Thiadiazole derivatives as inhibitors of cyclic GMP-AMP synthase and their use

Abstract

The present disclosure provides a compound of formula (I): JPEG2026501225000412.jpg44166 [Rings A and R in the formula 1 , R 2 , R 3 , R 4 and m are described herein] or pharmaceutically acceptable salts thereof, methods of preparation, methods of treatment, and pharmaceutical compositions containing same. The present disclosure further relates to the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the treatment of cGAS-related diseases and disorders.

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Nos. 63 / 433,987, filed December 20, 2022, and 63 / 501,320, filed May 10, 2023, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Abnormal accumulation of cytosolic DNA induces cytokines such as type I interferons, which are important for antibacterial defense but can also induce autoimmunity. This DNA signaling pathway requires the stimulator of interferon genes (STING) adaptor protein and the transcription factors NF-κB and IRF3, but the mechanism by which DNA is sensed was unknown until recently. It is now understood that mammalian cytosolic extracts synthesize cyclic GMP-AMP (cGAMP) from ATP and GTP in the presence of DNA, but not RNA, in vitro (WO2014099824). DNA transfection or DNA virus infection of mammalian cells also induces cGAMP production. cGAMP binds to STING, which leads to the activation of IRF3 and the induction of interferon-β (IFNβ). Thus, although cGAMP is the first cyclic dinucleotide in metazoans, it functions as an endogenous second messenger that induces interferon production in response to cytosolic DNA.

[0003] cGAMP synthase (cGAS) is an enzyme that mediates the synthesis of cyclic GMP-AMP and belongs to the nucleotidyl transferase family. Overexpression of cGAS activates the transcription factor IRF3 in a STING-dependent manner, resulting in the induction of IFN-β. Knockdown of cGAS inhibits IRF3 activation and IFN-β 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 interferon by generating the second messenger cGAMP.

[0004] The crucial role of cGAS in sensing cytosolic DNA has been demonstrated in various pathogenic bacteria, viruses, and retroviruses (US20210155625). In addition, cGAS is essential in various other biological processes, such as cellular senescence in monitoring potential cancer cells and recognizing ruptured micronuclei.

[0005] There is a need for therapeutic agents that target cGAS. Small molecule inhibitors specific for cGAS would be of great value in treating diseases caused by inappropriate cGAS activity and the resulting undesired type I interferon activity. The present disclosure is intended to fulfill this unmet need associated with current cGAS inhibitor therapies. Summary of the Invention

[0006] As used herein, a cGAS inhibitor of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R 1 , R 2 , R 3 , R 4 and m are as described herein.

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

[0008] Below are more detailed definitions of certain functional groups and chemical terms. Chemical elements are defined as defined in Handbook of Chemistry and Physics, 75 th The elements are identified according to the CAS version of the Periodic Table of the Elements, found on the front endpaper of the Ed., and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999, and Smith and March's Advanced Organic Chemistry, 5 th Edition, 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, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0009] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. 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 synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The compounds described herein may further include individual isomers that are substantially free of other isomers, and alternatively, mixtures of various isomers.

[0010] Unless otherwise specified, the compounds described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen with deuterium or tritium, 19 F 18 F or carbon 13 C or 14Compounds having the structures of the present invention except for the substitution of C-enriched carbons are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or as probes in biological assays.

[0011] When a range of values ​​is listed, it is intended to encompass each value and subrange subsumed within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 Alkyl is intended to be included.

[0012] "Alkyl" means a radical of a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, alkyl groups in each instance are independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In some embodiments, an alkyl group is an unsubstituted C 1-10 In some embodiments, the alkyl group is a substituted C 1-10 It is alkyl.

[0013] "Haloalkyl" refers to a substituted alkyl group, as defined herein, in which one or more of the hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. "Perhaloalkyl" is a subset of haloalkyl and refers to an alkyl group in which all of the hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro, forming a perfluoroalkyl group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro, forming a perchloroalkyl group. Examples of haloalkyl groups include -CF, -CFCF, -CFCFCF, -CCl, -CFCl, -CFCl, and the like.

[0014] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). C 2-4Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 In addition to alkenyl groups, examples include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, the alkenyl group in each instance is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In some embodiments, an alkenyl group is an unsubstituted C 2-10 In some embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0015] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 In addition to alkynyl groups, examples include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, an alkynyl group in any instance is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In some embodiments, an alkynyl group is an unsubstituted C 2-10 In some embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0016] "Carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3-14 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms ("C 3-9 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6 In addition to carbocyclyl groups, examples include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 In addition to the carbocyclyl group, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10As the preceding examples illustrate, in some embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system (containing fused, bridged, or spiro ring systems, such as a "tricyclic carbocyclyl"), which may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also refers to a group as defined above. Also included are ring systems in which the carbocyclyl ring is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the carbocyclyl ring; in such cases, the number of carbons refers to the number of carbons in the polycyclic ring system. Unless otherwise specified, the carbocyclyl group in each instance is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In some embodiments, a carbocyclyl group is an unsubstituted C 3-14 In some embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0017] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 In addition to cycloalkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are mentioned. 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 In addition to cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8) are included. Unless otherwise specified, cycloalkyl groups in each instance are independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In some embodiments, cycloalkyl groups are unsubstituted C 3-14 In some embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0018] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl"). It is understood that a ring sulfur or ring nitrogen may also exist in an oxygenated state, e.g., as an N-oxide (NO), sulfonyl (S(=O)2), or sulfinyl (S=O) ring heteroatom. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom where valence allows. Heterocyclyl groups are either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems (containing fused, bridged, or spiro ring systems, such as "tricyclic heterocyclyl"), and may be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes (i) polycyclic ring systems in which a heterocyclyl ring, as defined above, is fused (e.g., spirofused or cyclofused) to or connected by a bridge to one or more carbocyclyl groups, where the point of attachment may be on the carbocyclyl ring. Also included are (i) polycyclic ring systems in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, either on the heterocyclyl ring or on the heterocyclyl ring, or (ii) polycyclic ring systems in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocyclyl ring; in such cases (i) and (ii), the number of ring members refers to the number of ring members in the polycyclic ring system. Unless otherwise specified, heterocyclyl in each instance is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In some embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

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

[0020] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include 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, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7 tetrahydropyrano[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-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[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 within the cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl" (e.g., anthracyl). "Aryl" also includes polycyclic ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyls or heterocyclyls, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms refers to the number of carbon atoms in the polycyclic ring system. Unless otherwise specified, the aryl group in each instance is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, an aryl group is an unsubstituted C 6-14 In some embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0022] "Heteroaryl" refers to the 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 within the cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms provided within the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence allows. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes polycyclic ring systems in which the heteroaryl ring as defined above is (i) fused to one or more carbocyclyl or heterocyclyl groups with the point of attachment on the heteroaryl ring, or (ii) fused to one or more aryl groups with the point of attachment on either the aryl ring or the heteroaryl ring, and in such cases (i) and (ii), the number of ring members refers to the number of ring members in the fused polycyclic ring system. In polycyclic heteroaryl groups that do not contain ring heteroatoms in one ring (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on a ring that contains a ring heteroatom (e.g., 2-indolyl) or on a ring that does not contain a ring heteroatom (e.g., 5-indolyl).

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

[0024] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

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

[0026] "Partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties).

[0027] "Saturated" refers to a ring moiety that contains no double or triple bonds; that is, the ring contains single bonds everywhere.

[0028] The suffix "-ene" attached to a group indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, haloalkylene is a divalent moiety of haloalkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl. By way of example, alkylene can be linear or branched. C 1-6 The alkylene may further be C 1-4 It may be alkylene. 1-4 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.

[0029] "Salt" refers to all kinds of salt.

[0030] A "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and 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, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed using other methods used in the art, e.g., ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include 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, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0031] "Free base" refers to the neutral, non-ionized form of a compound, not a salt or a pharmaceutically acceptable salt.

[0032] "Leaving group" is an art-recognized term that refers to a molecular fragment, either an anion or a neutral molecule, that leaves with an electron pair in a heterolytic bond cleavage. See, for example, Smith, March Advanced 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] "Patient" or "subject" are used interchangeably herein and refer to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey. In certain embodiments, the patient or subject is a human.

[0034] "Effective amount" or "therapeutically effective amount" are used interchangeably herein and refer to an amount of a 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 a disease, disorder, or condition, in a subject in need thereof. An effective amount can include an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent. The effective amount of a compound can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and physical condition of the subject.

[0035] "Disease," "disorder," "condition," or "condition" are used interchangeably herein.

[0036] "Treating" or "treat" or "treatment" refers to 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 the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treating" may also include treatment of a cell in vitro or an animal model. It should be understood that references to "treating" or "treatment" include alleviating established symptoms of a condition, and thus include (1) delaying the appearance of clinical symptoms of a developing condition, disorder, or condition in a subject who may be affected by or susceptible to the condition, disorder, or condition but who has not yet suffered from or is not exhibiting clinical or subclinical symptoms of the condition, disorder, or condition; (2) preventing, alleviating, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment), or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., reversing the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms.

[0037] "Modulate," "modulating," and the like refer to the ability of a compound to alter the activity of a particular biological process in a cell (e.g., cGAS activity) relative to a vehicle.

[0038] "Inhibition," "inhibiting," "inhibit," and "inhibitor," etc., refer to the ability of a compound to reduce, slow, stop, or prevent the activity of a particular biological process in a cell (e.g., cGAS activity) relative to a vehicle.

[0039] The phrase "at least one" refers to one occurrence or more than one occurrence.

[0040] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (ie, to at least one) of the grammatical object of the article.

[0041] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated. DETAILED DESCRIPTION OF THE INVENTION

[0042] i.Compound As used herein, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-membered monocyclic heteroaryl; R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L3-(C3-C6 carbocyclyl), or -L3-(4- to 10-membered heterocyclyl), and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 1A and each R 1A are independently halogen, -OR 1B , -N(R1B )2, -SR 1B , -C(=O)OR 1B , -C(=O)N(R 1C )2, -(C1-C3 alkylene)-OR 1B , or -(C1-C3 alkylene)-SR 1B or two R's that appeared 1A are taken together to form =O; each R 1B are independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl, and the alkyl and the haloalkyl are independently selected from 0, 1, 2, 3, or 4 R 1D and each R 1C are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR 1F and each R 1D are independently halogen, -OR 1F , or -N(R 1F )2; each R 1F are 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 selected from 0, 1, 2, 3, or 4 R 1E and each R 1E are independently -(C1-C3 alkylene)-OR 1B , or -OR 1B or two R's that appeared 1E But together they form =O; R 2 is hydrogen or 0, 1, 2, 3 or 4 R 2A and each R 2A are independently halogen, -OR 2B , or -N(R 2B )2, and each R 2B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; Alternatively, R 1 and R 2and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 1A forming a 6- or 7-membered heterocyclyl substituted with; R 3 is C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3A is replaced by; Alternatively, R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with; Each R 3A are independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, ═O, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-PO(R 3C )2, -L1-OR 3B , -L1-N(R 3B )2, -L1-C(=O)N(R 3B )2, -L1-C(=O)OR 3B , -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3A groups, together with the atoms to which they are attached, combine to form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3B are independently hydrogen, C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and the alkyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3C are independently C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3D are independently halogen, -OR 3E , —CN, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E are independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; Each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl, and each R 4A and R 4B are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -C(=O)R 4C and R 4C is C1-C6 alkyl, or C1-C6 haloalkyl; each L and L is independently a bond, a C-C alkylene, or a C-C haloalkylene; m is 0, 1 or 2.

[0043] In some embodiments, provided herein are compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-membered monocyclic heteroaryl; R 1is a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl, and the alkyl, the alkenyl, and the alkynyl are independently selected from 0, 1, 2, 3, or 4 R 1A and each R 1A are independently halogen, -OR 1B , or -N(R 1B )2; each R 1B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 2 is hydrogen or 0, 1, 2, 3 or 4 R 2A and each R 2A are independently halogen, -OR 2B , or -N(R 2B )2, and each R 2B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 3 is C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3A is replaced by; Alternatively, R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with; Each R 3A are independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, ═O, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-OR 3B , -L1-N(R 3B)2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3A groups, together with the atoms to which they are attached, combine to form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3B are independently hydrogen, C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and the alkyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3C are independently C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3D are independently halogen, -OR 3E , C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl, and each R 4A and R 4B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each L and L is independently a bond, a C-C alkylene, or a C-C haloalkylene; m is 0, 1 or 2.

[0044] In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is 0, 1, 2, 3 or 4 R 1A and each R 1A independently -OR 1B and each R 1B are independently hydrogen or C1-C3 alkyl; R 2 is hydrogen or 0, 1, 2, 3 or 4 R 2A and each R 2A independently -OR 2B and each R 2B are independently hydrogen or C1-C3 alkyl; R 3 is C1-C 10 Alkyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3A is replaced by; Alternatively, R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with; Each R 3A are independently C1-C3 alkyl, halogen, ═O, -L1-CN, -L1-SO2R 3C , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3Agroups, together with the atoms to which they are attached, combine to form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3C are independently C1-C3 alkyl; Each R 3D are independently halogen or -OR 3E and; R 3E is C1-C3 alkyl; Each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl; each R 4A and R 4B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each L and L is independently a bond or a C-C alkylene; m is 1 or 2.

[0045] The present applicant has discovered that the -OR at the C3 position of the pyrone ring 1 Applicant has further discovered that compounds of formula (I) comprising the combination of a group R, an amino moiety at the C4 position of the pyrone ring, and a five-membered monocyclic heteroaryl ring A exhibit improvements in one or more desirable drug-like properties, such as improvements in unbound clearance, permeability, bioavailability, hcGAS potency and inhibitory activity, and / or solubility, compared to compounds lacking the combination. 3 -L is an exemplary substituent of 1 -OR 3BIt has been discovered that the incorporation of a -CH2OCH3 group can exhibit further improvements in one or more of these desirable properties. As a non-limiting example, as shown in Table D of the Examples, the inclusion of -CH2OCH3 in compound 103 results in compound 114, which has improved inhibitory activity in both the hcGAS Kinase glo assay and the hcGAS LCMS assay.

[0046] In some embodiments, the compound of Formula (I) comprises at least one R 3A The substituent -L1-OR 3B wherein L is a bond, C-C alkylene, or C-C haloalkylene; 3 is C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, or the heterocyclyl independently may be selected from the group consisting of 0, 1, 2, or 3 further R 3A It is substituted with a substituent.

[0047] For example, in some embodiments, the amino moiety at the C4 position of Formula (I) [ka] is a group of formula (ia), (ii-a) or (iii-a): [ka] wherein L 1 , R 3A , and R 3B is as defined herein; L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 is alkynylene; Ring B is C3-C 10carbocyclyl, or 4- to 10-membered heterocyclyl; Ring C is a 5- to 10-membered heterocyclyl; p is 0, 1, 2 or 3.

[0048] In some embodiments of Formula (I), the compound has the formula (I'): [ka] or a pharmaceutically acceptable salt thereof, wherein L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 alkynylene, and p is 0, 1, 2, or 3.

[0049] In some embodiments of Formula (I), the compound has the formula (I″): [ka] or a pharmaceutically acceptable salt thereof, wherein ring B is a C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.

[0050] In some embodiments of Formula (I), the compound has the formula (I'"): [ka] or a pharmaceutically acceptable salt thereof, wherein ring C is a 5-10 membered heterocyclyl and p is 0, 1, 2 or 3.

[0051] In some embodiments of Formula (I), the compound has the formula (I''): [ka] or a pharmaceutically acceptable salt thereof, wherein the nitrogen atom of the heteroaryl ring A is directly linked to the thiadiazole moiety.

[0052] Further embodiments are described below and further herein.

[0053] (a)R 1 , R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 2 , R 2A , R 2B , x, R 3 , R 3A , R 3B , R 3C , R 3D , R 3E , L1, and L3 As generally described herein, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L3-(C3-C6 carbocyclyl, or -L3-(4- to 10-membered heterocyclyl), and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 1A is replaced by; Each R 1A are independently halogen, -OR 1B , -N(R 1B )2, -SR 1B , -C(=O)OR 1B , -C(=O)N(R 1C )2, -(C1-C3 alkylene)-OR 1B , or -(C1-C3 alkylene)-SR 1B or two R's that appeared 1A together form =O; Each R 1B are independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl, and the alkyl and the haloalkyl are independently selected from 0, 1, 2, 3, or 4 R 1D is replaced by; Each R 1C are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR 1Fand; Each R 1D are independently halogen, -OR 1F , or -N(R 1F )2; Each R 1F are 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 selected from 0, 1, 2, 3, or 4 R 1E is replaced by; Each R 1E are independently -(C1-C3 alkylene)-OR 1B , or -OR 1B or two R's that appeared 1E together form =O.

[0054] In some embodiments, R 1 is a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl, and the alkyl, the alkenyl, and the alkynyl are independently selected from 0, 1, 2, 3, or 4 R 1A and each R 1A are independently halogen, -OR 1B , or -N(R 1B )2; each R 1B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0055] In some embodiments, R 1 is 0, 1, 2, 3 or 4 R 1A In some embodiments, R 1 is 0, 1, 2, 3 or 4 R 1A In some embodiments, R 1 is 0, 1, 2, 3 or 4 R 1A In some embodiments, R 1 is 0, 1, 2, 3 or 4 R 1Ais a C1-C2 alkyl substituted with

[0056] In some embodiments, R 1 is 0, 1, 2, 3 or 4 R 1A In some embodiments, R is a C-C alkenyl substituted with 1 is 0, 1, 2, 3 or 4 R 1A In some embodiments, R is a C-C alkenyl substituted with 1 is 0, 1, 2, 3 or 4 R 1A is a C2-C3 alkenyl substituted with

[0057] In some embodiments, R 1 is 0, 1, 2, 3 or 4 R 1A In some embodiments, R is a C2-C6 alkynyl substituted with 1 is 0, 1, 2, 3 or 4 R 1A In some embodiments, R is a C2-C4 alkynyl substituted with 1 is 0, 1, 2 or 3 R 1A is a C2-C3 alkynyl substituted with

[0058] In some embodiments, R 1 0 R 1A is a C1-C6 alkyl substituted with

[0059] In some embodiments, R 1 is one R 1A C1-C6 alkyl substituted with R 1A is halogen, -OR 1B , or -N(R 1B )2; each R 1B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0060] In some embodiments, R 1 is one R 1A C1-C6 alkyl substituted with R 1A -OR 1Band;R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0061] In some embodiments, R 1 is one R 1A C1-C6 alkyl substituted with R 1A -OR 1B and;R 1B is hydrogen.

[0062] In some embodiments, R 1 is one R 1A C1-C6 alkyl substituted with R 1A -OR 1B and;R 1B is C1-C3 alkyl.

[0063] In some embodiments, R 1 is one R 1A C1-C6 alkyl substituted with R 1A is -C(=O)N(R 1C )2; each R 1C are independently hydrogen or -OR 1B is.

[0064] In some embodiments, R 1 is one R 1A C1-C6 alkyl substituted with R 1A is -C(=O)N(R 1C )2; one of the R 1C is hydrogen and the other is -OR 1B is.

[0065] In some embodiments, R 1 is -L3-(C3-C6 carbocyclyl), wherein the carbocyclyl is selected from 0, 1, 2, 3, or 4 R 1A In some embodiments, R 1 is -L3-(C3-C4 carbocyclyl), wherein the carbocyclyl is selected from 0, 1, 2, 3, or 4 R 1AIn some embodiments, R 1 is -L3-(C3 carbocyclyl), wherein the carbocyclyl is selected from 0, 1, 2, 3, or 4 R 1A is replaced by .

[0066] In some embodiments, R 1 is -L3-(C3-C6 carbocyclyl), and the carbocyclyl is 1A is substituted with;R 1A -OR 1B In some embodiments, R 1 is -L3-(C3-C4 carbocyclyl), and the carbocyclyl is 1A is substituted with;R 1A -OR 1B In some embodiments, R 1 is -L3-(C3 carbocyclyl), and the carbocyclyl is a group selected from the group consisting of one R 1A is substituted with;R 1A -OR 1B is.

[0067] In some embodiments, R 1 is -L3-(C3-C6 carbocyclyl), and the carbocyclyl is 1A L3 is C1-C3 alkylene; R 1A -OR 1B In some embodiments, R 1 is -L3-(C3-C4 carbocyclyl), and the carbocyclyl is 1A L3 is C1-C3 alkylene; R 1A -OR 1B In some embodiments, R 1 is -L3-(C3 carbocyclyl), and the carbocyclyl is a group selected from the group consisting of one R 1A L3 is C1-C3 alkylene; R 1A -OR 1B is.

[0068] In some embodiments, R 1 -L3-(C 3-6 carbocyclyl), the carbocyclyl ring is [ka] is.

[0069] In some embodiments, R 1 is -L3-(4- to 10-membered heterocyclyl), and the heterocyclyl is selected from 0, 1, 2, 3, or 4 R 1A In some embodiments, R 1 is -L3-(5- to 6-membered heterocyclyl), and the heterocyclyl is selected from 0, 1, 2, 3, or 4 R 1A In some embodiments, R 1 is -L3-(6-membered heterocyclyl), wherein the heterocyclyl is selected from 0, 1, 2, 3, or 4 R 1A In some embodiments, R 1 is -L3-(5-membered heterocyclyl), wherein the heterocyclyl is selected from 0, 1, 2, 3, or 4 R 1A is replaced by .

[0070] In some embodiments, R 1 is -L3-(4- to 10-membered heterocyclyl), and the heterocyclyl is 1A L3 is a C1-C3 alkylene, and the alkylene is substituted with 0 R 1E In some embodiments, R 1 is -L3-(5- to 6-membered heterocyclyl), and the heterocyclyl is 1A L3 is a C1-C3 alkylene, and the alkylene is substituted with 0 R 1E In some embodiments, R 1 is -L3-(6-membered heterocyclyl), and the heterocyclyl is 1AL3 is a C1-C3 alkylene, and the alkylene is substituted with 0 R 1E is replaced by .

[0071] In some embodiments, R 1 is -L3-(4- to 10-membered heterocyclyl), and the heterocyclyl is 1A and L3 is a bond. In some embodiments, R 1 is -L3-(5- to 6-membered heterocyclyl), and the heterocyclyl is 1A and L3 is a bond. In some embodiments, R 1 is -L3-(5-membered heterocyclyl), and the heterocyclyl is 1A and L3 is a bond.

[0072] In some embodiments, R 1 When R is -L-(4- to 10-membered heterocyclyl), the heterocyclyl ring contains 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, R 1 When is -L3-(4- to 10-membered heterocyclyl), the heterocyclyl ring contains 1 or 2 ring heteroatoms independently selected from O, N and S.

[0073] In some embodiments, R 1 When R is -L-(7-10 membered heterocyclyl), the heterocyclyl ring contains 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, R 1 When is -L3-(7-10 membered heterocyclyl), the heterocyclyl ring contains 1 or 2 ring heteroatoms independently selected from O, N and S.

[0074] In some embodiments, R 1 When R is -L-(4- to 6-membered heterocyclyl), the heterocyclyl ring contains 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, R1 When is -L3-(4- to 6-membered heterocyclyl), the heterocyclyl ring contains 1 or 2 ring heteroatoms independently selected from O, N and S.

[0075] In some embodiments, R 1 When R is -L3-(5- to 6-membered heterocyclyl), the heterocyclyl ring contains 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, R 1 When is -L3-(5- to 6-membered heterocyclyl), the heterocyclyl ring contains 1 or 2 ring heteroatoms independently selected from O, N and S.

[0076] In some embodiments, R 1 When R is -L- (6-membered heterocyclyl), the heterocyclyl ring contains 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, R 1 When is -L3- (6-membered heterocyclyl), the heterocyclyl ring contains 1 or 2 ring heteroatoms independently selected from O, N and S.

[0077] In some embodiments, R 1 When R is -L- (5-membered heterocyclyl), the heterocyclyl ring contains 1 or 2 ring heteroatoms independently selected from O, N, and S. In some embodiments, R 1 When is -L3-(5-membered heterocyclyl), the heterocyclyl ring contains one ring O atom.

[0078] In some embodiments, R 1 When is -L3-(4- to 10-membered heterocyclyl), the heterocyclyl ring is [ka] is selected from.

[0079] As generally described herein, L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is independently selected from 0, 1, 2, 3, or 4 R 1E is replaced by .

[0080] In some embodiments, L3 is a bond.

[0081] In some embodiments, L3 independently represents 0, 1, 2, 3, or 4 R 1E In some embodiments, L is independently 0, 1, 2, 3, or 4 R 1E In some embodiments, L is independently 0, 1, or 2 R 1E is a C1 alkylene substituted with

[0082] In some embodiments, L3 independently represents 0 R 1E In some embodiments, L is independently 0 R 1E In some embodiments, L is a C-C alkylene substituted with 0 R 1E is a C1 alkylene substituted with

[0083] In some embodiments, at least one R 1A are independently halogen, -OR 1B , or -N(R 1B )2.

[0084] In some embodiments, at least one R 1A are independently halogen.

[0085] In some embodiments, at least one R 1A are independently -OR 1B , or -N(R 1B )2.

[0086] In some embodiments, at least one R 1A are independently -OR 1B is.

[0087] In some embodiments, at least one R 1A is independently —OH. In some embodiments, at least one R 1A is independently —O(C1-C3 alkyl).

[0088] In some embodiments, at least one R 1A are independently -N(R 1B )2.

[0089] In some embodiments, at least one occurrence of R 1A is -C(=O)OR 1B is.

[0090] In some embodiments, at least one occurrence of R 1A is -C(=O)N(R 1C )2.

[0091] In some embodiments, at least one R 1B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0092] In some embodiments, at least one R 1B are independently hydrogen.

[0093] In some embodiments, at least one R 1B is independently C1-C3 alkyl, or C1-C3 haloalkyl.

[0094] In some embodiments, at least one R 1B are independently C1-C3 alkyl.

[0095] In some embodiments, at least one R 1Bis independently C1-C3 haloalkyl.

[0096] In some embodiments, at least one R 1C are independently hydrogen.

[0097] In some embodiments, at least one R 1C are independently C1-C3 alkyl.

[0098] In some embodiments, at least one R 1C is independently C1-C3 haloalkyl.

[0099] In some embodiments, at least one R 1C are independently -OR 1B In some embodiments, at least one R 1C are independently -OCH3.

[0100] In some embodiments, R 1 is -CH3, -CH2-C(CH3)2-CH2OCH3, -CH2CH2OH, or -CH2CH2OCH3.

[0101] In some embodiments, R 1 is -CH3. In some embodiments, R 1 is —CH—C(CH)—CHOCH. In some embodiments, R 1 is —CHCHOH. In some embodiments, R 1 is -CH2CH2OCH3.

[0102] In some embodiments, R 1 teeth, [ka] is selected from.

[0103] As generally defined herein, R 2is hydrogen or 0, 1, 2, 3 or 4 R 2A and each R 2A are independently halogen, -OR 2B , or -N(R 2B )2, and each R 2B are independently hydrogen, C-C alkyl, or C-C haloalkyl; R 3 is C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3A or R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with

[0104] In some embodiments, R 2 is hydrogen or C1-C6 alkyl, and the alkyl is independently selected from 0, 1, 2, 3, or 4 R 2A and each R 2A are independently halogen, -OR 2B , or -N(R 2B )2, and each R 2B are independently hydrogen, C 1-3 Alkyl, or C 1-3 It is haloalkyl.

[0105] In some embodiments, R 2 is hydrogen or 0, 1, 2, 3 or 4 R 2A is a C1-C6 alkyl substituted with

[0106] In some embodiments, R 2 is hydrogen. In some embodiments, R 2is 0, 1, 2, 3 or 4 R 2A C1-C6 alkyl substituted with.

[0107] In some embodiments, R 2 0 R 2A is a C1-C6 alkyl substituted with

[0108] In some embodiments, R 2 is one R 2A is a C1-C6 alkyl substituted with

[0109] In some embodiments, R 2 is two R 2A In some embodiments, R 2 is three R 2A In some embodiments, R 2 is four R 2A is a C1-C6 alkyl substituted with

[0110] In some embodiments, at least one R 2A are independently halogen, -OR 2B , or -N(R 2B )2.

[0111] In some embodiments, at least one R 2A are independently halogen.

[0112] In some embodiments, at least one R 2A are independently -OR 2B is.

[0113] In some embodiments, at least one R 2A are independently —OH.

[0114] In some embodiments, at least one R 2A is independently —O(C1-C3 alkyl).

[0115] In some embodiments, at least one R 2A are independently -O(CH3).

[0116] In some embodiments, at least one R 2A are independently -N(R 2B )2.

[0117] In some embodiments, at least one R 2B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0118] In some embodiments, at least one R 2B are independently hydrogen.

[0119] In some embodiments, at least one R 2B is independently C1-C3 alkyl, or C1-C3 haloalkyl.

[0120] In some embodiments, at least one R 2B is independently C1-C3 alkyl.

[0121] In some embodiments, at least one R 2B is independently methyl. In some embodiments, at least one R 2B is independently ethyl. In some embodiments, at least one R 2B is independently propyl.

[0122] In some embodiments, at least one R 2B is independently C1-C3 haloalkyl.

[0123] In some embodiments, R 1 and R 2 and, together with the atoms to which they are attached, independently comprise 0, 1, 2, 3, or 4 R 1Aforming a 6- or 7-membered heterocyclyl substituted with

[0124] In some embodiments, R 1 and R 2 and, together with the atoms to which they are attached, independently comprise 0, 1, 2, 3, or 4 R 1A forming a 6-membered heterocyclyl substituted with

[0125] In some embodiments, R 1 and R 2 and 0 R along with the atoms to which they are attached 1A In some embodiments, R 1 and R 2 and, together with the atoms to which they are attached, form one R 1A In some embodiments, R 1 and R 2 and the atoms to which they are attached, 1A In some embodiments, R 1 and R 2 and the atoms to which they are attached, 1A In some embodiments, R 1 and R 2 and the atoms to which they are attached, form four R 1A forming a 6-membered heterocyclyl substituted with

[0126] In some embodiments, R 1 and R 2 and, together with the atoms to which they are bonded, [ka] where x is 0, 1, 2, 3, or 4. In some embodiments, R 1 and R 2 and, together with the atoms to which they are bonded, [ka] In some embodiments, R 1 and R 2 and, together with the atoms to which they are bonded, [ka] and x is 0, 1, 2, 3, or 4. In some embodiments, R 1 and R 2 and, together with the atoms to which they are bonded, [ka] is formed.

[0127] 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.

[0128] In some embodiments, R 3 is C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, or the heterocyclyl is independently selected from 0, 1, 2, 3, or 4 R 3A is replaced by .

[0129] In some embodiments, R 3 is C1-C 10 Alkyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the carbocyclyl, or the heterocyclyl independently has 0, 1, 2, 3, or 4 R 3Ais replaced by .

[0130] In some embodiments, R 3 is 0, 1, 2, 3 or 4 R 3A C1-C substituted with 10 It is alkyl.

[0131] In some embodiments, R 3 is C1-C 10 It is alkyl.

[0132] In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 3 is tert-butyl.

[0133] In some embodiments, R 3 is one R 3A C1-C substituted with 10 It is alkyl.

[0134] In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R3A In some embodiments, R 3 is one R 3A is tert-butyl substituted with

[0135] In some embodiments, R 3 is two R 3A C1-C substituted with 10 It is alkyl.

[0136] In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A is tert-butyl substituted with

[0137] In some embodiments, R 3 is three R 3A C1-C substituted with 10 It is alkyl.

[0138] In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3AIn some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3A is tert-butyl substituted with

[0139] In some embodiments, R 3 is four R 3A C1-C substituted with 10 It is alkyl.

[0140] In some embodiments, R 3 is 0, 1, 2, 3 or 4 R 3A C3-C substituted with 10 It is a carbocyclyl.

[0141] In some embodiments, R 3 is C3-C 10 It is a carbocyclyl.

[0142] In some embodiments, R 3 is a condensed C3-C 10 In some embodiments, R 3 is spiro C3-C 10 In some embodiments, R 3 is the bridge C3-C 10 It is a carbocyclyl.

[0143] In some embodiments, R 3 is C3 carbocyclyl. In some embodiments, R 3 is C4 carbocyclyl. In some embodiments, R 3 is a C5 carbocyclyl. In some embodiments, R 3is C6 carbocyclyl. In some embodiments, R 3 is a C7 carbocyclyl. In some embodiments, R 3 is C8 carbocyclyl. In some embodiments, R 3 is C9 carbocyclyl. In some embodiments, R 3 is C 10 It is a carbocyclyl.

[0144] In some embodiments, R 3 is one R 3A C3-C substituted with 10 It is a carbocyclyl.

[0145] In some embodiments, R 3 is one R 3A In some embodiments, R is a C3 carbocyclyl substituted with 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A In some embodiments, R 3 is one R 3A C replaced with 10 It is a carbocyclyl.

[0146] In some embodiments, R 3 is two R 3A C3-C substituted with 10 It is a carbocyclyl.

[0147] In some embodiments, R 3 is two R 3A In some embodiments, R is a C3 carbocyclyl substituted with 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R 3 is two R 3A C replaced with 10 It is a carbocyclyl.

[0148] In some embodiments, R 3 is three R 3A C3-C substituted with 10 It is a carbocyclyl.

[0149] In some embodiments, R 3 is three R 3A In some embodiments, R is a C3 carbocyclyl substituted with 3 is three R 3A In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R3A In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3A In some embodiments, R 3 is three R 3A C replaced with 10 It is a carbocyclyl.

[0150] In some embodiments, R 3 is four R 3A C3-C substituted with 10 It is a carbocyclyl.

[0151] In some embodiments, R 3 is 0, 1, 2, 3 or 4 R 3A is a 4- to 10-membered heterocyclyl substituted with

[0152] In some embodiments, R 3 is a 4- to 10-membered heterocyclyl.

[0153] In some embodiments, R 3 is a fused 6- to 10-membered heterocyclyl. In some embodiments, R 3 is spiro 6-10 membered heterocyclyl. In some embodiments, R 3 is a bridged 4- to 10-membered heterocyclyl.

[0154] In some embodiments, R 3 is a 4-membered heterocyclyl. In some embodiments, R 3 is a 5-membered heterocyclyl. In some embodiments, R 3 is a 6-membered heterocyclyl. In some embodiments, R 3 is a 7-membered heterocyclyl. In some embodiments, R 3 is an 8-membered heterocyclyl. In some embodiments, R 3is a 9-membered heterocyclyl. In some embodiments, R 3 is a 10-membered heterocyclyl.

[0155] In some embodiments, R 3 is one R 3A is a 4- to 10-membered heterocyclyl substituted with

[0156] In some embodiments, R 3 is one R 3A In some embodiments, R is a 4-membered heterocyclyl substituted with 3 is one R 3A In some embodiments, R is a 5-membered heterocyclyl substituted with 3 is one R 3A In some embodiments, R is a 6-membered heterocyclyl substituted with 3 is one R 3A In some embodiments, R is a 7-membered heterocyclyl substituted with 3 is one R 3A In some embodiments, R is an 8-membered heterocyclyl substituted with 3 is one R 3A In some embodiments, R is a 9-membered heterocyclyl substituted with 3 is one R 3A is a 10-membered heterocyclyl substituted by

[0157] In some embodiments, R 3 is two R 3A is a 4- to 10-membered heterocyclyl substituted with

[0158] In some embodiments, R 3 is two R 3A In some embodiments, R is a 4-membered heterocyclyl substituted with 3 is two R 3A In some embodiments, R is a 5-membered heterocyclyl substituted with 3 is two R 3A In some embodiments, R is a 6-membered heterocyclyl substituted with3 is two R 3A In some embodiments, R 3 is two R 3A In some embodiments, R is an 8-membered heterocyclyl substituted with 3 is two R 3A In some embodiments, R is a 9-membered heterocyclyl substituted with 3 is two R 3A is a 10-membered heterocyclyl substituted by

[0159] In some embodiments, R 3 is three R 3A is a 4- to 10-membered heterocyclyl substituted with

[0160] In some embodiments, R 3 is three R 3A In some embodiments, R is a 4-membered heterocyclyl substituted with 3 is three R 3A In some embodiments, R is a 5-membered heterocyclyl substituted with 3 is three R 3A In some embodiments, R is a 6-membered heterocyclyl substituted with 3 is three R 3A In some embodiments, R is a 7-membered heterocyclyl substituted with 3 is three R 3A In some embodiments, R is an 8-membered heterocyclyl substituted with 3 is three R 3A In some embodiments, R is a 9-membered heterocyclyl substituted with 3 is three R 3A is a 10-membered heterocyclyl substituted by

[0161] In some embodiments, R 3 is four R 3A is a 4- to 10-membered heterocyclyl substituted with

[0162] In certain embodiments, R 3teeth, [ka] where L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 alkynylene, and p is 0, 1, 2, or 3.

[0163] In certain embodiments, R 3 teeth, [ka] wherein ring B is C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.

[0164] In certain embodiments, R 3 -CH3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH(CH3)2, [ka] [ka] is.

[0165] In some embodiments, R 2 is hydrogen or C1-C6 alkyl, and R 3 is C1-C 10 It is alkyl.

[0166] In some embodiments, the amino moiety [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0167] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0168] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0169] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0170] In some embodiments, the group R 3 is the expression [ka] wherein L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 alkynylene, and p is 0, 1, 2, or 3.

[0171] In some embodiments, R 2is hydrogen or C1-C6 alkyl, and R 3 of [ka] an amino moiety having the formula (ia): [ka] is formed, where L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 alkynylene, and p is 0, 1, 2, or 3.

[0172] In some embodiments, L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 It is alkynylene.

[0173] In some embodiments, L3 is C1-C 10 In some embodiments, L3 is C1-C6 alkylene. In some embodiments, L3 is C1-C4 alkylene. In some embodiments, L3 is C1-C3 alkylene.

[0174] In some embodiments, L3 is C2-C 10 In some embodiments, L is C-C alkenylene. 10 It is alkynylene.

[0175] In some embodiments, the formula (ia) is [ka] The amino part of [ka] These include, but are not limited to:

[0176] In some embodiments, the formula (ia) is [ka] The amino part of [ka] These include, but are not limited to:

[0177] In some embodiments, R 2 is hydrogen or C1-C6 alkyl, and R 3 is C3-C 10 It is a carbocyclyl.

[0178] In some embodiments, the amino moiety [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0179] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0180] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0181] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0182] In some embodiments, R 2 is hydrogen or C1-C6 alkyl, and R 3is a 4- to 10-membered heterocyclyl.

[0183] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0184] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0185] In some embodiments, R 3 teeth, [ka] and ring B is C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.

[0186] In some embodiments, R 2 is hydrogen or C1-C6 alkyl, and R 3 of [ka] Formula (ii-a): [ka] an amino moiety having [ka] wherein ring B is C3-C 10carbocyclyl, or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.

[0187] In some embodiments, ring B is C3-C 10 It is a carbocyclyl or a 4- to 10-membered heterocyclyl.

[0188] In some embodiments, ring B is C3-C 10 In some embodiments, Ring B is a monocyclic C3-C8 carbocyclyl. In some embodiments, Ring B is a monocyclic C5-C7 carbocyclyl. In some embodiments, Ring B is a bicyclic C5-C8 carbocyclyl. In some embodiments, Ring B is a bicyclic C9-C 10 In some embodiments, ring B is a carbocyclyl. In some embodiments, ring B is a 4- to 10-membered heterocyclyl. In some embodiments, ring B is a monocyclic 4- to 8-membered heterocyclyl. In some embodiments, ring B is a monocyclic 4- to 6-membered heterocyclyl. In some embodiments, ring B is a monocyclic 5- to 6-membered heterocyclyl.

[0189] In some embodiments, an amino moiety within the scope of formula (ii-a) [ka] As for [ka] [ka] These include, but are not limited to:

[0190] In some embodiments, an amino moiety within the scope of formula (ii-a) [ka] As for [ka] These include, but are not limited to:

[0191] In some embodiments, R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with

[0192] In some embodiments, R 2 and R 3 and together with the atoms to which they are attached form 0, 1, 2, 3 or 4 R 3A forming a 4-membered heterocyclyl substituted with

[0193] In some embodiments, R 2 and R 3 and together with the atoms to which they are attached form a four-membered heterocyclyl.

[0194] In some embodiments, R 2 and R 3 and are combined with the atoms to which they are attached to form one R 3A forming a 4-membered heterocyclyl substituted with

[0195] In some embodiments, R 2 and R 3 and are linked together with the atoms to which they are attached, forming two R 3A forming a 4-membered heterocyclyl substituted with

[0196] In some embodiments, R 2 and R 3 and are linked together with the atoms to which they are attached, forming three R 3A forming a 4-membered heterocyclyl substituted with

[0197] In some embodiments, R 2 and R 3and together with the atoms to which they are attached form a 5-membered heterocyclyl.

[0198] In some embodiments, R 2 and R 3 and are combined with the atoms to which they are attached to form one R 3A forming a 5-membered heterocyclyl substituted with

[0199] In some embodiments, R 2 and R 3 and are linked together with the atoms to which they are attached, forming two R 3A forming a 5-membered heterocyclyl substituted with

[0200] In some embodiments, R 2 and R 3 and are linked together with the atoms to which they are attached, forming three R 3A forming a 5-membered heterocyclyl substituted with

[0201] In some embodiments, R 2 and R 3 and together with the atoms to which they are attached form a 6-membered heterocyclyl.

[0202] In some embodiments, R 2 and R 3 and are combined with the atoms to which they are attached to form one R 3A forming a 6-membered heterocyclyl substituted with

[0203] In some embodiments, R 2 and R 3 and are linked together with the atoms to which they are attached, forming two R 3A forming a 6-membered heterocyclyl substituted with

[0204] In some embodiments, R 2 and R 3 and are linked together with the atoms to which they are attached, forming three R 3Aforming a 6-membered heterocyclyl substituted with

[0205] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0206] In some embodiments, the amino moiety [ka] teeth, [ka] is selected from the group consisting of:

[0207] In some embodiments, the formula [ka] R in the amino part of 2 and R 3 The two are combined to form the formula [ka] wherein L1 is a bond, C1-C3 alkylene, or C1-C3 haloalkylene; ring C is a 5- to 10-membered heterocyclyl; and p is 0, 1, 2, or 3.

[0208] In some embodiments, an amino moiety within formula (iii-a) [ka] As for [ka] These include, but are not limited to:

[0209] As generally defined herein, each R 3A are independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, ═O, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-PO(R 3C )2, -L1-OR 3B , -L1-N(R 3B )2, -L1-C(=O)N(R 3B )2, -L1-C(=O)OR 3B , -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3A groups, together with the atoms to which they are attached, form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl independently contain 0, 1, 2, 3, or 4 R 3D is replaced by .

[0210] In some embodiments, each R 3A are independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, ═O, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3Agroups, together with the atoms to which they are attached, form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl independently contain 0, 1, 2, 3, or 4 R 3D is replaced by .

[0211] In some embodiments, each R 3A are independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, ═O, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1-(5- to 10-membered heteroaryl), wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by .

[0212] In some embodiments, each R 3A are independently C1-C3 alkyl, halogen, ═O, -L1-CN, -L1-SO2R 3C , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1-(5- to 10-membered heteroaryl), wherein the alkyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by .

[0213] In some embodiments, at least one R 3Aindependently, 0, 1, 2, 3 or 4 R 3D is a C1-C3 alkyl substituted with

[0214] In some embodiments, at least one R 3A are independently C1-C3 alkyl.

[0215] In some embodiments, at least one R 3A is independently one R 3D is a C1-C3 alkyl substituted with

[0216] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D is a C1-C3 alkyl substituted with

[0217] In some embodiments, at least one R 3A are independently halogen or ═O.

[0218] In some embodiments, at least one R 3A are independently halogen.

[0219] In some embodiments, at least one R 3A are independently F or Cl.

[0220] In some embodiments, at least one R 3A are independently F. In some embodiments, at least one R 3A are independently Cl.

[0221] In some embodiments, at least one R3A are independently =O.

[0222] In some embodiments, at least one R 3A are independently -L1-CN, -L1-SO2R 3C , -L1-OR 3B , or -L1-N(R 3B )2.

[0223] In some embodiments, at least one R 3A are independently -L1-CN.

[0224] In some embodiments, at least one R 3A are independently -CN.

[0225] In some embodiments, at least one R 3A are independently -(C1-C3 alkylene)-CN.

[0226] In some embodiments, at least one R 3A are independently -L1-SO2R 3C is.

[0227] In some embodiments, at least one R 3A are independently -SO2R 3C is.

[0228] In some embodiments, at least one R 3A are independently -(C1-C3 alkylene)-SO2R 3C is.

[0229] In some embodiments, at least one R 3A are independently -L1-PO(R 3C )2.

[0230] In some embodiments, at least one R 3A are independently -PO(R 3C )2.

[0231] In some embodiments, at least one R 3A are independently -L1-OR 3B is.

[0232] In some embodiments, at least one R 3A are independently -OR 3B is.

[0233] In some embodiments, at least one R 3A are independently -L1-C(=O)N(R 3B )2, or -L1-C(=O)OR 3B is.

[0234] In some embodiments, at least one R 3A are independently -C(=O)N(R 3B )2, or -C(=O)OR 3B is.

[0235] In some embodiments, at least one R 3A are independently -(C1-C3 alkylene)-OR 3B is.

[0236] In some embodiments, at least one R 3A are independently -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1-(5- to 10-membered heteroaryl), wherein the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by .

[0237] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D and -L1-(C3-C6 carbocyclyl) substituted with

[0238] In some embodiments, at least one R 3A is independently -L1-(C3-C6 carbocyclyl).

[0239] In some embodiments, at least one R 3A is independently one R 3D and -L1-(C3-C6 carbocyclyl) substituted with

[0240] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D and -L1-(C3-C6 carbocyclyl) substituted with

[0241] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D is -(C3-C6 carbocyclyl) substituted with

[0242] In some embodiments, at least one R 3A is independently -(C3-C6 carbocyclyl).

[0243] In some embodiments, at least one R 3A is independently one R 3D is -(C3-C6 carbocyclyl) substituted with

[0244] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D is -(C3-C6 carbocyclyl) substituted with

[0245] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D and -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with

[0246] In some embodiments, at least one R 3A is independently -(C1-C3 alkylene)-(C3-C6 carbocyclyl).

[0247] In some embodiments, at least one R 3A is independently one R 3D and -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with

[0248] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D and -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with

[0249] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D -L1-(4- to 6-membered heterocyclyl) substituted with

[0250] In some embodiments, at least one R 3A are independently -L1-(4- to 6-membered heterocyclyl).

[0251] In some embodiments, at least one R 3A is independently one R 3D -L1-(4- to 6-membered heterocyclyl) substituted with

[0252] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D -L1-(4- to 6-membered heterocyclyl) substituted with

[0253] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D -(4- to 6-membered heterocyclyl) substituted with

[0254] In some embodiments, at least one R 3A are independently -(4- to 6-membered heterocyclyl).

[0255] In some embodiments, at least one R 3A is independently one R 3D -(4- to 6-membered heterocyclyl) substituted with

[0256] In some embodiments, at least one R 3A are independently two R 3DIn some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D -(4- to 6-membered heterocyclyl) substituted with

[0257] In some embodiments, at least one hR 3A independently, 0, 1, 2, 3 or 4 R 3D and -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with

[0258] In some embodiments, at least one R 3A is independently -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl).

[0259] In some embodiments, at least one R 3A is independently one R 3D and -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with

[0260] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D and -(C1-C3 alkylene)-(4- to 6-membered heterocyclyl) substituted with

[0261] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R3D -L1-(C 6-10 aryl).

[0262] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D and -L1-(C6 aryl) substituted with

[0263] In some embodiments, at least one R 3A is independently -L1-(C6 aryl).

[0264] In some embodiments, at least one R 3A is independently one R 3D and -L1-(C6 aryl) substituted with

[0265] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D and -L1-(C6 aryl) substituted with

[0266] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D is -(C6 aryl) substituted with

[0267] In some embodiments, at least one R 3A is independently -(C6 aryl).

[0268] In some embodiments, at least one R 3A is independently one R 3Dis -(C6 aryl) substituted with

[0269] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D is -(C6 aryl) substituted with

[0270] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D is -(C1-C3 alkylene)-(C6 aryl) substituted with

[0271] In some embodiments, at least one R 3A is independently -(C1-C3 alkylene)-(C6 aryl).

[0272] In some embodiments, at least one R 3A is independently one R 3D is -(C1-C3 alkylene)-(C6 aryl) substituted with

[0273] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D is -(C1-C3 alkylene)-(C6 aryl) substituted with

[0274] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D and -L1-(5- to 10-membered heteroaryl) substituted with

[0275] In some embodiments, at least one R 3A is independently -L1-(5- to 10-membered heteroaryl).

[0276] In some embodiments, at least one R 3A is independently one R 3D and -L1-(5- to 10-membered heteroaryl) substituted with

[0277] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D and -L1-(5- to 10-membered heteroaryl) substituted with

[0278] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D is -(5-10 membered heteroaryl) substituted with

[0279] In some embodiments, at least one R 3A is independently -(5- to 10-membered heteroaryl).

[0280] In some embodiments, at least one R 3A is independently one R 3D is -(5-10 membered heteroaryl) substituted with

[0281] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, each R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D -(5-10 membered heteroaryl) substituted with

[0282] In some embodiments, at least one R 3A independently, 0, 1, 2, 3 or 4 R 3D and -(C1-C3 alkylene)-(5-10 membered heteroaryl) substituted with

[0283] In some embodiments, at least one R 3A is independently -(C1-C3 alkylene)-(5-10 membered heteroaryl).

[0284] In some embodiments, at least one R 3A is independently one R 3D and -(C1-C3 alkylene)-(5-10 membered heteroaryl) substituted with

[0285] In some embodiments, at least one R 3A are independently two R 3D In some embodiments, at least one R 3A are independently three R 3D In some embodiments, at least one R 3A are independently four R 3D and -(C1-C3 alkylene)-(5-10 membered heteroaryl) substituted with

[0286] In some embodiments, two R 3A The groups, together with the atoms to which they are attached, form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl.

[0287] In some embodiments, two R 3A The groups together with the atoms to which they are attached form a C6 aryl.

[0288] In some embodiments, two R 3A The groups, together with the atoms to which they are attached, form a 5-6 membered heteroaryl.

[0289] In some embodiments, two R 3A The groups together with the atoms to which they are attached form a C3-C6 carbocyclyl.

[0290] In some embodiments, two R 3A The groups, together with the atoms to which they are attached, form a 4- to 6-membered heterocyclyl.

[0291] As generally defined herein, each R 3B are independently hydrogen, C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and the alkyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by .

[0292] In some embodiments, at least one R 3B are independently hydrogen.

[0293] In some embodiments, each R 3B are independently C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and the alkyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3Dis replaced by .

[0294] In some embodiments, each R 3B is independently C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl.

[0295] In some embodiments, at least one R 3B independently, 0, 1, 2, 3 or 4 R 3D is a C1-C3 alkyl substituted with

[0296] In some embodiments, at least one R 3B is independently C1-C3 alkyl.

[0297] In some embodiments, at least one R 3B is independently one R 3D is a C1-C3 alkyl substituted with

[0298] In some embodiments, at least one R 3B are independently two R 3D is a C1-C3 alkyl substituted with

[0299] In some embodiments, at least one R 3B are independently three R 3D is a C1-C3 alkyl substituted with

[0300] In some embodiments, at least one R 3B are independently four R 3D is a C1-C3 alkyl substituted with

[0301] In some embodiments, at least one R 3B independently, 0, 1, 2, 3 or 4 R 3D is a C3-C6 carbocyclyl substituted with

[0302] In some embodiments, at least one R3B is independently a C3-C6 carbocyclyl.

[0303] In some embodiments, at least one R 3B is independently one R 3D is a C3-C6 carbocyclyl substituted with

[0304] In some embodiments, at least one R 3B are independently two R 3D is a C3-C6 carbocyclyl substituted with

[0305] In some embodiments, at least one R 3B are independently three R 3D is a C3-C6 carbocyclyl substituted with

[0306] In some embodiments, at least one R 3B are independently four R 3D is a C3-C6 carbocyclyl substituted with

[0307] In some embodiments, at least one R 3B independently, 0, 1, 2, 3 or 4 R 3D is a 4- to 6-membered heterocyclyl substituted with

[0308] In some embodiments, at least one R 3B is independently 4- to 6-membered heterocyclyl.

[0309] In some embodiments, at least one R 3B is independently one R 3D is a 4- to 6-membered heterocyclyl substituted with

[0310] In some embodiments, at least one R 3B are independently two R 3D is a 4- to 6-membered heterocyclyl substituted with

[0311] In some embodiments, at least one R 3B are independently three R 3D is a 4- to 6-membered heterocyclyl substituted with

[0312] In some embodiments, at least one R 3B are independently four R 3D 4-6 membered heterocyclyl substituted with.

[0313] As generally defined herein, each R 3C is independently C1-C3 alkyl, or C1-C3 haloalkyl.

[0314] In some embodiments, at least one R 3C is independently C1-C3 alkyl.

[0315] In some embodiments, at least one R 3C is independently C1-C3 haloalkyl.

[0316] As generally defined herein, each R 3D are independently halogen, -OR 3E , C1-C3 alkyl, or C1-C3 haloalkyl.

[0317] In another embodiment, each R 3D are independently halogen, -OR 3E , —CN, C1-C3 alkyl, or C1-C3 haloalkyl.

[0318] In some embodiments, each R 3D are independently halogen, or —OC1-C3 alkyl.

[0319] In some embodiments, at least one R 3D are independently halogen.

[0320] In some embodiments, at least one R3D are independently F or Cl.

[0321] In some embodiments, at least one R 3D are independently F. In some embodiments, at least one R 3D are independently Cl.

[0322] In some embodiments, at least one R 3D are independently -OR 3E is.

[0323] In some embodiments, at least one R 3D are independently —OC1-C3 alkyl.

[0324] In some embodiments, at least one R 3D is -CN.

[0325] As generally defined herein, each R 3E are independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

[0326] In some embodiments, each R 3E are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0327] In some embodiments, at least one R 3E are independently hydrogen.

[0328] In some embodiments, at least one R 3E is independently C1-C3 alkyl.

[0329] In some embodiments, at least one R 3E is independently C1-C3 haloalkyl.

[0330] As generally defined herein, each L1 is independently a bond, C1-C3 alkylene, or C1-C3 haloalkylene.

[0331] In some embodiments, each L1 is independently a bond or a C1-C3 alkylene.

[0332] In some embodiments, at least one L1 is independently a bond.

[0333] In some embodiments, at least one L1 is independently C1-C3 alkylene.

[0334] In some embodiments, at least one L1 is independently a branched C1-C3 alkylene.

[0335] In some embodiments, at least one L is independently a C alkylene. In some embodiments, at least one L is independently a C alkylene. In some embodiments, at least one L is independently a C alkylene. In some embodiments, at least one L is independently a C alkylene.

[0336] (b) Ring A, R 4 , L2, and m As generally defined herein, Ring A is a 5-membered monocyclic heteroaryl.

[0337] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0338] In some embodiments, ring A is a 5-membered monocyclic heteroaryl containing one ring nitrogen atom.

[0339] In some embodiments, ring A is a 5-membered monocyclic heteroaryl containing two ring nitrogen atoms.

[0340] In some embodiments, ring A is a 5-membered monocyclic heteroaryl containing one ring oxygen atom.

[0341] In some embodiments, ring A is a 5-membered monocyclic heteroaryl containing one ring nitrogen atom and one ring oxygen atom.

[0342] In some embodiments, ring A is a 5-membered monocyclic heteroaryl containing one ring sulfur atom.

[0343] In some embodiments, ring A is a 5-membered monocyclic heteroaryl containing one ring nitrogen atom and one ring sulfur atom.

[0344] In some embodiments, ring A is a pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, or thiazole ring.

[0345] In some embodiments, ring A is [ka] is.

[0346] In some embodiments, ring A is [ka] is.

[0347] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0348] In some embodiments, ring A is of formula (xvii-b): [ka] is a 5-membered monocyclic heteroaryl directly linked to the thiadiazole via the N atom, such as given below:

[0349] Exemplary Ring A ring systems within the scope of formula (xvii-b) include: [ka] These include, but are not limited to:

[0350] As generally defined herein, each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl; R 4A and R 4B are each independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, -C(=O)R 4C and R 4Cis C1-C6 alkyl, or C1-C6 haloalkyl; each L2 is a bond, C1-C3 alkylene, or C1-C3 haloalkylene; and m is 0, 1, or 2.

[0351] As generally defined herein, each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl; R 4A and R 4B are each independently hydrogen, C 1-3 Alkyl, or C 1-3 each L2 is a bond, C1-C3 alkylene, or C1-C3 haloalkylene; and m is 0, 1, or 2.

[0352] In some embodiments, each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl.

[0353] In some embodiments, at least one R 4 are independently halogen.

[0354] In some embodiments, at least one R 4 are independently -F or -Cl.

[0355] In some embodiments, at least one R 4 is independently -F. In some embodiments, at least one R 4 are independently —Cl.

[0356] In some embodiments, at least one R 4 are independently -CN.

[0357] In some embodiments, at least one R4 independently, -L2-OR 4A is.

[0358] In some embodiments, at least one R 4 are independently -OR 4A is.

[0359] In some embodiments, at least one R 4 are independently -(C1-C3 alkylene)-OR 4A is.

[0360] In some embodiments, at least one R 4 are independently -(C alkylene)-OR 4A is.

[0361] In some embodiments, at least one R 4 are independently -(C2 alkylene)-OR 4A is.

[0362] In some embodiments, at least one R 4 are independently -(C alkylene)-OR 4A is.

[0363] In some embodiments, at least one R 4 are independently —OH.

[0364] In some embodiments, at least one R 4 is independently —(C1-C3 alkylene)-OH.

[0365] In some embodiments, at least one R 4 is independently -(C1 alkylene)-OH.

[0366] In some embodiments, at least one R 4 is independently -(C2 alkylene)-OH.

[0367] In some embodiments, at least one R 4 is independently -(C alkylene)-OH.

[0368] In some embodiments, at least one R 4 is independently —O(C1-C3 alkyl).

[0369] In some embodiments, at least one R 4 is independently —(C1-C3 alkylene)-O(C1-C3 alkyl).

[0370] In some embodiments, at least one R 4 is independently -(C1 alkylene)-O(C1-C3 alkyl).

[0371] In some embodiments, at least one R 4 is independently -(C2 alkylene)-O(C1-C3 alkyl).

[0372] In some embodiments, at least one R 4 is independently -(C alkylene)-O(C-C alkyl).

[0373] In some embodiments, at least one R 4 are independently -N(R 4B )2.

[0374] In some embodiments, at least one R 4 are independently -L2-N(R 4B )2.

[0375] In some embodiments, at least one R 4 are independently -(C1-C3 alkylene)-N(R 4B )2.

[0376] In some embodiments, at least one R 4are independently -NH2.

[0377] In some embodiments, at least one R 4 are independently -L2-NH2.

[0378] In some embodiments, at least one R 4 are independently -(C1-C3 alkylene)-NH2.

[0379] In some embodiments, at least one R 4 are independently -NH(R 4B )

[0380] In some embodiments, at least one R 4 are independently -L2-NH(R 4B )

[0381] In some embodiments, at least one R 4 are independently -(C1-C3 alkylene)-NH(R 4B )

[0382] In some embodiments, at least one R 4 are independently —N(C1-C3 alkyl)2.

[0383] In some embodiments, at least one R 4 are independently -L2-N(C1-C3 alkyl)2.

[0384] In some embodiments, at least one R 4 are independently -(C1-C3 alkylene)-N(C1-C3 alkyl)2.

[0385] In some embodiments, at least one R 4 is independently C1-C6 alkyl.

[0386] In some embodiments, at least one R4 is independently methyl. In some embodiments, at least one R 4 is independently ethyl. In some embodiments, at least one R 4 is independently propyl. In some embodiments, at least one R 4 is independently isopropyl. In some embodiments, at least one R 4 is independently butyl. In some embodiments, at least one R 4 is independently isobutyl. In some embodiments, at least one R 4 is independently tert-butyl.

[0387] In some embodiments, at least one R 4 is independently C1-C6 haloalkyl.

[0388] In some embodiments, at least one R 4 is independently halomethyl. In some embodiments, at least one R 4 is independently haloethyl. In some embodiments, at least one R 4 is independently halopropyl. In some embodiments, at least one R 4 is independently haloisopropyl. In some embodiments, at least one R 4 is independently halobutyl. In some embodiments, at least one R 4 is independently haloisobutyl. In some embodiments, at least one R 4 is independently halo tert-butyl.

[0389] In some embodiments, each occurrence of R 4 are independently selected from the group consisting of -CH3, -CH2CH3, -CHF2, -CF3, -Cl, -CN, -NH2, and -CH2OH.

[0390] In some embodiments, at least one occurrence of R 4 are independently -CH3, or -CH2CH3.

[0391] In some embodiments, at least one occurrence of R 4 are independently -CHF2, or -CF3.

[0392] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0393] In some embodiments, the Ring A ring system of formula (xvii-b) is [ka] is selected from the group consisting of:

[0394] In some embodiments, ring A is [ka] is.

[0395] As generally defined herein, each L2 is independently a bond, a C1-C3 alkylene, or a C1-C3 haloalkylene.

[0396] In some embodiments, each L2 is independently a bond or a C1-C3 alkylene.

[0397] In some embodiments, at least one L2 is independently a bond.

[0398] In some embodiments, at least one L2 is independently C1-C3 alkylene.

[0399] In some embodiments, at least one L is independently a C alkylene. In some embodiments, at least one L is independently a C alkylene. In some embodiments, at least one L is independently a C alkylene. In some embodiments, at least one L is independently a C alkylene.

[0400] As generally defined herein, m is 0, 1, or 2.

[0401] In some embodiments, m is 0.

[0402] In some embodiments, m is 1 or 2.

[0403] In some embodiments, m is 1. In some embodiments, m is 2.

[0404] (c) Minor category For the compounds of the present disclosure, the variables ring A, R 1 , R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 2 , R 2A , R 2B , x, R 3 , R 3A , R 3B , R 3C , R 3D , R 3E , R 4 , R 4A , R 4B , R 4C , L1, L2, L3, and m may each be selected from groups described herein, where applicable, and the variables ring A, R 1 , R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 2 , R 2A , R 2B , x, R 3 , R3A , R 3B , R 3C , R 3D , R 3E , R 4 , R 4A , R 4B , R 4C Any group described herein as any of L, L, L, L, and m may be incorporated into the variables ring A, R, and R, where applicable. 1 , R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 2 , R 2A , R 2B , x, R 3 , R 3A , R 3B , R 3C , R 3D , R 3E , R 4 , R 4A , R 4B , R 4C It is understood that any of the groups described herein may be combined as one or more of the remainder of L, L, L, L, and m. Further exemplary combinations of the above embodiments are contemplated herein.

[0405] For example, in some embodiments where ring A is a group of formula (ii-b), the compound of formula (I) has formula (Ia): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at C4 is a group of formula (ia). In certain embodiments, the amino moiety at C4 is a group of formula (ib). In certain embodiments, the amino moiety at C4 is a group of formula (ic). In certain embodiments, R 1 is methyl (—CH). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ia), wherein R1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0406] In some embodiments, where ring A is a group of formula (iv-b), the compound of formula (I) has formula (Ib): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at C4 is a group of formula (ia). In certain embodiments, the amino moiety at C4 is a group of formula (ib). In certain embodiments, the amino moiety at C4 is a group of formula (ic). In certain embodiments, R 1 is methyl (—CH). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ib), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0407] In some embodiments, where ring A is a group of formula (vb), the compound of formula (I) has formula (Ic): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at C4 is a group of formula (ia). In certain embodiments, the amino moiety at C4 is a group of formula (ib). In certain embodiments, the amino moiety at C4 is a group of formula (ic). In certain embodiments, R 1 is methyl (—CH). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ic), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0408] In some embodiments, where ring A is a group of formula (vi-b), the compound of formula (I) has formula (Id): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at C4 is a group of formula (ia). In certain embodiments, the amino moiety at C4 is a group of formula (ib). In certain embodiments, the amino moiety at C4 is a group of formula (ic). In certain embodiments, R 1 is methyl (—CH). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Id), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0409] In some embodiments, where ring A is a group of formula (vii-b), the compound of formula (I) has formula (Ie): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at C4 is a group of formula (ia). In certain embodiments, the amino moiety at C4 is a group of formula (ib). In certain embodiments, the amino moiety at C4 is a group of formula (ic). In certain embodiments, R 1 is methyl (—CH). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ie), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0410] In some embodiments, where ring A is a group of formula (xiii-b), the compound of formula (I) has the formula (If): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at C4 is a group of formula (ia). In certain embodiments, the amino moiety at C4 is a group of formula (ib). In certain embodiments, the amino moiety at C4 is a group of formula (ic). In certain embodiments, R 1 is methyl (—CH). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has the formula (If), where R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0411] In some embodiments, where ring A is a group of formula (xiv-b), the compound of formula (I) has formula (Ig): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at C4 is a group of formula (ia). In certain embodiments, the amino moiety at C4 is a group of formula (ib). In certain embodiments, the amino moiety at C4 is a group of formula (ic). In certain embodiments, R 1 is methyl (—CH). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has the formula (Ig), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0412] In some embodiments where ring A is a group of formula (ii-b) and the amino moiety at C4 is a group of formula (ia), the compound of formula (I) has the formula (Ia-1): [ka] or a pharmaceutically acceptable salt thereof, wherein L3 is C1-C10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 alkynylene, and p is 0, 1, 2, or 3. In some embodiments, the compound has formula (Ia-1), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0413] In some embodiments where ring A is a group of formula (ii-b) and the amino moiety at C4 is a group of formula (ii-a), the compound of formula (I) has the formula (Ia-2): [ka] or a pharmaceutically acceptable salt thereof, wherein ring B is a C3-C 10 carbocyclyl, or 4-10 membered heterocyclyl, and p is 0, 1, 2, or 3. In some embodiments, the compound has formula (Ia-2), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0414] In some embodiments where ring A is a group of formula (ii-b) and the amino moiety at C4 is a group of formula (iii-a), the compound of formula (I) has formula (Ia-3): [ka] or a pharmaceutically acceptable salt thereof, wherein ring C is 4-10 membered heterocyclyl and p is 0, 1, 2, or 3. In some embodiments, the compound has formula (Ia-3), wherein R 1 is methyl and m is 1 or 2.

[0415] In some embodiments where ring A is a group of formula (xiii-b) and the amino moiety at C4 is a group of formula (ia), the compound of formula (I) has the formula (If-1): [ka] or a pharmaceutically acceptable salt thereof, wherein L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 alkynylene, and p is 0, 1, 2, or 3. In some embodiments, the compound has the formula (If-1), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0416] In some embodiments where ring A is a group of formula (xiii-b) and the amino moiety at C4 is a group of formula (ii-a), the compound of formula (I) has the formula (If-2): [ka] or a pharmaceutically acceptable salt thereof, wherein ring B is a C3-C 10 carbocyclyl, or 4-10 membered heterocyclyl, and p is 0, 1, 2, or 3. In some embodiments, the compound has the formula (If-2), wherein R 1 is methyl and R 2 is hydrogen and m is 1 or 2.

[0417] In some embodiments where ring A is a group of formula (xiii-b) and the amino moiety at C4 is a group of formula (iii-a), the compound of formula (I) has the formula (If-3): [ka] or a pharmaceutically acceptable salt thereof, wherein ring C is a 4- to 10-membered heterocyclyl and p is 0, 1, 2, or 3. In some embodiments, the compound has formula (If-3), wherein R 1 is methyl and m is 1 or 2.

[0418] R 1 and R 2and are cyclized to form a 6-membered heterocyclic ring, the compound of Formula (I-BC-a) or (I-BC-b): [ka] or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4.

[0419] In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

[0421] In some embodiments, the compound of formula (I) is selected from a pharmaceutically acceptable salt of any one of the compounds in Table 1 or Table 2.

[0422] In some embodiments, the compound of formula (I) is a free base selected from any one of the compounds in Table 1 or Table 2.

[0423] Tables 1 and 2 below also provide the location of the compounds in the Examples (Ex) by Example Number (Ex) or as provided in Table A (TA) of the Examples. An asterisk ( * ) indicates that an arbitrary stereochemistry has been assigned. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 [Table 1-56] [Table 1-57] [Table 1-58] [Table 1-59] [Table 1-60] [Table 1-61] [Table 1-62] [Table 1-63] [Table 1-64] [Table 2-1] [Table 2-2] [Table 2-3]

[0424] In some embodiments, the compound is Compound 3 * , compound 4 * , compound 10, compound 21 * , compound 22 * , compound 67a * , compound 67b * , compound 73, compound 74, compound 77, compound 83, compound 107a * , compound 107b * , compound 108a * , compound 108b *, Compound 114, Compound 121, Compound 127, Compound 161, Compound 182, Compound 196, Compound 197, Compound 213, or a pharmaceutically acceptable salt of any of the foregoing.

[0425] ii. Pharmaceutical Compositions In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable carriers include excipients, diluents, and surfactants.

[0426] In some embodiments, the compounds of the present disclosure, or pharmaceutical compositions comprising same, may be administered in an amount effective to treat a disorder in a subject.

[0427] Administration can be accomplished by any mode of administration, exemplary modes including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, intravaginal, buccal, rectal, or topical modes of administration.

[0428] Depending on the intended mode of administration, the compounds and compositions of the present disclosure may be in solid, semi-solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, or the like, sometimes in unit dosage amounts consistent with conventional pharmaceutical practice.

[0429] Similarly, the compounds and compositions of the present disclosure can also be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously or intramuscularly in a form suitable for these types of administration.For example, parenteral administration of injectables is generally used for subcutaneous, intramuscular or intravenous injection and infusion.Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for dissolving in liquid before injection.

[0430] Exemplary pharmaceutical compositions include a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, such as: a) a diluent, such as purified water, triglyceride oil, e.g., hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, e.g., EPA or DHA, or esters or triglycerides thereof, or mixtures thereof, omega-3 fatty acid or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, or the like; In the case of tablets, additionally, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, waxes, and / or polyvinylpyrrolidone; if desired, d) disintegrants, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersing agents, 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.

[0431] iii.Treatment method 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 amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0432] 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.

[0433] In some embodiments, the present disclosure provides methods of modulating cGAS activity (e.g., in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments, the disease or disorder is associated with implicated cGAS activity. In some embodiments, the disease or disorder is a disease or disorder in which cGAS activity has been implicated.

[0435] In some embodiments, 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).

[0436] 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.

[0437] In some embodiments, the present disclosure provides 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).

[0438] In some aspects, the present disclosure provides the 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.

[0439] In some aspects, the present disclosure provides the 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.

[0440] The present disclosure provides compounds that function as modulators of cGAS activity.

[0441] In one embodiment, the modulation is inhibition.

[0442] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or a cGAS-related disease in a subject determined to carry a non-silent germline or somatic mutation in cGAS.

[0443] In some aspects, the disease or disorder is cancer, hi some embodiments, the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, stomach cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, pancreatic cancer, penile cancer, testicular germ cell cancer, thymic carcinoma, thymic carcinoma, lung cancer, ovarian cancer, or prostate cancer.

[0444] In some embodiments, 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.

[0445] In some embodiments, the disease or disorder is a kidney disease. In certain embodiments, the kidney disease is an acute kidney disease, a chronic kidney disease, or an orphan kidney disease. In certain embodiments, the chronic kidney disease is diabetic nephropathy.

[0446] In some embodiments, the disease or disorder is a skin disease, hi certain embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0447] In some embodiments, the disease or disorder is rheumatic disease. In certain embodiments, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis. In some embodiments, the disease or disorder is liver disease. In certain embodiments, the liver disease is non-alcoholic steatohepatitis (NASH).

[0448] In some embodiments, the disease or disorder is a cardiovascular disease. In certain embodiments, the cardiovascular disease is cardiomyopathy, atherosclerosis, or peripheral arterial disease (PAD).

[0449] In some embodiments, the disease or disorder is a metabolic disease, hi particular embodiments, the metabolic disease is obesity-induced insulin resistance.

[0450] In some embodiments, the disease or disorder is a cGAS-associated disease in a subject determined to carry a germline or somatic non-silent mutation in cGAS.

[0451] 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 erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), scleroderma, Aicardi-Goutières syndrome, dermatomyositis, systemic sclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, or Sjogren's syndrome (SS).

[0452] In some embodiments, the disease or disorder is inflammation of any tissue or organ of the body, including musculoskeletal inflammation, vascular inflammation, neurological inflammation, gastrointestinal inflammation, ocular inflammation, reproductive system inflammation, and other inflammation.

[0453] In some embodiments, musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly a condition affecting skeletal joints, including those of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knee, ankle, and foot, as well as a condition affecting the tissues that connect 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 cystica). Ocular inflammation refers to inflammation of any structure of the eye, including the eyelid. Examples of inflammation of the eye include blepharitis, cutis laxa, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, entropion, and uveitis. Examples of inflammation of the nervous system include encephalitis, Guillain-Barré syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, and schizophrenia.

[0454] Examples of inflammation of the vascular or lymphatic system include atherosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[0455] Examples of inflammatory conditions of the digestive system include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), ileitis, and proctitis.

[0456] 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.

[0457] In some embodiments, the disease or disorder is an autoimmune condition with an inflammatory component, such as systemic lupus erythematosus, cutaneous lupus erythematosus, acute universalis, Behcet's disease, Chagas' disease, chronic fatigue syndrome, autonomic neuropathy, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes mellitus, giant cell arteritis, Gut-Pasture's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Henoch-Schönlein purpura, Kawasaki disease, and microscopic colonic leukemia. These include rheumatoid arthritis, 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, Sjögren's syndrome, Aicardi-Goutières syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0458] In some embodiments, the disease or disorder is a T cell-mediated hypersensitivity condition with an inflammatory component, such as contact hypersensitivity, contact dermatitis (including that caused by poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0459] 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 stomatitis, transplant rejection (involving kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small intestine, skin allograft, skin allograft, serum sickness, and graft-versus-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sézary syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, and cancer-related hypercalcemia. skin rash, pemphigus, bullous herpetiform dermatitis, 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 iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute leukemia in children, regional enterocolitis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, and sepsis.

[0460] iv. Preparation method Compounds of formula (I) can be synthesized according to general schemes 1-10 as provided below. Non-limiting examples of this general synthesis are further described in the Examples.

[0461] For example, as shown in General Scheme 1, 3-hydroxy-2-oxo-2H-pyran-6-carboxylic acid of formula (A) or a salt thereof can be prepared by reacting R a C 1-6 Alkyl or C 1-6 The group R as defined herein may be protected as an alkyl ester of formula (B) or a salt thereof, which may then be halogenated at C4 to provide a compound of formula (C) or a salt thereof, wherein X is Cl, Br, or I. 1Deprotection of the alkyl ester of formula (D) or its salt can provide a compound of formula (D) or its salt. a can result in a carboxylic acid compound of formula (D) or a salt thereof, in which [ka]

[0462] As shown in General Scheme 2, a hydrazinecarbothioamide of formula (G) or a salt thereof and R 4 and m as defined herein with a carboxylic acid-containing compound of formula (F-1) or a cyano-containing compound of formula (F-2), or a salt thereof, can provide a 1,3,4-thiadiazol-2-amine of formula (H-1), or a salt thereof. Alternatively, as shown in General Scheme 3, in which the nitrogen atom of the heteroaryl ring A is directly linked to the thiadiazole moiety and R 4 and m is as defined herein, can be prepared by coupling a 5-halo-1,3,4-thiadiazol-2-amine of formula (M), where Y is Cl, Br or I, or a salt thereof, with an amine of formula (L), or a salt thereof. [ka] [ka]

[0463] As shown in General Scheme 4, an amine of formula (K) or a salt thereof can be reacted with a compound of formula R a C 1-6 Alkyl or C 1-6 Cross-coupling with an alkyl ester of formula (D) or salt thereof to form a haloalkyl can provide an amine compound of formula (N) or salt thereof. The amine compound of formula (N) or salt thereof can then be deprotected to form the R a can result in an amine compound of formula (N) or a salt thereof in which [ka]

[0464] R in the formula a hydrogen, C 1-6 Alkyl or C 1-6 The compounds of the above formulas (D) and (N) or salts thereof which are haloalkylated, and the amine compounds of formula (H-1) or (H-2) or salts thereof can each be used as intermediates in preparing the compound of formula (I) or salts thereof.

[0465] For example, as shown in General Scheme 5, an amine of formula (H-1) or a salt thereof can be reacted with a compound represented by the formula R a hydrogen, C 1-6 Alkyl or C 1-6 Peptide coupling with a haloalkylated compound of formula (D) or a salt thereof can provide an amide compound of formula (J-1) or a salt thereof, which can then be cross-coupled with an amine of formula (K) or a salt thereof to provide a compound of formula (I) or a salt thereof. [ka]

[0466] Alternatively, as shown in General Scheme 6, an amine of formula (H-2) or a salt thereof can be reacted with a compound represented by the formula R a hydrogen, C 1-6 Alkyl or C 1-6 Peptide coupling with a compound of formula (D) or a salt thereof that is haloalkyl can provide an amide compound of formula (J-2) or a salt thereof. Subsequent cross-coupling of the amide compound of formula (J-2) or a salt thereof with an amine of formula (K) or a salt thereof can provide a compound of formula (I"") or a salt thereof, in which the nitrogen atom of the heteroaryl ring A is directly linked to the thiadiazole moiety. [ka]

[0467] Compounds of formula (J-1) and (J-2), and salts thereof, are also referred to herein as "halopyrone reagents," and compounds of formula (K), and salts thereof, are also referred to herein as "amine reagents."

[0468] In another embodiment, as shown in General Scheme 7, an amine of formula (H-1) or a salt thereof is reacted with a compound represented by the formula R a hydrogen, C 1-6 Alkyl or C 1-6 Peptide coupling with a haloalkylated compound of formula (N), or a salt thereof, can provide a compound of formula (I), or a salt thereof. [ka]

[0469] In yet another embodiment, as shown in General Scheme 8, an amine of formula (H-2) or a salt thereof is reacted with an amine of formula (H-3) or a salt thereof, a hydrogen, C 1-6 Alkyl or C 1-6 Peptide coupling with a compound of formula (N) or a salt thereof to a haloalkyl can provide a compound of formula (I'''') or a salt thereof, in which the nitrogen atom of the heteroaryl ring A is directly linked to the thiadiazole moiety. [ka]

[0470] The compounds of formula (N) and their salts are also called "aminopyrone reagents," and the compounds of formulas (H-1) and (H-2) and their salts are also called "ADT amine reagents."

[0471] R in the formula 1 is the group -CH2CH2-OH, and R 2 In still other embodiments, as shown in General Schemes 9 and 10, where R is hydrogen, the bicyclic compounds of Formula (I-BC-a) and (I-BC-b) are1 to 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. [ka] [ka]

[0472] v. Biological Assay Once produced, compounds designed, selected, and / or optimized by the above methods can be characterized to determine whether the compounds have biological activity using a variety of assays known to those of skill in the art. For example, the compounds described herein can be characterized to determine whether they have the predicted activity, binding activity, and / or binding specificity by conventional assays, including but not limited to the assays described below.

[0473] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it may 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.

[0474] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the disclosed compounds, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays for determining hcGAS potency and inhibitory activity, unbound clearance, solubility, and permeability.

[0475] In some embodiments, compounds of the present disclosure can be tested for their human cGAS (h-cGAS) inhibitory activity using known procedures, for example, the methodology reported in Lama et al., Nature Communications (2019) 10:2261 (2019). See also the biological assay methods in the Examples.

[0476] In some embodiments, compounds of the present disclosure can be tested for unbound clearance according to known procedures, such as those described in Miller et al., J. Med. Chem. (2020) 63:12156-12170. For example, unbound clearance (Clu) can be calculated by dividing the total clearance measured in blood or plasma ("CL" in mL / min / kg) by the unbound fraction (fu) of plasma.

[0477] In some embodiments, the solubility of the compounds of the present disclosure can be determined according to known procedures, such as those 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, kinetic solubility in a physiologically relevant medium can be measured using serial dilutions and a 2-hour incubation period followed by filtration and reported in μM by LC-MS / MS. Thermodynamic solubility in a physiologically relevant medium can be measured after 24 hours of incubation followed by filtration and reported in mg / mL by LC-MS / MS.

[0478] In some embodiments, the permeability of compounds of the present disclosure can be determined according to known procedures, such as those described in Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, permeability across a cell membrane can be measured using either Caco-2 or MDCK-MDR1 cell lines in Transwell plates after measuring the compound in both the apical and basolateral chambers, and expressed as apparent permeability Papp AB. -6 It may be reported in cm / s. vi. Further Embodiments

[0479] Embodiment 1. A compound of formula (I): [ka] [During the ceremony, Ring A is a 5-membered monocyclic heteroaryl; R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L3-(C3-C6 carbocyclyl), or -L3-(4- to 10-membered heterocyclyl), and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 1A and each R1A are independently halogen, -OR 1B , -N(R 1B )2, -SR 1B , -C(=O)OR 1B , -C(=O)N(R 1C )2, -(C1-C3 alkylene)-OR 1B , or -(C1-C3 alkylene)-SR 1B or two R's that appeared 1A are taken together to form =O; each R 1B are independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl, and said alkyl and said haloalkyl are independently selected from 0, 1, 2, 3, or 4 R 1D and each R 1C are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR 1F and each R 1D are independently halogen, -OR 1F , or -N(R 1F )2; each R 1F are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein said alkylene is independently selected from 0, 1, 2, 3, or 4 R 1E and each R 1E are independently -(C1-C3 alkylene)-OR 1B , or -OR 1B or two R's that appeared 1E But together they form =O; R 2 is hydrogen or 0, 1, 2, 3 or 4 R 2A and each R 2A are independently halogen, -OR 2B , or -N(R 2B )2, and each R 2B are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; Alternatively, R 1 and R2 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 1A forming a 6- or 7-membered heterocyclyl substituted with; R 3 is C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3A is replaced by; Alternatively, R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with; Each R 3A are independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, ═O, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-PO(R 3C )2, -L1-OR 3B , -L1-N(R 3B )2, -L1-C(=O)N(R 3B )2, or -L1-C(=O)OR 3B , -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3A groups, together with the atoms to which they are attached, combine to form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3Dis replaced by; Each R 3B are independently hydrogen, C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and the alkyl, carbocyclyl, and heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3C are independently C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3D are independently halogen, -OR 3E , —CN, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E are independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; Each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl, and each R 4A and R 4B are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -C(=O)R 4C and R 4C is C1-C6 alkyl, or C1-C6 haloalkyl; each L and L is independently a bond, a C-C alkylene, or a C-C haloalkylene; m is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

[0480] Embodiment 2. Ring A is a 5-membered monocyclic heteroaryl; R 1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and the alkyl, the alkenyl, and the alkynyl are independently selected from 0, 1, 2, 3, or 4 R 1A and each R 1A are independently halogen, -OR 1B, or -N(R 1B )2; each R 1B is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 2 is hydrogen or 0, 1, 2, 3 or 4 R 2A and each R 2A are independently halogen, -OR 2B , or -N(R 2B )2, and each R 2B is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 3 But C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3A is replaced by; Alternatively, R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with; Each R 3A are independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, ═O, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3Agroups, together with the atoms to which they are attached, combine to form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3B are independently hydrogen, C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6-membered heterocyclyl, and the alkyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3C is independently C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3D are independently halogen, -OR 3E , C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl, and each R 4A and R 4B is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each L1 and L2 is independently a bond, C1-C3 alkylene, or C1-C3 haloalkylene; m is 0, 1 or 2; 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0481] Embodiment 3. The amino moiety [ka] is a group of formula (ia), (ii-a) or (iii-a): [ka] [During the ceremony, L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 is alkynylene; Ring B is C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl; Ring C is a 5- to 10-membered heterocyclyl; p is 0, 1, 2 or 3. 3. The compound of embodiment 1 or 2, wherein:

[0482] Embodiment 4. The compound has the formula (I'): [ka] [Wherein L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 alkynylene, and p is 0, 1, 2, or 3. or a pharmaceutically acceptable salt thereof.

[0483] Embodiment 5. The compound has the formula (I″): [ka] wherein ring B is C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3. or a pharmaceutically acceptable salt thereof.

[0484] Embodiment 6. The compound has Formula (I'"): [ka] wherein ring C is a 5- to 10-membered heterocyclyl and p is 0, 1, 2, or 3. or a pharmaceutically acceptable salt thereof.

[0485] Embodiment 7. The compound has Formula (I""): [ka] wherein the nitrogen atom of the heteroaryl ring A is directly linked to the thiadiazole moiety. or a pharmaceutically acceptable salt thereof.

[0486] Embodiment 8. R 1 but 0, 1, 2, 3 or 4 R 1A or a pharmaceutically acceptable salt thereof.

[0487] Embodiment 9. R 1 is -CH3, -CH2-C(CH3)2-CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, [ka] or a pharmaceutically acceptable salt thereof.

[0488] Embodiment 10. R 2 The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0489] Embodiment 11. R 3 but 0, 1, 2, 3 or 4 R 3A C1-C substituted with 10 The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0490] Embodiment 12. R 3 but 0, 1, 2, 3 or 4 R 3A C3-C substituted with 10 The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, which is carbocyclyl.

[0491] Embodiment 13. R 3 but 0, 1, 2, 3 or 4 R 3A 11. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein R is 4-10 membered heterocyclyl substituted with R.

[0492] Embodiment 14. R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A or a pharmaceutically acceptable salt thereof.

[0493] Embodiment 15. R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A or a pharmaceutically acceptable salt thereof.

[0494] Embodiment 16. [ka] but, [ka] [ka] [ka] [ka] [ka] 16. The compound of any one of embodiments 1-15, selected from the group consisting of:

[0495] Embodiment 17. [ka] but, [ka] 17. The compound of embodiment 16, selected from the group consisting of:

[0496] Embodiment 18. [ka] but, [ka] 17. The compound of embodiment 16, selected from the group consisting of:

[0497] Embodiment 19. [ka] but, [ka] 17. The compound of embodiment 16, selected from the group consisting of:

[0498] Embodiment 20. Ring A is [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0499] Embodiment 21. Ring A is [ka] 21. The compound of embodiment 20, wherein:

[0500] Embodiment 22. Each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,

[0501] Embodiment 23. Each R 4 is independently -CH3, -CH2CH3, -CHF2, -CF3, -Cl, -CN, -NH2, or -CH2OH, or a pharmaceutically acceptable salt thereof.

[0502] Embodiment 24. A compound of any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, wherein L1 is a bond or C1-C3 alkylene.

[0503] Embodiment 25. A compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein L2 is a bond or C1-C3 alkylene.

[0504] Embodiment 26. A compound of any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0505] Embodiment 27. A compound of any one of embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0506] Embodiment 28. Ring A is [ka] 21. The compound of embodiment 20, wherein:

[0507] Embodiment 29. Ring A is [ka] 29. The compound of embodiment 28, wherein:

[0508] Embodiment 30. The compound has formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ia-2), (Ia-3), (If-1), (If-2), (If-3), (I-BC-a) or (I-BC-b): [ka] [ka] [ka] wherein x is 0, 1, 2, 3, or 4. or a pharmaceutically acceptable salt thereof.

[0509] Embodiment 31. R 1 but 0, 1, 2, 3 or 4 R 1A and each R 1A but independently -OR 1B and each R 1B are independently hydrogen or C1-C3 alkyl; R 2 is hydrogen or 0, 1, 2, 3 or 4 R 2A and each R 2A but independently -OR 2B and each R 2B are independently hydrogen or C1-C3 alkyl; R 3But C1-C 10 Alkyl, C3-C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R 3A is replaced by; Alternatively, R 2 and R 3 and, together with the atoms to which they are attached, independently contain 0, 1, 2, 3, or 4 R 3A forming a 4- to 10-membered heterocyclyl substituted with; Each R 3A are independently C1-C3 alkyl, halogen, ═O, -L1-CN, -L1-SO2R 3C , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C 6-10 aryl), or -L1- (5- to 10-membered heteroaryl), or two R 3A groups, together with the atoms to which they are attached, combine to form a C6 aryl, a 5- to 6-membered heteroaryl, a C3-C6 carbocyclyl, or a 4- to 6-membered heterocyclyl, and the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, or 4 R 3D is replaced by; Each R 3C are independently C1-C3 alkyl; Each R 3D are independently halogen or -OR 3E and; R 3E is C1-C3 alkyl; Each R 4 are independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl; each L1 and L2 is independently a bond or a C1-C3 alkylene; m is 1 or 2; The compound of embodiment 2, or a pharmaceutically acceptable salt thereof.

[0510] Embodiment 32. The compound of embodiment 1 or 2, wherein the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0511] Embodiment 33. The compound of embodiment 32, wherein the compound is Compound 3, Compound 4, Compound 10, Compound 21, Compound 22, Compound 67a, Compound 67b, Compound 73, Compound 74, Compound 77, Compound 83, Compound 107a, Compound 107b, Compound 108a, Compound 108b, Compound 114, Compound 121, Compound 127, Compound 161, Compound 182, Compound 196, Compound 197, Compound 213, or a pharmaceutically acceptable salt thereof.

[0512] Embodiment 34. A compound of formula (I): [ka] [In the formula, rings A, R 1 , R 2 , R 3 , R 4 and m is defined in embodiment 1 or 2. or a salt thereof, comprising reacting a compound of formula (H-1) or a salt thereof with a compound of formula (N) or a salt thereof: [ka] [In the formula, R a is hydrogen, C 1-6 Alkyl, or C 1-6 haloalkyl] and carrying out peptide coupling of the formula (I) to give a compound of formula (I) or a salt thereof.

[0513] Embodiment 35. The compound of formula (H-1) or a salt thereof is represented by formula (H-2): [ka] or a salt thereof, wherein the process comprises reacting a compound of formula (I""): [ka] 35. The method of embodiment 34, resulting in:

[0514] Embodiment 36. A compound of Formula (K) or a salt thereof with a compound of Formula (D) or a salt thereof: [ka] [In the formula, R a is C 1-6 Alkyl, or C 1-6 haloalkyl, and X is Cl, Br, or I. 36. The method of embodiment 34 or 35, further comprising cross-coupling of: to provide a compound of formula (N) or a salt thereof.

[0515] Embodiment 37. A compound of formula (I): [ka] [In the formula, rings A, R 1 , R 2 , R 3 , R 4 and m is defined in embodiment 1 or 2. or a salt thereof, comprising reacting an amine of formula (K) or a salt thereof with a compound of formula (J-1) or a salt thereof: [ka] wherein X is Cl, Br or I. to provide a compound of formula (I) or a salt thereof.

[0516] Embodiment 38. The compound of formula (J-1) or a salt thereof is represented by formula (J-2): [ka] or a salt thereof, wherein the process comprises reacting a compound of formula (I""): [ka] 38. The method of embodiment 37, resulting in:

[0517] Embodiment 39. A compound of formula (H-1) or a salt thereof with a compound of formula (D) or a salt thereof: [ka] 38. The method of embodiment 37, further comprising carrying out a peptide coupling of formula (J-1) to provide a compound of formula (J-1) or a salt thereof.

[0518] Embodiment 40. A compound of formula (H-2) or a salt thereof with a compound of formula (D) or a salt thereof: [ka] 39. The method of embodiment 38, further comprising carrying out a peptide coupling of formula (J-1) to provide a compound of formula (J-2) or a salt thereof.

[0519] Embodiment 41. A hydrazinecarbothioamide of Formula (G) or a salt thereof with a carboxylic acid-containing compound of Formula (F-1) or a salt thereof, or a nitrile-containing compound of Formula (F-2) or a salt thereof: [ka] 40. The method of embodiment 33 or 39, further comprising carrying out the reaction of: to provide a compound of formula (H-1) or a salt thereof.

[0520] Embodiment 42. A compound of formula (M), wherein Y is Cl, Br or I, or a salt thereof, and an amine of formula (L), or a salt thereof: [ka] 41. The method of embodiment 35 or 40, further comprising coupling of: to provide a compound of formula (H-2) or a salt thereof.

[0521] Embodiment 43. (a) protecting a compound of formula (A) or a salt thereof to form an alkyl ester of formula (B): [ka] [In the formula, R a is C 1-6 Alkyl, or C 1-6 haloalkyl] or bringing about its salt; (b) halogenating a compound of formula (B) or a salt thereof to obtain a compound of formula (C): [ka] wherein X is Cl, Br or I. or bringing about its salt; (c) protecting the hydroxyl group of the compound of formula (C) or a salt thereof to obtain a compound of formula (D): [ka] [In the formula, R 1 is defined in embodiment 1. or a salt thereof; and (d) optionally deprotecting the compound of formula (D) or salt thereof to form R a to give a carboxylic acid of formula (D) 41. The method of any one of embodiments 36, 39 and 40, further comprising:

[0522] Embodiment 44. A compound of Formula (I-BC-a): [ka] [In the formula, rings A, R 1 , R 3 , R 4 and m are defined in embodiment 1. or a salt thereof, comprising the step of: [ka] wherein LG is a leaving group. or a salt thereof.

[0523] Embodiment 45. The compound of formula (I-BC-a) or a salt thereof is a compound of formula (I-BC-b): [ka] or a salt thereof; wherein the compound of formula (P-1) has the formula (P-2): [ka] or a salt thereof.

[0524] Embodiment 46. The compound of formula (P-1) or a salt thereof, or the compound of formula (P-2) or a salt thereof is represented by formula (IX-1) or formula (IX-2): [ka] 46. ​​The method of embodiment 44 or 45, wherein the compound is prepared by converting the terminal —OH of

[0525] Embodiment 47. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0526] Embodiment 48. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound described in any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 47.

[0527] Embodiment 49. The method of embodiment 48, wherein the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or a cGAS-related disease in a subject determined to harbor a non-silent germline or somatic mutation in cGAS.

[0528] Embodiment 50. A method of modulating cGAS activity, comprising contacting a cell with a compound of any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 47. [Example]

[0529] In order that the present 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 the disclosure in any way.

[0530] Analysis method Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz where indicated and at 300.3 K unless otherwise noted, and chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded with 8, 16, or 32 scans using a Bruker Avance 400 instrument. Typical NMR solvents include deuterated dimethyl sulfoxide (DMSO-d) and deuterated methanol (CDOD).

[0531] Liquid chromatography-mass spectrometry (LCMS) chromatograms and spectra were recorded using a Shimadzu LCMS-2020. The injection volume was 0.7–8.0 μl, and the flow rate was typically 0.8 or 1.2 mL / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) with positive ion electrospray ionization. The MS range was 100–1000 Da. The mobile phase of water and / or acetonitrile (MeCN) may contain modifiers such as trifluoroacetic acid (TFA), formic acid (FA), or ammonium carbonate (NH4HCO3) (typically 0.01–0.04%). ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (min).

[0532] Purification / Isolation Methods. The synthetic methods describe the purification and / or isolation chromatographic methods employed in the purification and / or isolation of the exemplified compounds. Rf = retention factor; RT = retention time (min); Prep HPLC = preparative high performance liquid chromatography.

[0533] The star ( * ) indicates that an arbitrary stereochemistry has been assigned. The future tense ("may be prepared / synthesized") describes an example that is to be performed.

[0534] Synthesis method Example 1: 4-((1,3-dimethoxypropan-2-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 10) [ka] Example 1 - Part A: Preparation of 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid [ka] Step 1: To 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. The resulting mixture was then stirred at 80 °C overnight. 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 with water (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-hydroxy-6-oxopyran-2-carboxylate (85 g, 43% yield). LCMS (ES, m / z) = 171 [M+1]+.

[0535] Step 2: To a stirred solution of methyl 5-hydroxy-6-oxopyran-2-carboxylate (1.0 g, 5.9 mmol, 1.0 equiv.) in acetic acid (AcOH) (25 mL, 323 mmol) was added N-bromosuccinimide (NBS) (1.25 g, 7.02 mmol, 1.19 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 2 hours and then diluted with water (70 mL). The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 70 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous NaSO. 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) (3:7) to give methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (800 mg, 55% yield). LCMS (ES, m / z) = 247 [M-1]-.

[0536] Step 3: To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (4.0 g, 16 mmol, 1.0 equiv.) in dichloromethane (DCM) (50 mL) was added diisopropylethylamine (DIEA) (11.0 g, 85.1 mmol, 5.30 equiv.) and methyl trifluoromethanesulfonate (TfOMe) (13.0 g, 79.2 mmol, 4.93 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The mixture was then diluted with water (200 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (2 × 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 give methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (3.0 g, 71% yield). LCMS (ES, m / z) = 263 [M+1]+.

[0537] Step 4: To methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (10.0 g, 38.02 mmol, 1.00 equiv.) was added HCl (6 M) (200 mL, 65.8 mmol). The mixture was stirred at 80 °C for 4 h and then concentrated under reduced pressure to give 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (9.5 g), which was used directly without further purification. LCMS (ES, m / z) = 249 [M+1].

[0538] Example 1 - Part B: Preparation of 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine [ka] Step 1: A mixture of 5-bromo-1,3,4-thiadiazol-2-amine (200 g, 1110 mmol, 1.0 equiv.), diisopropylethylamine (DIEA) (431 g, 3333 mmol, 3.0 equiv.), and pyrazole (90.76 g, 1333 mmol, 1.2 equiv.) in 1,4-dioxane was stirred at 80° C. for 3 hours. The resulting mixture was concentrated in vacuo, 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 give 5-(pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (100 g, 54% yield), which was used directly in the next step without further purification.

[0539] Step 2: A mixture of 5-(pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (100 g, 598 mmol, 1.0 equiv.), tosylic 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 at 110 °C for 2 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (9:1) to give 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (90.3 g, 61% yield). LCMS (ES, m / z) = 246.1 [M+1]+.

[0540] Step 3: A solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (50.0 g, 204 mmol, 1.0 equiv.) in THF was treated with n-butyllithium (n-BuLi) (97.8 mL, 245 mmol, 1.2 equiv.) at −78 °C under N2 (nitrogen gas) for 1 h, followed by the dropwise addition of methyl iodide (CHI) (34.7 g, 245 mmol, 1.2 equiv.) at −78 °C. The resulting mixture was stirred at room temperature under N2 for 2 h. The reaction was quenched with saturated NH4Cl (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 give 2-(2,5-dimethylpyrrol-1-yl)-5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazole (40 g, 76% yield). LCMS (ES, m / z) = 260.0 [M+1]+.

[0541] Step 4: To a room temperature solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazole (7.0 g, 27 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (14 mL) and HO (28 mL) was added trifluoroacetic acid (TFA) (28 mL). The resulting mixture was stirred at 50 °C for 2 hours and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 10% to 20% gradient in 10 min; wavelength: 254 nm) to give 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (also referred to as 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine) (3.0 g, 58% yield). LCMS(ES, m / z)=181.95[M+1]+.

[0542] Example 1 - Part C: Preparation of 4-((1,3-dimethoxypropan-2-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide [ka] Step 1: To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (12.0 g, 48.2 mmol, 1.00 equiv.) in N,N-dimethylformamide (DMF) (150 mL) was added hydroxybenzotriazole (HOBt) (13.02 g, 96.38 mmol, 2.00 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (27.81 g, 145.05 mmol, 3.01 equiv.), and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (the product of Step 4, Part B of Example 1) (9.00 g, 49.7 mmol, 1.03 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then quenched by the addition of water (70 mL). The precipitated solid was collected by filtration and washed with acetonitrile (5 × 3 mL) to give 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (11.0 g, 55% yield). LCMS (ES, m / z) = 412 [M+1].

[0543] Step 2: A stirred solution of 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (also referred to herein as 4-bromo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide) (100 mg, 0.243 mmol, 1.00 equiv.) (“halopyrone reagent”) in N,N-dimethylform To a solution of the amide (DMF) (3.5 mL) at room temperature was added 1,3-dimethoxypropan-2-amine ("amine reagent") (60 mg, 0.50 mmol, 2.1 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (40 mg, 0.086 mmol, 0.35 equiv.), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (40 mg, 0.048 mmol, 0.20 equiv.), and CsCO (240 mg, 0.737 mmol, 3.04 equiv.). The resulting mixture was stirred under N2 (nitrogen gas) at 100 for 3 hours. The resulting mixture was filtered, the filter cake was washed with acetonitrile (1 x 3 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; wavelength: 254 nm), followed by further purification by chiral preparative HPLC (conditions: Xselect CSH C18 OBD column 30 × 150 mm 5 μm; mobile phase, acetonitrile (MeCN) and water (29% water + 0.05% trifluoroacetic acid (TFA)) to 39% in 10 min, hold at 39% for 2 min; wavelength: 254 nm) to give 4-((1,3-dimethoxypropan-2-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 10) (25.4 mg, yield 23.2%). LCMS(ES, m / z)=451.20[M+1]+.1 H NMR(400MHz,DMSO-d6)δ7.78(d,J=1.6Hz,1H),7.44(s,1H),6.44(d,J=1.6Hz,1H ),4.14-4.09(m,1H),3.69(s,3H),3.50-3.43(m,4H),3.38(s,6H),2.68(s,3H).

[0544] Example 2: 3-Methoxy-4-(((1R,2R)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 3 * ), and 3-methoxy-4-(((1S,2S)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 4 * ) [ka] Racemic trans-3-methoxy-4-((-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared according to Step 2 of Part C of Example 1, using trans-2-methoxycyclopentan-1-amine hydrochloride as the "amine reagent" and 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (the product of Step 1 of Part C of Example 1, designated the "halopyrone reagent"). The separation of the constituent enantiomers of racemic trans-3-methoxy-4-((-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide was carried out by preparative chiral HPLC (conditions: column: chiral ART Amylose-SA, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: methanol (MeOH):dichloromethane (DCM) = 1:1; flow rate: 20 mL / min; gradient: 60% B to 60% B in 10 min; wavelength: 220 / 254 nm; RT1 (min): 6.99; RT2 (min): 9.03; sample solvent: MeOH) was used to obtain two enantiomers with arbitrary stereochemical assignment: 3-methoxy-4-(((1R,2R)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 3). * ), first eluting peak, LCMS (ES, m / z) = 447.10 [M+1] +, 1H NMR(400MHz,DMSO-d6)δ13.32(br,1H),7.79(d,J=1.6Hz,1H),7.42(s,1H),7.01(d,J=8.4Hz, 1H),6.45(d,J=1.6Hz,1H),3.96-3.92(m,1H),3.79-3.68(m,1H),3.69(s,3H),3.25(s,3H),2 0.68 (s,3H), 2.10-1.90 (m,2H), 1.73-1.51 (m,4H); and 3-methoxy-4-(((1S,2S)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 4 * ), second eluting peak, LCMS (ES, m / z) = 447.10 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.32(br,1H),7.79(d,J=1.6Hz,1H),7.42(s,1H),7.01(d,J=8.4Hz,1H),6.45(d,J=1.2Hz,1H),3 .93(d,J=8.0Hz,1H),3.75(q,J=5.6Hz,1H),3.69(s,3H),3.25(s,3H),2.68(s,3H),2.10-1.90(m,2H),1.73-1.51(m,4H).

[0545] Example 3: 4-(((cis)-2-hydroxycyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 23, rac-23), 4-(((1S,2R)-2-hydroxycyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 23a * ), and 4-(((1R,2S)-2-hydroxycyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 23b* ) [ka] To a stirred solution of 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (100 mg, 0.243 mmol, 1 equiv.) (product of Step 1, Part C of Example 1; "halopyrone reagent") in N,N-dimethylformamide (DMF) (1.5 mL) was added cis-2-aminocyclopentan-1-ol hydrochloride (81 mg, 0.59 mmol, 2.45 equiv.) ("amine reagent"), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuxphos Pd G3) (39 mg, 0.049 mmol, 0.20 equiv.), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (tBuxphos) (32 mg, 0.075 mmol, 0.31 equiv.), and cesium carbonate (230 mg, 0.71 mmol, 2.91 equiv.) were added. The resulting mixture was stirred at 100 °C under N2 (nitrogen gas) for 1 h. The resulting mixture was filtered, and the filter cake was washed with acetonitrile (MeCN) (3 × 3 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography (conditions: mobile phase: MeCN in water, gradient from 10% to 50% in 10 min; wavelength: 254 nm). Further purification by preparative HPLC (conditions: XBridge Prep Phenyl OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 13% B to 27% B, 27% B in 8 min; wavelength: 254 nm) gave the title compound (Compound 23a * and compound 23b * ) (7.2 mg, 6.8% yield). LCMS (ES, m / z) = 433.15 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ7.75(d,J=1.6Hz,1H),7.32(s,1H),6.42(d,J=1.6Hz,1H),6.15(br,1H),5.14(d,J=4.8Hz,1H),4 .10-4.05(m,1H),3.92-3.85(m,1H),3.73(s,3H),2.67(s,3H),2.04-1.97(m,1H),1.89-1.77(m,2H),1.62-1.57(m,3H).

[0546] Example 4: N-(5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 136) [ka] Step 1: To a stirred solution of 4-chlorothiophene-3-carbonitrile (270 mg, 1.88 mmol, 1.00 equiv.) in trifluoroacetic acid (TFA) (3.00 mL) was added thiosemicarbazide (257 mg, 2.82 mmol, 1.50 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) / HO = 3:2) to give 5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-amine (260 mg, 64% yield). LCMS (ES, m / z) = 218.0 [M+1]+.

[0547] Step 2: To a stirred solution of 5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-amine (200 mg, 0.92 mmol, 1.00 equiv.) and 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4, Part A of Example 1) (343 mg, 1.38 mmol, 1.50 equiv.) in acetonitrile (MeCN) (2.00 mL) at room temperature was added N-methylimidazole (NMI) (377 mg, 4.60 mmol, 5.00 equiv.) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (335 mg, 1.20 mmol, 1.3 equiv.). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography (MeCN / water = 3:1) to give 4-bromo-N-[5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (80 mg, 18% yield). LCMS (ES, m / z) = 448.0 [M+1]+.

[0548] Step 3: Following the procedure outlined for the preparation of compound 23 in Example 3, N-(5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 136) was prepared from 4-bromo-N-[5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent." LCMS (ES, m / z) = 443.0 [M+1]+. 1 H NMR (400 MHz, methanol-d₄) δ 8.10 (s, 1H), 7.57 (s, 1H), 7.35 (s, 1H), 3.79 (s, 3H), 3.66-3.57 (m, 4H), 3.40 (s, 3H).

[0549] Example 5: N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((cis)-2-hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 7, rac-7), N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2-hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 7a * ), and N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1R,2S)-2-hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 7b * ) [ka] Steps 1-2: Following Steps 1-2 of Example 4, using 3-chlorothiophene-2-carbonitrile instead of 4-chlorothiophene-3-carbonitrile, 4-bromo-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide was prepared. LCMS (ES, m / z) = 448.0 [M+1].

[0550] Step 3: Following Step 2 of Part C of Example 1, N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2-hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 7a) was prepared using cis-2-aminocyclopentan-1-ol hydrochloride as the "amine reagent" and 4-bromo-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent." *), and N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1R,2S)-2-hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 7b * ) was prepared as a racemic mixture. LCMS (ES, m / z) = 468.85 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.47(br,1H),7.93(d,J=5.6Hz,1H),7.43(s,1H),7.32(d,J=5.6Hz,1H),6.25-6.18(m,1H),5.20 -5.09(m,1H),4.11-4.07(m,1H),3.97-3.81(m,1H),3.74(s,3H),2.08-1.98(m,1H),1.92-1.71(m,2H),1.71-1.44(m,3H).

[0551] Example 6: (R)-4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 21 * ), and (S)-4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 22 * ) [ka] Step 1: To a solution of methyl 5-hydroxy-6-oxopyran-2-carboxylate (25.0 g, 147 mmol, 1.00 equiv.) in acetic acid (AcOH) (300 mL) was added N-iodosuccinimide (NIS) (39.0 g, 173 mmol, 1.18 equiv.) in small portions at room temperature. The resulting mixture was stirred at 80 °C for 20 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (EtOAc) (1 L), washed with water (3 × 100 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (3:2) to give methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (20.0 g, 46% yield). LCMS (ESI, m / z) = 295 [M-1].

[0552] Step 2: To a solution of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (20.0 g, 67.6 mmol, 1.00 equiv.) in dichloromethane (DCM) (250 mL) was added diisopropylethylamine (DIEA) (26.0 g, 201 mmol, 2.98 equiv.) at room temperature. To the above mixture was added triflate ester (33.0 g, 201 mmol, 2.98 equiv.) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature, then poured into water and extracted with DCM (3 × 500 mL). The combined organic layer was washed with water (3 × 100 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) (4:1) to give methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (19.0 g, 91% yield). LCMS (ESI, m / z) = 311 [M+1]+.

[0553] Step 3: A solution of methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (5.0 g, 16 mmol, 1.0 equiv) in 100 mL of 6 M HCl was stirred at 80° C. for 4 h. The resulting mixture was then concentrated under reduced pressure to give 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (3.8 g, 80% yield). LCMS (ESI, m / z) = 295 [M-1]-.

[0554] Step 4: A solution of 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (2.60 g, 8.78 mmol, 1.00 equiv.), hydroxybenzotriazole (HOBT) (1.80 g, 13.3 mmol, 1.52 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (3.60 g, 18.8 mmol, 2.14 equiv.), and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (the product of Step 4, Part B of Example 1) (1.40 g, 7.72 mmol, 0.88 equiv.) in N,N-dimethylformamide (DMF) (40 mL) was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (20 mL). The precipitated solid was collected by filtration and washed with acetonitrile (MeCN) (5 × 1 mL) to give 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (also referred to herein as 4-iodo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide) (3.1 g, 77% yield). LCMS (ESI, m / z) = 460 [M+1]+.

[0555] Step 5: 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (100 mg, 0.218 mmol, 1 equiv.) as the "halopyrone reagent" and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle) A mixture of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [RuPhos (2-(2'-amino-1,1'-biphenyl)] (RuPhos) (20 mg, 0.043 mmol, 0.20 equiv.), CsCO (212 mg, 0.651 mmol, 2.99 equiv.), and 1-cyclopropyl-2-methoxyethanamine (25 mg, 0.217 mmol, 1.00 equiv.) as the "amine reagent" in N,N-dimethylformamide (DMF) (5.0 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The residue was directly purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min; detector, UV 254 nm), followed by drying in an oven under vacuum to give 140 mg of crude material. The crude material was further purified by preparative HPLC using the following conditions (X Select CSH Prep C18 OBD column, 19 × 250 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile (MeCN); flow rate: 20 mL / min; gradient: 25% B to 30% B in 8 min, 30% B; wavelength: 254 nm; RT1 (min): 8), and then dried in an oven under vacuum to give 70 mg of racemic 4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide.The separation of the constituent enantiomers was carried out under the following conditions: Chiral preparative HPLC was performed using IF, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: methanol:dichloromethane (methanol (MeOH):dichloromethane (DCM)) = 1:1; flow rate: 20 mL / min; gradient: 70% B to 70% B in 17 min; wavelength: 254 / 220 nm; RT1 (min): 7.81; RT2 (min): 12.17; sample solvent: MeOH:DCM = 1:1) to give two enantiomers with arbitrarily assigned stereochemistry: (R)-4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 21). * ), first eluting peak, LCMS (ES, m / z) = 447.16 [M+1] + 1 H NMR(400MHz,DMSO-d6)δ7.78(d,J=1.6Hz,1H),7.33(s,1H),6.44(d,J=1.6Hz,1H),3.68(s,3H) ,3.53(d,J=6.0Hz,2H),3.38-3.33(m,1H),3.25(s,3H),2.67(s,3H),1.06-1.02(m,1H),0.54-0 0.48 (m, 1H), 0.46-0.42 (m, 1H), 0.39-0.30 (m, 2H); and (S)-4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 22 * ), second eluting peak, LCMS (ES, m / z) = 447.16 [M+1] + , 1H NMR(400MHz,DMSO-d6)δ7.78(d,J=1.6Hz,1H),7.32(s,1H),6.44(d,J=1.6Hz,1H),3.68(s,3H),3.53(d,J=5.6Hz,2H),3 .49-3.46(m,1H),3.26(s,3H),2.67(s,3H),1.07-1.02(m,1H),0.56-0.50(m,1H),0.49-0.42(m,1H),0.35-0.28(m,2H).

[0556] Example 7: 4-(((cis)-2-hydroxycycloheptyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 26, rac-26), 4-(((1S,2R)-2-hydroxycycloheptyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 26a * ), and 4-(((1R,2S)-2-hydroxycycloheptyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 26b * ) [ka] To a stirred solution of 4-iodo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (50 mg, 0.11 mmol, 1.00 equiv.) (product of Step 4 of Example 6; “halopyrone reagent”) in N,N-dimethylformamide (DMF) (1.25 mL) at room temperature was added (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (rac-BINAP) (10 mg, 0.016 mmol, 0.15 equiv.), rac-BINAP-Pd-G3 ([1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphane) (1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphane) (1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl) ...). Methanesulfonic acid, palladium, 2-phenylaniline (15 mg, 0.015 mmol, 0.14 equiv.), cesium carbonate (174 mg, 0.534 mmol, 4.90 equiv.), and cis-2-aminocycloheptan-1-ol hydrochloride (20 mg, 0.121 mmol, 1.11 equiv.) ("amine reagent") were added. The resulting mixture was stirred at 100 °C under N2 (nitrogen gas) for 1 h. The mixture was then directly purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water (5 mmol / L NH4HCO3), gradient 20% to 50% over 15 min; detector, UV 254 nm). The crude product (20 mg) was then further purified by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (23% MeCN to 31% in 8 min)) to give the title compound (Compound 26a * and compound 26b * ) (3.9 mg, 7.6% yield). LCMS (ES, m / z) = 461.05 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ7.76(d,J=1.6Hz,1H),7.24(s,1H),6.42(d,J=1.6Hz,1H),6.22(br,1H),5.10-5.02( m,1H),3.95-3.90(m,1H),3.78-3.66(m,1H),3.65(s,3H),2.67(s,3H),1.96-1.61(m,6H),1.61-1.33(m,4H).

[0557] Example 8: 4-(((cis)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 28, rac-28), 4-(((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 28a * ), and 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 28b * ) [ka] To a stirred solution of 4-iodo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Step 4 of Example 6) (200 mg, 0.436 mmol, 1 equiv.) (“halopyrone reagent”) in N,N-dimethylformamide (DMF) (2.5 mL) was added CuI (20 To the resulting mixture were added cis-1-amino-2,3-dihydro-1H-inden-2-ol (80 mg, 0.536 mmol, 1.23 equiv.) ("amine reagent"). The resulting mixture was stirred at 80 °C under N (nitrogen gas) for 40 min. The mixture was then purified directly by C reverse-phase flash chromatography (acetonitrile (MeCN) in water (5 mmol / L NH4HCO3), gradient 10% to 50% in 10 min; detector, UV 254 nm). The crude product (40 mg) was then further purified by preparative HPLC (Xselect CSH C18 OBD column 30 × 150 mm 5 μm; mobile phase, water (0.05% trifluoroacetic acid (TFA)) and acetonitrile (MeCN) (31% MeCN to 41% in 10 min)) to give 4-(((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 28a * ) and 4-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 28b * ) to give a racemic mixture (3.4 mg, 1.6% yield). LCMS (ES, m / z) = 481.05 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ11.42(br,1H),7.89(d,J=8.8Hz,1H),7.83(d,J=1.6Hz,1H),7.28-7.19(m,4H),7.10(s,1H),6.4 8(d,J=1.6Hz,1H),5.41-5.25(m,2H),4.54-4.96(m,1H),3.39(s,3H),3.16-3.09(m,1H),2.90-2.82(m,1H),2.71(s,3H).

[0558] Example 9: 4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 29) [ka] 4-Bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Step 1, Part C of Example 1; "halopyrone reagent") (100 mg, 0.24 mmol, 1.00 equiv.) ("halopyrone reagent") and 4-aminotetrahydro-2H-thiopyran 1,1-dioxide (125 mg, 0.84 mmol, 3.45 equiv.) ("amine reagent") were reacted with N,N-dimethylformamide. To a stirred solution of tris(dibenzylideneacetone)dipalladium(0)dibenzylideneacetone (Pd(dba)) (20 mg, 0.04 mmol, 0.14 equiv.), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (rac-BINAP) (32 mg, 0.05 mmol, 0.21 equiv.), and cesium carbonate (240 mg, 0.74 mmol, 3.04 equiv.) in dichloromethane (DMF) (5 mL) at room temperature was added under N2 (nitrogen gas). The resulting mixture was stirred at 120 °C under N2 for 2 h. The resulting mixture was diluted with water (40 mL) and extracted with ethyl acetate (EtOAc) (3 × 50 mL). The organic extract was concentrated under reduced pressure, and the residue was purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (0.05% trifluoroacetic acid (TFA)), mobile phase B: methanol (MeOH); flow rate: 20 mL / min; gradient: 53% B to 58% B in 8 min; wavelength: 254 nm) to give 4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 29) (10.6 mg, 9.0% yield). LCMS (ESI, m / z) = [M+1] + = 481.1. 1 H NMR(400MHz,CD3OD)δ7.68(d,J=1.6Hz,1H),7.40(s,1H),6.35(d,J=1.6Hz,1H),4 .10-4.02(m,1H),3.83(s,3H),3.40-3.35(m,4H),2.74(s,3H),2.35-2.26(m,4H).

[0559] Example 10: N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 131) [ka] Step 1: A 250 mL round-bottom flask was charged with methyl 3-chloro-1H-pyrrole-2-carboxylate (2.40 g, 15.0 mmol, 1.00 equiv.) and tetrahydrofuran (THF) (20 mL, 247 mmol, 16.4 equiv.) at room temperature. To the mixture was added NaH (1.44 g, 60.0 mmol, 3.99 equiv.) in small portions at 0° C. The resulting mixture was stirred for an additional 1 hour at 0° C. Then, methyl iodide (MeI) (6.48 g, 45.6 mmol, 3.04 equiv.) was added dropwise to the mixture at 0° C. The resulting mixture was then stirred overnight at room temperature. The reaction was then quenched by the addition of HCl (1 N) (40 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (EtOAc) (3×40 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous NaSO. 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 give methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylate (1.7 g, 71% yield). LCMS (ESI, m / z) = 173.85 [M+1].

[0560] Step 2: Methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylate (750 mg, 4.32 mmol, 1.00 equiv) and methanol (MeOH) (4.0 mL, 99 mmol, 23 equiv) were added to a 40 mL vial at room temperature. To the above mixture was added room temperature HO (4.0 mL, 222 mmol, 51.4 equiv) containing NaOH (330 mg, 8.25 mmol, 1.91 equiv). The resulting mixture was stirred at 50 °C for an additional 2 h. The mixture was then acidified to pH 6 with HCl (3 M). The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 30 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-1-methylpyrrole-2-carboxylic acid (580 mg, 80% yield). LCMS(ESI, m / z)=160.00[M+1]+.

[0561] Step 3: A 40 mL vial was charged with 3-chloro-1-methylpyrrole-2-carboxylic acid (2.20 g, 13.8 mmol, 1.00 equiv.), N,N-dimethylformamide (DMF) (20 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (15.7 g, 41.4 mmol, 3.00 equiv.), diisopropylethylamine (DIEA) (5.42 g, 41.9 mmol, 3.04 equiv.), and NHCl (2.97 g, 55.6 mmol, 4.03 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The reaction was then quenched with water at room temperature, and the aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and then concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 20% to 50% gradient in 10 min; UV 254 nm detector) to give 3-chloro-1-methylpyrrole-2-carboxamide (1.47 g, 60% yield). LCMS (ESI, m / z) = 159.05 [M+1]+.

[0562] Step 4: A 40 mL vial was charged with 3-chloro-1-methylpyrrole-2-carboxamide (1.40 g, 8.83 mmol, 1.00 equiv.), dichloroethane (DCE) (20 mL), and methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (6.29 g, 26.4 mmol, 2.99 equiv.) at room temperature. The resulting mixture was stirred at 50 °C for 2 h. The reaction was then quenched with room temperature water and extracted with dichloromethane (DCM) (3 × 20 mL). The combined organic layers were washed with water (3 × 20 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) (70:30) to give 3-chloro-1-methylpyrrole-2-carbonitrile (940 mg, 68% yield). 1 H NMR (400MHz, DMSO-d6) δ7.24 (d, J = 2.8 Hz, 1H), 6.34 (d, J = 2.8 Hz, 1H), 3.74 (s, 3H).

[0563] Step 5: A mixture of 3-chloro-1-methylpyrrole-2-carbonitrile (100 mg, 0.71 mmol, 1.00 equiv.) and thiosemicarbazide (200 mg, 2.19 mmol, 3.09 equiv.) in trifluoroacetic acid (TFA) (5.00 mL, 67.3 mmol, 94.6 equiv.) was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 30% to 40% gradient in 10 min; UV detector at 254 nm) to give 5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-amine (45 mg, 26% yield). LCMS (ESI, m / z) = 215.00 [M+1]+.

[0564] Step 6: To a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (770 mg, 3.09 mmol, 1.00 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, 3.54 equiv.), and 5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-amine (616 mg, 2.87 mmol, 0.93 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with acetonitrile (3 × 10 mL) to give 4-bromo-N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (also referred to herein as 4-bromo-N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide) (910 mg, 65% yield). 1 H NMR (400MHz, DMSO-d6) δ13.67(s,1H),7.66(s,1H),7.18(d,J=2.8Hz,1H),6.34(d,J=2.8Hz,1H),4.00(s,3H),3.95(s,3H).

[0565] Step 7: Following Step 2 of Part C of Example 1, N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 131) was prepared using 4-bromo-N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent" and propan-2-amine as the "amine reagent." LCMS (ES, m / z) = 424.05 [M+1]+. 1H NMR(400MHz,DMSO-d6)δ7.30(s,1H),7.13(d,J=2.8Hz,1H),6.70(d,J=8.8Hz,1H),6.3 1(d,J=2.8Hz,1H),3.94(s,3H),3.91-3.84(m,1H),3.68(s,3H),1.23(d,J=5.6Hz,6H).

[0566] Example 11: N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 53 * ), and N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1R,2S)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 54 * ) [ka] Racemic N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1,2-cis)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide, prepared according to Step 2 of Part C of Example 1, using 4-bromo-N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (the product of Step 6 of Example 10) as the "halopyrone reagent" and (1,2-cis)-2-aminocyclobutan-1-ol as the "amine reagent." The constituent enantiomers of racemic N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1,2-cis)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide were separated by preparative chiral HPLC (conditions: column: chiral ART cellulose-SC, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: methanol:dichloromethane (MeOH / DCM) = 1:1; flow rate: 20 mL). / min; gradient: 50% B to 50% B in 21.5 min; wavelength: 220 / 254 nm; RT1 (min): 10.66; RT2 (min): 13.55; sample solvent: MeOH:DCM = 1:1) gave two enantiomers with arbitrary stereochemistry assignment: N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 53 * ), first eluting peak, LCMS (ES, m / z) = 452.0 [M+1]+, 1H NMR(400MHz,DMSO-d6)7.23-7.14(m,2H),6.59(br,1H),6.34(d,J=2.8Hz,1H),5.50-5.43(d,J= 5.6Hz,1H),4.42-4.34(t,J=3.6Hz,1H),4.21-4.11(d,1H),3.95(s,3H),3.75(s,3H),2.21-2.0 6 (m, 2H), 2.01-1.91 (m, 1H), 1.89-1.88 (m, 1H); and N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1R,2S)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 54 * ), second eluting peak, LCMS (ES, m / z) = 452.0 [M+1]+, 1 H NMR(400MHz,DMSO-d6)7.23-7.14(m,2H),6.59(br,1H),6.34(d,J=2.8Hz,1H),5.50-5.43(d,J=5.6Hz,1H),4.42-4.34( t,J=3.6Hz,1H),4.21-4.11(d,1H),3.95(s,3H),3.75(s,3H),2.21-2.06(m,2H),2.01-1.91(m,1H),1.89-1.88(m,1H).

[0567] Example 12: 4-(((1R,2S)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 73 * ), and 4-(((1S,2R)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 74 * ) [ka] Racemic 4-(((1,2-cis)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared according to Step 2 of Part C of Example 1 using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (the product of Step 4 of Example 6) as the "halopyrone reagent" and (1,2-cis)-2-aminocyclopentane-1-carbonitrile 2,2,2-trifluoroacetate as the "amine reagent." The enantiomers of racemic 4-(((1,2-cis)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide were separated by preparative chiral HPLC (column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: methanol (MeOH):dichloromethane (DCM) = 1:1; flow rate: 20 mL / min; gradient: 90% B to 90% B in 17 min; wavelength: 220 / 254 nm; RT1 (min): 6.85; RT2 (min): 10.82; sample solvent: MeOH:DCM = 1:1) gave two enantiomers with arbitrary stereochemistry assignment: 4-(((1R,2S)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 73). * ), first eluting peak, LCMS (ES, m / z) = 442.1 [M+1] +, 1HNMR(400MHz,DMSO-d6)δ13.35(s,1H),7.79(s,1H),7.45(s,1H),7.19(d,J=8.8Hz,1H),6.45( s,1H),4.43-4.38(m,1H),3.72(s,3H),3.46-3.40(m,1H),2.68(s,3H),2.14-2.03(m,2H),2.0 2-1.91 (m, 2H), 1.62-1.46 (m, 1H), 1.61-1.47 (m, 1H); and 4-(((1S,2R)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 74 * ), second eluting peak, LCMS (ES, m / z) = 442.10 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),7.79(s,1H),7.45(s,1H),7.19(d,J=8.8Hz,1H),6.45(s,1H),4.43-4.38(m,1H),3 .72(s,3H),3.46-3.40(m,1H),2.68(s,3H),2.14-2.03(m,2H),2.02-1.91(m,2H),1.62-1.46(m,1H),1.61-1.47(m,1H).

[0568] Example 13: 3-Methoxy-4-((2-methoxyethyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 75) [ka] Following Step 2 of Part C of Example 1, 3-methoxy-4-((2-methoxyethyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 75) was prepared using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of Step 4 of Example 6) as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent." LCMS (ES, m / z) = 407.05 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ13.31(s,1H),7.78(d,J=1.6Hz,1H),7.39(s,1H),7.06(br,1 H),6.44(d,J=1.6Hz,1H),3.69(s,3H),3.52-3.48(m,4H),3.29(s,3H),2.51(s,3H).

[0569] Example 14: 3-Methoxy-4-(((1S,2R)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 79 * ), and 3-methoxy-4-(((1R,2S)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 80 * ) [ka] Racemic 3-methoxy-4-(((1,2-cis)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared according to Step 2 of Part C of Example 1 using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (the product of Step 4 of Example 6) as the "halopyrone reagent" and cis-2-(methoxymethyl)cyclopentanamine as the "amine reagent." The enantiomers of racemic 3-methoxy-4-(((1,2-cis)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide were separated by preparative chiral HPLC (conditions: Chiral ART Amylose-SA, 2 × 25 cm, 5 μm; Mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), Mobile phase B: ethanol (EtOH):dichloromethane (DCM) = 1:1; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 9.5 min; RT1 (min): 7.14; RT2 (min): 8.71; Sample solvent: ethanol / dichloromethane (EtOH:DCM) = 1:1) was used to obtain two enantiomers with arbitrary stereochemistry assignment: 3-methoxy-4-(((1S,2R)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 79) * ), first eluting peak, LCMS (ES, m / z) = 461.10 [M+1] +, 1H NMR(400MHz,DMSO-d6)δ7.78(d,J=1.6Hz,1H),7.41(s,1H),6.73(d,J=8.4Hz,1H),6.43(d,J=1.6Hz ,1H),4.22-4.12(m,1H),3.71(s,3H),3.31(s,2H),3.18(s,3H),2.68(s,3H),2.39-2.28(m,1H),2. 07-1.99 (m, 1H), 1.83-1.62 (m, 2H), 1.58-1.44 (m, 2H); and 3-methoxy-4-(((1R,2S)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 80 * ), second eluting peak, LCMS (ES, m / z) = 461.10 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ7.78(d,J=1.6Hz,1H),7.41(s,1H),6.73(d,J=8.4Hz,1H),6.43(d,J=1.6Hz,1H),4.22-4.12(m,1H),3. 71(s,3H),3.31(s,2H),3.18(s,3H),2.68(s,3H),2.39-2.28(m,1H),2.07-1.99(m,1H),1.83-1.62(m,2H),1.58-1.44(m,2H).

[0570] Example 15: (R)-4-((2-methoxy-1-phenylethyl)amino)-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 200) [ka] Step 1: To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2, Part A of Example 1) (5.0 g, 20 mmol, 1.0 equiv.) and 2-methoxyethanol (2.0 g, 26 mmol, 1.3 equiv.) in tetrahydrofuran (THF) at room temperature, triphenylphosphine (PPh3) (8.0 g, 30 mmol, 1.5 equiv.) was added in small portions. The resulting mixture was stirred for 10 minutes at 0 °C. Di-tert-butyl azodicarboxylate (DBAD) (7.0 g, 30 mmol, 1.5 equiv.) was then added dropwise at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was then diluted with ethyl acetate (EtOAc) (600 mL), washed with water (3 × 200 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) (1:3) to give methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylate (3.7 g, 60% yield). LCMS (ESI, m / z) = 307,309 [M+1].

[0571] Step 2: A solution of methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylate (1700 mg, 5.54 mmol, 1.00 equiv) in 6 M HCl (30 mL) was stirred at 80 °C for 3 h. The resulting mixture was then concentrated under reduced pressure, diluted with ethyl acetate (EtOAc) (200 mL), washed with brine (3 × 10 mL), and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure to give 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+1].

[0572] Step 3: 4-Bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid (1200 mg, 4.09 mmol, 1.00 equiv.) and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (also referred to as 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine) (preparation of Step 4, Part B of Example 1) To a stirred solution of 820 mg (4.52 mmol, 1.11 equiv.) of HCl in 21 mL of N,N-dimethylformamide (DMF) was added 1110 mg (8.22 mmol, 2.01 equiv.) of hydroxybenzotriazole (HOBT) and 2355 mg (12.3 mmol, 3.00 equiv.) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then diluted with 40 mL of water. The precipitated solid was collected by filtration to give 4-bromo-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (also referred to herein as 4-bromo-5-(2-methoxyethoxy)-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide) (1.3 g, 70% yield). LCMS (ESI, m / z) = 458.05 [M+1]+.

[0573] Step 4: Following Step 2 of Part C of Example 1, (R)-4-((2-methoxy-1-phenylethyl)amino)-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 200) was prepared using 4-bromo-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent" and (R)-2-methoxy-1-phenylethan-1-amine as the "amine reagent." LCMS (ESI, m / z) = 527.20 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ13.38(br,1H),7.74(s,1H),7.44-7.40(m,4H),7.31-7.27(m,1H),7.15(s,1H),6.82-6. 76(m,1H),6.40(s,1H),5.15-5.06(m,1H),4.14-4.02(m,2H),3.70-3.59(m,4H),3.34-3.24(s,6H),2.65(s,3H).

[0574] Example 16: (R)—N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-((2-methoxy-1-phenylethyl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 201) [ka] According to Steps 3-4 of Example 15, 5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-amine was used in place of 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine, and 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid (the product of Step 2 of Example 15) was used as the "halopyrone reagent." (R)-N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-((2-methoxy-1-phenylethyl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (compound 201) was prepared by coupling with (R)-2-methoxy-1-phenylethan-1-amine as the "amine reagent." LCMS (ESI, m / z) = 560.20 [M+1]+. 1 H NMR(300MHz,DMSO-d6)δ13.33(br,1H),7.48-7.30(m,5H),7.31-7.14(m,2H),6.82-6.76(m,1H),6.32 (d,J=2.8Hz,1H),5.15-5.06(m,1H),4.16-4.03(m,2H),3.94(s,3H),3.70-3.58(m,4H),3.33(s,6H).

[0575] Example 17: (S)-3-Methoxy-4-(3-(methoxymethyl)pyrrolidin-1-yl)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 87) [ka] 4-Bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Step 1, Part C of Example 1; “halopyrone reagent”) (50 mg, 0.12 mmol, 1.0 equiv.) and (3S)-3-(methoxymethyl)pyrrolidine (27 mg, 0.24 mmol, 2.00 equiv.) (“amine reagent”) in N,N-dimethylformamide (DMF) (0.5 mL) were dissolved in 100 mL of HCl. To a mixture containing 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (26 mg, 0.048 mmol, 0.40 equiv.), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3) (21 mg, 0.024 mmol, 0.20 equiv.), and KCO (50 mg, 0.36 mmol, 3.0 equiv.) was added. The resulting mixture was stirred at 100 °C under N for 1 h. The mixture was then purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water (0.1% trifluoroacetic acid (TFA)), 10% to 50% gradient in 10 min; UV detector at 254 nm) to give (S)-3-methoxy-4-(3-(methoxymethyl)pyrrolidin-1-yl)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 87) (20 mg, 38% yield). LCMS (ESI, m / z) = 447.1 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ7.61(s,1H),6.92(s,1H),6.30(s,1H),3.79-3.64(m,2H),3.61(s,4H),3.4 2-3.38(m,3H),3.38-3.35(m,1H),3.29(s,3H),2.60(s,3H),2.02-1.98(m,1H),1.68-1.66(m,1H).

[0576] Example 18: (R)—N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 94) [ka] Following Step 2 of Part C of Example 1, (R)—N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 94) was prepared using 4-bromo-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (the product of Step 2 of Example 5) as the "halopyrone reagent" and (R)-1-methoxypropan-2-amine as the "amine reagent." LCMS (ESI, m / z) = 457.00 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ7.68(d,J=5.2Hz,1H),7.16(d,J=5.2Hz,1H),7.06(s,1H),6.38-6.36(m,1H),3 .91-3.85(m,1H),3.65(s,3H),3.41-3.38(m,2H),3.29(s,3H),3.29(s,3H),1.18(d,J=6.4Hz,1H,3H).

[0577] Example 19: (S)-3-Methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 100 * ), and (R)-3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 101 * ) [ka] Racemic 3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared according to Step 2 of Part C of Example 1 using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (the product of Step 4 of Example 6) as the "halopyrone reagent" and 3-(methoxymethyl)tetrahydrofuran-3-amine as the "amine reagent." The constituent enantiomers of racemic 3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide were separated by preparative chiral HPLC (Chiral ART Cellulose-SA, 2 × 25 cm, 5 μm; Mobile Phase A: hexane (0.1% trifluoroacetic acid (TFA)), Mobile Phase B: ethanol (EtOH):dichloromethane (DCM) = 1:1; Flow Rate: 20 mL / min; Gradient : 50% B to 50% B in 9.5 min; Wavelength: 220 / 254 nm; RT1 (min): 7.15; RT2 (min): 9.27; Sample solvent: methanol (MeOH):DCM=1:1 to give two enantiomers with arbitrary stereochemistry: (S)-3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 100 *), first eluting peak, LCMS (ESI, m / z) = 463.1 [M+1]+, 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.21 (s, 1H), 6.63 (s, 1H), 6.45 (s, 1H), 3.99-3.78 (m, 4H), 3.72 (s, 3H), 3.61 (d, J = 9.6 Hz, 1H), 3.53 (d, J = 9.6 Hz, 1H), 3.33 (s, 3H), 2.68 (s, 3H), 2.22-2.18 (m, 2H); and (R)-3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 101 * ), second eluting peak, LCMS (ESI, m / z) = 463.1 [M+1]+, 1 H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.21(s,1H),6.63(s,1H),6.45(s,1H),3.99-3.78(m,4H),3.7 2(s,3H),3.61(d,J=9.6Hz,1H),3.53(d,J=9.6Hz,1H),3.33(s,3H),2.68(s,3H),2.22-2.18(m,2H).

[0578] Example 20: 3-Methoxy-4-(((cis)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 108, rac-108), 3-methoxy-4-(((trans)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-2-oxo-2H-pyran-6-carboxamide (1S,3R)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 109, rac-109), 3-methoxy-4-(((1S,3R)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 108a *), and 3-methoxy-4-(((1R,3S)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 108b * ), and 3-methoxy-4-(((1S,3S)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 109a * ), and 3-methoxy-4-(((1R,3R)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 109b * ) [ka] According to Step 2 of Part C of Example 1, 3-methoxy-4-((3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared using 3-methoxycyclopentan-1-amine hydrochloride as the "amine reagent" and 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (the product of Step 1 of Part C of Example 1) as the "halopyrone reagent." Separation of the diastereoisomers was achieved using preparative HPLC (XBridge Prep Phenyl OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile (MeCN); flow rate: 60 mL / min; gradient: 15% B to 20% B in 8 min, 20% B; wavelength: 254 nm) to afford two pairs of diastereomeric enantiomers with arbitrarily assigned stereochemistry: 3-methoxy-4-(((1S,3R)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 108a), isolated as a racemic mixture. * ), and 3-methoxy-4-(((1R,3S)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 108b * ), LCMS(ESI, m / z)=447.15[M+1]+, 1H NMR(400MHz,DMSO-d6)δ7.66(d,J=1.6Hz,1H),7.11(s,1H),6.70(d,J=8.0Hz,1H),6.35(d,J=1.6Hz ,1H),4.15-4.10(m,1H),3.91-3.87(m,1H),3.65(s,3H),3.21(s,3H),2.62(s,3H),2.12-1.90(m,3H) ), 1.83-1.78 (m, 1H), 1.71-1.50 (m, 2H); and 3-methoxy-4-(((1S,3S)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 109a) isolated as a racemic mixture. * ), and 3-methoxy-4-(((1R,3R)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 109b * ), LCMS(ESI, m / z)=447.20[M+1]+, 1 H NMR(400MHz,DMSO-d6)δ7.68(d,J=1.6Hz,1H),7.15(s,1H),6.52(br,1H),6.36(d,J=1.6Hz,1H),4.09-4.04(m,1H), 3.86-3.82(m,1H),3.66(s,3H),3.22(s,3H),2.63(s,3H),2.22-2.15(m,1H),1.97-1.91(m,1H),1.85-1.64(m,4H).

[0579] Example 21: 4-((3-hydroxybicyclo[1.1.1]pentan-1-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 126), and 3-methoxy-4-((3-methoxybicyclo[1.1.1]pentan-1-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 126-OMe) [ka] Step 1: Following Step 2 of Part C of Example 1, 5-methoxy-4-({3-methoxybicyclo[1.1.1]pentan-1-yl}amino)-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (Compound 126-OMe) was prepared using 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (the product of Step 1 of Part C of Example 1) as the "halopyrone reagent" and 3-methoxybicyclo[1.1.1]pentan-1-amine as the "amine reagent." LCMS (ESI, m / z) = 445.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ7.67(d,J=1.8Hz,1H),7.21(s,1H),6.36(s,1H),3.6 4(d,J=2.4Hz,3H),3.24(d,J=2.3Hz,3H),2.60(s,3H),2.24(d,J=2.3Hz,6H).

[0580] Step 2: To a solution of 5-methoxy-4-({3-methoxybicyclo[1.1.1]pentan-1-yl}amino)-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (compound 126-OMe) (80 mg, 0.180 mmol, 1.00 equiv) in dichloromethane (DCM) (3 mL) was added a solution of BBr3 (0.80 mL, 0.80 mmol, 4.44 equiv) in DCM (1 M) at 0° C. The resulting mixture was stirred for 30 min at 0° C. The reaction was quenched with methanol (MeOH) at 0 °C and then directly purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; UV 254 nm detector) to give 4-({3-hydroxybicyclo[1.1.1]pentan-1-yl}amino)-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (compound 126) (12 mg, 15% yield). LCMS (ESI, m / z) = 431.10 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ13.50(s,1H),7.79(d,J=1.6Hz,1H),7.68(s,1H),7.24(s ,1H),6.45(d,J=1.6Hz,1H),6.38(s,1H),3.69(s,3H),2.68(s,3H),2.21(s,6H).

[0581] Example 22: N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-((2-hydroxyethyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 129), and N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 129-OMe) [ka] Step 1: According to Step 7 of Example 10, using 4-bromo-N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (the product of Step 6 of Example 10) as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent," N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (compound 129-OMe) was prepared. LCMS (ESI, m / z) = 440.0 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ13.36(s,1H),7.32(s,1H),7.13(d,J=3.0Hz,1H),7.01(s ,1H),6.31(d,J=2.9Hz,1H),3.94(s,3H),3.68(s,3H),3.48(s,2H),2.48(s,1H).

[0582] Step 2: To a solution of N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (compound 129-OMe) (180 mg, 0.41 mmol, 1.00 equiv) in acetonitrile (MeCN) (3 mL) was added NaI (307 mg, 2.04 mmol, 5.00 equiv) and trimethylsilyl chloride (TMSCl) (222 mg, 2.04 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight and then directly purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm) to give the crude product (40 mg), which was further purified by preparative HPLC (YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and MeCN (15% to 25% MeCN in 10 min; detector, UV 254 nm) to give N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-((2-hydroxyethyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 129) (4.3 mg, yield 2.5%). LCMS(ESI, m / z)=426.00[M+1]+. 1 H NMR(400MHz,DMSO-d6)δ7.26(s,1H),7.09(d,J=2.8Hz,1H),6.89(s,1H),6.28(d,J=2.8Hz, 1H), 4.87(t,J=5.6Hz,1H),3.92(s,3H),3.68(s,3H),3.56-3.49(m,2H),3.38-3.35(m,2H).

[0583] Example 23: 4-((2-hydroxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 130) [ka] Step 1: 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Step 1, Part C of Example 1; "halopyrone reagent") (200 mg, 0.485 mmol, 1.00 equiv.) and (2-aminoethoxy)(tert-butyl)dimethylsilane ("amine reagent") (851 mg, 4.85 mmol, 10.0 equiv.) To a stirred mixture of 1,2-dimethyl-3,4-trimethyl-2,4-trimethyl-1,2 ... After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; UV 254 nm detector) to give 4-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (48 mg, 19% yield). LCMS (ESI, m / z) = 507.2 [M+1]+. TBS = tert-butyldimethylsilyl.

[0584] Step 2: A solution of 4-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (30 mg, 0.059 mmol, 1.00 equiv) in HCl (4 M in 1,4-dioxane) (1.5 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure and purified by preparative HPLC (conditions: SHIMADZU: column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH₄HCO₃) and acetonitrile (MeCN) (8% MeCN to 20% in 10 min); detector, UV 254 nm) to give 4-((2-hydroxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 130) (9.3 mg, 40% yield). LCMS (ESI, m / z) = 393.0 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ7.70(d,J=1.6Hz,1H),7.22(s,1H),6.85(t,J=6.4Hz,1H),6.38(d,J=1. 6Hz, 1H), 4.88 (t, J=5.6Hz, 1H), 3.68 (s, 3H), 3.56-3.53 (m, 2H), 3.37-3.34 (m, 2H), 2.64 (s, 3H).

[0585] Example 24: N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((1R,2S)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 132 * ), and N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((1S,2R)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 133 * ) [ka] Step 1: To a solution of 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 3 in Example 6) (150 mg, 0.51 mmol, 1.00 equiv.) in acetonitrile (MeCN) (2 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (200 mg, 0.713 mmol, 1.41 equiv.) and N-methylimidazole (NMI) (166 mg, 2.02 mmol, 3.99 equiv.) at room temperature. 5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-amine (product of Step 5 in Example 10) (109 mg, 0.51 mmol, 1 equiv.) was added, and the resulting mixture was stirred at room temperature for 0.5 hours and then concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase flash chromatography (eluting with acetonitrile / water (5:1)) to give N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide (120 mg, 47% yield).

[0586] Step 2: Racemic N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-6-oxopyran-2-carboxamide was prepared according to Example 14 using N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent" and rac-(1,2-cis)-2-methoxycyclobutan-1-amine hydrochloride as the "amine reagent." N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((1R,2S)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 132) was prepared and its constituent enantiomers were separated to give two enantiomers with arbitrary stereochemical assignments: N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((1R,2S)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 132) * ), first eluting peak, LCMS (ESI, m / z) = 466.05 [M+1] +, 1 H NMR (400 MHz, DMSO-d6) δ 7.20 (s, 1H), 7.12 (d, J = 2.8 Hz, 1H), 6.58 (br, 1H), 6.31 (d, J = 2.8 Hz, 1H), 4.41-4.35 (m, 1H), 4.10-4.06 (m, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.22 (s, 3H), 2.19-1.97 (m, 4H); and N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((1S,2R)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 133 * ), second eluting peak, LCMS (ESI, m / z) = 466.05 [M+1] + , 1H NMR(400MHz,DMSO-d6)δ7.20(s,1H),7.12(d,J=2.8Hz,1H),6.58(br,1H),6.31(d,J=2.8Hz,1H), 4.41-4.35(m,1H),4.10-4.06(m,1H),3.93(s,3H),3.72(s,3H),3.22(s,3H),2.19-1.97(m,4H).

[0587] Example 25: N-(5-(5-chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-5-methoxy-4-(2-methoxyethylamino)-6-oxo-6H-pyran-2-carboxamide (Compound 134) [ka] Step 1: To a stirred solution of 5-bromo-1,3,4-thiadiazol-2-amine (13.8 g, 76.6 mmol, 1.00 equiv.) and 4-fluoro-1H-pyrazole (7.96 g, 92.5 mmol, 1.21 equiv.) in dioxane (80 mL) at room temperature, diisopropylethylamine (DIEA) (29.8 g, 231 mmol, 3.01 equiv.) was added. The resulting mixture was stirred at 80 °C overnight. The mixture was then diluted with water and extracted with ethyl acetate (EtOAc) (3 × 1 L). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), and the precipitated solid was collected by filtration and washed with EtOAc (3×10 mL) to give 5-(4-fluoropyrazol-1-yl)-1,3,4-thiadiazol-2-amine (5.0 g, 35% yield). LCMS (ESI, m / z) = 186 [M+1]+.

[0588] Step 2: To a stirred solution of 5-(4-fluoropyrazol-1-yl)-1,3,4-thiadiazol-2-amine (5.0 g, 27 mmol, 1.0 equiv.) and 2,5-hexanedione (4.62 g, 40.5 mmol, 1.50 equiv.) in toluene (20 mL) was added tosylic acid (TsOH) (0.93 g, 5.40 mmol, 0.20 equiv.) at room temperature. The resulting mixture was stirred at 100 °C for 1 h and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (7:1) to give 2-(2,5-dimethylpyrrol-1-yl)-5-(4-fluoropyrazol-1-yl)-1,3,4-thiadiazole (3.0 g, 42% yield). LCMS (ESI, m / z): 264 [M+1]+.

[0589] Step 3: To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(4-fluoropyrazol-1-yl)-1,3,4-thiadiazole (1.0 g, 3.8 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (5 mL) was added lithium diisopropylamide (LDA) (3.80 mL, 3.80 mmol, 1.00 equiv.) at −78°C under N2 (nitrogen gas). After 30 min, hexachloroethane (900 mg, 3.80 mmol, 1.00 equiv.) in THF (2 mL) at −78°C was added to the above mixture under N2. The resulting mixture was stirred at −78°C for 2 h under N2. The mixture was then quenched with saturated NH4Cl and extracted with ethyl acetate (EtOAc) (3 × 100 mL). The combined organic layers were washed with water (3 × 10 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 (acetonitrile (MeCN) in water (0.1% trifluoroacetic acid (TFA)), 10% to 50% gradient in 10 min; UV detector at 254 nm) to give 2-(5-chloro-4-fluoropyrazol-1-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (600 mg, 53% yield). LCMS (ESI, m / z) = 298 [M+1]+.

[0590] Step 4: To a stirred solution of 2-(5-chloro-4-fluoropyrazol-1-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (200 mg, 0.672 mmol, 1.00 equiv) in HO / THF (2:1, 3 mL) was added trifluoroacetic acid (TFA) (2 mL) dropwise at room temperature. The resulting mixture was stirred at 50 °C for 2 h and then concentrated in vacuo. The resulting residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 0% to 100% gradient in 10 min; UV detector at 254 nm) to give 5-(5-chloro-4-fluoropyrazol-1-yl)-1,3,4-thiadiazol-2-amine (70 mg, 47% yield). LCMS (ESI, m / z) = 220 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ8.16 (d, J=4.3Hz, 1H), 7.55 (s, 2H).

[0591] Step 5: 4-Bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4, Example 1, Part A) (113 mg, 0.45 mmol, 1.00 equiv.) and 5-(5-chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (100 mg, 0.45 mmol, 1.00 equiv.) were dissolved in N,N-dimethylformamide (DMF) (1 To a stirred solution of 1-((dimethylamino)(dimethylimino)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU) (258 mg, 0.68 mmol, 1.50 equiv.) and diisopropylethylamine (DIEA) (176 mg, 1.36 mmol, 3.00 equiv.) in 100 mL of HCl (HCl, HCl, HCl, HCl) was added at 0 °C under N (nitrogen gas). The resulting mixture was stirred at room temperature under N for 16 h. The mixture was then diluted with water and extracted with ethyl acetate (EtOAc) (3 × 50 mL), and the combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluting with methanol / dichloromethane (MeOH / DCM) (1:4) to give 4-bromo-N-(5-(5-chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (80 mg, 29% yield). LCMS (ESI, m / z) = 450.1 [M+1]+.

[0592] Step 6: Following Step 2 of Part C of Example 1, using 4-bromo-N-(5-(5-chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent," N-(5-(5-chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-5-methoxy-4-(2-methoxyethylamino)-6-oxo-6H-pyran-2-carboxamide (Compound 134) was prepared. LCMS (ESI, m / z) = 445.0 [M+1]+.1 H NMR (400MHz, CD3OD) δ7.97(d,J=4.4Hz,1H),7.42(s,1H),3.83(s,3H),3.58(s,3H),3.39(s,4H).

[0593] Example 26: N-(5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 135) [ka] Step 1: To a stirred solution of 2-chlorothiophene-3-carboxylic acid (1.0 g, 6.15 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (10 mL) was added carbonyldiimidazole (CDI) (1.50 g, 9.22 mmol, 1.5 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 hour. A solution of ammonia in methanol (7N NH3 / MeOH) (10 mL) was added dropwise to the mixture over 1 hour at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes and then concentrated under reduced pressure. The residue was then purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water (0.1% trifluoroacetic acid (TFA)), 10% to 50% gradient over 10 minutes) to give 2-chlorothiophene-3-carboxamide (770 mg, 77% yield). LCMS (ESI, m / z) = 162 [M+1] + .

[0594] Step 2: To a stirred solution of 2-chlorothiophene-3-carboxamide (350 mg, 2.17 mmol, 1.00 equiv.) in dichloroethane (DCE) (5 mL) was added N-(triethylammoniumsulfonyl)methylcarbamate (Burgess reagent) (1.50 g, 6.50 mmol, 3.00 equiv.) at room temperature. The resulting mixture was stirred at 60 °C for 1 h and then concentrated under reduced pressure. The resulting residue was then purified by C18 reverse-phase flash chromatography (MeCN in water (0.1% trifluoroacetic acid (TFA)), 10% to 50% gradient in 10 min) to give 2-chlorothiophene-3-carbonitrile (200 mg, 64% yield). LCMS (ESI, m / z) = 144 [M+1]+.

[0595] Step 3: To a stirred solution of 2-chlorothiophene-3-carbonitrile (1.20 g, 8.36 mmol, 1.00 equiv.) in trifluoroacetic acid (TFA) (10 mL) was added thiosemicarbazide (1.14 g, 12.5 mmol, 1.50 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 1 h and then concentrated under reduced pressure. The residue was then purified by C18 reverse-phase flash chromatography (MeCN in water, 30% to 40% gradient in 10 min) to give 5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-amine (800 mg, 44% yield). LCMS (ESI, m / z) = 218 [M+1]+.

[0596] Step 4: To a stirred solution of 5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-amine (100 mg, 0.46 mmol, 1.0 equiv.) in acetonitrile (3 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (385 mg, 1.37 mmol, 2.99 equiv.), N-methylimidazole (NMI) (376 mg, 4.58 mmol, 9.97 equiv.), and 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (137 mg, 0.55 mmol, 1.20 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with acetonitrile (5 × 4 mL). The recovered solid was then purified by C18 reverse-phase flash chromatography (MeCN in water, gradient from 10% to 50% in 10 min) to give 4-bromo-N-[5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (70 mg, 34% yield). LCMS (ESI, m / z) = 448 [M+1]+.

[0597] Step 5: To a stirred solution of 4-bromo-N-[5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide ("halopyrone reagent") (160 mg, 0.357 mmol, 1.00 equiv.) and 2-methoxyethan-1-amine ("amine reagent") (32 mg, 0.43 mmol, 1.19 equiv.) in N,N-dimethylformamide (DMF) (4 mL) at room temperature was added CFCOONa (160 mg, 1.18 mmol, To the resulting mixture were added (3.30 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (63 mg, 0.14 mmol, 0.38 equiv.), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (160 mg, 1.05 mmol, 2.95 equiv.), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (63 mg, 0.075 mmol, 0.21 equiv.). The resulting mixture was stirred at 100 °C under N2 (nitrogen gas) for 1 h. The resulting solid was filtered and washed with acetonitrile (MeCN) (10 × 3 mL). The filtrate was then concentrated under reduced pressure, and the resulting residue was purified by C18 reverse-phase flash chromatography (MeCN in water, gradient from 10% to 50% in 10 min) to give the crude product, which was then purified by preparative HPLC (column: XBridge Prep OBD Further purification by C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile (MeCN); flow rate: 60 mL / min; gradient: 20% B to 28% B in 8 min; wavelength: 220 nm; RT1 (min): 6.58) gave N-(5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 135) (4.4 mg, 2.8% yield). LCMS (ESI, m / z) = 442.95 [M+1]+. 1H NMR (400MHz, DMSO-d6) δ7.68-7.56(m,2H),7.21(s,1H),3.66(s,3H),3.49-3.40(m,4H),3.28(s,3H).

[0598] Example 27: N-(5-(2-cyano-4-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 137) [ka] Step 1: To a stirred solution of 5-bromo-1,3,4-thiadiazol-2-amine (10.0 g, 55.5 mmol, 1.00 equiv.) and 2,5-hexanedione (8.93 g, 78.2 mmol, 1.41 equiv.) in toluene (100 mL) was added tosylic acid (TsOH) (1.92 g, 11.15 mmol, 0.20 equiv.) at room temperature. The resulting mixture was stirred at 120 °C for 2 h. The resulting mixture was concentrated under reduced pressure and diluted with water (300 mL). The mixture was extracted with ethyl acetate (EtOAc) (3 × 400 mL), and the combined organic layers were washed with water (3 × 100 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 give 2-bromo-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (6.0 g, 42% yield).

[0599] Step 2: To a stirred solution of 2-bromo-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (1.00 g, 3.87 mmol, 1.00 equiv.), 4-methylthiophen-3-ylboronic acid (0.83 g, 5.81 mmol, 1.50 equiv.) in dioxane (10 mL) at room temperature was added [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3) (1.40 g, 1.55 mmol, 0.40 equiv.), KCO (1.07 g, 7.75 mmol, 2.00 equiv.). The resulting mixture was stirred under N2 (nitrogen gas) at 80 °C overnight and then concentrated in vacuo. The resulting residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN):HO = 1:1)) to give 2-(2,5-dimethylpyrrol-1-yl)-5-(4-methylthiophen-3-yl)-1,3,4-thiadiazole (460 mg, 39% yield). LCMS (ESI, m / z) = 276.0 [M+1]+.

[0600] Step 3: To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(4-methylthiophen-3-yl)-1,3,4-thiadiazole (400 mg, 1.45 mmol, 1.00 equiv) in tetrahydrofuran (THF) (60 mL) was added n-butyllithium (nBuLi) (0.87 mL, 2.18 mmol, 1.50 equiv) in 2.5 M THF dropwise at −78° C. under N. The reaction mixture was stirred at −78° C. for 1 h, after which a solution of I (184 mg, 0.73 mmol, 0.50 equiv) in 2 mL of THF was added dropwise, and the mixture was stirred for another 1 h. The reaction was then quenched by the addition of saturated NH Cl (aq) (10 mL) at 0° C. and extracted with ethyl acetate (EtOAc) (3 × 50 mL). The resulting mixture was concentrated in vacuo, and the residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN):HO=9:1) to give 2-(2,5-dimethylpyrrol-1-yl)-5-(2-iodo-4-methylthiophen-3-yl)-1,3,4-thiadiazole (160 mg, 25% yield). LCMS (ESI, m / z)=402.0 [M+1]+.

[0601] Step 4: To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(2-iodo-4-methylthiophen-3-yl)-1,3,4-thiadiazole (120 mg, 0.31 mmol, 1.00 equiv.) in N,N-dimethylacetamide (DMAC) (3 mL) was added Zn(CN) (72 mg, 0.61 mmol, 2.00 equiv.), XantPhos (266 mg, 0.46 mmol, 1.50 equiv.), PdCl (82 mg, 0.46 mmol, 1.50 equiv.), and diisopropylethylamine (DIEA) (79 mg, 0.61 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred overnight at 100 °C under N (nitrogen gas). The mixture was then diluted with water and extracted with ethyl acetate (EtOAc) (3 × 20 mL). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (EtOAc / PE) (3:1) to give 3-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]-4-methylthiophene-2-carbonitrile (80 mg, 78% yield). LCMS (ESI, m / z) = 301.0 [M+1]+.

[0602] Step 5: To a stirred solution of 3-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]-4-methylthiophene-2-carbonitrile (50 mg, 0.17 mmol, 1.00 equiv.) in HO (0.7 mL) was added trifluoroacetic acid (TFA) (0.7 mL). The resulting mixture was stirred overnight at room temperature under an air atmosphere. The mixture was then concentrated under reduced pressure to give 3-(5-amino-1,3,4-thiadiazol-2-yl)-4-methylthiophene-2-carbonitrile (50 mg, 95% yield). LCMS (ESI, m / z) = 223 [M+1]+.

[0603] Step 6: To a stirred solution of 3-(5-amino-1,3,4-thiadiazol-2-yl)-4-methylthiophene-2-carbonitrile (35 mg, 0.16 mmol, 1.00 equiv.), 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (118 mg, 0.47 mmol, 3.00 equiv.) in acetonitrile (MeCN) (1 mL) was added N-methylimidazole (NMI) (65 mg, 0.79 mmol, 5.00 equiv.), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (53 mg, 0.19 mmol, 1.20 equiv.). The resulting mixture was stirred under air at room temperature overnight and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (MeCN:HO=1:1) to give 4-bromo-N-[5-(2-cyano-4-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (30 mg, 38% yield). LCMS (ESI, m / z)=453 [M+1]+.

[0604] Step 7: Following Step 2 of Part C of Example 1, N-(5-(2-cyano-4-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 137) was prepared using 4-bromo-N-[5-(2-cyano-4-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent." LCMS (ESI, m / z) = 448 [M+1]; 1 H NMR (400 MHz, methanol-d₄) δ 7.65 (s, 1H), 7.37 (s, 1H), 3.79 (s, 3H), 3.62–3.58 (m, 4H), 3.41 (s, 3H), 2.47 (s, 3H).

[0605] Example 28: N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 138) [ka] Step 1: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile (210 mg, 0.89 mmol, 1.00 equiv) in dioxane (1.4 mL) and water (7 mL) at room temperature was added 2-bromo-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (product of Step 1 of Example 27) (272 mg, 1.05 mmol, 1.18 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) (65 mg, 0.089 mmol, 0.10 equiv), and potassium carbonate (378 mg, 2.74 mmol, 3.06 equiv). The resulting mixture was stirred under nitrogen (N) at 90° C. for 3 hours, then cooled to room temperature and diluted with water (200 mL). The mixture was extracted with ethyl acetate (EtOAc) (3×200 mL), and the combined organic layers were washed with water (100 mL) and dried over anhydrous NaSO. 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 give 4-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]thiophene-3-carbonitrile (128 mg, 38% yield). LCMS (ESI, m / z) = 287 [M+1].

[0606] Step 2: To a stirred solution of 4-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]thiophene-3-carbonitrile (120 mg, 0.419 mmol, 1.00 equiv.) in dichloromethane (DCM) (0.24 mL) was added water (0.24 mL) and trifluoroacetaldehyde (0.6 mL) at room temperature. The resulting mixture was stirred at 50 °C for 3 hours. The resulting solid was collected by filtration and washed with acetonitrile (MeCN) (0.5 mL) to give 4-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-3-carbonitrile (32 mg, 36% yield). LCMS (ESI, m / z) = 209 [M+1]+.

[0607] Step 3: To a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (137 mg, 0.550 mmol, 1.00 equiv.) in acetonitrile (MeCN) (4.7 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (233 mg, 0.83 mmol, 1.51 equiv.) and N-methylimidazole (NMI) (136 mg, 1.66 mmol, 3.01 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. Then, 4-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-3-carbonitrile (103 mg, 0.495 mmol, 0.90 equiv.) was added to the above mixture, and the resulting mixture was stirred at room temperature overnight. The resulting solid was collected by filtration and washed with MeCN (1 × 2 mL) to give 4-bromo-N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (63 mg, 25% yield). LCMS (ESI, m / z) = 439 [M+1]+.

[0608] Step 4: Following Step 2 of Part C of Example 1, using 4-bromo-N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent," prepared N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 138). LCMS (ES, m / z) = 433.95 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ13.51(br,1H),8.70(s,1H),8.45(s,1H),7.I37(s,1H),7.04(s,1H),3.65(s,3H),3.48-3.39(m,4H),3.27(s,3H).

[0609] Example 29: N-(5-(4-chloroisothiazol-5-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 139) [ka] Step 1: To a stirred solution of 4-chloroisothiazole-5-carboxylic acid (600 mg, 3.67 mmol, 1.00 equiv.) in POCl (5 mL) was added thiosemicarbazide (540 mg, 5.926 mmol, 1.62 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 5 hours, then concentrated in vacuo and diluted with ethyl acetate (EtOAc) (200 mL). The resulting solution was neutralized to pH 8 with NaOH (aq., 1 M) and extracted with ethyl acetate (EtOAc) (3 × 30 mL). The combined organic layers were washed with water and brine (3 × 5 mL) and dried over anhydrous NaSO. 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 give 5-(4-chloro-1,2-thiazol-5-yl)-1,3,4-thiadiazol-2-amine (200 mg, 25% yield). LCMS (ESI, m / z) = 218.9 [M+1]+.

[0610] Step 2: To a stirred solution of 5-(4-chloro-1,2-thiazol-5-yl)-1,3,4-thiadiazol-2-amine (70 mg, 0.32 mmol, 1.0 equiv.) and 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (160 mg, 0.64 mmol, 2.01 equiv.) in acetonitrile (MeCN) (5 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (270 mg, 0.96 mmol, 3.01 equiv.) and N-methylimidazole (NMI) (270 mg, 3.29 mmol, 10.3 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting solid was collected by filtration and washed with acetonitrile to give 4-bromo-N-[5-(4-chloro-1,2-thiazol-5-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (100 mg, 69% yield). LCMS (ESI, m / z) = 448.85 [M+1]+.

[0611] Step 3: Following Step 2 of Part C of Example 1, using 4-bromo-N-[5-(4-chloro-1,2-thiazol-5-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent," prepared N-(5-(4-chloroisothiazol-5-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 139). LCMS (ESI, m / z) = 444.00 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ8.65 (s, 1H), 7.10 (s, 1H), 3.65 (s, 3H), 3.52-3.40 (m, 4H), 3.29 (s, 3H).

[0612] Example 30: N-(5-(4-cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 140) [ka] Step 1: To a stirred solution of 2-bromo-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (product of Step 1 of Example 27) (2.50 g, 9.68 mmol, 1.00 equiv.) and 2-methylthiophen-3-ylboronic acid (1.66 g, 11.7 mmol, 1.21 equiv.) in dioxane (18 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) (0.80 g, 1.09 mmol, 0.11 equiv.), HO (3 mL), and KCO (2.70 g, 19.5 mmol, 2.02 equiv.) were added dropwise at room temperature under nitrogen (N). The resulting mixture was stirred at 80° C. under N for 4 h. The mixture was then diluted with water and extracted with ethyl acetate (EtOAc) (3 × 30 mL). The combined organic layers were washed with water and brine (3 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 2-(2,5-dimethylpyrrol-1-yl)-5-(2-methylthiophen-3-yl)-1,3,4-thiadiazole (1.5 g, 56% yield). LCMS (ESI, m / z) = 276 [M+1].

[0613] Step 2: To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(2-methylthiophen-3-yl)-1,3,4-thiadiazole (1.50 g, 5.45 mmol, 1.00 equiv.) in HO (2 mL) and tetrahydrofuran (THF) (1 mL) was added trifluoroacetic acid (TFA) (2 mL) dropwise at room temperature. The resulting mixture was stirred at 50 °C for 5 h and then concentrated in vacuo. The residue was then purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 0% to 100% gradient in 10 min; UV detector at 254 nm) to give 5-(2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-amine (600 mg, 56% yield). LCMS (ESI, m / z) = 198 [M+1]+.

[0614] Step 3: To a stirred solution of 5-(2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-amine (500 mg, 2.54 mmol, 1.00 equiv.) in trifluoroacetic acid (TFA) (20 mL) was added Br (3.0 g, 19 mmol, 7.4 equiv.) dropwise at room temperature. The resulting mixture was stirred at 80 °C overnight. The mixture was then quenched with saturated NaHSO and extracted with ethyl acetate (EtOAc) (3 × 30 mL). The combined organic layers were washed with water and brine (3 × 5 mL) and dried over anhydrous NaSO. 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 give 5-(4,5-dibromo-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-amine (800 mg, 89% yield). LCMS (ESI, m / z) = 355 [M+1] + .

[0615] Step 4: To a stirred solution of 5-(4,5-dibromo-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-amine (700 mg, 1.97 mmol, 1.00 equiv.) and 2,5-hexanedione (336 mg, 2.94 mmol, 1.49 equiv.) in toluene (5 mL) was added tosylic acid (TsOH) (112 mg, 0.65 mmol, 0.33 equiv.) at room temperature. The resulting mixture was stirred at 100° C. overnight and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (5:1) to give 2-(4,5-dibromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (600 mg, 70% yield). LCMS (ESI, m / z) = 433 [M+1] + .

[0616] Step 5: To a stirred solution of 2-(4,5-dibromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (600 mg, 1.38 mmol, 1.00 equiv.) in acetic acid (AcOH) (5 mL) and HO (5 mL) was added Zn (540 mg, 8.26 mmol, 5.96 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The mixture was then diluted with water and extracted with ethyl acetate (EtOAc) (3 × 50 mL). The combined organic layer was washed with water and brine (3 × 5 mL) and dried over anhydrous NaSO. 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 give 2-(4-bromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (440 mg, 90% yield). LCMS (ESI, m / z) = 355 [M+1]+.

[0617] Step 6: To a stirred solution of 2-(4-bromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (440 mg, 1.24 mmol, 1.00 equiv.) in NMP (5 mL) was added CuCN (230 mg, 2.57 mmol, 2.07 equiv.) at room temperature. The resulting mixture was stirred at 150 °C for 3 h. The mixture was then extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with water and brine (3 × 5 mL) and dried over anhydrous NaSO. 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) (5:1) to give 4-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methylthiophene-3-carbonitrile (300 mg, 80% yield). LCMS (ESI, m / z) = 301 [M+1]+.

[0618] Step 7: To a stirred solution of 4-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methylthiophene-3-carbonitrile (300 mg, 0.99 mmol, 1.00 equiv.) in HO (2 mL) and tetrahydrofuran (THF) (1 mL) was added trifluoroacetic acid (TFA) (2 mL) dropwise at room temperature. The resulting mixture was stirred at 50 °C for 2 hours and then concentrated in vacuo. The resulting residue was then purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 0% to 100% gradient in 10 minutes; UV detector at 254 nm) to give 4-(5-amino-1,3,4-thiadiazol-2-yl)-5-methylthiophene-3-carbonitrile (130 mg, 58% yield). LCMS (ESI, m / z) = 222 [M+1] + .

[0619] Step 8: To a stirred solution of 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 3 of Example 6) (192 mg, 0.649 mmol, 1.07 equiv.) and 4-(5-amino-1,3,4-thiadiazol-2-yl)-5-methylthiophene-3-carbonitrile (120 mg, 0.608 mmol, 1.00 equiv.) in N,N-dimethylformamide (DMF) (5 mL) at room temperature was added hydroxybenzotriazole (HOBT) (102 mg, 0.755 mmol, 1.24 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (141 mg, 0.736 mmol, 1.21 equiv.). The resulting mixture was stirred at 50° C. for 3 hours. The resulting solid was collected by filtration and washed with DMF (3 × 1 mL) to give N-[5-(4-cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide (200 mg, 69% yield). LCMS (ESI, m / z) = 500 [M+1]+.

[0620] Step 9: Following Step 2 of Part C of Example 1, N-(5-(4-cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 140) was prepared using 2-methoxyethan-1-amine as the "amine reagent" and N-[5-(4-cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent." LCMS (ESI m / z) = 448.05 [M+1]+. 1 H NMR (300MHz, DMSO-d6) δ8.52(s,1H),7.20(s,1H),6.91(s,1H),3.66(s,3H),3.52-3.42(m,4H),3.29(s,3H),2.63(s,3H).

[0621] Example 31: N-(5-(5-ethyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 141) [ka] Step 1: To a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (product of Step 2, Part B of Example 1) (6.0 g, 24 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (150 mL), n-butyllithium (n-BuLi) (12 mL, 30 mmol, 1.2 equiv.) in hexane (2.5 M) was added dropwise over 15 minutes at −78° C. under N2 (nitrogen gas). The resulting mixture was stirred at −78° C. for an additional 1.5 hours. Ethyl iodide (4500 mg, 28.85 mmol, 1.18 equiv.) was then added dropwise to the mixture at −78° C. under N2. The resulting mixture was stirred at room temperature for an additional 1.5 hours. The reaction was then quenched with saturated NH4Cl (aq.) at 0° C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 x 300 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (9:1) to give 2-(2,5-dimethylpyrrol-1-yl)-5-(5-ethylpyrazol-1-yl)-1,3,4-thiadiazole (5100 mg, 72% yield). LCMS (ESI, m / z) = 274.0 [M+1]+.

[0622] Step 2: To a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(5-ethylpyrazol-1-yl)-1,3,4-thiadiazole (5000 mg, 19.28 mmol, 1.00 equiv) in THF (10 mL) was added HO (20 mL) and trifluoroacetic acid (TFA) (20 mL) at room temperature. The resulting mixture was stirred at 60 °C for 4 h and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 10% to 50% gradient in 15 min, UV detector, 254 nm) to give 5-(5-ethylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (3000 mg, 82% yield). LCMS (ESI, m / z) = 196.0 [M+1]+.

[0623] Step 3: To a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (200 mg, 0.80 mmol, 1.00 equiv.) in acetonitrile (MeCN) (5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (270 mg, 0.96 mmol, 1.20 equiv.), N-methylimidazole (NMI) (132 mg, 1.61 mmol, 2.00 equiv.), and 5-(5-ethylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (157 mg, 0.80 mmol, 1.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting solid was collected by filtration and washed with acetonitrile. The solid was then purified by trituration with acetonitrile and water (15 mL) to give 4-bromo-N-[5-(5-ethylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (150 mg, 39% yield). LCMS (ESI, m / z) = 425.9 [M+1]+.

[0624] Step 4: Following Step 2 of Part C of Example 1, N-(5-(5-ethyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 141) was prepared using 2-methoxyethan-1-amine as the "amine reagent" and 4-bromo-N-[5-(5-ethylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent." LCMS (ESI, m / z) = 421.10 [M+1]+. 1H NMR(400MHz,DMSO-d6)δ7.70(d,J=1.6Hz,1H),7.22(s,1H),6.38(d,J=1.6Hz,1H),3.6 4(s,3H),3.50-3.41(m,4H),3.26(s,3H),3.05(q,J=7.2Hz,2H),1.23(t,J=7.2Hz,3H).

[0625] Example 32: (R)—N-(5-(5-(hydroxymethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 142) [ka] Step 1: To a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (product of Step 2, Part B of Example 1) (5.0 g, 20 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (100 mL), n-butyllithium (n-BuLi) (8.97 mL, 22.4 mmol, 1.10 equiv.) was added dropwise over 5 minutes at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. Ethyl fumarate (4.53 g, 61.1 mmol, 3.00 equiv.) was then added dropwise over 5 minutes at −78° C. The mixture was stirred at −78° C. for an additional 1 hour and then quenched with saturated NH4Cl (aq.) at 0° C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3×100 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 give 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazole-3-carbaldehyde (3.5 g, 56% yield). LCMS (ESI, m / z) = 274.2 [M+1]+.

[0626] Step 2: To a solution of 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazole-3-carbaldehyde (3.5 g, 13 mmol, 1.0 equiv) in methanol (MeOH) (50 mL) was added NaBH4 (2.42 g, 64.0 mmol, 5.00 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h and then quenched with HCl (1 M) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 60 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (6:1) to give {2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazol-3-yl}methanol (3.3 g, 84% yield). LCMS(ESI, m / z)=276.0[M+1]+.

[0627] Step 3: To a solution of {2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazol-3-yl}methanol (3.3 g, 12 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (16 mL) was added HO (16 mL) and trifluoroacetic acid (TFA) (20 mL) at room temperature. The resulting mixture was stirred at 60 °C for 5 h and then concentrated under reduced pressure. The residue was then purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; UV detector at 254 nm) to give [2-(5-amino-1,3,4-thiadiazol-2-yl)pyrazol-3-yl]methanol (1.5 g, 57% yield). LCMS (ESI, m / z) = 198.0 [M+1]+.

[0628] Step 4: To a solution of 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 6, Step 3) (2.25 g, 7.61 mmol, 1.00 equiv.) in N,N-dimethylformamide (DMF) (20 mL) was added hydroxybenzotriazole (HOBT) (1.54 g, 11.4 mmol, 1.50 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.92 g, 15.2 mmol, 2.00 equiv.), and [2-(5-amino-1,3,4-thiadiazol-2-yl)pyrazol-3-yl]methanol (1.5 g, 7.6 mmol, 1.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was then quenched with water at room temperature. The resulting solid was collected by filtration and washed with water. The filtrate was concentrated under reduced pressure to give N-{5-[5-(hydroxymethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-yl}-4-iodo-5-methoxy-6-oxopyran-2-carboxamide (2.0 g, 50% yield). LCMS (ESI, m / z) = 475.9 [M+1]+.

[0629] Step 5: Following Step 2 of Part C of Example 1, (R)-N-(5-(5-(hydroxymethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 142) was prepared using (R)-1-methoxypropan-2-amine as the "amine reagent" and N-{5-[5-(hydroxymethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-yl}-4-iodo-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent." LCMS (ESI, m / z) = 437.10 [M+1]+. 1H NMR(400MHz,DMSO-d6)δ7.83(d,J=1.6Hz,1H),7.40(s,1H),6.57(d,J=1.6Hz,1H),4.94(d,J=1. 0Hz,2H),4.02-3.97(m,1H),3.67(s,3H),3.43-3.32(m,2H),3.27(s,3H),1.17(d,J=6.4Hz,3H).

[0630] Example 33: N-(5-(5-(difluoromethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 144) [ka] Step 1: To a stirred solution of 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazole-3-carbaldehyde (the product of Step 1 of Example 32) (700 mg, 2.56 mmol, 1.00 equiv.) in dichloromethane (DCM) (5 mL) was added diethylaminosulfur trifluoride (DAST) (826 mg, 5.12 mmol, 2.00 equiv.) at 0° C. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The reaction was then quenched by the addition of water (2 mL) at room temperature and extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers were 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 give 2-[5-(difluoromethyl)pyrazol-1-yl]-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (300 mg, 40% yield).

[0631] Step 2: To a solution of 2-[5-(difluoromethyl)pyrazol-1-yl]-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (300 mg, 1.02 mmol, 1.00 equiv) in tetrahydrofuran (THF) (1 mL) and HO (0.5 mL) was added trifluoroacetic acid (TFA) (0.5 mL) at 0 °C. The resulting mixture was stirred at 60 °C under air for 2 h. The mixture was then 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 give 5-[5-(difluoromethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-amine (190 mg, 86% yield). LCMS (ESI, m / z) = 218.0 [M+1].

[0632] Step 3: To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (the product of Step 4, Part A of Example 1) (218 mg, 0.87 mmol, 1.00 equiv.) in acetonitrile (MeCN) (1 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (294 mg, 1.05 mmol, 1.20 equiv.), N-methylimidazole (NMI) (215 mg, 2.62 mmol, 3.00 equiv.), and 5-[5-(difluoromethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-amine (190 mg, 0.875 mmol, 1.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature for an additional 50 minutes. The resulting solid was collected by filtration and washed with MeCN (3 × 10 mL) to give 4-bromo-N-{5-[5-(difluoromethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-yl}-5-methoxy-6-oxopyran-2-carboxamide (220 mg, 56% yield). LCMS (ESI, m / z) = 447.9 [M+1]+.

[0633] Step 4: Following Step 2 of Part C of Example 1, using 4-bromo-N-{5-[5-(difluoromethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-yl}-5-methoxy-6-oxopyran-2-carboxamide as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent," N-(5-(5-(difluoromethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 144) was prepared. LCMS (ESI, m / z) = 443.1 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.72(t,J=50.2Hz,1H),7.15(s,1H),6.97(s,1H),6.82(s,1H),3.67(s,3H),3.48(s,4H),3.29(s,3H).

[0634] Example 34: N-(5-(3-cyanothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 145) [ka] Step 1: A solution of thiophene-3-carbonitrile (500 mg, 4.58 mmol, 1.00 equiv.), 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) (123 mg, 0.458 mmol, 0.10 equiv.), and bis(1,5-cyclooctadiene)di-mu-methoxydiiridium(I) [Ir(OMe)(COD)] (304 mg, 0.458 mmol, 0.10 equiv.) in hexane (2 mL) was stirred under N2 (nitrogen gas) at room temperature for 2 minutes. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (586 mg, 4.58 mmol, 1.00 equiv.) was added dropwise to the mixture over 2 minutes at 0 °C. The resulting mixture was stirred at room temperature for an additional 48 hours and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1:1) to give 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile (220 mg, 20% yield).

[0635] Steps 2-5: Following Steps 1-4 of Example 28, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile was used in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile to give 2-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-3-carbonitrile (the product of Step 3 of this Example), which was then coupled with 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid. Coupling with 2-methoxyethan-1-amine as the "amine reagent" gave 4-bromo-N-(5-(3-cyanothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent," and N-(5-(3-cyanothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 145) was prepared. LCMS (ESI, m / z) = 434.00 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),7.80(s,1H),7.06(s,1H),6.74(t,J=5.6Hz,1H),3.65(s,3H),3.48-3.46(m,4H),3.29(s,3H).

[0636] Example 35: N-[5-(5-chloropyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 148) [ka] Step 1: To a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (product of Step 2, Part B of Example 1) (1000 mg, 4.077 mmol, 1.00 equiv.) in tetrahydrofuran (THF) was added n-butyllithium (n-BuLi) (2.4 mL, 6.0 mmol, 1.5 equiv.) dropwise at −78° C. under N. The solution was stirred at −78° C. for 1 hour, and then hexachloroethane (CCl) (1000 mg, 4.22 mmol, 1.04 equiv.) was added dropwise at −78° C. The resulting mixture was stirred at room temperature under N for 2 hours and then quenched with saturated NH.sub.4Cl (aq.) at 0° C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3×30 mL). The extract was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (9:1) to give 2-(5-chloropyrazol-1-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (880 mg, 76% yield). LCMS (ESI, m / z) = 280.0 [M+1]+.

[0637] Step 2: To a solution of 2-(5-chloropyrazol-1-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (880 mg, 3.15 mmol, 1.00 equiv.) in THF (1 mL) and HO (2 mL) was added trifluoroacetic acid (TFA) (2 mL, 27 mmol, 8.6 equiv.) at room temperature. The resulting mixture was stirred at 60 °C for 3 h and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 10% to 30% gradient in 7 min; UV detector at 254 nm) to give 5-(5-chloropyrazol-1-yl)-1,3,4-thiadiazol-2-amine (390 mg, 61% yield). LCMS (ESI, m / z) = 202.0 [M+1]+.

[0638] Step 3: 4-Bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4, Example 1, Part A) (300 mg, 1.21 mmol, 1.00 equiv.) and 5-(5-chloropyrazol-1-yl)-1,3,4-thiadiazol-2-amine (270 mg, 1.34 mmol, 1.11 equiv.) in N,N-dimethylformamide (DMF) (3 mL) To a solution containing 1-((dimethylamino)(dimethylimino)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU) (692 mg, 1.82 mmol, 1.51 equiv.) and diisopropylethylamine (DIEA) (469 mg, 3.63 mmol, 3.01 equiv.) was added under N2 (nitrogen gas) at 0 °C. The resulting mixture was stirred at room temperature under N2 for 16 h, then diluted with water and extracted with ethyl acetate (EtOAc) (3 × 100 mL). The combined organic layer was dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with methanol (MeOH) / dichloromethane (DCM) (1:4) to give 4-bromo-N-[5-(5-chloropyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (also referred to herein as 4-bromo-N-(5-(5-chloro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide) (400 mg, 69% yield). LCMS (ES, m / z) = 432.2 [M+1]+.

[0639] Step 4: Following Step 2 of Part C of Example 1, using 4-bromo-N-(5-(5-chloro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent" and 2-methoxyethan-1-amine as the "amine reagent," N-[5-(5-chloropyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 148) was prepared. LCMS (ESI, m / z) = 427.0 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ13.52(br,1H),8.02(d,J=2.0Hz,1H),7.41(s,1H),7.0 8(br,1H),6.85(d,J=2.0Hz,1H),3.69(s,3H),3.51-3.48(m,4H),3.29(s,3H).

[0640] Example 36: 4-(bicyclo[1.1.1]pentan-1-ylamino)-3-(3-methoxy-2,2-dimethylpropoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 149) [ka] Step 1: To a stirred solution of 2,2-dimethylpropane-1,3-diol (10.0 g, 96.0 mmol, 1.00 equiv.) in tetrahydrofuran (THF) (100 mL) was added NaH (3.60 g, 150 mmol, 1.56 equiv.) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes, and then methyl iodide (CHI) (16.0 g, 113 mmol, 1.17 equiv.) was added at 0 °C. The resulting mixture was stirred at room temperature overnight and then quenched with saturated NH Cl (aq.) at room temperature. The resulting mixture was poured into water and extracted with ethyl acetate (EtOAc) (3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL) and brine (3 × 100 mL) and dried over anhydrous Na SO . 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) (4:1) to give 3-methoxy-2,2-dimethylpropan-1-ol (2.9 g, 25% yield). LCMS (ES, m / z) = 119 [M+1]+.

[0641] Step 2: To a stirred solution of 3-methoxy-2,2-dimethylpropan-1-ol (479 mg, 4.06 mmol, 2.02 equiv.) and methyl 4-bromo-3-hydroxy-2-oxo-2H-pyran-6-carboxylate (product of Step 4, Part A, Example 1) (500 mg, 2.01 mmol, 1.00 equiv.) in THF (5 mL) was added triphenylphosphine (PPh) (800 mg, 3.05 mmol, 1.52 equiv.) at room temperature. To the above mixture was added DBAD (700 mg, 3.04 mmol, 1.51 equiv.) at 0° C. The resulting mixture was stirred at 60° C. for an additional 1 h, then poured into water and extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with water (3 × 100 mL) and brine (3 × 100 mL) and dried over anhydrous NaSO. 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) (85:15) to give methyl 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-2-oxo-2H-pyran-6-carboxylate (544 mg, 77% yield). LCMS (ES, m / z) = 349 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ7.40 (s, 1H), 4.06 (s, 2H), 3.85 (s, 3H), 3.24 (s, 3H), 3.20 (s, 2H), 0.97 (s, 6H).

[0642] Step 3: To a solution of methyl 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-2-oxo-2H-pyran-6-carboxylate (540 mg, 1.55 mmol, 1.00 equiv.) was added HCl (6 M) in water (10 mL) at room temperature. The resulting mixture was stirred at 80 °C overnight and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 0% to 100% gradient (HO:MeCN = 1:1) in 10 min) to give 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-2-oxo-2H-pyran-6-carboxylic acid (370 mg, 71% yield). LCMS (ES, m / z) = 335 [M+1]+.

[0643] Step 4: 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-2-oxo-2H-pyran-6-carboxylic acid (310 mg, 0.925 mmol, 1.00 equiv.) and 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 4, Part B of Example 1) (260 mg, 1.44 mmol, 1.55 equiv.) with N,N-dimethyl To a stirred solution of 1-((dimethylamino)(dimethylimino)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU) (530 mg, 1.39 mmol, 1.51 equiv.) and diisopropylethylamine (DIEA) (180 mg, 1.39 mmol, 1.51 equiv.) in formamide (DMF) (3 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting solid was collected by filtration and washed with water (5 × 5 mL) to give 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (310 mg, 67% yield). LCMS (ES, m / z) = 498 [M+1] + .

[0644] Step 5: Following Step 2 of Part C of Example 1, 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (bicyclo[1.1.1]pentan-1-ylamino)-3-(3-methoxy-2,2-dimethylpropoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 149) was prepared using 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent" and bicyclo[1.1.1]pentan-1-amine as the "amine reagent." LCMS(ES, m / z)=501.15[M+1]+. 1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.33(s,1H),6.71(s,1H),6.45(s,1H),3.67(s ,2H),3.32(s,3H),3.26(s,2H),2.68(s,3H),2.56(s,1H),2.20(s,6H),0.94(s,6H).

[0645] Example 37: (R)-3-Methoxy-4-(3-methoxy-2-oxopyrrolidin-1-yl)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 150) [ka] Step 1: To a stirred solution of (3R)-3-hydroxypyrrolidin-2-one (390 mg, 3.86 mmol, 1.99 equiv.) and methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (product of Step 2, Example 6) (600 mg, 1.94 mmol, 1.00 equiv.) in dioxane (9 mL) was added [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CPhos Pd G3) (50 mg, 0.061 mmol, 0.19 equiv.), 2'-(dicyclohexylphosphanyl)-N 2 ,N 2 ,N 6 ,N 6CPhos (172 mg, 0.394 mmol, 0.20 equiv.) and cesium carbonate (1880 mg, 5.77 mmol, 2.98 equiv.) were added at room temperature under N2 (nitrogen gas). The resulting mixture was stirred at 100 °C under N2 (nitrogen gas) for 1 h and then directly purified by silica gel column chromatography (50%-100%) eluting with petroleum ether / ethyl acetate (PE / EtOAc) to give methyl 4-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]-5-methoxy-6-oxopyran-2-carboxylate (90 mg, 13% yield). LCMS (ES, m / z) = 284 [M+1]+.

[0646] Step 2: To a stirred solution of methyl 4-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]-5-methoxy-6-oxopyran-2-carboxylate (50 mg, 0.18 mmol, 1.0 equiv.) in dichloromethane (DCM) (0.6 mL) was added AgO (50 mg, 0.22 mmol, 1.22 equiv.) and MeI (0.6 mL) at room temperature. The resulting mixture was stirred at 50 °C for 2 hours. The resulting mixture was then filtered, and the filter cake was washed with dichloromethane (DCM) (3 × 10 mL). The filtrate was concentrated under reduced pressure to give methyl 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6-oxopyran-2-carboxylate (40 mg, 61% yield). LCMS (ES, m / z) = 298 [M+1]+.

[0647] Step 3: To a stirred solution of methyl 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6-oxopyran-2-carboxylate (40 mg, 0.14 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (1 mL) was added trimethyltin hydroxide (37 mg, 0.20 mmol, 1.52 equiv.) at room temperature. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure to give 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6-oxopyran-2-carboxylic acid (30 mg), which was used directly without further purification. LCMS (ES, m / z): 284 [M+H] + .

[0648] Step 4: To a stirring solution of 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6-oxopyran-2-carboxylic acid (“aminopyrone reagent”) (80 mg, 0.28 mmol, 1.0 equiv.) in N,N-dimethylformamide (DMF) (2 mL) at room temperature was added hydroxybenzotriazole (HOBT) (60 mg, 0.44 mmol, 1.57 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (108 mg, 0.56 mmol, 1.99 equiv.), and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 4, Part B of Example 1; “ADT amine reagent”) (50 mg, 0.28 mmol, 0.98 equiv.). The resulting mixture was stirred at room temperature for 2 hours and then directly purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water (0.1% trifluoroacetic acid (TFA)), gradient from 20% to 40% in 10 minutes; detector, UV 254 nm) to give the crude product, which was then purified by chiral preparative HPLC (SHIMADZU: column, Xselect CSH C18 OBD column 30 × 150 mm Further purification with 5 μm; mobile phase, water (0.05% TFA) and MeCN (29% MeCN to 39% in 10 min) gave (R)-3-methoxy-4-(3-methoxy-2-oxopyrrolidin-1-yl)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 150) (7.4 mg, 5.8% yield). LCMS (ES, m / z): 447.1 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ7.89-7.70(m,2H),6.44(d,J=1.2Hz,1H),4.18(t,J=8.0Hz,1H),3.9 2(s,3H),3.85-3.74(m,2H),3.48(s,3H),2.67(s,3H),2.56-2.51(m,1H),2.03-1.94(m,1H).

[0649] Example 38: 3-Methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 152) [ka] Step 1: According to Step 5 of Example 6, using methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (the product of Step 2 of Example 6) and 1-(methoxymethyl)cyclopentan-1-amine, methyl 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6-carboxylate was prepared. LCMS (ES, m / z) = 312 [M+1].

[0650] Steps 2-3: Following Steps 3-4 of Example 37, methyl 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6-carboxylate was used instead of methyl 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6-oxopyran-2-carboxylate to obtain 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6-carboxylate as the "aminopyrone reagent." The resulting carboxylic acid was then coupled with 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 4, Part B of Example 1) as the "ADT amine reagent" to prepare 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 152). LCMS (ES, m / z) = 461.1 [M+1]+. 1H NMR(300MHz,DMSO-d6)δ7.79(d,J=1.6Hz,1H),7.27(s,1H),6.45(d,J=1.6Hz,1H),6.17(s,1H) ),3.71(s,3H),3.46(s,2H),3.30(s,3H),2.68(s,3H),1.96-1.91(m,4H),1.74-1.63(m,4H).

[0651] Example 39: 3-methoxy-4-(((cis)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 153, rac-153), 3-methoxy-4-(((1S,2R)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 153a * ), and 3-methoxy-4-(((1R,2S)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 153b * ) [ka] Step 1: According to Step 5 of Example 6, Rac-5-methoxy-4-{[cis-2-methoxycyclopentyl]amino}-6-oxopyran-2-carboxylic acid ester was prepared using methyl 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylate and (1,2-cis)-2-methoxycyclopentan-1-amine hydrochloride. LCMS (ES, m / z) = 298 [M+1].

[0652] Step 2: To a stirred solution of methyl rac-5-methoxy-4-{[cis-2-methoxycyclopentyl]amino}-6-oxopyran-2-carboxylate (81 mg, 0.27 mmol, 1.0 equiv.) in dimethylformamide (DMF) (5 mL) was added methyl iodide (360 mg, 2.54 mmol, 9.31 equiv.) and potassium tert-butoxide (122 mg, 1.09 mmol, 3.99 equiv.) at 0 °C. The resulting mixture was stirred overnight at room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (EtOAc) (3 × 100 mL). The combined organic layer was washed with brine (50 mL) and 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) (1:1) to give methyl rac-5-methoxy-4-{[cis-2-methoxycyclopentyl](methyl)amino}-6-oxopyran-2-carboxylate (63 mg, 66% yield). LCMS (ES, m / z) = 312 [M+1].

[0653] Steps 3-4: Following Steps 3-4 of Example 37, methyl rac-5-methoxy-4-{[cis-2-methoxycyclopentyl](methyl)amino}-6-oxopyran-2-carboxylate was used in place of methyl 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6-oxopyran-2-carboxylate to give rac-3-methoxy-4-(((1,2-cis)-2-methoxycyclopentyl)(methyl)amino)-2-oxo-2H-pyran-6-carboxylic acid as the "aminopyrone reagent" and then 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6-oxopyran-2-carboxylate as the "ADT amine reagent." Methyl rac-5-methoxy-4-{[cis-2-methoxycyclopentyl](methyl)amino}-6-oxopyran-2-carboxylate was then coupled with N-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 4, Part B of Example 1) to give 3-methoxy-4-(((1S,2R)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 153a * ) and 3-methoxy-4-(((1R,2S)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 153b * ) was prepared as a racemic mixture. LCMS (ES, m / z) = 461.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.40(br,1H),7.78(s,1H),7.33(s,1H),6.44(s,1H),4.26-4.20(m,1H),3.87-3.79(m,1 H),3.68(s,3H),3.22(s,3H),3.10(s,3H),2.67(s,3H),2.04-1.97(m,1H),1.79-1.65(m,4H),1.53-1.47(m,1H).

[0654] Example 40: N-(5-(3,5-dichloroisothiazol-4-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 156) [ka] Step 1: To a mixture of (2-methoxyethyl)[(4-methoxyphenyl)methyl]amine (1000 mg, 5.12 mmol, 1.00 equiv.) and methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (product of Step 2, Example 6) (1000 mg, 3.22 mmol, 0.63 equiv.) in N,N-dimethylformamide (DMF) (10 mL) was added CuI (205 mg, 1.08 mmol, 0.21 equiv.), N,N-diethyl-2-hydroxybenzamide (198 mg, 1.02 mmol, 0.20 equiv.), and KCO (1000 mg, 7.24 mmol, 1.41 equiv.). The resulting mixture was stirred under N at 100 °C for 1 h and then diluted with water (50 mL). The mixture was extracted with ethyl acetate (EtOAc) (3 × 150 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1:2) to give methyl 5-methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-carboxylate (600 mg, 31% yield). LCMS (ES, m / z) = 378.0 [M+1].

[0655] Step 2: To a mixture of methyl 5-methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-carboxylate (190 mg, 0.503 mmol, 1.00 equiv.) in tetrahydrofuran (THF) (2 mL) was added trimethyltin hydroxide (137 mg, 0.758 mmol, 1.50 equiv.). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude product, 5-methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-carboxylic acid, was used directly in the next step without further purification. LCMS (ES, m / z) = 364.0 [M+1].

[0656] Step 3: 5-Methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-carboxylic acid (“aminopyrone reagent”) (190 mg, 0.523 mmol, 1.00 equiv.) and 5-(3,5-dichloro-1,2-thiazol-4-yl)-1,3,4-thiadiazol-2-amine (133 mg, 0.525 mmol, 1.00 equiv.) as the “ADT amine reagent” (which was prepared according to Step 1 of Example 29). To a mixture of N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (300 mg, 1.07 mmol, 2.04 equiv.) and N-methylimidazole (NMI) (130 mg, 1.58 mmol, 3.03 equiv.) in acetonitrile (MeCN) (3 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (300 mg, 1.07 mmol, 2.04 equiv.). The resulting mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL). The mixture was extracted with EtOAc (5 x 20 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 residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1:1) to give N-[5-(3,5-dichloro-1,2-thiazol-4-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-carboxamide (70 mg, 22% yield). LCMS (ES, m / z) = 598.0 [M+1] +. PMB = 4-methoxybenzyl.

[0657] Step 4: A 25 mL round-bottom flask was charged with N-[5-(3,5-dichloro-1,2-thiazol-4-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-carboxamide (50 mg, 0.084 mmol, 1.00 equiv.) and trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was then purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water, 10% to 50% gradient in 20 min; detector, UV 254 nm) to give N-(5-(3,5-dichloroisothiazol-4-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 156) (11 mg, 27% yield). LCMS (ES, m / z) = 477.95 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ7.42 (s, 1H), 7.10 (s, 1H), 3.70 (s, 3H), 3.49 (t, J = 2.4Hz, 4H), 3.29 (s, 3H).

[0658] Example 41: 4-((2-hydroxyethyl)(2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 157), 4-((2-(benzyloxy)ethyl)(2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl- (1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 157-OBn), 4-(bis(2-hydroxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 158) [ka] Step 1: To a stirred mixture of 2-(benzyloxy)acetaldehyde (1.0 g, 6.66 mmol, 1.0 equiv.) and 2-methoxyethan-1-amine (666 mg, 8.87 mmol, 1.33 equiv.) in dichloroethane (DCE) (50 mL) was added triethylamine (NEt) (1.0 g, 9.9 mmol, 1.5 equiv.) and sodium triacetoxyborohydride (NaBH(OAc)) (2.46 g, 11.6 mmol, 1.74 equiv.). The resulting mixture was stirred at room temperature for 1 h and then quenched with NaHCO at room temperature. The mixture was extracted with dichloromethane (DCM). The organic layer was washed with water and dried over anhydrous NaSO. 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 give [2-(benzyloxy)ethyl](2-methoxyethyl)amine (700 mg, 46% yield). LCMS (ES, m / z) = 210 [M+1].

[0659] Step 2: To a stirred mixture of [2-(benzyloxy)ethyl](2-methoxyethyl)amine (430 mg, 2.05 mmol, 1.00 equiv.) and methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (product of Step 3, Part A of Example 1) (443 mg, 1.68 mmol, 0.82 equiv.) in N,N-dimethylformamide (DMF) (5 mL) was added (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (140 mg, 0.167 mmol, 0.08 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (157 mg, 0.336 mmol, 0.16 equiv.), and cesium carbonate (1196 mg, 3.67 mmol, 1.79 equiv.) were added. The resulting mixture was stirred at 110 °C for 1 h and then directly purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water (5 mmol / L NH4HCO3), gradient from 0% to 100% in 30 min; UV detector at 254 nm) to give 4-{[2-(benzyloxy)ethyl](2-methoxyethyl)amino}-5-methoxy-6-oxopyran-2-carboxylic acid (190 mg, 24% yield). LCMS (ES, m / z) = 378 [M+1] + .

[0660] Step 3: To a stirred mixture of 4-{[2-(benzyloxy)ethyl](2-methoxyethyl)amino}-5-methoxy-6-oxopyran-2-carboxylic acid (“aminopyrone reagent”) (180 mg, 0.477 mmol, 1.00 equiv.) and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 4, Part B of Example 1; “ADT amine reagent”) (83 mg, 0.46 mmol, 0.96 equiv.) in N,N-dimethylformamide (DMF) (2 mL) was added hydroxybenzotriazole (HOBT) (124 mg, 0.918 mmol, 1.92 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (264 mg, 1.38 mmol, 2.89 equiv.). The resulting mixture was stirred at room temperature under air for 1 hour, and then extracted with ethyl acetate (EtOAc). The organic layer was washed with brine and 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) (1:1) to give 4-{[2-(benzyloxy)ethyl](2-methoxyethyl)amino}-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (also referred to herein as 4-((2-(benzyloxy)ethyl)(2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide; Compound 157-OBn) (75 mg, 29% yield). LCMS (ES, m / z) = 541 [M+1]+.

[0661] Step 4: To a stirred mixture of 4-{[2-(benzyloxy)ethyl](2-methoxyethyl)amino}-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (compound 157-OBn) (50 mg, 0.092 mmol, 1.00 equiv.) in dichloromethane (DCM) (0.5 mL) was added BBr3 (0.6 mL, 0.6 mmol, 6.47 equiv.) in DCM (1 M) at 0 °C. The resulting mixture was stirred at room temperature for 40 min and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge Shield RP18 Purification by OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: acetonitrile (MeCN); flow rate: 60 mL / min; gradient: 10% B to 20% B, 20% B in 10 min; wavelength: 254 nm; RT1 (min): 8.8, RT2 (min): 9.8) gave 4-((2-hydroxyethyl)(2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (2.9 mg, 6.5% yield) (compound 157), first eluting peak, LCMS (ES, m / z) = 451.15 [M+1]+. 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.06 (d, J = 1.2 Hz, 1H), 6.31 (d, J = 0.8 Hz, 1H), 4.86 (t, J = 4.8 Hz, 1H), 3.59-3.52 (m, 11H), 3.29 (s, 3H), 2.60 (s, 3H); and 4-(bis(2-hydroxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (4.3 mg, 9.7% yield) (compound 158), second eluting peak, LCMS (ES, m / z) = 437.1 [M+1]+. 1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.07(d,J=1.2Hz,1H),6.30(d,J=0.8Hz 1H), 4.94-4.82(m, 2H), 3.62-3.60(m, 4H), 3.47-3.48(m, 7H), 2.59(s, 3H) were obtained.

[0662] Example 42: 4-(((cis)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 159, rac-159), 4-(((1S,2R)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 159a * ), and 4-(((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 159b * ) [ka] Step 1: Following the procedure outlined in Step 1 of Example 40, 4-((cis-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid was prepared using cis-2-(methylamino)cyclopentan-1-ol and methyl 4-iodo-3-methoxy-2-oxo-2H-pyran-6-carboxylate (also referred to herein as methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate; the product of Step 2 of Example 6). LCMS (ES, m / z) = 284.0 [M+1]+.

[0663] Step 2: To a solution of 4-((cis-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid (40 mg, 0.14 mmol, 1.00 equiv.) in N,N-dimethylformamide (DMF) (2 mL) was added hydroxybenzotriazole (HOBT) (29 mg, 0.215 mmol, 1.52 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (54 mg, 0.282 mmol, 1.99 equiv.), and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (the product of Step 4, Part B of Example 1) (23 mg, 0.127 mmol, 0.90 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC (SHIMADZU: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (19% MeCN to 27% in 8 min; detector, UV 254 nm) to give 4-(((1S,2R)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 159a * ), and 4-(((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 159b * ) was obtained as a racemic mixture (14 mg, 23% yield). LCMS (ES, m / z) = 447.10 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.12(s,1H),6.32(s,1H),4.20-4.18(s,1H),4.06-4.03(m,1H ),3.65(s,3H),3.12(s,3H),2.59(s,3H),2.07-1.95(m,1H),1.94-1.71(m,3H),1.51-1.45(m,2H).

[0664] Example 43: 3-Methoxy-4-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 160) [ka] Step 1: To a stirred solution of (3S,4S)-4-aminooxolan-3-ol (300 mg, 2.91 mmol, 1.00 equiv.) in acetonitrile (MeCN) (500 mL) was added benzyl bromide (BnBr) (1200 mg, 7.02 mmol, 2.41 equiv.), K2CO3 (900 mg, 6.51 mmol, 2.24 equiv.), and tetra-n-butylammonium bromide (TBAB) (180 mg, 0.56 mmol, 0.19 equiv.) at room temperature. The resulting mixture was stirred overnight at room temperature and then diluted with water (50 mL). The mixture was then extracted with ethyl acetate (EtOAc) (3 × 50 mL). The combined organic layers were washed with brine (2 × 8 mL) and 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) (1:1) to give (3S,4S)-4-(dibenzylamino)oxolan-3-ol (760 mg, 92% yield). LCMS (ES, m / z) = 284 [M+1].

[0665] Step 2: To a solution of (3S,4S)-4-(dibenzylamino)oxolan-3-ol (760 mg, 2.68 mmol, 1.00 equiv.) in tetrahydrofuran (THF) (10 mL) was added 60% NaH in mineral oil (220 mg, 5.50 mmol, 2.05 equiv.) at 0 °C. The mixture was stirred for 30 min, after which methyl iodide (MeI) (1530 mg, 10.78 mmol, 4.02 equiv.) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water at room temperature and extracted with ethyl acetate (EtOAc) (3 × 70 mL). The combined organic layers were washed with brine (2 × 10 mL) and 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) (4:1) to give (3S,4S)-N,N-dibenzyl-4-methoxyoxolan-3-amine (700 mg, 88% yield). LCMS (ES, m / z) = 298 [M+1].

[0666] Step 3: To a solution of (3S,4S)-N,N-dibenzyl-4-methoxyoxolan-3-amine (350 mg, 1.18 mmol, 1.00 equiv.) in tetrahydrofuran (THF) (20 mL), Pd / C (150 mg, 1.41 mmol, 1.20 equiv.) and 2 M HCl (5.5 mL, 11.00 mmol, 9.35 equiv.) were added. The mixture was stirred under H (gas) at room temperature for 2 hours. The resulting mixture was filtered through a Celite pad and concentrated under reduced pressure to give crude (3S,4S)-4-methoxytetrahydrofuran-3-amine hydrochloride (200 mg), which was used without further purification. LCMS (ES, m / z) = 118 [M+1].

[0667] Step 4: According to Step 5 of Example 6, using 4-iodo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (the product of Step 4 of Example 6) as the "halopyrone reagent" and (3S,4S)-4-methoxytetrahydrofuran-3-amine hydrochloride as the "amine reagent," 3-methoxy-4-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 160) was prepared. LCMS (ES, m / z) = 449.1 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=1.6Hz,1H),7.36(s,1H),6.45(d,J=1.6Hz,1H),6.25(br,1H),4.47-4.4 1(m,1H),4.03-3.96(m,2H),3.91-3.82(m,2H),3.72(s,3H),3.65-3.62(m,1H),3.33(s,3H),2.66(s,3H).

[0668] Example 44: (S)-3-Methoxy-4-((1-methoxy-3-phenylpropan-2-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 165) [ka] Step 1: To a stirred solution of L-phenylalaninol (1.0 g, 6.61 mmol, 1.0 equiv.) in methanol (MeOH) (30 mL) was added di-tert-butyl dicarbonate (BocO) (2.90 g, 13.3 mmol, 2.01 equiv.) at room temperature. The resulting mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in ethyl acetate (EtOAc) (100 mL) and washed with water (2 × 10 mL), causing a solid to precipitate from the solution. The resulting solid was collected and dried in an oven under reduced pressure. The solid was then purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (5:1) to give tert-butyl N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]carbamate (1.13 g, 48% yield). LCMS (ES, m / z) = 252 [M+1]+.

[0669] Step 2: To a stirred solution of tert-butyl N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]carbamate (940 mg, 3.74 mmol, 1.00 equiv.) in dimethylformamide (DMF) (19 mL), methyl iodide (MeI) (1594 mg, 11.23 mmol, 3.00 equiv.) was added and stirred at 0 °C for 15 min. To the above mixture was added potassium tert-butoxide (630 mg, 5.61 mmol, 1.50 equiv.) at 0 °C. The resulting mixture was stirred for an additional 2 h at room temperature. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The mixture was then diluted with water (150 mL), and the aqueous layer was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (5:1) to give tert-butyl N-[(2S)-1-methoxy-3-phenylpropan-2-yl]carbamate (845 mg, 60% yield). LCMS (ES, m / z) = 266 [M+1].

[0670] Step 3: A stirred solution of tert-butyl N-[(2S)-1-methoxy-3-phenylpropan-2-yl]carbamate (780 mg, 2.94 mmol, 1.00 equiv) in HCl in dioxane (7.8 mL, 4.0 M) was stirred at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with water (100 mL) and neutralized to pH 8 with saturated NaHCO3 (aq). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 150 mL). The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / EtOAc) (1:1) to give (2S)-1-methoxy-3-phenylpropan-2-amine (370 mg, 44% yield). LCMS (ES, m / z) = 166 [M+1]+.

[0671] Step 4: According to Step 5 of Example 6, using 4-iodo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (the product of Step 4 of Example 6) as the "halopyrone reagent" and (2S)-1-methoxy-3-phenylpropan-2-amine as the "amine reagent," (S)-3-methoxy-4-((1-methoxy-3-phenylpropan-2-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 165) was prepared. LCMS (ES, m / z) = 497.16 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ7.61(d,J=1.2Hz,1H),7.33-7.26(m,4H),7.18(dd,J=2.0,8.8Hz 1H),6.90(s,1H),6.47(s,1H),6.31(s,1H),4.03-3.97(m,1H),3.57(s ,3H),3.47-3.43(m,2H),3.31(s,3H),2.92-2.88(m,2H),2.60(s,3H).

[0672] Example 45: 3-Methoxy-4-(((2R,3S)-3-methoxybutan-2-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 166) [ka] Step 1: To a solution of (2S,3R)-3-aminobutan-2-ol hydrochloride (600 mg, 4.78 mmol, 1.00 equiv.) in methanol (MeOH) (10 mL) was added anisaldehyde (1.95 g, 14.3 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 0.5 hours. To the above mixture was added sodium cyanoborohydride (NaBHCN) (200 mg, 3.18 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours and then concentrated under reduced pressure. The residue was then purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN) in water (0.1% formic acid (FA)), 10% to 50% gradient in 10 min; UV 254 nm detector) to give (2S,3R)-3-{bis[(4-methoxyphenyl)methyl]amino}butan-2-ol (720 mg, 40% yield). LCMS (ES, m / z) = 330 [M+1]+. PMB = para-methoxybenzyl.

[0673] Step 2: To a solution of (2S,3R)-3-{bis[(4-methoxyphenyl)methyl]amino}butan-2-ol (1.10 g, 3.34 mmol, 1.00 equiv) in tetrahydrofuran (THF) (30 mL) was added NaH (60% in mineral oil, 262 mg, 6.56 mmol, 2.00 equiv) in small portions at 0 °C. The resulting mixture was stirred for an additional 0.5 h at 0...

Claims

1. Compounds of formula (I): 【Chemistry 1】 [During the ceremony, Ring A is a 5-membered monocyclic heteroaryl; R １ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, -L ３ -(C ３ -C ６ carbocyclyl), or -L ３ -(4- to 10-membered heterocyclyl), wherein said alkyl, said alkenyl, said alkynyl, said carbocyclyl, and said heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R １Ａ and each R １Ａ are independently halogen, —OR １Ｂ , -N(R １Ｂ ) ２ , -SR １Ｂ , -C(=O)OR １Ｂ , -C(=O)N(R １Ｃ ) ２ , -(C １ -C ３ alkylene)-OR １Ｂ , or -(C １ -C ３ alkylene)-SR １Ｂ or two R １Ａ are taken together to form =O; each R １Ｂ are independently hydrogen, C １ -C ４ Alkyl, or C １ -C ４ haloalkyl, wherein said alkyl and said haloalkyl are independently 0, 1, 2, 3 or 4 R １Ｄ and each R １Ｃ are independently hydrogen, C １ -C ３ Alkyl, C １ -C ３ haloalkyl, or -OR １Ｆ and each R １Ｄ are independently halogen, —OR １Ｆ , or -N(R １Ｆ ) ２ and each R １Ｆ are independently hydrogen, C １ -C ３ Alkyl, or C １ -C ３ haloalkyl; L of the group R 1 ３ is a bond, C １ -C ３ Alkylene, or -(C １ -C ３ alkylene)-O-, wherein said alkylene is independently selected from 0, 1, 2, 3, or 4 R １Ｅ and each R １Ｅ are independently -(C １ -C ３ alkylene)-OR １Ｂ , or -OR １Ｂ or two R １Ｅ are taken together to form =O; R ２ is hydrogen or 0, 1, 2, 3 or 4 R ２Ａ C substituted with １ -C ６ alkyl, and each R ２Ａ are independently halogen, —OR ２Ｂ , or -N(R ２Ｂ ) ２ and each R ２Ｂ are independently hydrogen, C １ -C ３ Alkyl, or C １ -C ３ haloalkyl; Or, R １ and R ２ and, together with the atoms to which they are attached, independently comprise 0, 1, 2, 3, or 4 R １Ａ forming a 6- or 7-membered heterocyclyl substituted with; R ３ is C １ -C １０ Alkyl, C ２ -C １０ Alkenyl, C ２ -C １０ Alkynyl, C ３ -C １０ carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the carbocyclyl, and the heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R ３Ａ is substituted with; Or, R ２ and R ３ and, together with the atoms to which they are attached, independently comprise 0, 1, 2, 3, or 4 R ３Ａ forming a 4- to 10-membered heterocyclyl substituted with; Each R ３Ａ are independently １ -C ３ Alkyl, C ２ -C ３ Alkenyl, C ２ -C ３ Alkynyl, halogen, ═O, -L １ -CN, -L １ -SOR ３Ｃ , -L １ -SO ２ R ３Ｃ , -L １ -SR ３Ｂ , -L １ -PO(R ３Ｃ ) ２ , -L １ -OR ３Ｂ , -L １ -N(R ３Ｂ ) ２ , -L １ -C(=O)N(R ３Ｂ ) ２ , or -L １ -C(=O)OR ３Ｂ , -L １ -(C ３ -C ６ carbocyclyl), -L １ -(4- to 6-membered heterocyclyl), -L １ -(C ６－１０ aryl), or -L １ -(5- to 10-membered heteroaryl), or two R ３Ａ The groups, together with the atoms to which they are attached, form a C ６ Aryl, 5- to 6-membered heteroaryl, C ３ -C ６ carbocyclyl, or 4- to 6-membered heterocyclyl, and the alkyl, the alkenyl, the alkynyl, the carbocyclyl, the heterocyclyl, the aryl, and the heteroaryl are independently selected from 0, 1, 2, 3, or 4 R ３Ｄ is substituted with; Each R ３Ｂ are independently hydrogen, C １ -C ３ Alkyl, C ３ -C ６ carbocyclyl, or 4- to 6-membered heterocyclyl, wherein said alkyl, said carbocyclyl, and said heterocyclyl are independently selected from 0, 1, 2, 3, or 4 R ３Ｄ is substituted with; Each R ３Ｃ are independently １ -C ３ Alkyl, or C １ -C ３ haloalkyl; Each R ３Ｄ are independently halogen, —OR ３Ｅ , -CN,C １ -C ３ Alkyl, or C １ -C ３ haloalkyl; Each R ３Ｅ are independently hydrogen, C １ -C ４ Alkyl, or C １ -C ４ haloalkyl; Each R ４ are independently halogen, —CN, —L ２ -OR ４Ａ , -L ２ -N(R ４Ｂ ) ２ , C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, and each R ４Ａ and R ４Ｂ are independently hydrogen, C １ -C ３ Alkyl, C １ -C ３ haloalkyl, or —C(═O)R ４Ｃ and R ４Ｃ is C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; Each L １ and L ２ are independently a bond, C １ -C ３ Alkylene, or C １ -C ３ haloalkylene; m is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

2. (i) an amino moiety 【Chemistry 2】 is the formula 【Transformation 3】 and the compound has the formula (I'): 【Chemistry 4】 [In the formula, L ３ is C １ -C １０ Alkylene, C ２ -C １０ Alkenylene, or C ２ -C １０ alkynylene, and p is 0, 1, 2, or 3. or a pharmaceutically acceptable salt thereof; or (ii) an amino moiety 【Transformation 5】 is the formula 【Transformation 6】 and the compound has the formula (I″): 【Transformation 7】 wherein ring B is C 3 -C 10 carbocyclyl or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3. or a pharmaceutically acceptable salt thereof; or (iii) an amino moiety 【Transformation 8】 is the formula 【Chemistry 9】 and the compound has the formula (I'"): 【Chemistry 10】 wherein ring C is a 5- to 10-membered heterocyclyl and p is 0, 1, 2, or 3.

10. The compound of claim 1, wherein the compound has the formula:

3. The compound has formula (I""): 【Chemistry 11】 wherein the nitrogen atom of heteroaryl ring A is directly linked to the thiadiazole moiety.

10. The compound of claim 1, wherein the compound has the formula:

4. R １ is 0, 1, 2, 3 or 4 R １Ａ C substituted with １ -C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

5. R １ が、-CH ３ 、-CH ２ -C(CH) ３ ) ２ -CH ２ OCH ３ 、-CH ２ CH ２ OH、-H ２ CH ２ OCH ３ 、 【Chemistry 12】 2. The compound of claim 1, wherein:

6. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

7. R ３ is 0, 1, 2, 3 or 4 R ３Ａ C substituted with １ -C １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

8. An amino moiety 【Chemistry 13】 but, 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

9. Ring A is 【Chemistry 19】 2. The compound of claim 1, wherein:

10. Each R ４ are independently -CH ３ , -CH ２ CH ３ , -CHF ２ , -CF ３ , -Cl, -CN, -NH ２ , or -CH ２ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R is OH.

11. Ring A is 【Chemistry 20】 10. The compound of claim 9, wherein:

12. The compound represented by formula (I-a), (I-b), (I-c), (I-d), (I-e), (If), (I-g), (I-a-1), (I-a-2), (I-a-3), (If-1), (If-2), (If-3), (I-BC-a) or (I-BC-b): 【Chemistry 20】 【Chemistry 20】 【Chemistry 20】 wherein x is 0, 1, 2, 3, or 4.

10. The compound of claim 1, wherein the compound has the formula:

13. The compound is: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 or a pharmaceutically acceptable salt thereof.

14. The compound 【Chemistry 21】 or a pharmaceutically acceptable salt thereof.

15. The compound 【Chemistry 22】 or a pharmaceutically acceptable salt thereof.

16. The isotopically enriched compound of formula (I) of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound comprises one or more isotopically enriched atoms selected from the group consisting of deuterium, tritium, 18 F, 13 C and 14 C.

17. Compounds of formula (I): 【Chemistry 23】 [In the formula, ring A, R １ , R ２ , R ３ , R ４ and m are defined in claim 1. or a salt thereof, comprising the steps of: (i) a compound of formula (H-1) or a salt thereof and a compound of formula (N) or a salt thereof: 【Chemistry 24】 [In the formula, R ａ is hydrogen, C １－６ Alkyl, or C １－６ haloalkyl] to provide a compound of formula (I) or a salt thereof; or (ii) an amine of formula (K) or a salt thereof and a compound of formula (J-1) or a salt thereof: 【Chemistry 25】 wherein X is Cl, Br or I. to provide a compound of formula (I) or a salt thereof, The method.

18. Compound of formula (I-BC-a): 【Chemistry 26】 [In the formula, ring A, R １ , R ３ , R ４ and m are defined in claim 1, and x is 0, 1, 2, 3, or 4. or a salt thereof, comprising the step of: 【Chemistry 27】 wherein LG is a leaving group. or a salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

20. 20. The pharmaceutical composition of claim 19 for treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is inflammation, an autoimmune disease, cancer, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a rheumatic disease, or a psychological disorder.

21. The pharmaceutical composition of claim 20, wherein the disease or disorder is systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), chilblain lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), scleroderma, Aicardi-Goutieres syndrome, dermatomyositis, systemic sclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, or Sjogren's syndrome (SS).

22. The pharmaceutical composition of claim 19 for regulating cGAS activity in a cell.

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