 4.95 (s, 1H), 4.15 (t, J= 4.8 Hz, 2H), 3.87 (s, 3H), 3.74 (t, J= 4.8 Hz, 2H), 2.68 (s, 3H).

[0613] Example 19: 3-methoxy-4-((5-(methoxymethyl)pyrimidin-2-yl)amino)-JV-(5-(5-methyl-LH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 57) S4

[0614] 3-methoxy-4-((5-

[0615] (methoxymethyl)pyrimidin-2-yl)amino)- A / - (5-(5-methyr-1H-pyrazol-T-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6- carooxamide

[0616]

[0518] Step 1: To a stirred solution of (2-chloropyrimidin-5-yl)methanol (1.50 g, 10.4 mmol, 1 equiv) in methanol (3 mL) was added bis[(4-methoxyphenyl)methyl]amine (5.34 g, 20.8 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for overnight at 80 °C then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1:3)) to afford (2-{bis[(4- methoxyphenyl)methyl] amino} pyrimidin-5-yl)methanol (1.60g, 79% yield). LCMS (ES, m / z) = 366.0 [M+l]+.

[0617]

[0519] Step 2: To a stirred solution of (2-{bis[(4-methoxyphenyl)methyl]amino}pyrimidin-5- yl)methanol (1.40 g, 3.83 mmol, 1 equiv) in tetrahydrofuran (THF) (14 mL) was added sodium hydride (NaH) (184 mg, 7.66 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 0.5 h at 0 °C then methyl iodide (Mel) (652 mg, 4.59 mmol, 1.2 equiv) was added. The resulting mixture was stirred for 1 h at room temperature then quenched by the addition of water (10 mL) at 0 °C. The aqueous layer was then extracted with ethyl acetate (EtOAc) (3 x 20 mL). The organic extracts were combined and concentrated under reduced pressure. The resulting residue was then purified by C18 reverse phase flash chromatography (eluting with acetonitrile / H2O = 3: 1) to afford 5- (methoxymethyl)-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (1.5 g, 86% yield). LCMS (ES, m / z) = 380.0[M+l]+.

[0618]

[0520] Step 3: 5-(methoxymethyl)-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (1.3 g, 4.21 mmol, 1 equiv) was dissolved in 2,2,2-trifluoroacetic acid (TFA) (8 m ) at room temperature. The resulting mixture was stirred for 2 h at 70 °C then concentrated under reduced pressure. The crude product was then purified by C 18 reverse phase flash chromatography (eluting with acctonitrilc / tLO = 3: 1) to afford 5-(methoxymethyl)pyrimidin-2-amine (200 mg, 45% yield). LCMS (ES, m / z) = 140.0[M+l]+.

[0619]

[0521] Step 4: 3-methoxy-4-((5-(methoxymethyl)pyrimidin-2-yl)amino)- / V-(5-(5-methyl-lH-pyrazol- l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 57) was prepared according to Example 1 Step 10 using 5-(methoxymethyl)pyrimidin-2-amine as the “amine reagent” and 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo- 2H-pyran-6-carboxamide (product of step 9, Example 1) as the “halo-pyrone reagent”. LCMS (ES, m / z) = 471.0 [M+l]+; 'HNMR (300 MHz, Methanol-d4) 5 8.93 (s, 1H), 8.63 (s, 2H), 7.62 (s, 1H), 6.31 (s, 1H), 4.47 (s, 2H), 3.98 (s, 3H), 3.44 (s, 3H), 2.66 (s, 3H).

[0620] Example 20: 3-methoxy-4-((4-(2-methoxyethoxy)pyrimidin-2-yl)amino)- / V-(5-(5-methyl-LH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 58)

[0621]

[0522] Step 1: To a stirred solution of 2,4-dichloropyrimidine (4.00 g, 26.8 mmol, 1 equiv) and 2- methoxyethanol (2.04 g, 26.8 mmol, 1 equiv) in acetonitrile (MeCN) (40 mL) was added CS2CO3 (17.5 g, 53.7 mmol, 2 equiv) at room temperature. The resulting mixture was then stirred for 1 h at 80 °C, then filtered, the filter cake was washed with MeCN (3 x 10 mL), and the resulting solution was concentrated under vacuum. The residue was then purified by C18 reverse phase flash chromatography (mobile phase, MeCN in water, 20% gradient in 10 min; detector, UV 254 nm) to provide 2-chloro-4-(2 -methoxyethoxy) pyrimidine (3.00 g, 59% yield).

[0622]

[0523] Step 2: To a stirred solution of 2-chloro-4-(2 -methoxyethoxy) pyrimidine (500 mg, 2.65 mmol, 1 equiv) in N-methyl pyrrolidine (NMP) (2 mL) and NH3.H2O (2 mL) was added Cu (249 mg, 3.92 mmol, 1.5 equiv) at room temperature. The resulting mixture was then stirred for overnight at 100 °C under nitrogen atmosphere. The resulting solids were filtered and the filtrate was diluted with ethyl acetate (EtOAc) (200 mL), then washed with water (3 xlO mL), and brine (20 mL), and dried over Na2SC>4. After filtration, the filtrate was concentrated under vacuum and the residue was purified by Cl 8 reverse phase flash chromatography (mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide 4-(2-methoxyethoxy) pyrimidin-2-amine (150 mg, 33% yield). LCMS (ES, m / z) = 170 [M+H]+.

[0623]

[0524] Step 3: 3-methoxy-4-((4-(2-methoxyethoxy)pyrimidin-2-yl)amino)- / V-(5-(5-methyl-lH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 58) was prepared according to Example 1 Step 10 using 4-(2-methoxyethoxy) pyrimidin-2 -amine as the “amine reagent” and 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo- 2H-pyran-6-carboxamide (product of step 9, Example 1) as the “halo-pyrone reagent”. LCMS (ES, m / z) = 501.15 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 8.71 (s, 1H), 8.38 (d, J= 5.6 Hz, 1H), 7.68 (d, J= 2.0 Hz, 1H), 6.58 (d, J= 5.6 Hz, 1H), 6.36 (s, 1H), 4.60 - 4.56 (m, 2H), 3.87 (s, 3H), 3.81 - 3.73 (m, 2H), 3.30 (s, 3H), 2.63 (s, 3H).

[0624] Example 21: 4-((4-(2-hydroxyethoxy)pyrimidin-2-yl)amino)-3-methoxy-A-(5-(5-methyl-LH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 59) and 4-((4-

[0625] (2-(tert-butoxy)ethoxy)pyrimidin-2-yl)amino)-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 59-OtBu)

[0626] Compound 59-OtBu

[0627] 4-((4-(2-( t ert-butox y )et hox y )py ri m i d i n-2- yl)amino)-3-methoxy- A / -(5-(5-methyl-1 H- pyrazol-1-yl)-1 ,3,4-tniadiazol-2-yl)-2-oxo- 2H-pyran-6-carboxamide

[0525] Step 1: To a stirred solution of 2-(tert-butoxy)ethan-l-ol (2.9 g, 24.5 mmol, 1.2 equiv) in N,N- dimethylformamide (DMF) (20 mL) was added NaH (0.73 g, 30.4 mmol, 1.5 equiv) at 0 °C. To the above mixture was then added 2,4-dichloropyrimidine (3.0 g, 20 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred for an additional 3 h at room temperature then poured into water and extracted with ethyl acetate (EtOAc) (3 x 200 mL). The combined organic layers were washed with water (3 x 20 mL), and brine (30 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by C18 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient in 10 min (LLOMeCN = 3:2); detector, UV 254 nm) to provide 4-(2-(tert-butoxy)ethoxy)-2-chloropyrimidine (3.52 g, 76% yield). LCMS (ES, m / z) = 231 [M+l]+.

[0628]

[0526] Step 2: To a stirred solution of 4-[2-(tert-butoxy)ethoxy]-2 -chloropyrimidine (500 mg, 2.17 mmol, 1 equiv) in N-methyl pyrrolidine (NMP) (3 mL) was added Cu (50 mg, 0.79 mmol, 0.4 equiv) and NH3.H2O (3 mL, 25%) at room temperature. The resulting mixture was stirred for 2 h at 100 °C then cooled to rt and diluted with ethyl acetate (EtOAc) (200 mL). The mixture was then washed with water (3 x 10 mL), and brine (20 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated under vacuum and the residue was purified by C18 reverse phase flash chromatography (mobile phase, MeCN in water, 0% to 100% gradient in 10 min (H2O:MeCN = 65:35); detector, UV 254 nm) to provide 4-[2-(tert-butoxy)ethoxy]pyrimidin-2-amine (190 mg, 41% yield). LCMS (ES, m / z) = 212 [M+l]+.

[0629]

[0527] Step 3: To a stirred solution of 4-[2-(tert-butoxy)ethoxy]pyrimidin-2-amine (“amine reagent”) (92 mg, 0.44 mmol, 1 equiv) and 4-bromo-3-methoxy-N-(5-(5-methyl-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 9, Example 1; “halo-pyrone reagent”) (220 mg, 0.534 mmol, 1.2 equiv) in N,N-dimethylformamide (DMF) (2 mL) was added (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl) [2-(2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (75 mg, 0.090 mmol, 0.2 equiv), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (85 mg, 0.182 mmol, 0.4 equiv) and CS2CO3 (220 mg, 0.675 mmol, 1.6 equiv) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere then cooled to rt and directly purified by C18 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient in 10 min; (FLOMeCN = 1: 1) detector, UV 254 nm) to provide 4-((4-(2-(tert- butoxy)ethoxy)pyrimidin-2-yl)amino)-3-methoxy-N-(5-(5-methyl- IH-pyrazol- 1 -yl)- 1 ,3,4-thiadiazol- 2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 59-OtBu) (164 mg, 69% yield). LCMS (ES, m / z) = 543.2 [M+l]+.

[0630]

[0528] Step 4: 4-((4-(2-(tert-butoxy)ethoxy)pyrimidin-2-yl)amino)-3-methoxy-N-(5-(5-methyl-lH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 59-OtBu) (80 mg, 0.147 mmol, 1 equiv) was added into a solution of HC1 (4 M in 1,4-dioxane, 4 mL) at room temperature. The resulting mixture was stirred for overnight at 80 °C then concentrated under reduced pressure. The crude product was then purified by Prep-HPLC (XBridge Shield RP18 OBD Column, 30* 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile (MeCN); Flow rate: 60 mL / min; Gradient: 40% B to 50% B in 10 min, 50% B; Wave Length: 254 nm) to afford 4-((4-(2-hydroxyethoxy)pyrimidin-2-yl)amino)-3-methoxy-JV-(5 -(5 -methyl- 1H- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 59) (28 mg, 39% yield). LCMS (ES, m / z) = 487.05[M+l]+; ’H NMR (400 MHz, DMSO-d6) 5 8.96 (s, 1H), 8.78 (s, 1H), 8.37 (d, J= 6.0 Hz, 1H), 7.69 (d, J= 6.0 Hz, 1H), 6.57 (d, J= 1.6 Hz, 1H), 6.37 (d, J= 1.6 Hz, 1H), 4.53 (t, J= 5.2 Hz, 2H), 3.87 (s, 3H), 3.83 (t, J= 5.2 Hz, 2H), 2.64 (s, 3H).

[0631] Example 22: A-(5-(3-chlorothiophen-2-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(pyridin-3- ylamino)-2 / 7-pyran-6-carboxamide (Compound 60) -

[0632]

[0529] Step 1: To a solution of methyl 4-bromo-5-methoxy-6-oxopyran-2 -carboxylate (product of Example 1, Step 3) (300 mg, 1.14 mmol, 1 equiv) in dioxane (5 mL) was added 3 -aminopyridine (161 mg, 1.71 mmol, 1.5 equiv), (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'- amino-l,T-biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (191 mg, 0.23 mmol, 0.2 equiv), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (160 mg, 0.34 mmol, 0.3 equiv) and CS2CO3 (743 mg, 2.28 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere then concentrated under reduced pressure. The crude residue was then purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1: 1)) to afford methyl 5-methoxy-6-oxo-4-(pyridin-3- ylamino)pyran-2 -carboxylate (210 mg, 53% yield). LCMS (ES, m / z) = 277.10 [M+H]+.

[0633]

[0530] Step 2: Into a 40 mL vial was added methyl 5-methoxy-6-oxo-4-(pyridin-3-ylamino)pyran-2- carboxylate (200 mg, 0.724 mmol, 1 equiv) and cone. HC1 (5 mL) at room temperature. The resulting mixture was stirred for 1 h at 80 °C then concentrated under reduced pressure. The crude residue obtained was purified by Cl 8 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide 5-methoxy-6- oxo-4-(pyridin-3-ylamino)pyran-2-carboxylic acid (50 mg, 26% yield). LCMS (ES, m / z) = 263.10 [M+H]+.

[0634]

[0531] Step 3: To a solution of 5-methoxy-6-oxo-4-(pyridin-3-ylamino)pyran-2-carboxylic acid (“amino-pyrone reagent”) (100 mg, 0.381 mmol, 1 equiv) in MeCN (3 mL) was added chloro- N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (128 mg, 0.457 mmol, 1.2 equiv), N-methylimidazole (NMI) (62.6 mg, 0.762 mmol, 2 equiv) and 5-(3-chlorothiophen-2-yl)- l,3,4-thiadiazol-2-amine (product of Example 13, Step 3; “ADT amine reagent”) (83.0 mg, 0.381 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The solids were then collected by filtration and washed with acetonitrile and then triturated with acetonitrile (3 mL) and H2O (1 mL) to provide JV-(5-(3-chlorothiophen-2-yl)-l,3,4-thiadiazol-2-yl)- 3-methoxy-2-oxo-4-(pyridin-3-ylamino)-2H-pyran-6-carboxamide (Compound 60) (27.5 mg, 15.5% yield). LCMS (ES, m / z) = 461.90 [M+H]+; ’HNMR (400 MHz, DMSO-d6) 59.25 (s, 1H), 8.54 (d, J= 2.4 Hz, 1H), 8.44-8.42 (m, 1H), 7.92 (d, J= 5.4 Hz, 1H), 7.71-7.68 (m, 1H), 7.49-7.46 (m, 1H), 7.34 - 7.24 (m, 2H), 3.81 (s, 3H).

[0635] Example 23: 3-(2-(methoxyamino)-2-oxoethoxy)-JV-(5-(5-methyl-LH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-4-(pyrimidin-2-ylamino)-2 / 7-pyran-6-carboxamide (Compound 61), tertbutyl 2-((6-((5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)carbamoyl)-2-oxo-4-(pyrimidin- 2-ylamino)-2H-pyran-3-yl)oxy)acetate (Compound 61-CC>2tBu), and 2-((6-((5-(5-methyl-lH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)carbamoyl)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-3- yl)oxy)acetic acid (Compound 6I-CO2H)

[0636] Compound 61-CO2tBu tert-butyl 2-((6-((5-(5-methyl-1 H- pyrazol-1-yl)-1 ,3,4-thiadiazol-2- y I )c arb am oy I )-2-ox o-4-(py ri m i di n -2- ylamino)-2 H-pyran-3-yl)oxy)acetate

[0637]

[0532] Step 1: To a solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2 -carboxylate (product of Example 1, Step 2) (4.0 g, 16 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (20 m ) was added K2CO3 (6.7 g, 48 mmol, 3 equiv) and tert-butyl 2-bromoacetate (8.0 g, 41 mmol, 2.6 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C then diluted with water (100 m ) and extracted with ethyl acetate (EtOAc) (3 x 100 mb). The organic extracts were combined, washed with water (3 x 10 mb), and brine (50 mb), and dried over anhydrous sodium sulfate. After fdtration, the solution was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (7:3)) to afford methyl 4-bromo-5-[2-(tert-butoxy)-2-oxoethoxy]-6-oxopyran-2 -carboxylate (5.29 g, 82% yield). LCMS (ES, m / z) = 363.05 [M+H]+.

[0638]

[0533] Step 2: Into the solution of methyl 4-bromo-5-[2-(tert-butoxy)-2-oxoethoxy]-6-oxopyran-2- carboxylate (2.0 g, 5.5 mmol, 1 equiv) in dioxane (40 mL) was added 2-aminopyrimidine (0.8 g, 8.4 mmol, 1.5 equiv), (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (0.8 g, 0.96 mmol, 0.2 equiv), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (0.4 g, 0.86 mmol, 0.2 equiv) and CS2CO3 (5.24 g, 16.1 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The mixture was then allowed to cool down to room temperature and diluted with ethyl acetate (EtOAc) (300 mL). The solution was washed with water (3 x 20 mL), and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by C 18 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 10% to 30% gradient in 10 min; detector, UV 254 nm) to provide 5-[2- (tert-butoxy)-2-oxoethoxy]-6-oxo-4-(pyrimidin-2-ylamino)pyran-2-carboxylic acid (450 mg, 20% yield). LCMS (ES, m / z) = 364.0 [M+H]+.

[0639]

[0534] Step 3: To a solution of 5-[2-(tert-butoxy)-2-oxoethoxy]-6-oxo-4-(pyrimidin-2-ylamino)pyran- 2-carboxylic acid (“amino-pyrone reagent”) (500 mg, 1.38 mmol, 1 equiv) in acetonitrile (MeCN) (10 mL) were added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (560 mg, 2 mmol, 1.45 equiv), N-methylimidazole (NMI) (550 mg, 6.70 mmol, 5 equiv) and 5-(5- methylpyrazol-l-yl)-l,3,4-thiadiazol-2-amine (product of Example 1, step 8; “ADT amine reagent”) (250 mg, 1.38 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The precipitated solids were then collected by fdtration and washed with acetonitrile (4 x 5 mL) and lyophilized to provide tert-butyl 2-((6-((5-(5-methyl-lH-pyrazol-l-yl)- l,3,4-thiadiazol-2-yl)carbamoyl)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-3-yl)oxy)acetate (Compound 61-CC>2tBu) (300 mg, 41% yield). LCMS (ES, m / z) = 527.0 [M+H]+.

[0640]

[0535] Step 4: To a solution of tert-butyl 2-((6-((5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2- yl)carbamoyl)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-3-yl)oxy)acetate (Compound 61-CC>2tBu) (330 mg, 0.63 mmol, 1 equiv) in dichloromethane (DCM) (5 mL) were added trifluoroacetic acid (TFA) (5 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature then concentrated under reduced pressure to provide 2-((6-((5-(5-methyl-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)carbamoyl)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-3-yl)oxy)acetic acid (Compound 6I-CO2H) (440 mg) which was used as is without further purification. LCMS (ES, m / z) = 471.10 [M+H]+.

[0641]

[0536] Step 5: Into a solution of 2-((6-((5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2- yl)carbamoyl)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-3-yl)oxy)acetic acid (Compound 61- CO2H) (200 mg, 0.42 mmol, 1 equiv) in acetonitrile (MeCN) (10 mL) was added chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (TCFH) (180 mg, 0.64 mmol, 1.51 equiv), N- methylimidazole (NMI) (400 mg, 4.87 mmol, 11.5 equiv) and O-methylhydroxylamine hydrochloride (200 mg, 2.40 mmol, 5.6 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The precipitated solids were then collected by filtration and washed with acetonitrile (3 x 5 mL). The solids were then purified by Prep-HPLC (XBridge Shield RP18 OBD Column, 30* 150 mm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (15% MeCN up to 25% in 10 min); Detector, UV254nm) to afford 3-(2-(methoxyamino)-2- oxocthoxy )-A-(5 -(5-methyl- IH-pyrazol- 1 -yl)- 1 ,3 ,4-thiadiazol-2-yl)-2-oxo-4-(pyrimidin-2-ylamino)- 2 / / -pyran-6-carboxamidc (Compound 61) (26 mg, 12% yield). LCMS (ES, m / z) = 500.10 [M+H]+;1H NMR (400 MHz, DMSO-d6) 5 13.65 (s, 1H), 11.57 (s, 1H), 9.93 (s, 1H), 8.81 - 8.48 (m, 3H), 7.73 (d, J= 1.6 Hz, 1H), 7.19-7.16 (m, 1H), 6.40 (d, J= 1.6 Hz, 1H), 4.62 (s, 2H), 3.65 (s, 3H), 2.65 (s, 3H).

[0642] Example 24: JV-(5-(5-amino-LH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2- yl)amino)-3-(2-methoxyethoxy)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 63) and N-(5-(5- acetamido-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2-yl)amino)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 63-Ac)

[0643]

[0644] Compound 63-Ac

[0645] / V-(5-(5-acetamido-1 / - / -pyrazol-1- yI)-T,3,4-thiadiazol-2-yr)-4-((3- fluoropyridin-2-yl)amino)-3-(2- methoxyefhoxy)-2-oxo-2 / - / -pyran-6- carboxamide

[0646]

[0537] Step 1: To a solution of methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2 -carboxylate (product of Example 3, Step 1) (3.0 g, 9.8 mmol, 1 equiv) and 3-fluoropyridin-2-amine (1.5 g, 13 mmol, 1.4 equiv) in N,N-dimethylformamide (DMF) (10 m ) was added 2-di-tert-butylphosphino- 2',4',6'-triisopropylbiphenyl (tBuXPhos) (0.83 g, 1.95 mmol, 0.2 equiv), [(2-di-tert-butylphosphino- 2', 4', 6'-triisopropyl-l,l'-biphenyl)-2-(2'-amino- 1,1 '-biphenyl)] palladium(II) methanesulfonate (tBuXPhos Pd Gs) (0.78 g, 0.98 mmol, 0.1 equiv) and CS2CO3 (6.37 g, 19.5 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere then was purified directly by C 18 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 0%to 100% gradient in 10 min; detector, UV 254 nm) to provide methyl 4-((3-fluoropyridin-2-yl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxylate (810 mg, 24% yield). LCMS (ES, m / z) = 339[M+1]+.

[0647]

[0538] Step 2: Methyl 4-[(3-fluoropyridin-2-yl)amino]-5-(2-methoxyethoxy)-6-oxopyran-2- carboxylate (700 mg, 2.07 mmol, 1 equiv) was added into hydrochloric acid (2 m , 6 M) at room temperature. The resulting mixture was stirred for 3 h at room temperature then concentrated under reduced pressure. The crude residue was then purified by C18 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient in 10 min; detector, UV 254 nm) to provide 4-[(3-fluoropyridin-2-yl)amino]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid (140 mg, 21% yield). LCMS (ES, m / z) = 325[M+1]+.

[0648]

[0539] Step 3: To a stirred solution of 4-[(3-fluoropyridin-2-yl)amino]-5-(2-methoxyethoxy)-6- oxopyran-2 -carboxylic acid (“amino-pyrone reagent”) (120 mg, 0.37 mmol, 1 equiv) and N-[2-(5- amino-l,3,4-thiadiazol-2-yl)pyrazol-3-yl] acetamide (product of Example 9, Step 3; “ADT amine reagent”) (96 mg, 0.43 mmol, 1.2 equiv) in N,N-dimethylformamide (DMF) (5 m ) was added hydroxybenzotriazole (HoBt) (96 mg, 0.71 mmol, 1.92 equiv) and l-ethyl-3-(3- dimethylaminopropyi)carbodiiniide (EDC1) (144 mg, 0.75 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 3 h at 50 °C. The precipitated solids were collected by filtration and washed with water (3 x 1 m ) and acetonitrile (MeCN) (2 x 3 mb) to provide N-(5-(5-acetamido- lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2-yl)amino)-3-(2-methoxyethoxy)-2- oxo-2H-pyran-6-carboxamide (Compound 63-Ac) (50 mg, 25% yield). ECMS (ESI, m / z) = 531 [M+H]+.

[0649]

[0540] Step 4: To N-(5-(5-acetamido-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-4-((3-fluoropyridin-2- yl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 63-Ac) (20 mg, 0.038 mmol, 1 equiv) was added cone. HC1 (1 mb) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The mixture was neutralized to pH 7 with saturated aqueous NaHCOs. The precipitated solids were then collected by filtration and washed with water (3 x 1 mb) and acetonitrile (MeCN) (3 x 3 mb) to provide / V-(5-(5-amino-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2- yl)-4-((3-fluoropyridin-2-yl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 63) (8.3 mg, 43% yield). ECMS (ESI, m / z) = 489.10 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 13.43 (s, 1H), 8.56 (s, 2H), 8.23 (d, J= 4.8 Hz, 1H), 7.83 (dd, J= 11.2, 8.0 Hz, 1H), 7.49 (d, J= 2.0 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.65 (s, 2H), 5.45 (d, J= 2.0 Hz, 1H), 4.28 - 4.23 (m, 2H), 3.62 - 3.57 (m, 2H), 3.28 (s, 3H).

[0650] Example 25: JV-(5-(5-amino-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4- (phenylamino)-2 / 7-pyran-6-carboxamide (Compound 64) and N-(5-(5-acetamido-lH-pyrazol-l- yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(phenylamino)-2H-pyran-6-carboxamide (Compound 64-Ac) Compound 64

[0651] Compound 64-Ac A / -(5-(5-amino-1 H-py razol-1 -y I)- 1 ,3 4-thiadiazol-2-y()-3-methoxy-

[0652] A / -(5-(5-acetamido-1 H-py razol-1 - 2-oxo-4-(phenylamino)-2 H- l)-1 ,3,4-thiadiazol-2-yl)-3-methoxy- pyran-6-carboxamide !-oxo-4-(phenylamino)-2 H-pyran-6- carboxamide

[0653]

[0541] Step 1: To a stirred solution of methyl 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylate (product of Example 1, Step 3) (500 mg, 1.90 mmol, 1 equiv) in ethanol (EtOH) (6 m ) was added aniline (885 mg, 9.50 mmol, 5 equiv) at room temperature under nitrogen atmosphere. The resulting solution was stirred for 24 h at 50 °C under nitrogen atmosphere. The resulting mixture was then diluted with water (50 m ) and adjusted pH to 2 with aq. HC1 (2 M). The resulting solution was extracted with ethyl acetate (EtOAc) (3 x 100 mb) and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (9: 1)) to afford methyl methyl 3-methoxy-2-oxo-4-(phenylamino)-2H-pyran-6-carboxylate (50 mg, 9.6% yield). ECMS (ES, m / z) = 276.1 [M+H]+.

[0654]

[0542] Step 2: A solution of methyl 3-methoxy-2-oxo-4-(phenylamino)-2H-pyran-6-carboxylate (160 mg, 0.58 mmol, 1 equiv) in hydrochloric acid (3 mb, 6M) was stirred for 4 h at 80 °C. The resulting mixture was then concentrated under reduced pressure to afford 3-methoxy-2-oxo-4-(phenylamino)- 2H-pyran-6-carboxylic acid (120 mg, 79% yield) which was used directly in the next step without further purification. ECMS (ES, m / z) = 261.9 [M+H]+.

[0655]

[0543] Step 3: To a stirred solution of 3-methoxy-2-oxo-4-(phenylamino)-2H-pyran-6-carboxylic acid (“amino-pyrone reagent”) (60 mg, 0.23 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (1 mb) was added hydroxybenzotriazole (HoBt) (47 mg, 0.35 mmol, 1.5 equiv), l-ethyl-3-(3- dimetliylaminopropyljcarbodiimide (EDCI) (88 mg, 0.46 mmol, 2 equiv) and N-[2-(5-amino-l,3,4- thiadiazol-2-yl)pyrazol-3-yl] acetamide (product of Example 9, Step 3; “ADT amine reagent”) (51 mg, 0.23 mmol, 1 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature then diluted with water (5 mL). The precipitated solids were collected by filtration and washed with water (2 x 1 mL) and acetonitrile (MeCN) (2 x 1 mL) to afford N-(5-(5-acetamido-lH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(phenylamino)-2H-pyran-6-carboxamide (Compound 64-Ac) (80 mg, 74% yield). LCMS (ES, m / z) = 468.3 [M+H]+.

[0656]

[0544] Step 4 : A solution ofN-(5-(5-acetamido-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2- oxo-4-(phenylamino)-2H-pyran-6-carboxamide (Compound 64-Ac) (70 mg, 0.15 mmol, 1 equiv) and trifluoroacetic acid (TFA) (1 mL) in tetrahydrofuran (THF) (0.5 mL) and H2O (0.5 mL) was stirred for 12 h at 50 °C. The resulting mixture was then concentrated under reduced pressure and the crude product was purified by Prep-HPLC (XSelect CSH Fluoro Phenyl, 30* 150 mm; Mobile Phase A: acetonitrile (MeCN), Mobile Phase B: water (0.05% TFA); Flow rate: 60 mL / min; Gradient: 33% B to 43% B in 8 min, 43% B; Wave Length: 254 / 220 nm) to afford / V-(5-(5-amino- IH-pyrazol-l-yl)- l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(phenylamino)-2H-pyran-6-carboxamide (Compound 64) (2.3 mg, 3.6% yield). LCMS (ES, m / z) = 426.0 [M+H]+l; ’H NMR (400 MHz, DMSO-d6) 5 9.17 (s, 1H), 7.50 - 7.41 (m, 3H), 7.31 - 7.19 (m, 4H), 6.70-6.64 (m, 2H), 5.44 (d, J= 1.2 Hz, 1H), 3.81 (s, 3H).

[0657] Example 26: 2V-(5-(3-chloro-l-methyl-LH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-3-(2- hydroxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2 / 7-pyran-6-carboxamide (Compound 65)

[0658] Compound 65

[0659] M-(5-(3-chloro-1-methyl-1 H-pyrrol-2-yl)-1 ,3,4- thiadiazol-2-yl)-3-(2-hydroxyethoxy)-2-oxo-4-

[0660] (pyrimidin-2-ylamino)-2 H-pyran-6- carboxamide

[0661]

[0545] Step 1: To a stirred solution of methyl 4-bromo-3 -hydroxy-2 -oxo-2H-pyran-6-carboxylate (product of Example 1, Step 2) (1.6 g, 6.4 mmol, 1 equiv), 2-(tert-butoxy)ethan-l-ol (837 mg, 7.08 mmol, 1.1 equiv) and PPhs (2.54 g, 9.66 mmol, 1.5 equiv) in tetrahydrofuran (THF) (16 mL) was added di-tert-butyl azodidicarboxylate (DBAD) (2.23 g, 9.67 mmol, 1.5 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 12 h at room temperature under nitrogen atmosphere then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (10: 1)) to afford methyl 4-bromo-3-(2-(tert-butoxy)ethoxy)-2-oxo-2H-pyran-6-carboxylate (1290 mg, 57% yield). LCMS (ES, m / z) = 349.2 [M+H]+.

[0662]

[0546] Step 2: To a stirred solution of methyl 4-bromo-3-(2-(tert-butoxy)ethoxy)-2-oxo-2H-pyran-6- carboxylate (1 g, 2.86 mmol, 1 equiv), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,T- biphenyl)[2-(2'-amino-l,T-biphenyl)]palladium(II) methane sulfonate (XantPhos Pd G3) (510 mg, 0.57 mmol, 0.2 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (330 mg, 0.57 mmol, 0.2 equiv) and CS2CO3 (1.86 g, 5.71 mmol, 2 equiv) in dioxane (20 mb) was added 2- aminopyrimidine (540 mg, 5.68 mmol, 2 equiv) at room temperature under nitrogen atmosphere and the resulting solution was stirred for 1 h at 100 °C under nitrogen atmosphere then concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography (eluting with dichloromethane (DCM) / methanol (MeOH) (10: 1)) to afford methyl 3-(2-(tert- butoxy)ethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-6-carboxylate (770 mg, 74% yield). LCMS (ES, m / z): 364.1 [M+H]+.

[0663]

[0547] Step 3: A solution of methyl 3-(2-(tert-butoxy)ethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H- pyran-6-carboxylate (500 mg, 1.38 mmol, 1 equiv) in hydrochloric acid (7 mb, 6M) was stirred for 1 h at 80 °C. The resulting mixture was then concentrated under reduced pressure to afford 3-(2- hydroxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-6-carboxylic acid (350 mg, 87% yield) which was used directly in the next step without further purification. LCMS (ES, m / z) = 294.2[M+H]+.

[0664]

[0548] Step 4: To a stirred solution of 3-(2-hydroxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H- pyran-6-carboxylic acid (“amino-pyrone reagent”) (250 mg, 0.85 mmol, 1 equiv) in N,N- dimethylformamide (DMF) (2.5 mb) was added hydroxybenzotriazole (HoBt) (230 mg, 1.70 mmol, 2 equiv), l-ethyl-3-(3~dimethylaminopropyl)carbodiimide (EDCI) (491 mg, 2.56 mmol, 3 equiv) and 5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2-amine (product of Example 2, Step 5; “ADT amine reagent”) (183 mg, 0.85 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The mixture was then directly purified by Prep-HPLC (XBridge Shield RP18 OBD Column, 30* 150 mm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (20% MeCN up to 30% in 10 min)) to afford A-(5 -(3 -chloro- 1 -methyl- 1H- pyrrol-2-yl)- l,3,4-thiadiazol-2-yl)-3-(2-hydroxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran- 6-carboxamide (Compound 65) (3.4 mg, 0.8% yield). LCMS (ES, m / z) = 490.05 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 59.39 (s, 1H), 8.69-8.66 (m, 3H), 7.17-7.15 (m, 1H), 7.07 (s, 1H), 6.27 (d, J = 2.8 Hz, 1H), 5.46 (t, J= 4.0 Hz, 1H), 4.14 (t, J= 4.4 Hz, 2H), 3.92 (s, 3H), 3.66 (t, J= 4.4 Hz, 2H).

[0665] Example 27: JV-(5-(5-cyano-LH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4- (phenylamino)-2 / 7-pyran-6-carboxamide (Compound 66)

[0666] Compound 66

[0667] A / -(5-(5-cyano-1r / -pyrazol-1-yl)-1 ,3,4- thiadiazol-2-yl)-3-methoxy-2-oxo-4- (phenylamino)-2 / 7-pyran-6-carboxamide

[0668]

[0549] Step 1: To a stirred solution of 2-(2,5-dimethylpyrrol-l-yl)-5-(pyrazol-l-yl)-l,3,4-thiadiazole (product of Example 1, Step 6) (6.0 g, 24 mmol, 1 equiv) in tetrahydrofuran (THF) (70 mL) was added n-butyl lithium (n-BuLi) (11.7 mL, 29.4 mmol, 1.2 equiv, 2.5 M) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. To the above mixture was then added iodine (18.6 g, 73.4 mmol, 3.0 equiv) in THF (20 mL) in small portions over 30 min at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for an additional 40 min at -78 °C. And then the resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 100 mL), washed with sat.

[0669] Na2S20s (2 x 100 mL), brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ether / ethyl acetate (PE / EtOAc) (15: 1) to afford 2-(2,5-dimethyl-lH- pyrrol- l-yl)-5-(5-iodo- IH-pyrazol- 1 -yl)- 1 ,3,4-thiadiazole (6.8 g, 75% yield) as a light yellow solid. LCMS (ES, m / z): 372 [M+H]+. 1H NMR (400 MHz, DMSO-tL) 5 7.98 (d, J= 1.8 Hz, 1H), 6.99 (d, J= 1.8 Hz, 1H), 5.97 (s, 2H), 2.25 (s, 6H).

[0550] Step 2: To a stirred solution of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-(5-iodo-lH-pyrazol-l-yl)- 1,3,4-thiadiazole (400 mg, 1.08 mmol, 1 equiv) in N-methyl pyrrolidine (NMP) (5 mL) was added CuCN (200 mg, 2.23 mmol, 2.1 equiv) at room temperature. The resulting mixture was stirred for 1 h at 150 °C under nitrogen atmosphere. The solids were then fdtered off and the fdtrate diluted with water and extracted with ethyl acetate (EtOAc) (3 x 100 mL). The combined organic layers were washed with water (4 x 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (5: 1)) to afford l-(5-(2,5- dimethyl-lH-pyrrol-l-yl)-l,3,4-thiadiazol-2-yl)-lH-pyrazole-5-carbonitrile (233 mg, 76% yield). LCMS (ES, m / z) = 271 [M+H]+.

[0670]

[0551] Step 3: To a stirred solution of l-(5-(2,5-dimethyl-lH-pyrrol-l-yl)-l,3,4-thiadiazol-2-yl)-lH- pyrazole-5 -carbonitrile (220 mg, 0.81 mmol, 1 equiv) in H2O (1 mL) was added trifluoroacetic acid (TFA) (3 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (5: 1)) to afford l-(5- amino-l,3,4-thiadiazol-2-yl)-lH-pyrazole-5-carbonitrile (133 mg, 85% yield). LCMS (ES, m / z) = 193 [M+H]+.

[0671]

[0552] Step 4: To a stirred solution of 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid (product of Example 3, Step 4) (259 mg, 1.04 mmol, 2 equiv) and l-(5-amino-l,3,4-thiadiazol-2- yl)-lH-pyrazole-5-carbonitrile (100 mg, 0.52 mmol, 1 equiv) in acetonitrile (MeCN) (3 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (438 mg, 1.56 mmol, 3.00 equiv) and N-methylimidazole (NMI) (427 mg, 5.20 mmol, 10 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 3 mL) to provide 4-bromo-N-(5-(5- cyano- IH-pyrazol- 1 -yl)- 1 ,3 ,4-thiadiazol-2-yl)-3 -methoxy-2-oxo-2H-pyran-6-carboxamide (150 mg, 65% yield). LCMS (ES, m / z) = 423 [M+H]+.

[0672]

[0553] Step 5 : A-(5-(5-cyano-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4- (phenylamino)-2H-pyran-6-carboxamide (Compound 66) was prepared according to Example 1 Step 10 using aniline as the “amine reagent” and 4-bromo-N-(5-(5-cyano-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the “halo-pyrone reagent”. LCMS (ES, m / z) = 436.07 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 9.13 (s, 1H), 8.17 (d, J= 2.0 Hz, 1H), 7.61 (d, J= 2.0 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.31 - 7.17 (m, 4H), 3.80 (s, 3H).

[0673] Example 28: 3-methoxy-4-(methyl(phenyl)amino)- / V-(5-(5-methyl-LH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 67)

[0674] Compound 67

[0675] 3-methoxy-4-(methyl(phenyl)amino)- / V- (5-(5-methy[-1H-pyrazol-1-yl)-1 ,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6- carboxamide

[0676]

[0554] Step 1: To a stirred solution of methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (product of Example 1, Step 3) (2.0 g, 7.6 mmol, 1 equiv) in ethanol (EtOH) (60 m ) was added diisopropylethylamine (DIEA) (1.97 g, 15.2 mmol, 2 equiv) and methylaniline (978 mg, 9.12 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1 h at 50 °C then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (PE / EtOAc) (2:3)) to afford ethyl 3-methoxy-4- (methyl(phenyl)amino)-2-oxo-2H-pyran-6-carboxylate (300 mg, 13% yield). LCMS (ES, m / z) = 304.0 [M+H]+.

[0677]

[0555] Step 2: To a stirred solution of ethyl 3-methoxy-4-(methyl(phenyl)amino)-2-oxo-2H-pyran-6- carboxylate (“amino-pyrone reagent”) (100 mg, 0.35 mmol, 1 equiv) and 5-(5-methyl-lH-pyrazol- l-yl)-l,3,4-thiadiazol-2-amine (product of Example 1, Step 8; “ADT amine reagent”) (80 mg, 0.44 mmol, 1.3 equiv) in tetrahydrofuran (THF) (0.7 mb) was added lithium bis(trimethylsilyl)amide (LiHMDS) (0.5 mb of a 1 M soln in THF, 0.5 mmol, 1.5 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere then concentrated under reduced pressure. The crude product was then purified by Prep-HPLC (XBridge Prep Phenyl OBD Column, 19*250 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile (MeCN); Flow rate: 25 mL / min; Gradient: 30% B to 33% B in 8 min, 33% B; Wave Length: 254 nm) to afford 3-methoxy-4-(methyl(phenyl)amino)- / V-(5-(5-methyl- IH-pyrazol- 1 -yl)- 1 ,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (7.5 mg, 4.8% yield). LCMS (ES, m / z) = 439.10 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 13.59 (s, 1H), 7.76 (s, 1H), 7.44-7.40 (m, 2H), 7.26- 7.21 (m, 3H), 7.06 (s, 1H), 6.43 (s, 1H), 3.64 (s, 3H), 3.58 (s, 3H), 2.66 (s, 3H).

[0678] Example 29: 4-((4-(2-cyanoethoxy)pyrimidin-2-yl)amino)-3-methoxy-A-(5-(5-methyl-LH- pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2 / 7-pyran-6-carboxamide (Compound 69)

[0679]

[0556] Step 1: To a stirred solution of 4-((4-(2 -hydroxyethoxy )pyrimidin-2-yl)amino)-3-methoxy-N- (5-(5-methyl-lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound

[0680] 59 of Example 21) (300 mg, 0.62 mmol, 1 equiv) in dichloromethane (DCM) (6 mL) was added triethylamine (TEA) (250 mg, 2.47 mmol, 4 equiv) and methanesulfonyl methanesulfonate (MS2O) (220 mg, 1.26 mmol, 2.1 equiv) at room temperature. The resulting mixture was stirred for 3 h at

[0681] 60 °C then concentrated under reduced pressure to provide crude 2-((2-((3-methoxy-6-((5-(5-methyl- lH-pyrazol-l-yl)-l,3,4-thiadiazol-2-yl)carbamoyl)-2-oxo-2H-pyran-4-yl)amino)pyrimidin-4- yl)oxy)ethyl methanesulfonate, which was used directly in the next step without further purification. LCMS (ES, m / z) = 565 [M+l]+.

[0682]

[0557] Step 2: To a stirred solution of 2-((2-((3-methoxy-6-((5-(5-methyl-lH-pyrazol-l-yl)-l,3,4- thiadiazol-2-yl)carbamoyl)-2-oxo-2H-pyran-4-yl)amino)pyrimidin-4-yl)oxy)ethyl methane-sulfonate (120 mg, 0.213 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (2 mL) was added NaCN (20 mg, 0.41 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 1 h at 80 °C then purified directly by Cl 8 reverse phase flash chromatography (mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient in 10 min (H2O:MeCN=25:75); detector, UV 254 nm) followed by additional purification by Prep-HPLC (Xselect CSH C18 OBD Column 30* 150mm 5pm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: acetonitrile (MeCN); Flow rate: 60 mL / min;

[0683] Gradient: 25% B to 35% B in 10 min, 35% B to 35% B in 12 min, 35% B; Wave Length: 254 / 220 nm) to afford 4-((4-(2-cyanoethoxy)pyrimidin-2-yl)amino)-3-methoxy- / V-(5-(5-methyl- IH-pyrazol- l-yl)-l,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 69) (10.2 mg, 7.9% yield). LCMS (ES, m / z) = 496.10 [M+l]+; ’H NMR (400 MHz, DMSO-d6) 5 13.39 (br, 1H), 10.55 (br, 1H), 7.79 (d, J= 1.6 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.26 (s, 1H), 6.45 (s, 1H), 5.64 (d, J= 1.6 Hz, 1H), 4.23 (t, J= 6.4 Hz, 2H), 3.76 (s, 3H), 2.97 (t, J= 6.4 Hz, 2H), 2.68 (s, 3H).

[0684] Example 30: 2V-(5-(3-chloro-l-methyl-LH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)-5-oxo-l-(pyrimidin-

[0685] 2-yl)-l,2,3,5-tetrahydropyrano[3,4-b] [l,4]oxazine-7-carboxamide (Compound 70)

[0686]

[0687]

[0558] Step 1: To a stirred solution of N-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2- yl)-3-(2-hydroxyethoxy)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-6-carboxamide (Compound 65, Example 26) (100 mg, 0.204 mmol, 1 equiv) in dichloromethane (DCM) (2 mL) was added methanesulfonic anhydride (284 mg, 1.63 mmol, 8 equiv) and diisopropylethylamine (DIEA) (80 mg, 0.62 mmol, 3 equiv) at 0 °C. The resulting solution was stirred for 24 h at room temperature then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with DCM / methanol (MeOH) (12: 1)) to afford 2-((6-((5 -(3 -chloro- 1- methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol-2-yl)carbamoyl)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran- 3-yl)oxy)ethyl methane sulfonate (130 mg, 100% yield). LCMS (ES, m / z) = 568.2 [M+H]+.

[0688]

[0559] Step 2: To a stirred solution of 2-((6-((5-(3-chloro-l-methyl-lH-pyrrol-2-yl)-l,3,4-thiadiazol- 2-yl)carbamoyl)-2-oxo-4-(pyrimidin-2-ylamino)-2H-pyran-3-yl)oxy)ethyl methane sulfonate (90 mg, 0.16 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (1.5 mL) was added tetrabutylammonium bromide (TBAB) (15 mg, 0.047 mmol, 0.3 equiv), K2CO3 (66 mg, 0.48 mmol, 3 equiv) and trimethylsilyl cyanide (TMSCN) (33 mg, 0.33 mmol, 2.1 equiv) at room temperature. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (20 mL) at room temperature, and extracted with ethyl acetate (EtOAc) (3 x 30 mL). The combined organic layers were washed with brine (20 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure and the crude product was purified by Prep-HPLC (XBridge Shield RP18 OBD Column, 30* 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile (MeCN); Flow rate: 60 mL / min; Gradient: 20% B to 35% B in 10 min, 35% B; Wave Length: 254 nm) to afford X-(5-(3-chloro-l-methyl-lH-pyrrol-2-yl)- l,3,4-thiadiazol-2-yl)-5-oxo-l-(pyrimidin-2-yl)-l,2,3,5-tetrahydropyrano[3,4-b][l,4]oxazine-7- carboxamide (Compound 70) (1.6 mg, 2.1% yield). LCMS (ES, m / z) = 471.95 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 8.73 (d, J= 4.8 Hz, 2H), 8.04 (s, 1H), 7.17 (s, 1H), 6.99 (s, 1H), 6.21 (s, 1H), 4.36-4.31(m, 2H), 4.18-4.12 (m, 2H), 3.87 (s, 3H).

[0689]

[0560] Compounds provided in below Table A were, or may be, synthesized following the Procedures as described. LC-MS data is provided for each synthesized compound. Dashed lines (— ) indicate no data available.

[0690] Assay Methods

[0691]

[0561] cGAS catalyzes the cyclization of ATP and GTPto produce cGAMP, which is the activating ligand of STING. Human cGAS (hcGAS) inhibition can thus be quantified by measuring how much cGAMP is formed either indirectly, by monitoring ATP-depletion as in the hcGAS Kinase-Glo assay (as described below), or directly, such as using the hcGAS LCMS assay (as described below). 1. hcGAS Kinase-Glo assay

[0692]

[0562] Compounds were tested for their human-cGAS (h-cGAS) inhibition activity using the methodology reported in Lama et al., “Development of human cGAS-specific small molecule inhibitors for repression of dsDNA-triggered interferon expression”, Nature Communications 10, Article number: 2261 (2019), with slight changes to some conditions as shown in Table B.

[0693]

[0563] The results of the assay, expressed in IC50 values, are reported in Table D with the following designations: A represents an IC50 value < 0.01 pM; B represents an IC50 value > 0.01 pM and < 0.03 pM; C represents an IC50 value > 0.03 pM and < 0.1 pM; D represents an IC50 value > 0.1.

[0694] 2. hcGAS LCMS assay

[0695]

[0564] Compounds were tested for their h-cGAS inhibition activity using direct measurement of cGAMP production by LC / MS. Briefly, compounds were incubated with enzyme and substrates for 4 hours (see Table C), before the reaction was stopped with 3 volumes of 70 / 30 Acetonitrile / H2O mix containing 0.15 uM CGAMP-13CIO15N5 as internal standard and mixed for 5 min. After centrifugation (3700 rpm, 10 min, 10° Celsius), 100 uL of each reaction was collected and mixed to equal volume of acetonitrile (MeCN). Samples were then analyzed on Qexactive (Column: XBridge BEH Amide Column, 130A, 3.5 pm, 3 mm x 50 mm, Mobile phase A: lOmM Ammonium acetate in 95 / 5 H2O / MeCN (0.5% DMSO), Mobile phase B: MeCN (0.5% DMSO).

[0696]

[0565] The results of the assay, expressed as IC50 values, are reported in Table D with the following designations: A represents an IC50 value < 0.005 pM; B represents an IC50 value > 0.005 pM and < 0.02 pM; C represents an IC50 value > 0.02 pM and < 0.06 pM; D represents an IC50 value > 0.06 and < 0.2 pM; E represents an IC50 value > 0.2.

[0697] 3. Activity Data

[0698]

[0566] Activity data obtained from the above described assay methods is provided in Table D.

[0699] Dashed lines (— ) indicate no data available.

[0700] Other Embodiments

[0701]

[0567] Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0702]

[0568] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims or embodiments is introduced into another claim or embodiment. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where the present disclosure recites elements presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be further understood that when any variable (e.g. , an R group) is present more than one time in a given Markush structure (e.g. , 2 or more times), and that variable may be selected from a given list of two or more elements, unless otherwise stated or understood within the context of the present disclosure, that variable (e.g. , the R group) at each repeated occurrence (e.g., 2 or more times) is independent of each other, being independently selected from that given list.

[0703]

[0569] It should also be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure also consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are understood to be included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0704]

[0570] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the present disclosure, the present disclosure shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0705]

[0571] The scope of the present embodiments described herein is not intended to be limited to the above Description, but also includes that as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein:Ring A is a 5-membered monocyclic heteroaryl;R1is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -Ls- Cs-Ce carbocyclyl), or -L3-(4- to 10- membered heterocyclyl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently halogen, -OR1B, -N(R1B)2, -SR1B, -C(=O)OR1B, -C(=O)N(R1C)2, -(C1-C3 alkylene)-OR1B, or -(C1-C3 alkylene)-SR1B; or two instances of R1Aare taken together to form =0; each R1Bis independently hydrogen, C1-C4 alkyl, or Ci-C4haloalkyl, wherein the alkyl and haloalkyl are independently substituted with 0, 1, 2, 3, or 4 R1D; each R1Cis independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR1F; each R1Dis independently halogen, -OR1F, or -N(R1F)2; and each R1Fis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is independently substituted with 0, 1, 2, 3, or 4 R1E; and each R1Eis independently -(C1-C3 alkylene)-OR1Bor -OR1B, or two instances of R1Eare taken together to form =0;R2is hydrogen or Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R2A; each R2Ais independently halogen, -OR2B, or -N(R2B)2; and each R2Bis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; or R1and R2are joined, with the atoms to which they are attached, to form a 6- or 7- membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A;Ring B is a Ce-Cio aryl or 5- to 10-membered heteroaryl; each R3Ais independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, -Li-CN, -Li- SOR3C, -LI-SO2R3C, -LI-SR3B, -LI-PO(R3C)2, -LI-OR3B, -LI-N(R3B)2, -LI-C(=O)N(R3B)2or -Li- C(=O)OR3B, -Li-(C3-Ce carbocyclyl), -Li-(4- to 6-membered heterocyclyl), -Li-(Ce-io aryl), or -Li-(5- to 10-membered heteroaryl), or two R3Agroups are joined, with the atoms to which they are attached, to form Ce aryl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl areindependently substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen, C1-C3 alkyl, CNC, carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Cis independently C1-C3 alkyl or C1-C3 haloalkyl; each R3Dis independently halogen, -OR3E, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; each R3Eis independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; each R4is independently halogen, -CN, -L2-OR4A, -L2-N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R4Aand R4Bis independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -C(=O)R4C, wherein R4Cis Ci-Ce alkyl or Ci-Ce haloalkyl; each Li and L2 is independently a bond, C1-C3 alkylene, or C1-C3 haloalkylene; p is 0, 1, 2, 3, or 4; and m is 0, 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl substituted with 0, 1, 2, 3, or 4 R3A.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 6-membered heteroaryl, wherein the heteroaryl has 1 or 2 ring N atoms.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5 -membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N and O.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one R3Asubstituent is -Li-CN, in order to provide a Ring B of formula:wherein Ring B is Ce aryl or 5- or 6-membered heteroaryl, and p is 0, 1, 2, or 3.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from one of the following formulae:(vii-c).

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

8. The compound of any one of claims 1-5, wherein the compound is of Formula (I-e-1),(I-e-2), (I-e-3), or (I-f):or a pharmaceutically acceptable salt thereof.

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

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

11. The compound of any one of claims 1-5, wherein the compound is of Formula (I'), (I"), (I'"),(I-BC-a), or (I-BC-b):or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently halogen, -CN, -OR3B, or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently -CH2OCH3, -CH2OH, -OCH3, -OH, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2CN, -CN, or F.

14. The compound of any one of claims 1-6 or 11-13, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

18. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein Ring A is of one of the following formulae:

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A is of one of the following formulae:

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R4is independently halogen, -CN, -L2-OR4A, -L2-N(R4B)2, Ci-Ce alkyl, or Ci-Cehaloalkyl.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -CH3, -CHF2, Cl, -CN, or -NH2.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 1.

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 2.

26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 0.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 1.

28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 2.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently -OR1B, -C(=O)OR1B, or -C(=O)N(R1C)2; each R1Bis independently hydrogen or C1-C3 alkyl; and each R1Cis independently hydrogen, C1-C3 alkyl, or -OR1B;R2is hydrogen or R1and R2are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R1A; each R3Ais independently C1-C3 alkyl, halogen, -Li-CN, or -LI-OR3B, and wherein the alkyl is independently substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D; each R3Cis independently C1-C3 alkyl; each R3Dis independently halogen, -CN, or -OR3E;R3Eis hydrogen or C1-C3 alkyl; each R4is independently halogen, -CN, -L2-OR4A, or -L2-N(R4B)2; and each R4Aand R4Bare independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each Li and L2is independently a bond or C1-C3 alkylene; p is 0, 1, or 2; and m is 1 or 2.

30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl substituted with 0, 1, 2, 3, or 4 R1A; each R1Ais independently -OR1Bor -C(=O)N(R1C)2; each R1Bis independently hydrogen or C1-C3 alkyl; and each R1Cis independently hydrogen, C1-C3 alkyl, or -OR1B;R2is hydrogen; each R3Ais independently C1-C3 alkyl, halogen, -CN, or -OR3B, wherein the alkyl is substituted with 0, 1, 2, 3, or 4 R3D; each R3Bis independently hydrogen or C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R3D; each R3Dis independently halogen, -CN, or -OR3E;R3Eis hydrogen or C1-C3 alkyl; each R4is independently halogen, -CN, -N(R4B)2, Ci-Ce alkyl, or Ci-Ce haloalkyl;each R4Bis independently hydrogen or C1-C3 alkyl; p is 0, 1, or 2; and m is 1 or 2.

31. The compound of claim 1, wherein the compound is selected from those in Table 1, and pharmaceutically acceptable salts thereof.

32. A pharmaceutical composition comprising the compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

33. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32.

34. A method of modulating cGAS activity in a cell comprising contacting a cell with a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32.

35. A method of preparing a compound of F ormula (I) :or a salt thereof, wherein Ring A, Ring B, R1, R2, R3A, R4, p and m are defined in claim 1, the method comprising peptide coupling of a compound of Formula (H-l), or salt thereof, with a compound of Formula (N), or salt thereof:wherein Rais hydrogen, Ci-6 alkyl or Ci-6 haloalkyl, to provide a compound of Formula (I), or salt thereof.

36. The method of claim 35, wherein the compound of Formula (H-l), or salt thereof, is of Formula (H-2):salt thereof, and wherein the method provides a compound of Formula (I'):(I'), or salt thereof.

37. The method of claim 35 or 36, further comprising cross-coupling a compound of Formula (K), or salt thereof, with a compound of Formula (D), or salt thereof,wherein Rais Ci-6 alkyl or Ci-6 haloalkyl, R3is Ring B, and X is Cl, Br, or I, to provide a compound of Formula (N), or salt thereof.

38. A method of preparing a compound of Formula (I) :or a salt thereof, wherein Ring A, Ring B, R1, R2, R3A, R4, p and m are defined in claim 1, the method comprising cross-coupling of the amine of Formula (K), or salt thereof, with a compound of Formula(J-l), or salt thereof:wherein R3is Ring B and X is Cl, Br, or I, to provide a compound of Formula (I), or salt thereof.

39. The method of claim 38, wherein the compound of Formula ( J-l), or salt thereof, is of Formula ( J-2):(J-2), or salt thereof, and wherein the method provides a compound of Formula (I'):(I'), or salt thereof.

40. The method of claim 38, further comprising peptide coupling of a compound of Formula (FI-1), or salt thereof, with a compound of Formula (D), or salt thereof:to provide a compound of Formula (J-l), or salt thereof.

41. The method of claim 39, further comprising peptide coupling of a compound of Formula (FI-2), or salt thereof, with a compound of Formula (D), or salt thereof:to provide a compound of Formula (J-2), or salt thereof.

42. The method of claim 35 or 40, further comprising reacting a hydrazine carbothioamide of Formula (G), or salt thereof, with a carboxylic acid containing compound of Formula (F-l), or salt thereof, or nitrile containing compound of Formula (F-2), or salt thereof:to provide a compound of Formula (H-l), or salt thereof.

43. The method of claim 36 or 41, further comprising coupling a compound Formula (M), or salt thereof, wherein Y is Cl, Br, or I, with an amine of Formula (L), or salt thereof:to provide a compound of Formula (H-2), or salt thereof.

44. The method of any one of claims 37, 40, and 41, further comprising:(d) Protecting a compound of Formula (A), or salt thereof, to provide an alkyl ester of Formula (B):or salt thereof, wherein Rais Ci-e alkyl or Ci-e haloalkyl;(e) Halogenating the compound of Formula (B), or salt thereof, to provide a compound of Formula (C):or salt thereof, wherein X is Cl, Br, or I;(f) Protecting the hydroxyl group of the compound of Formula (C), or salt thereof, to provide a compound of Formula (D):or salt thereof, wherein R1is as defined in claim 1 ; and(d) optionally, deprotecting the compound of Formula (D), or salt thereof, to provide a carboxylic acid of Formula (D), wherein Rais hydrogen.

45. A method of preparing a compound of Formula (I-BC-a):r salt thereof; wherein Ring A, R3A, R4, p and m are defined in claim 1, the method comprising cyclizing a compound of Formula (L-l):r salt thereof, wherein LG is a leaving group.

46. The method of claim 45, wherein the compound of Formula (I-BC-a), or salt thereof, is ofFormula (I-BC-b):(I-BC-b), or salt thereof; and the compound of Formula (L-l), or salt thereof, is of Formula (L-2):or salt thereof.

47. The method of claim 45 or 46, wherein the compound of Formula (L-l), or salt thereof, or compound of Formula (L-2), or salt thereof, is prepared by conversion of the terminal -OH of Formula (I") or of Formula (I'"):, of,

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