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 U.S. Provisional Patent Application No. 63 / 433,987 filed December 20, 2022, and U.S. Provisional Patent Application No. 63 / 501,320 filed May 10, 2023, under Section 119(e) of the U.S. Patent Act, the entire contents of each of these applications are incorporated herein by reference. [Background technology]

[0002] Abnormal accumulation of cytosolic DNA induces cytokines such as type I interferons, which are important for antimicrobial defense but can also induce autoimmunity. This DNA signaling pathway requires the interferon gene-stimulating factor (STING) adapter protein, as well as the transcription factors NF-κB and IRF3, but the mechanism by which DNA is sensed remained unclear until recently. It is now understood that mammalian cytosolic extracts synthesize cyclic GMP-AMP (cGAMP) from ATP and GTP in the presence of DNA, 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 IRF3 activation and interferon-beta (IFNβ) induction. Thus, although cGAMP is the first cyclic dinucleotide in metazoans, it functions as an endogenous secondary messenger that induces interferon production in response to cytosolic DNA.

[0003] cGAMP synthase (cGAS) is an enzyme involved in the synthesis of cyclic GMP-AMP and belongs to the nucleotide transferase family. Overexpression of cGAS leads to STING-dependent activation of the transcription factor IRF3 and induction of IFNβ. Knockdown of cGAS inhibits IRF3 activation and IFNβ induction induced by DNA transfection or DNA viral infection. cGAS binds to cytoplasmic DNA and catalyzes cGAMP synthesis. These findings indicate that cGAS is a cytosolic DNA sensor that induces interferon by generating cGAMP, a second messenger.

[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 indispensable in various other biological processes, such as cellular senescence in monitoring potential cancer cells and the recognition of fragmented micronuclei.

[0005] There is a need for therapeutic agents that target cGAS. Small molecule inhibitors that are specific to cGAS would be of great value in treating diseases caused by inappropriate cGAS activity and the resulting undesirable type I interferon activity. This disclosure is intended to address this unmet need related to current cGAS inhibitory therapies. [Overview of the project]

[0006] In this specification, the cGAS inhibitor of formula (I): [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where rings A and R in the formula are provided. 1 , R 2 , R 3 , R 4 And m are described in this specification.

[0007] Further provided are methods for preparation, treatment, and pharmaceutical compositions containing the same. definition

[0008] The following provides more detailed definitions of specific functional groups and chemical terms. Chemical elements are defined in Handbook of Chemistry and Physics, 75. th The elements are identified according to the CAS version of the periodic table of elements on the front cover of the ed., and specific functional groups are generally defined as described in the relevant literature. In addition, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito, 1999, and *Smith and March 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 This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0009] The compounds described herein may contain one or more chiral 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 in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be isolated from the mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), and formation and crystallization of chiral salts, or the desired 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, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The compounds described herein may further include individual isomers substantially free of other isomers and, alternatively, mixtures of various isomers.

[0010] Unless otherwise indicated, it is also intended that the compounds described herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen being replaced by deuterium or tritium, 19 F being 18 replaced by 13 C or 14Compounds having the structure of the present invention, except that they are replaced with 13C-enriched carbon, are included within the scope of this 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 within that 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 It is intended to include alkyl groups.

[0012] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C"). 1-10 This refers to an alkyl group having 1 to 9 carbon atoms ("C"). In some embodiments, an alkyl group has 1 to 9 carbon atoms. 1-9 (alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1-8 (alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1-7 ("alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6 (alkyl). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5 (alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 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) and n-octyl (C8). Unless otherwise specified, each alkyl group is independently either unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In some embodiments, the alkyl group is unsubstituted C 1-10 It is an alkyl group (e.g., -CH3). 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 hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodine. "Perhaloalkyl" is a subset of haloalkyl, referring to an alkyl group in which all hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodine. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C"). 1-8 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 6 carbon atoms ("C"). 1-6 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 4 carbon atoms ("C"). 1-4("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 3 carbon atoms ("C"). 1-3 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 2 carbon atoms ("C"). 1-2 Haloalkyl groups are defined as follows: In some embodiments, all haloalkyl hydrogen atoms are replaced with fluoro atoms to form a perfluoroalkyl group. In some embodiments, all haloalkyl hydrogen atoms are replaced with chloro atoms to form a perchloroalkyl group. Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, and -CF2Cl.

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

[0015] "Alkynnyl" is a radical of a linear or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., one, two, three, or four triple bonds). 2-10 This refers to an "alkynyl" group. In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2-3"Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., as in 1-butynyl). 2-4 Examples of alkynyl groups, though not limited to them, include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 In addition to alkynyl groups, examples include pentynyl (C5) and hexynyl (C6). Further examples of alkynyls include heptynyl (C7) and octinyl (C8). Unless otherwise specified, each alkynyl group is independently either unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In some embodiments, the alkynyl group is unsubstituted C 2-10 It is an alkynyl group. In some embodiments, the alkynyl group is a substituted C 2-10 It is alkinyl.

[0016] A "carbocyrill" or "carbocyclic" is a non-aromatic ring system containing 3 to 14 ring carbon atoms ("C"). 3-14 This refers to a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms ("carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 10 ring carbon atoms ("C"). 3-10 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 9 ring carbon atoms ("C"). 3-9 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C"). 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C"). 3-7 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6Carbocyclyl). In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C"). 4-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5-6 ring carbon atoms ("C"). 5-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6 Examples of carbocyclyl groups, though not limited to them, include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-8 The carbocyryl group is not limited to the aforementioned C 3-6 In addition to the carbocyclyl group, other examples include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). Exemplary C 3-10 The carbocyryl group is not limited to the aforementioned C 3-8 In addition to the carbocyclyl group, cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9) are also available. 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10) and the like. As shown in the previous examples, in some embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic") or polycyclic (e.g., a bicyclic system ("bicyclic carbocyclic") or a tricyclic system ("tricyclic carbocyclic"), containing a fused ring system, a bridged ring system or a spiro ring system), and may be saturated or contain one or more carbon-carbon double bonds or triple bonds. "Carbocyclic" also includes a ring system in which the carbocyclic ring defined above is condensed with one or more aryl or heteroaryl groups and has a bonding point on the carbocyclic ring, and in such cases, the number of carbon atoms represents the number of carbon atoms in the polycyclic ring system. Unless otherwise specified, any carbocyclic group is independently unsubstituted ("unsubstituted carbocyclic") or substituted with one or more substituents ("substituted carbocyclic"). In some embodiments, the carbocyclic group is unsubstituted C 3-14 carbocyclic. In some embodiments, the carbocyclic group is substituted C 3-14 carbocyclic.

[0017] In some embodiments, "carbocyclic" is a monocyclic saturated carbocyclic group having 3 to 14 ring carbon atoms ("C 3-14 cycloalkyl"). In some embodiments, "carbocyclic" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, the 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, as mentioned earlier, C 5-6 In addition to cycloalkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are also mentioned. 3-8 Examples of cycloalkyl groups include, as mentioned earlier, C 3-6 In addition to cycloalkyl groups, examples include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In some embodiments, the cycloalkyl group is unsubstituted C 3-14 It is a cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted C 3-14 It is a cycloalkyl group.

[0018] A "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). It is understood that the ring sulfur or ring nitrogen may exist in an oxygenated state, for example, as an N-oxide (NO), sulfonyl (S(=O)2), or sulfinyl (S=O) ring heteroatom. In a heterocyclyl group containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, provided the valency is permissible. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl," including fused, bridging, or spirocyclic systems), and may be saturated or contain one or more carbon-carbon double or triple bonds. A heterocyclyl polycyclic system may contain one or more heteroatoms in one or both rings. A "heterocyclyl" can also be (i) a polycyclic system in which a heterocyclyl ring as defined above is fused (e.g., spiro-condensed or ring-condensed) with one or more carbocyclyl groups or linked to them by bridging, with the bond site on the carbocyclyl ring. The polycyclic ring system is either (i) or (ii) a polycyclic ring system in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, and the bond site is on the heterocyclyl ring, and in such cases (i) and (ii), the number of ring members represents the number of ring members in the polycyclic ring system. Unless otherwise specified, in all cases the heterocyclyl is either 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.

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

[0020] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxyranil, and thiranil. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxathiolanil, and dithiolanil. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanil. Examples of six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl.Examples of bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydroclomenyl, octahydroisoclomenyl, decahydronaphthilidinyl, decahydro-1,8-naphthilidinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthaliumidyl, naphthaliumidyl, chromanyl, clomenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7 Examples include, but are not limited to, tetrahydropyrano[3,4-b]pyrrol, 5,6-dihydro-4H-floo[3,2-b]pyrrol, 6,7-dihydro-5H-floo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofloo[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofloo[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthilidinyl.

[0021] "Aryl" is a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., one with 6, 10, or 14 pi electrons shared within the cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in an aromatic ring system. 6-14 This refers to "aryl". In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 The aryl group has 14 ring carbon atoms (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14"Aryl" (e.g., anthracyl). "Aryl" also includes polycyclic ring systems in which the aryl ring as defined above is fused with one or more carbocyryl or heterocyclyl rings, wherein the radical or bond site is on the aryl ring, in which case the number of carbon atoms represents the number of carbon atoms in the polycyclic ring system. Unless otherwise specified, in all cases, the aryl group is independently either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is unsubstituted C 6-14 It is aryl. In some embodiments, the aryl group is substituted C 6-14 It is Ariel.

[0022] "Heteroaryl" refers to 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) radical having a ring carbon atom and 1-4 ring heteroatoms provided within the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered ring heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, if the valency is permissible. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Hyperaryl" also includes polycyclic ring systems in which the heteroaryl ring as defined above is (i) fused with one or more carbocyrill or heterocyclyl groups with a bond site on the heteroaryl ring, or (ii) fused with one or more aryl groups with a bond site on either the aryl ring or the heteroaryl ring, in which case the number of ring members represents the number of ring members in the fused polycyclic ring system. In polycyclic heteroaryl groups that do not contain a ring heteroatom in one ring (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site may be on either ring, that is, on a ring containing 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, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom provided within the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a ring carbon atom provided within the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom provided within the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently either unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered ring heteroaryl. In some embodiments, the heteroaryl group is a substituted 5- to 14-membered ring heteroaryl.

[0024] Examples of exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, phenanthridine, dibenzofuranil, carbazolyl, acridinil, phenothiazinil, phenoxadinil, and phenazinil.

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

[0026] "Partially unsaturated" refers to a ring portion containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple unsaturated moieties, but not necessarily those containing aromatic groups (e.g., aryl or heteroaryl moieties).

[0027] "Saturated" refers to the ring portion that does not contain any double or triple bonds; in other words, the ring contains single bonds everywhere.

[0028] The suffix "-ene" indicates that the group is a divalent part. For example, alkylene is the divalent part of an alkyl group, haloalkylene is the divalent part of a haloalkyl group, alkenylene is the divalent part of an alkenyl group, alkynylene is the divalent part of an alkynyl group, heteroalkylene is the divalent part of a heteroalkyl group, heteroalkenylene is the divalent part of a heteroalkenyl group, heteroalkynylene is the divalent part of a heteroalkynyl group, carbocyclylene is the divalent part of a carbocyclyl group, heterocyclylene is the divalent part of a heterocyclyl group, arylene is the divalent part of an aryl group, and heteroarylene is the divalent part of a heteroaryl group. For example, alkylene can be linear or branched. 1-6 Alkylene may also be C 1-4 Alkylene may also be used. Example C 1-4 Examples of alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

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

[0030] A "pharmaceutically acceptable salt" is a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, or allergic reactions, and that is 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 from organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, 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, and 2-hydroxyethanesulfonate. Examples 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, and valerate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0031] A "free base" refers to a neutral, non-ionized form of a compound that is not a salt or a pharmaceutically acceptable salt.

[0032] "Leaving group" is a term understood in the art to refer to a molecular fragment, whether an anion or a neutral molecule, that leaves the body along with an electron pair during unequal bond cleavage. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of leaving groups include, but are not limited to, halos (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 mammals, e.g., humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates, e.g., monkeys, chimpanzees, baboons, or rhesus monkeys. In certain embodiments, the patient or subject is human.

[0034] "Effective dose" or "therapeutic effective dose" is used interchangeably herein and refers to the amount of a compound that is sufficient to produce 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 requiring such treatment. The effective dose may include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent. The effective dose of a compound may 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 subject's age, health status, and physical condition.

[0035] The terms "disease," "disorder," "medical condition," or "state" are used interchangeably in this specification.

[0036] "To treat" or "to cure" refers to the management and care of an object in need of treatment or care aimed at combating a disease, condition, or disorder in the object, including 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 "to treat" may also include the treatment of in vitro cell or animal models. It should be understood that “treating” or any reference to “treatment” includes alleviating an existing pathological condition or symptom, and therefore includes (1) delaying the onset of clinical symptoms of a developing condition, disorder, or pathological condition in an individual who is susceptible to or prone to the condition, disorder, or pathological condition but has not yet suffered from or exhibited any clinical or subclinical symptoms of the condition, disorder, or pathological condition; (2) preventing, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance treatment), or at least one of its clinical or subclinical symptoms; or (3) mitigating or weakening the disease, that is, reversing the condition, disorder, or pathological condition, or at least one of its clinical or subclinical symptoms.

[0037] "To regulate" or "to modulate" refers to the ability of a compound to relatively alter the activity of a specific biological process in a cell (e.g., cGAS activity) relative to the vehicle.

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

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

[0040] In this disclosure, the articles “a” and “an” are used to refer to one or more (i.e., at least one) grammatical objects of the article.

[0041] In this disclosure, the term "and / or" is used to mean either "and" or "or" unless otherwise indicated. [Modes for carrying out the invention]

[0042] i.Compound In this specification, compounds of formula (I): [ka] Or a pharmaceutically acceptable salt thereof is provided, in the formula, Ring A is a 5-membered monocyclic heteroaryl; R 1 The R is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L3-(C3-C6 carbocykyl), or -L3-(4-10 member heterocyclyl), and the alkyl, alkenyl, alkynyl, carbocykyl, and heterocyclyl independently have 0, 1, 2, 3, or 4 R 1A It is replaced by; each R 1A These 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 Alkilen)-SR 1B or two R's that appeared 1A However, together they form =O; each R 1B Each of these is independently hydrogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, wherein the alkyl group and the haloalkyl group independently contain 0, 1, 2, 3, or 4 R atoms. 1D It is replaced by; each R 1C These are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR 1F and; each R 1D These are, independently, halogen, -OR 1F , or -N(R 1F )2; each R 1F These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; L3 is a bond, a C1-C3 alkylene, or -(C1-C3 alkylene)-O-, where the alkylene independently has 0, 1, 2, 3, or 4 R 1E It is replaced by; each R 1E These are independently -(C1-C3 alkylene)-OR 1B , or -OR 1B or two R's that appeared 1E However, together they form the O symbol; R 2 is hydrogen, or 0, 1, 2, 3 or 4 R 2A It is a C1-C6 alkyl substituted with, and each R 2A These are, independently, halogen, -OR 2B , or -N(R 2B )2, and each R 2B These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; Alternatively, R 1 and R 2These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 1A It forms a 6-membered or 7-membered heterocycline substituted with; R 3 C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkinyl, C3-C 10 A carbocykrill or a 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocykrill, and heterocyclyl independently have 0, 1, 2, 3, or 4 R groups. 3A It has been replaced with; Alternatively, R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4-10 member heterocycline that is substituted with; Each R 3A These 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-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3A The groups, together with the atoms to which they are bonded, form a C6 aryl, a 5-6 membered heteroaryl, a C3-C6 carbocykyl, or a 4-6 membered heterocycline, and the alkyl, alkenyl, alkynyl, carbocykyl, heterocycline, aryl, and heteroaryl independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3B Each is independently hydrogen, a C1-C3 alkyl group, a C3-C6 carbocyryl group, or a 4-6 membered heterocycline, wherein the alkyl group, the carbocyryl group, and the heterocycline group independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3C These are independently C1-C3 alkyl or C1-C3 haloalkyl; Each R 3D These are, independently, halogen, -OR 3E It is -CN, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E These are independently hydrogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; Each R 4 These 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 These are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -C(=O)R 4C And R 4C These are C1-C6 alkyl or C1-C6 haloalkyl; Each L1 and L2 is independently a bond, a C1-C3 alkylene, or a C1-C3 haloalkylene; m is 0, 1, or 2.

[0043] In some embodiments, the compound of formula (I) is provided herein: [ka] or a pharmaceutically acceptable salt thereof, in the formula, Ring A is a 5-membered monocyclic heteroaryl; R 1The alkyl, alkenyl, and alkynyl groups are C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and each alkyl, alkenyl, and alkynyl group independently has 0, 1, 2, 3, or 4 R groups. 1A It is replaced by; each R 1A These are, independently, halogen, -OR 1B , or -N(R 1B )2; each R 1B These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; R 2 is hydrogen, or 0, 1, 2, 3 or 4 R 2A It is a C1-C6 alkyl substituted with, and each R 2A These are, independently, halogen, -OR 2B , or -N(R 2B )2, and each R 2B These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; R 3 C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkinyl, C3-C 10 A carbocykrill or a 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocykrill, and heterocyclyl independently have 0, 1, 2, 3, or 4 R groups. 3A It has been replaced with; Alternatively, R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4-10 member heterocycline that is substituted with; Each R 3A These 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-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3A The groups, together with the atoms to which they are bonded, form a C6 aryl, a 5-6 membered heteroaryl, a C3-C6 carbocykyl, or a 4-6 membered heterocycline, and the alkyl, alkenyl, alkynyl, carbocykyl, heterocycline, aryl, and heteroaryl independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3B Each is independently hydrogen, a C1-C3 alkyl group, a C3-C6 carbocyryl group, or a 4-6 membered heterocycline, wherein the alkyl group, the carbocyryl group, and the heterocycline group independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3C These are independently C1-C3 alkyl or C1-C3 haloalkyl; Each R 3D These are, independently, halogen, -OR 3E , C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; Each R 4 These 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 These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; Each L1 and L2 is independently a bond, a C1-C3 alkylene, or a C1-C3 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, where, R 1 This is 0, 1, 2, 3 or 4 R 1A It is a C1-C6 alkyl substituted with, and each R 1A These are independently -OR 1B And each R 1B However, independently, they are hydrogen or C1-C3 alkyl; R 2 is hydrogen, or 0, 1, 2, 3 or 4 R 2A It is a C1-C6 alkyl substituted with, and each R 2A -OR 2B And each R 2B These are independently hydrogen or a C1-C3 alkyl group; R 3 C1-C 10 Alkyl, C3-C 10 A carbocyclyl or a 4-10 membered heterocyclyl, wherein the alkyl, the carbocyclyl, and the heterocyclyl independently have 0, 1, 2, 3, or 4 R groups. 3A It has been replaced with; Alternatively, R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4-10 member heterocycline that is substituted with; Each R 3A These 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-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3AThe groups, together with the atoms to which they are bonded, form a C6 aryl, a 5-6 membered heteroaryl, a C3-C6 carbocykryl, or a 4-6 membered heterocycline, and the alkyl, carbocykryl, heterocycline, aryl, and heteroaryl independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3C These are independently C1-C3 alkyl groups; Each R 3D These are, independently, halogen or -OR 3E and; R 3E It is a C1-C3 alkyl group; Each R 4 These 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 These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; Each L1 and L2 is independently a bonded or C1-C3 alkylene; m is either 1 or 2.

[0045] The applicant has applied to the -OR at the C3 position of the pyron ring. 1 The applicant has found that compounds of formula (I) comprising a combination of group R, the 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 unbound clearance, permeability, bioavailability, hcGAS potency and inhibitory activity, and / or solubility, compared to compounds without this combination. The applicant further found that group R 3 -L is an exemplary substituent of 1 -OR 3BWe found that incorporating the group can lead to further improvements in one or more of these desirable properties. As a non-limiting example, as shown in Table D of the Examples, adding -CH2OCH3 to compound 103 results in compound 114 with improved inhibitory activity in both the hcGAS Kinase glo assay and the hcGAS LCMS assay.

[0046] In some embodiments, the compound of formula (I) contains at least one R 3A The substituent is -L1-OR 3B The formula includes, where L1 is a bond, a C1-C3 alkylene, or a C1-C3 haloalkylene, and R 3 C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkinyl, C3-C 10 A carbocyclyl or a 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl independently comprises 0, 1, 2, or 3 further R 3A It is substituted with a substituent.

[0047] For example, in some embodiments, the amino portion at position C4 of formula (I) [ka] is the base of formula (ia), (ii-a), or (iii-a): [ka] This is possible, and in the formula, L 1 , R 3A , and R 3B This is as specified herein; L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 It is alkynylene; Ring B is C3-C 10They are carbocyclyls, or 4- to 10-membered heterocyclyls; Ring C is a 5-10 membered heterocyclyl; p is 0, 1, 2, or 3.

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

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

[0050] In some embodiments of formula (I), the compound is formula (I'''): [ka] A compound having the formula, or a pharmaceutically acceptable salt thereof, wherein the 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 is formula (I''''): [ka] A compound having the formula, or a pharmaceutically acceptable salt thereof, wherein the nitrogen atom of 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 The R is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L3-(C3-C6 carbocyrill, or -L3-(4-10 member heterocyclyl), and the alkyl, alkenyl, alkynyl, carbocyrill, and heterocyclyl independently have 0, 1, 2, 3, or 4 R 1A It has been replaced with; Each R 1A These 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 Alkilen)-SR 1B or two R's that appeared 1A Together they form the O; Each R 1B Each of these is independently hydrogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, wherein the alkyl group and the haloalkyl group independently contain 0, 1, 2, 3, or 4 R atoms. 1D It has been replaced with; Each R 1C These are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR 1Fand; Each R 1D These are, independently, halogen, -OR 1F , or -N(R 1F )2; Each R 1F These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; L3 is a bond, a C1-C3 alkylene, or -(C1-C3 alkylene)-O-, where the alkylene independently has 0, 1, 2, 3, or 4 R 1E It has been replaced with; Each R 1E These are independently -(C1-C3 alkylene)-OR 1B , or -OR 1B or two R's that appeared 1E However, together they form the O symbol.

[0054] In some embodiments, R 1 The alkyl, alkenyl, and alkynyl groups are C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and each alkyl, alkenyl, and alkynyl group independently has 0, 1, 2, 3, or 4 R groups. 1A It is replaced by; each R 1A These are, independently, halogen, -OR 1B , or -N(R 1B )2; each R 1B These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group.

[0055] In some embodiments, R 1 This is 0, 1, 2, 3 or 4 R 1A It is a C1-C6 alkyl substituted with R. In some embodiments, 1 This is 0, 1, 2, 3 or 4 R 1A It is a C1-C4 alkyl substituted with R. In some embodiments, 1 This is 0, 1, 2, 3 or 4 R 1A It is a C1-C3 alkyl substituted with R. In some embodiments, 1 This is 0, 1, 2, 3 or 4 R 1AIt is a C1-C2 alkyl group substituted with [a specific compound].

[0056] In some embodiments, R 1 This is 0, 1, 2, 3 or 4 R 1A It is a C2-C6 alkenyl substituted with R. In some embodiments, R 1 This is 0, 1, 2, 3 or 4 R 1A It is a C2-C4 alkenyl substituted with R. In some embodiments, R 1 This is 0, 1, 2, 3 or 4 R 1A It is a C2-C3 alkenyl substituted with [the specified compound].

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

[0058] In some embodiments, R 1 There are 0 R 1A It is a C1-C6 alkyl group substituted with [a specific compound].

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

[0060] In some embodiments, R 1 This is one R 1A It is a C1-C6 alkyl substituted with R 1A is -OR 1BAnd; R 1B These are hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group.

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

[0062] In some embodiments, R 1 This is one R 1A It is a C1-C6 alkyl substituted with; R 1A is -OR 1B And; R 1B It is a C1-C3 alkyl group.

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

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

[0065] In some embodiments, R 1 It is -L3-(C3-C6 carbocyclyl), and this carbocyclyl has 0, 1, 2, 3 or 4 R 1A It is replaced by R 1 It is -L3-(C3-C4 carbocyclyl), and this carbocyclyl has 0, 1, 2, 3 or 4 R 1AIt is replaced by R 1 It is -L3-(C3 carbocyclyl), and this carbocyclyl has 0, 1, 2, 3 or 4 R 1A It has been replaced with.

[0066] In some embodiments, R 1 It is -L3-(C3-C6 carbocyclyl), and this carbocyclyl has one R 1A It is replaced with;R 1A is -OR 1B In some embodiments, R 1 It is -L3-(C3-C4 carbocyclyl), and this carbocyclyl has one R 1A It is replaced with;R 1A is -OR 1B In some embodiments, R 1 It is -L3-(C3 carbocyclyl), and this carbocyclyl has one R 1A It is replaced with;R 1A is -OR 1B That is the case.

[0067] In some embodiments, R 1 It is -L3-(C3-C6 carbocyclyl), and this carbocyclyl has one R 1A It is substituted with; L3 is a C1-C3 alkylene; R 1A is -OR 1B In some embodiments, R 1 It is -L3-(C3-C4 carbocyclyl), and this carbocyclyl has one R 1A It is substituted with; L3 is a C1-C3 alkylene; R 1A is -OR 1B In some embodiments, R 1 It is -L3-(C3 carbocyclyl), and this carbocyclyl has one R 1A It is substituted with; L3 is a C1-C3 alkylene; R 1A is -OR 1B That is the case.

[0068] In some embodiments, R 1 -L3-(C 3-6 If it is a carbocyclyl, the carbocyclyl ring is [ka] That is the case.

[0069] In some embodiments, R 1 This is a -L3- (4-10 member heterocyclil), and this heterocyclil has 0, 1, 2, 3 or 4 R 1A It is replaced by R 1 This is a -L3- (5-6 member heterocycline), and this heterocycline has 0, 1, 2, 3 or 4 R 1A It is replaced by R 1 This is -L3- (a 6-membered heterocyclyl), and this heterocyclyl has 0, 1, 2, 3 or 4 R 1A It is replaced by R 1 This is a -L3- (5-membered heterocyclyl), and this heterocyclyl has 0, 1, 2, 3 or 4 R 1A It has been replaced with.

[0070] In some embodiments, R 1 This is -L3- (4-10 member heterocycline), and this heterocycline has 0 R 1A It is substituted with; L3 is a C1-C3 alkylene, and the alkylene has 0 R 1E It is replaced by R 1 This is -L3- (5-6 member heterocycline), and this heterocycline has 0 R 1A It is substituted with; L3 is a C1-C3 alkylene, and the alkylene has 0 R 1E It is replaced by R 1 This is -L3- (6-membered heterocyclyl), and this heterocyclyl has 0 R 1AIt is substituted with; L3 is a C1-C3 alkylene, and the alkylene has 0 R 1E It has been replaced with.

[0071] In some embodiments, R 1 This is -L3- (4-10 member heterocycline), and this heterocycline has 0 R 1A It is replaced by; L3 is a bond. In some embodiments, R 1 This is -L3- (5-6 member heterocycline), and this heterocycline has 0 R 1A It is replaced by; L3 is a bond. In some embodiments, R 1 This is -L3- (5-membered heterocyclyl), and this heterocyclyl has 0 R 1A It is replaced by; L3 is a join.

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

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

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

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

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

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

[0078] In some embodiments, R 1 If it is -L3- (4-10 member heterocyclyl), the heterocyclyl ring is [ka] Selected from.

[0079] As generally described herein, L3 is a bond, a C1-C3 alkylene, or -(C1-C3 alkylene)-O-, and the alkylene independently has 0, 1, 2, 3 or 4 R 1E It has been replaced with.

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

[0081] In some embodiments, L3 is independently 0, 1, 2, 3, or 4 R 1E It is a C1-C3 alkylene substituted with R. In some embodiments, L3 is independently 0, 1, 2, 3 or 4 R 1E It is a C1-C2 alkylene substituted with R. In some embodiments, L3 is independently 0, 1 or 2 R 1E It is a C1 alkylene substituted with [the specified compound].

[0082] In some embodiments, L3 is independently 0 R 1E It is a C1-C3 alkylene substituted with. In some embodiments, L3 is independently 0 R 1E It is a C1-C2 alkylene substituted with. In some embodiments, L3 is 0 R 1E It is a C1 alkylene substituted with [the specified compound].

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

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

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

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

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

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

[0089] In some embodiments, at least one R appears 1A is -C(=O)OR 1B That is the case.

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

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

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

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

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

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

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

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

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

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

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

[0101] In some embodiments, R 1 is -CH3. In some embodiments, R 1 It is -CH2-C(CH3)2-CH2OCH3. In some embodiments, R 1 is -CH2CH2OH. In some embodiments, R 1 It is -CH2CH2OCH3.

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

[0103] As generally specified herein, R 2is hydrogen, or 0, 1, 2, 3 or 4 R 2A It is a C1-C6 alkyl substituted with, and each R 2A These are, independently, halogen, -OR 2B , or -N(R 2B )2, and each R 2B R is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; 3 C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkinyl, C3-C 10 A carbocykrill or a 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocykrill, and heterocyclyl independently have 0, 1, 2, 3, or 4 R groups. 3A It is replaced with; or R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4- to 10-membered heterocycline that is substituted with [a specific compound].

[0104] In some embodiments, R 2 is hydrogen or a C1-C6 alkyl group, wherein the alkyl group independently has 0, 1, 2, 3, or 4 R atoms. 2A It is replaced by each R 2A These are, independently, halogen, -OR 2B , or -N(R 2B )2, and each R 2B These are, independently, hydrogen and C 1-3 Alkyl, or C 1-3 It is a haloalkyl group.

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

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

[0107] In some embodiments, R 2 There are 0 R 2A It is a C1-C6 alkyl group substituted with [a specific compound].

[0108] In some embodiments, R 2 This is one R 2A It is a C1-C6 alkyl group substituted with [a specific compound].

[0109] In some embodiments, R 2 This is two R 2A It is a C1-C6 alkyl substituted with R. In some embodiments, 2 This is 3 R 2A It is a C1-C6 alkyl substituted with R. In some embodiments, 2 This is 4 R 2A It is a C1-C6 alkyl group substituted with [a specific compound].

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

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

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

[0113] In some embodiments, at least one R 2A It is independently -OH.

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

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

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

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

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

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

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

[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 It is independently propyl.

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

[0123] In some embodiments, R 1 and R 2 And, along with the atom to which they are bonded, independently have 0, 1, 2, 3 or 4 R 1AIt forms a 6-membered or 7-membered heterocycline that is substituted with [a specific compound].

[0124] In some embodiments, R 1 and R 2 And, along with the atom to which they are bonded, independently have 0, 1, 2, 3 or 4 R 1A It forms a 6-membered heterocycline that is substituted with [a specific compound].

[0125] In some embodiments, R 1 and R 2 And, along with the atoms to which they are bonded, 0 R 1A It forms a 6-membered heterocycline substituted with R. In some embodiments, R 1 and R 2 And together with the atoms to which they are bonded, one R 1A It forms a 6-membered heterocycline substituted with R. In some embodiments, R 1 and R 2 And, along with the atoms to which they are bonded, two R 1A It forms a 6-membered heterocycline substituted with R. In some embodiments, R 1 and R 2 And, along with the atoms to which they are bonded, there are three R 1A It forms a 6-membered heterocycline substituted with R. In some embodiments, R 1 and R 2 And, along with the atoms to which they are bonded, there are 4 R 1A It forms a 6-membered heterocycline that is substituted with [a specific compound].

[0126] In some embodiments, R 1 and R 2 and, along with the atoms to which they are bonded, [ka] It forms a equation where x is 0, 1, 2, 3, or 4. In some embodiments, R 1 and R 2 and, along with the atoms to which they are bonded, [ka] It forms R 1 and R 2 and, along with the atoms to which they are bonded, [ka] It forms a and x is 0, 1, 2, 3 or 4. In some embodiments, R 1 and R 2 and, along with the atoms to which they are bonded, [ka] It forms a structure.

[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 C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkinyl, C3-C 10 A carbocyclyl or a 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl independently comprises 0, 1, 2, 3, or 4 R 3A It has been replaced with.

[0129] In some embodiments, R 3 C1-C 10 Alkyl, C3-C 10 A carbocyclyl or a 4-10 membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl independently has 0, 1, 2, 3, or 4 R 3AIt has been replaced with.

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

[0131] In some embodiments, R 3 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 isobutyl. In some embodiments, R 3 It is tert-butyl.

[0133] In some embodiments, R 3 This is one R 3A C1-C replaced by 10 It is alkyl.

[0134] In some embodiments, R 3 This is one R 3A It is a methyl substituted with R. In some embodiments, 3 This is one R 3A It is ethyl substituted with R. In some embodiments, 3 This is one R 3A It is a propyl substituted with R. In some embodiments, R 3 This is one R 3A It is an isopropyl substituted with R. In some embodiments, R 3 This is one R 3A It is butyl substituted with R. In some embodiments, 3 This is one R3A It is isobutyl substituted with R. In some embodiments, 3 This is one R 3A It is tert-butyl substituted with [a specific compound].

[0135] In some embodiments, R 3 This is two R 3A C1-C replaced by 10 It is alkyl.

[0136] In some embodiments, R 3 This is two R 3A It is a methyl substituted with R. In some embodiments, 3 This is two R 3A It is ethyl substituted with R. In some embodiments, 3 This is two R 3A It is a propyl substituted with R. In some embodiments, R 3 This is two R 3A It is an isopropyl substituted with R. In some embodiments, R 3 This is two R 3A It is butyl substituted with R. In some embodiments, 3 This is two R 3A It is isobutyl substituted with R. In some embodiments, 3 This is two R 3A It is tert-butyl substituted with [a specific compound].

[0137] In some embodiments, R 3 This is 3 R 3A C1-C replaced by 10 It is alkyl.

[0138] In some embodiments, R 3 This is 3 R 3A It is a methyl substituted with R. In some embodiments, 3 This is 3 R 3A It is ethyl substituted with R. In some embodiments, 3 This is 3 R 3AIt is a propyl substituted with R. In some embodiments, R 3 This is 3 R 3A It is an isopropyl substituted with R. In some embodiments, R 3 This is 3 R 3A It is butyl substituted with R. In some embodiments, 3 This is 3 R 3A It is isobutyl substituted with R. In some embodiments, 3 This is 3 R 3A It is tert-butyl substituted with [a specific compound].

[0139] In some embodiments, R 3 This is 4 R 3A C1-C replaced by 10 It is alkyl.

[0140] In some embodiments, R 3 This is 0, 1, 2, 3 or 4 R 3A C3-C replaced by 10 It is carbocyclyl.

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

[0142] In some embodiments, R 3 is condensation C3-C 10 It is carbocyclyl. In some embodiments, R 3 is Spiro C3-C 10 It is carbocyclyl. In some embodiments, R 3 This is the bridge C3-C 10 It is carbocyclyl.

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

[0144] In some embodiments, R 3 This is one R 3A C3-C replaced by 10 It is carbocyclyl.

[0145] In some embodiments, R 3 This is one R 3A It is a C3 carbocykyl substituted with R. In some embodiments, R 3 This is one R 3A It is a C4 carbocykyl substituted with R. In some embodiments, R 3 This is one R 3A It is a C5 carbocykyl substituted with R. In some embodiments, R 3 This is one R 3A It is a C6 carbocykyl substituted with R. In some embodiments, R 3 This is one R 3A It is a C7 carbocykyl substituted with R. In some embodiments, R 3 This is one R 3A It is a C8 carbocyric substituted with R. In some embodiments, 3 This is one R 3A It is a C9 carbocyryl substituted with R. In some embodiments, R 3 This is one R 3A C replaced by 10 It is carbocyclyl.

[0146] In some embodiments, R 3 This is two R 3A C3-C replaced by 10 It is carbocyclyl.

[0147] In some embodiments, R 3 This is two R 3A It is a C3 carbocykyl substituted with R. In some embodiments, R 3 This is two R 3A It is a C4 carbocykyl substituted with R. In some embodiments, R 3 This is two R 3A It is a C5 carbocykyl substituted with R. In some embodiments, R 3 This is two R 3A It is a C6 carbocykyl substituted with R. In some embodiments, R 3 This is two R 3A It is a C7 carbocykyl substituted with R. In some embodiments, R 3 This is two R 3A It is a C8 carbocyric substituted with R. In some embodiments, 3 This is two R 3A It is a C9 carbocyryl substituted with R. In some embodiments, R 3 This is two R 3A C replaced by 10 It is carbocyclyl.

[0148] In some embodiments, R 3 This is 3 R 3A C3-C replaced by 10 It is carbocyclyl.

[0149] In some embodiments, R 3 This is 3 R 3A It is a C3 carbocykyl substituted with R. In some embodiments, R 3 This is 3 R 3A It is a C4 carbocykyl substituted with R. In some embodiments, R 3 This is 3 R 3A It is a C5 carbocykyl substituted with R. In some embodiments, R 3 This is 3 R 3A It is a C6 carbocykyl substituted with R. In some embodiments, R 3 This is 3 R3A It is a C7 carbocykyl substituted with R. In some embodiments, R 3 This is 3 R 3A It is a C8 carbocyric substituted with R. In some embodiments, 3 This is 3 R 3A It is a C9 carbocyryl substituted with R. In some embodiments, R 3 This is 3 R 3A C replaced by 10 It is carbocyclyl.

[0150] In some embodiments, R 3 This is 4 R 3A C3-C replaced by 10 It is carbocyclyl.

[0151] In some embodiments, R 3 This is 0, 1, 2, 3 or 4 R 3A These are 4- to 10-membered heterocyclines that have been substituted.

[0152] In some embodiments, R 3 These are 4-10 membered heterocyclines.

[0153] In some embodiments, R 3 R is a condensed 6-10 member heterocycline. In some embodiments, R 3 R is a 6-10 membered heterocycline spiro. In some embodiments, R 3 These are cross-linked 4-10 membered heterocyclines.

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

[0155] In some embodiments, R 3 This is one R 3A These are 4- to 10-membered heterocyclines that have been substituted.

[0156] In some embodiments, R 3 This is one R 3A It is a four-membered heterocycline substituted with R. In some embodiments, R 3 This is one R 3A It is a 5-membered heterocycline substituted with R. In some embodiments, R 3 This is one R 3A It is a 6-membered heterocycline substituted with R. In some embodiments, 3 This is one R 3A It is a 7-membered heterocycline substituted with R. In some embodiments, 3 This is one R 3A It is an 8-membered heterocycline substituted with R. In some embodiments, R 3 This is one R 3A It is a 9-membered heterocycline substituted with R. In some embodiments, 3 This is one R 3A It is a 10-membered heterocycline that has been substituted with [the specified compound].

[0157] In some embodiments, R 3 This is two R 3A These are 4- to 10-membered heterocyclines that have been substituted.

[0158] In some embodiments, R 3 This is two R 3A It is a four-membered heterocycline substituted with R. In some embodiments, R 3 This is two R 3A It is a 5-membered heterocycline substituted with R. In some embodiments, R 3 This is two R 3A It is a 6-membered heterocycline substituted with R. In some embodiments,3 This is two R 3A A 7-membered heterocycline substituted with R. In some embodiments, R 3 This is two R 3A It is an 8-membered heterocycline substituted with R. In some embodiments, R 3 This is two R 3A It is a 9-membered heterocycline substituted with R. In some embodiments, 3 This is two R 3A It is a 10-membered heterocycline that has been substituted with [the specified compound].

[0159] In some embodiments, R 3 This is 3 R 3A These are 4- to 10-membered heterocyclines that have been substituted.

[0160] In some embodiments, R 3 This is 3 R 3A It is a four-membered heterocycline substituted with R. In some embodiments, R 3 This is 3 R 3A It is a 5-membered heterocycline substituted with R. In some embodiments, R 3 This is 3 R 3A It is a 6-membered heterocycline substituted with R. In some embodiments, 3 This is 3 R 3A It is a 7-membered heterocycline substituted with R. In some embodiments, 3 This is 3 R 3A It is an 8-membered heterocycline substituted with R. In some embodiments, R 3 This is 3 R 3A It is a 9-membered heterocycline substituted with R. In some embodiments, 3 This is 3 R 3A It is a 10-membered heterocycline that has been substituted with [the specified compound].

[0161] In some embodiments, R 3 This is 4 R 3A These are 4- to 10-membered heterocyclines that have been substituted.

[0162] In a particular embodiment, R 3teeth, [ka] In the formula, L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 It is an alkynylene, and p is 0, 1, 2, or 3.

[0163] In a particular embodiment, R 3 teeth, [ka] In the formula, ring B is C3-C 10 It is a carbocyclyl, or a 4- to 10-membered heterocyclyl, where p is 0, 1, 2, or 3.

[0164] In a particular embodiment, R 3 -CH3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH(CH3)2, [ka] [ka] That is the case.

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

[0166] In some embodiments, the amino portion [ka] teeth, [ka] [ka] It is selected from the group consisting of the following.

[0167] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

[0168] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

[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] That is the case.

[0170] In some embodiments, base R 3 is, formula [ka] It has the following characteristics, where L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 It is an alkynylene, and p is 0, 1, 2, or 3.

[0171] In some embodiments, R 2Let R be hydrogen or a C1-C6 alkyl group. 3 of [ka] The amino portion having formula (ia): [ka] A is formed, and in the formula, L3 is C1-C 10 Alkylene, C2-C 10 Alkenylene, or C2-C 10 It is an 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 It is an alkylene. In some embodiments, L3 is a C1-C6 alkylene. In some embodiments, L3 is a C1-C4 alkylene. In some embodiments, L3 is a C1-C3 alkylene.

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

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

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

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

[0178] In some embodiments, the amino portion [ka] teeth, [ka] [ka] It is selected from the group consisting of the following.

[0179] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

[0180] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

[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] That is the case.

[0182] In some embodiments, R 2 is hydrogen, or a C1-C6 alkyl group, and R 3These are 4-10 membered heterocyclines.

[0183] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

[0184] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

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

[0186] In some embodiments, R 2 Let R be hydrogen or a C1-C6 alkyl group. 3 of [ka] Let equation (ii-a) be: [ka] amino portion having [ka] A ring is formed, and in the formula, ring B is C3-C 10It is a carbocyclyl, or a 4- to 10-membered heterocyclyl, where p is 0, 1, 2, or 3.

[0187] In some embodiments, ring B is C3-C 10 They are carbocyclyls or 4-10 membered heterocyclyls.

[0188] In some embodiments, ring B is C3-C 10 It is a carbocyclyl. 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 It 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, the amino portion within the range of formula (ii-a) [ka] As for, [ka] [ka] These include, but are not limited to, the following:

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

[0191] In some embodiments, R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4- to 10-membered heterocycline that is substituted with [a specific compound].

[0192] In some embodiments, R 2 and R 3 These atoms bond together with the atoms they are bonded to, resulting in 0, 1, 2, 3, or 4 R atoms. 3A It forms a four-membered heterocycline that is substituted with [a specific compound].

[0193] In some embodiments, R 2 and R 3 These atoms, along with the atoms to which they are bonded, form a four-membered heterocycline.

[0194] In some embodiments, R 2 and R 3 And, together with the atom to which they are bonded, form one R 3A It forms a four-membered heterocycline that is substituted with [a specific compound].

[0195] In some embodiments, R 2 and R 3 And, along with the atoms to which they are bonded, two R 3A It forms a four-membered heterocycline that is substituted with [a specific compound].

[0196] In some embodiments, R 2 and R 3 And, along with the atoms to which they are bonded, three R 3A It forms a four-membered heterocycline that is substituted with [a specific compound].

[0197] In some embodiments, R 2 and R 3These atoms, along with the atoms to which they are bonded, form a five-membered heterocycline.

[0198] In some embodiments, R 2 and R 3 And, together with the atom to which they are bonded, form one R 3A It forms a 5-membered heterocycline that is substituted with [a specific compound].

[0199] In some embodiments, R 2 and R 3 And, along with the atoms to which they are bonded, two R 3A It forms a 5-membered heterocycline that is substituted with [a specific compound].

[0200] In some embodiments, R 2 and R 3 And, along with the atoms to which they are bonded, three R 3A It forms a 5-membered heterocycline that is substituted with [a specific compound].

[0201] In some embodiments, R 2 and R 3 These atoms, along with the atoms to which they are bonded, form a six-membered heterocycline.

[0202] In some embodiments, R 2 and R 3 And, together with the atom to which they are bonded, form one R 3A It forms a 6-membered heterocycline that is substituted with [a specific compound].

[0203] In some embodiments, R 2 and R 3 And, along with the atoms to which they are bonded, two R 3A It forms a 6-membered heterocycline that is substituted with [a specific compound].

[0204] In some embodiments, R 2 and R 3 And, along with the atoms to which they are bonded, three R 3AIt forms a 6-membered heterocycline that is substituted with [a specific compound].

[0205] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

[0206] In some embodiments, the amino portion [ka] teeth, [ka] It is selected from the group consisting of the following.

[0207] In some embodiments, the formula [ka] The R in the amino portion 2 and R 3 The two are connected, and the formula [ka] The amino portion is formed by L1 being a bond, C1-C3 alkylene, or C1-C3 haloalkylene, the ring C being a 5-10 membered heterocyclyl, and p being 0, 1, 2, or 3.

[0208] In some embodiments, the amino portion within the range of formula (iii-a) [ka] As for, [ka] These include, but are not limited to, the following:

[0209] As generally specified herein, each R 3A These 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-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3A The groups, together with the atoms to which they are bonded, form a C6 aryl, a 5-6 membered heteroaryl, a C3-C6 carbocykyl, or a 4-6 membered heterocycline, and the alkyl, alkenyl, alkynyl, carbocykyl, heterocycline, aryl, and heteroaryl independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with.

[0210] Several embodiments, each R 3A These 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-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3AThe base, together with the atoms to which they are attached, forms a C6 aryl, 5- to 6-member heteroaryl, C3-C6 carbocyclic, or 4- to 6-member heterocyclic, and the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 R 3D groups.

[0211] In some embodiments, each R 3A is 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 carbocyclic), -L1-(4- to 6-member heterocyclic), -L1-(C 6-10 aryl), or -L1-(5- to 10-member heteroaryl), and the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 R 3D groups.

[0212] In some embodiments, each R 3A is independently C1-C3 alkyl, halogen, =O, -L1-CN, -L1-SO2R 3C , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclic), -L1-(4- to 6-member heterocyclic), -L1-(C 6-10 aryl), or -L1-(5- to 10-member heteroaryl), and the alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 R 3D groups.

[0213] In some embodiments, at least one R 3AThese are independently 0, 1, 2, 3, or 4 R 3D It is a C1-C3 alkyl group substituted with [a specific compound].

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

[0215] In some embodiments, at least one R 3A Independently, one R 3D It is a C1-C3 alkyl group substituted with [a specific compound].

[0216] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a C1-C3 alkyl substituted with R. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a C1-C3 alkyl substituted with R. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a C1-C3 alkyl group substituted with [a specific compound].

[0217] In some embodiments, at least one R 3A These are, independently, halogens, or =O.

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

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

[0220] In some embodiments, at least one R 3A F is independent of the other. In some embodiments, at least one R 3A These are independently Cl.

[0221] In some embodiments, at least one R3A These two conditions are independently equal to O.

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

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

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

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

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

[0227] In some embodiments, at least one R 3A It is independently, -SO2R 3C That is the case.

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

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

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

[0231] In some embodiments, at least one R 3A Independently, -L1-OR 3B That is the case.

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

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

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

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

[0236] In some embodiments, at least one R 3A These are independently -L1-(C3-C6 carbocyclyl), -L1-(4-6 member heterocyclyl), and -L1-(C 6-10 The aryl, the heterocyclyl, the aryl, and the heteroaryl are independently 0, 1, 2, 3, or 4 R 3D It has been replaced with.

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

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

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

[0240] In some embodiments, at least one R 3A is independently -L1-(C3-C6 carbocyclic) substituted with two R 3D s. In some embodiments, at least one R 3A is independently -L1-(C3-C6 carbocyclic) substituted with three R 3D s. In some embodiments, at least one R 3A is independently -L1-(C3-C6 carbocyclic) substituted with four R 3D s.

[0241] In some embodiments, at least one R 3A is independently -(C3-C6 carbocyclic) substituted with zero, one, two, three or four R 3D s.

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

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

[0244] In some embodiments, at least one R 3A is independently -(C3-C6 carbocyclic) substituted with two R 3D s. In some embodiments, at least one R3A These are independently, 3 R 3D It is a (C3-C6 carbocyclyl) substituted with. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a (C3-C6 carbocyclyl) substituted with -.

[0245] In some embodiments, at least one R 3A These are independently 0, 1, 2, 3, or 4 R 3D It is a -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with [the specified compound].

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

[0247] In some embodiments, at least one R 3A Independently, one R 3D It is a -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with [the specified compound].

[0248] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with R. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with R. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a -(C1-C3 alkylene)-(C3-C6 carbocyclyl) substituted with [the specified compound].

[0249] In some embodiments, at least one R 3A These are independently 0, 1, 2, 3, or 4 R 3D It is a -L1- (4-6 member heterocycline) that has been substituted with [the specified character].

[0250] In some embodiments, at least one R 3A It is independently -L1- (a 4-6 member heterocycline).

[0251] In some embodiments, at least one R 3A Independently, one R 3D It is a -L1- (4-6 member heterocycline) that has been substituted with [the specified character].

[0252] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a -L1- (4-6 member heterocycline) substituted with R. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -L1- (4-6 member heterocycline) substituted with R. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a -L1- (4-6 member heterocycline) that has been substituted with [the specified character].

[0253] In some embodiments, at least one R 3A These are independently 0, 1, 2, 3, or 4 R 3D It is a substituted (4-6 member heterocyclyl)

[0254] In some embodiments, at least one R 3A These are independently (4-6 member heterocyclines).

[0255] In some embodiments, at least one R 3A Independently, one R 3D It is a substituted (4-6 member heterocyclyl)

[0256] In some embodiments, at least one R 3A These are two R's, independently. 3DIt is a substituted (4-6 member heterocycline). In some embodiments, at least one R 3A These are independently, 3 R 3D It is a substituted (4-6 member heterocycline). In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a substituted (4-6 member heterocyclyl)

[0257] In some embodiments, at least one h R 3A These are independently 0, 1, 2, 3, or 4 R 3D It is a -(C1-C3 alkylene)-(4-6 member heterocyclyl) substituted with -(C1-C3 alkylene)-.

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

[0259] In some embodiments, at least one R 3A Independently, one R 3D It is a -(C1-C3 alkylene)-(4-6 member heterocyclyl) substituted with -(C1-C3 alkylene)-.

[0260] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a -(C1-C3 alkylene)-(4-6 member heterocycline) substituted with R. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -(C1-C3 alkylene)-(4-6 member heterocycline) substituted with R. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a -(C1-C3 alkylene)-(4-6 member heterocyclyl) substituted with -(C1-C3 alkylene)-.

[0261] In some embodiments, at least one R 3A These are independently 0, 1, 2, 3, or 4 R3D -L1-(C 6-10 It is Ariel.

[0262] In some embodiments, at least one R 3A These are independently 0, 1, 2, 3, or 4 R 3D This is the -L1-(C6 aryl) substituted with [the specified character].

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

[0264] In some embodiments, at least one R 3A Independently, one R 3D This is the -L1-(C6 aryl) substituted with [the specified character].

[0265] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a -L1-(C6 aryl) substituted with. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -L1-(C6 aryl) substituted with. In some embodiments, at least one R 3A These are, independently, 4 R 3D This is the -L1-(C6 aryl) substituted with [the specified character].

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

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

[0268] In some embodiments, at least one R 3A Independently, one R 3DIt is a -(C6 aryl) substituted with.

[0269] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a -(C6 aryl) substituted with. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -(C6 aryl) substituted with. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a -(C6 aryl) substituted with.

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

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

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

[0273] In some embodiments, at least one R 3A These are two R's, independently. 3D Substituted with -(C1-C3 alkylene)-(C6 aryl). In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -(C1-C3 alkylene)-(C6 aryl) substituted with. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a -(C1-C3 alkylene)-(C6 aryl) substituted with

[0274] In some embodiments, at least one R 3A These are independently 0, 1, 2, 3, or 4 R 3D It is a -L1- (5-10 member heteroaryl) substituted with .

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

[0276] In some embodiments, at least one R 3A Independently, one R 3D It is a -L1- (5-10 member heteroaryl) substituted with .

[0277] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a -L1- (5-10 member heteroaryl) substituted with R. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -L1- (5-10 member heteroaryl) substituted with R. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a -L1- (5-10 member heteroaryl) substituted with .

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

[0279] In some embodiments, at least one R 3A These are independently -(5-10 member heteroaryl).

[0280] In some embodiments, at least one R 3A Independently, one R 3D It is a substituted (5-10 member heteroaryl)

[0281] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a substituted (5-10 member heteroaryl) with R. In some embodiments, each R 3A These are independently, 3 R 3D It is a (5-10 member heteroaryl) substituted with R. In some embodiments, at least one R 3A These are, independently, 4 R 3D Substituted with -(5-10 member heteroaryl).

[0282] In some embodiments, at least one R 3A These are independently 0, 1, 2, 3, or 4 R 3D It is a -(C1-C3 alkylene)-(5-10 member heteroaryl) substituted with [the specified compound].

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

[0284] In some embodiments, at least one R 3A Independently, one R 3D It is a -(C1-C3 alkylene)-(5-10 member heteroaryl) substituted with [the specified compound].

[0285] In some embodiments, at least one R 3A These are two R's, independently. 3D It is a -(C1-C3 alkylene)-(5-10 member heteroaryl) substituted with R. In some embodiments, at least one R 3A These are independently, 3 R 3D It is a -(C1-C3 alkylene)-(5-10 member heteroaryl) substituted with R. In some embodiments, at least one R 3A These are, independently, 4 R 3D It is a -(C1-C3 alkylene)-(5-10 member heteroaryl) substituted with [the specified compound].

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

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

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

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

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

[0291] As generally specified herein, each R 3B These are independently hydrogen, a C1-C3 alkyl group, a C3-C6 carbocyryl group, or a 4-6 membered heterocycline, and the alkyl group, the carbocyryl group, and the heterocycline group independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with.

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

[0293] Several embodiments, each R 3B These are independently a C1-C3 alkyl, a C3-C6 carbocyryl, or a 4-6 membered heterocycline, and the alkyl, carbocyryl, and heterocycline independently have 0, 1, 2, 3, or 4 R 3DIt has been replaced with.

[0294] Several embodiments, each R 3B These are independently C1-C3 alkyl, C3-C6 carbocyrill, or 4-6 membered heterocycline.

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

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

[0297] In some embodiments, at least one R 3B Independently, one R 3D It is a C1-C3 alkyl group substituted with [a specific compound].

[0298] In some embodiments, at least one R 3B These are two R's, independently. 3D It is a C1-C3 alkyl group substituted with [a specific compound].

[0299] In some embodiments, at least one R 3B These are independently, 3 R 3D It is a C1-C3 alkyl group substituted with [a specific compound].

[0300] In some embodiments, at least one R 3B These are, independently, 4 R 3D It is a C1-C3 alkyl group substituted with [a specific compound].

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

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

[0303] In some embodiments, at least one R 3B Independently, one R 3D It is a C3-C6 carbocyclyl substituted with [the specified compound].

[0304] In some embodiments, at least one R 3B These are two R's, independently. 3D It is a C3-C6 carbocyclyl substituted with [the specified compound].

[0305] In some embodiments, at least one R 3B These are independently, 3 R 3D It is a C3-C6 carbocyclyl substituted with [the specified compound].

[0306] In some embodiments, at least one R 3B These are, independently, 4 R 3D It is a C3-C6 carbocyclyl substituted with [the specified compound].

[0307] In some embodiments, at least one R 3B These are independently 0, 1, 2, 3, or 4 R 3D It is a 4-6 member heterocycline that has been substituted with [a specific compound].

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

[0309] In some embodiments, at least one R 3B Independently, one R 3D It is a 4-6 member heterocycline that has been substituted with [a specific compound].

[0310] In some embodiments, at least one R 3B These are two R's, independently. 3D It is a 4-6 member heterocycline that has been substituted with [a specific compound].

[0311] In some embodiments, at least one R 3B These are independently, 3 R 3D It is a 4-6 member heterocycline that has been substituted with [a specific compound].

[0312] In some embodiments, at least one R 3B These are, independently, 4 R 3D A 4-6 member heterocycline substituted with [a specific compound].

[0313] As generally specified herein, each R 3C These are independently C1-C3 alkyl or C1-C3 haloalkyl.

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

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

[0316] As generally specified herein, each R 3D These are, independently, halogen, -OR 3E It is a C1-C3 alkyl or C1-C3 haloalkyl group.

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

[0318] Several embodiments, each R 3D These are independently halogens or -OC1-C3 alkyl groups.

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

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

[0321] In some embodiments, at least one R 3D F is independent of the other. In some embodiments, at least one R 3D These are independently Cl.

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

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

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

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

[0326] Several embodiments, each R 3E These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group.

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

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

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

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

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

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

[0333] In some embodiments, at least one L1 is independently a 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 L1 is independently a C1 alkylene. In some embodiments, at least one L1 is independently a C2 alkylene. In some embodiments, at least one L1 is independently a C3 alkylene.

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

[0337] In some embodiments, ring A is a five-membered monocyclic heteroaryl comprising one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

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

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

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

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

[0343] In some embodiments, ring A is a five-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] That is the case.

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

[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] That is the case.

[0348] In some embodiments, ring A is given by formula (xvii-b): [ka] It is a five-membered monocyclic heteroaryl directly linked to thiadiazole via an N atom, as given by [equation].

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

[0350] As generally specified herein, each R 4 These are, independently, halogen, -CN, -L2-OR 4A -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl, R 4A and R 4B These are, independently, hydrogen and C 1-3 Alkyl, C 1-3 Haloalkyl, -C(=O)R 4C And R 4CL2 is a C1-C6 alkyl or C1-C6 haloalkyl; each L2 is a bond, a C1-C3 alkylene or C1-C3 haloalkylene; m is 0, 1 or 2.

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

[0352] Several embodiments, each R 4 These 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 These are halogens, independently.

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

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

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

[0357] In some embodiments, at least one R4 Independently, -L2-OR 4A That is the case.

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

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

[0360] In some embodiments, at least one R 4 These are independently -(C1 alkylene)-OR 4A That is the case.

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

[0362] In some embodiments, at least one R 4 This is independently -(C3 alkylene)- OR 4A That is the case.

[0363] In some embodiments, at least one R 4 It is independently -OH.

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

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

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

[0367] In some embodiments, at least one R 4 It is independently -(C3 alkylene)-OH.

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

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

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

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

[0372] In some embodiments, at least one R 4 These are independently -(C3 alkylene)-O(C1-C3 alkyl).

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

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

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

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

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

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

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

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

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

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

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

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

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

[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 It is independently tert-butyl.

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

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

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

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

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

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

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

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

[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 bonded or C1-C3 alkylene.

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

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

[0399] In some embodiments, at least one L2 is independently a C1 alkylene. In some embodiments, at least one L2 is independently a C2 alkylene. In some embodiments, at least one L2 is independently a C3 alkylene.

[0400] As generally specified 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 The compounds disclosed herein have variable rings A and 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 can each be selected from the groups described herein where applicable, as well as the variable elements rings 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 L1, L2, L3, and m, where applicable, is a variable element of 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 It is understood that these can be combined with any of the remaining groups described herein as L1, L2, L3, and m. Further exemplary combinations of the embodiments described herein are also contemplated.

[0405] For example, in some embodiments where ring A is a group of formula (ii-b), the compound of formula (I) is formula (Ia): [ka] A compound having, or a pharmaceutically acceptable salt thereof. In certain embodiments, the C4 amino moiety is the group of formula (ia). In certain embodiments, the C4 amino moiety is the group of formula (ib). In certain embodiments, the C4 amino moiety is the group of formula (ic). In certain embodiments, R 1 is methyl (-CH3). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ia), where R1 is methyl, and R 2 m is hydrogen, and m is either 1 or 2.

[0406] In some embodiments where ring A is a group of formula (iv-b), the compound of formula (I) is: [ka] A compound having, or a pharmaceutically acceptable salt thereof. In certain embodiments, the C4 amino moiety is the group of formula (ia). In certain embodiments, the C4 amino moiety is the group of formula (ib). In certain embodiments, the C4 amino moiety is the group of formula (ic). In certain embodiments, R 1 is methyl (-CH3). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ib), where R 1 is methyl, and R 2 m is hydrogen, and m is either 1 or 2.

[0407] In some embodiments where ring A is the base of formula (vb), the compound of formula (I) is formula (Ic): [ka] A compound having, or a pharmaceutically acceptable salt thereof. In certain embodiments, the C4 amino moiety is the group of formula (ia). In certain embodiments, the C4 amino moiety is the group of formula (ib). In certain embodiments, the C4 amino moiety is the group of formula (ic). In certain embodiments, R 1 is methyl (-CH3). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ic), where R 1 is methyl, and R 2 m is hydrogen, and m is either 1 or 2.

[0408] In some embodiments where ring A is the group of formula (vi-b), the compound of formula (I) is: [ka] A compound having, or a pharmaceutically acceptable salt thereof. In certain embodiments, the C4 amino moiety is the group of formula (ia). In certain embodiments, the C4 amino moiety is the group of formula (ib). In certain embodiments, the C4 amino moiety is the group of formula (ic). In certain embodiments, R 1 is methyl (-CH3). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Id), where R 1 is methyl, and R 2 m is hydrogen, and m is either 1 or 2.

[0409] In some embodiments where ring A is the group of formula (vii-b), the compound of formula (I) is: [ka] A compound having, or a pharmaceutically acceptable salt thereof. In certain embodiments, the C4 amino moiety is the group of formula (ia). In certain embodiments, the C4 amino moiety is the group of formula (ib). In certain embodiments, the C4 amino moiety is the group of formula (ic). In certain embodiments, R 1 is methyl (-CH3). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has formula (Ie), where R 1 is methyl, and R 2 m is hydrogen, and m is either 1 or 2.

[0410] In some embodiments where ring A is the group of formula (xiii-b), the compound of formula (I) is: [ka] A compound having, or a pharmaceutically acceptable salt thereof. In certain embodiments, the C4 amino moiety is the group of formula (ia). In certain embodiments, the C4 amino moiety is the group of formula (ib). In certain embodiments, the C4 amino moiety is the group of formula (ic). In certain embodiments, R 1 is methyl (-CH3). 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 m is hydrogen, and m is either 1 or 2.

[0411] In some embodiments where ring A is the group of formula (xiv-b), the compound of formula (I) is formula (Ig): [ka] A compound having, or a pharmaceutically acceptable salt thereof. In certain embodiments, the C4 amino moiety is the group of formula (ia). In certain embodiments, the C4 amino moiety is the group of formula (ib). In certain embodiments, the C4 amino moiety is the group of formula (ic). In certain embodiments, R 1 is methyl (-CH3). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound has the formula (Ig), where R 1 is methyl, and R 2 m is hydrogen, and m is either 1 or 2.

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

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

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

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

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

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

[0418] R 1 and R 2In some embodiments where the compounds are cyclized to form a six-membered heterocyclic ring, the compound of formula (I-BC-a) or (I-BC-b) is: [ka] A pharmaceutically acceptable salt thereof is provided, where 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 one pharmaceutically acceptable salt of any of the compounds in Table 1 or Table 2.

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

[0423] Tables 1 and 2 below also provide the location of the compounds in Example (Ex), either by Example Number (Ex) or as provided in Table A(TA) of the Examples. The asterisk (#) next to the compound number (#) indicates the location of the compounds in Example (Ex). * ) 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 any pharmaceutically acceptable salt of any of the above.

[0425] ii. Pharmaceutical compositions In some embodiments, the disclosure provides pharmaceutical compositions 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 containing them, may be administered in amounts effective for treating a disorder in a subject.

[0427] Administration can be carried out by any mode of administration. Exemplary modes include systemic or topical administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration.

[0428] Depending on the intended mode of administration, the compounds and compositions of this disclosure may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, or similar, and may sometimes be in a unit dose that conforms to conventional pharmaceutical practices.

[0429] Similarly, the compounds and compositions of this disclosure may also be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, in forms suitable for these types of administration. For example, parenteral administration of injectable preparations is generally used for injection and infusion subcutaneously, intramuscularly, or intravenously. Injectable preparations may be prepared in conventional forms, either as a liquid solution or a suspension, or in a solid form suitable for dissolution in a liquid before injection.

[0430] Illustrated pharmaceutical compositions include compounds of the Disclosure or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, for example, a) diluents, for example, purified water, triglyceride oils, for example hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate Thorium, sodium acetate, sodium chloride, and / or polyethylene glycol; in the case of tablets, further c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g., glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g., acacia, tragacanth or sodium alginate, wax, and / or polyvinylpyrrolidone; d) disintegrants, e.g., starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings, and sweeteners; f) emulsifiers or dispersants, e.g., 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 emulsifiers; and / or g) a tablet or gelatin capsule containing an agent that enhances the absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400 or PEG200.

[0431] iii.Treatment method In some embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a certain amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure.

[0432] In some embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering an effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0433] In some embodiments, the Disclosure provides a method for modulating cGAS activity (for example, in vitro or in vivo), comprising contacting cells with an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments, the disease or disorder is associated with the cGAS activity that is believed to be involved. In some embodiments, the disease or disorder is a disease or disorder that is believed to be related to cGAS activity.

[0435] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in modulating cGAS activity (e.g., in vitro or in vivo).

[0436] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating diseases or disorders disclosed herein.

[0437] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for modulating cGAS activity (e.g., in vitro or in vivo).

[0438] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease or disorder disclosed herein.

[0439] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease or disorder disclosed herein.

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

[0441] In one embodiment, regulation is inhibition.

[0442] In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disorder, graft-versus-host disease, allodynia, or cGAS-related disease in subjects determined to carry germline or somatic nonsilent mutations in cGAS.

[0443] In some embodiments, the disease or disorder is cancer. In some embodiments, cancer is bladder cancer, bone cancer, brain tumor, breast cancer, cardiac tumor, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, cancer of the head, spine and neck, Kaposi's sarcoma, kidney cancer, pancreatic cancer, penile cancer, testicular germ cell carcinoma, 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, vasodilatory ataxia, 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 a rare kidney disease. In certain embodiments, the chronic kidney disease is diabetic nephropathy.

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

[0447] In some embodiments, the disease or disorder is a 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 a 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 artery disease (PAD).

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

[0450] In some embodiments, the disease or disorder is a cGAS-related disorder in a subject determined to harbor germline or somatic non-silent mutations 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), frostbite-like lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), scleroderma, Ecardi-Goutier syndrome, dermatomyositis, systemic sclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, or sjögren's disease. Ren It is syndrome (SS).

[0452] In some embodiments, the disease or disorder is inflammation of any tissue or organ of the body, which includes inflammation of the musculoskeletal system, inflammation of the blood vessels, inflammation of the nerves, inflammation of the digestive system, inflammation of the eyes, inflammation of the reproductive system, and other inflammations.

[0453] In some embodiments, musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly those affecting the skeletal joints, including the joints of the hands, wrists, elbows, shoulders, jaw, spine, neck, buttocks, knees (knews), ankles, and feet, as well as those affecting the tissues that connect muscles to bone, 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), tendinitis, synovitis, tenosynovitis, bursitis, fibroitis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, pubic osteitis, and cystic fibrous osteitis). Ocular inflammation refers to inflammation of any structure of the eye, including the eyelids. Examples of inflammation of the eye include blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, entropion, and uveitis. Examples of inflammation of the nervous system include encephalitis, Guillain-Barré syndrome, meningitis, neuromuscular totonia, 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, panentotitis, 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, fallopian tube-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[0457] In some embodiments, the disease or disorder is an autoimmune condition having an inflammatory component. Such conditions include systemic lupus erythematosus, cutaneous lupus erythematosus, acute generalized alopecia, Behçet'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, Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Henoch-Schönlein purpura, Kawasaki disease, and microscopic colon These include inflammation, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus syndrome, optic neuritis, Audrey thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, Ecardi-Goutier 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 disorder with an inflammatory component. Such conditions include 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, fibrosis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleurisy, pneumonitis, prostatitis, pyelonephritis, and stomatitis, graft rejection (involving kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small intestine, allogeneic cutaneous grafts, serum sickness, and graft-versus-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sézary syndrome, congenital adrenal hyperplasia, non-suppurative thyroiditis, and cancer-related hypercalcemia. These include 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 of the eye, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, chemotherapy for fulminant or disseminated pulmonary tuberculosis, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute leukemia in children, focal enteritis, 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 to 10, as provided below. Examples further illustrate non-limiting examples of this general synthesis.

[0461] For example, as shown in general scheme 1, 3-hydroxy-2-oxo-2H-pyran-6-carboxylic acid or a salt of formula (A) is R in the formula a to C 1-6 Alkyl or C 1-6 The alkyl ester of formula (B) or a salt thereof may be protected as a haloalkyl, and then the C4 position may be halogenated to obtain the compound of formula (C) or a salt thereof, where X in the formula is Cl, Br, or I. The group R as defined herein 1Hydroxyl protection by can yield the compound of formula (D) or a salt thereof. Deprotection of the alkyl ester of formula (D) or a salt thereof yields R in the formula a A carboxylic acid compound of formula (D) or a salt thereof, in which the θ is hydrogen, can be obtained. [ka]

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

[0463] As shown in General Scheme 4, the amine of formula (K) or a salt thereof, R in the formula a to C 1-6 Alkyl or C 1-6 By cross-coupling with an alkyl ester of formula (D) or a salt thereof, which is a haloalkyl compound, an amine compound of formula (N) or a salt thereof may be obtained. Then, the amine compound of formula (N) or a salt thereof is deprotected, and R in the formula is obtained. a A amine compound of formula (N) or a salt thereof, with hydrogen as the base, can be obtained. [ka]

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

[0465] For example, as shown in general scheme 5, the amine of formula (H-1) or a salt thereof is R in the formula a hydrogen, C 1-6 Alkyl or C 1-6 By peptide coupling a compound of formula (D) or a salt thereof, which is designated as a haloalkyl compound, an amide compound of formula (J-1) or a salt thereof may be obtained. Subsequently, by cross-coupling the amide compound of formula (J-1) or a salt thereof with an amine of formula (K) or a salt thereof, a compound of formula (I) or a salt thereof may be obtained. [ka]

[0466] Alternatively, as shown in general scheme 6, the amine of formula (H-2) or a salt thereof, in the formula R a hydrogen, C 1-6 Alkyl or C 1-6 By peptide coupling a compound of formula (D) or a salt thereof, which is a haloalkyl compound, an amide compound of formula (J-2) or a salt thereof may be obtained. Subsequently, by cross-coupling the amide compound of formula (J-2) or a salt thereof with an amine of formula (K) or a salt thereof, a compound of formula (I'''') or a salt thereof may be obtained, where the nitrogen atom of heteroaryl ring A in the formula is directly linked to the thiadiazole moiety. [ka]

[0467] The compounds of formulas (J-1) and (J-2), as well as their salts, are also referred to herein as "halopyrone reagents," and the compound of formula (K) and its salts are also referred to herein as "amine reagents."

[0468] In other embodiments, such as those shown in General Scheme 7, the amine of formula (H-1) or a salt thereof is used as R in the formula. a hydrogen, C 1-6 Alkyl or C 1-6 Compound (I) or a salt thereof can be obtained by peptide coupling with a compound of formula (N) or a salt thereof that is designated as a haloalkyl compound. [ka]

[0469] In further embodiments, such as those shown in General Scheme 8, the amine of formula (H-2) or a salt thereof is used, where R in the formula a hydrogen, C 1-6 Alkyl or C 1-6 By peptide coupling a compound of formula (N) or a salt thereof, which is a haloalkyl compound, a compound of formula (I'''') or a salt thereof may be obtained, where the nitrogen atom of the heteroaryl ring A in the formula is directly linked to the thiadiazole moiety. [ka]

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

[0471] R in the formula 1 Let R be the base -CH2CH2-OH. 2 In further other embodiments, such as those shown in general schemes 9 and 10 where is hydrogen, the bicyclic compounds of formulas (I-BC-a) and (I-BC-b) are R1 It can be formed by converting the terminal -OH to a leaving group (LG) as defined herein, and then cyclization. In certain embodiments, the leaving group is a sulfonyl-substituted hydroxyl group, for example, -O-tosyl, -O-mesyl, or O-besyl. [ka] [ka]

[0472] v. Biological assays Compounds designed, selected, and / or optimized by the above methods may, upon production, be characterized using various assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, the compounds described herein may be characterized using conventional assays, including, but not limited to, the assays described below, to determine whether they possess the predicted activity, binding activity, and / or binding specificity.

[0473] Furthermore, high-throughput screening can be used to expedite 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 may include, but are not limited to, one or more different assay techniques, including those described below.

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

[0475] In some embodiments, the compounds of this disclosure may 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, the compounds of the present disclosure may be tested for unbound clearance by known procedures, for example, the procedure described in Miller et al., J.Med.Chem. (2020) 63:12156-12170. For example, unbound clearance (Clu) may be calculated by dividing the total clearance ("CL" in mL / min / kg) measured in blood or plasma by the unbound fraction (fu) of plasma.

[0477] In some embodiments, the solubility of the compounds of this disclosure may be determined by known procedures, e.g., 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 suitable medium may be measured using serial dilution and a 2-hour incubation period followed by filtration, and may be reported in μM units by LC-MS / MS. Thermodynamic solubility in a physiologically suitable medium may be measured by LC-MS / MS after a 24-hour incubation followed by filtration, and may be reported in mg / mL units.

[0478] In some embodiments, the permeability of the compounds of this disclosure may be determined by known procedures, e.g., by the procedure described in Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, permeability across the cell membrane may be measured using either the Caco-2 or MDCK-MDR1 cell line in a Transwell plate after measuring the compound in both the apical and basal chambers, with apparent permeability Papp AB as 10 -6 It may be reported in units of cm / s. vi. Further Embodiments

[0479] Embodiment 1. Compound of formula (I): [ka] [During the ceremony, Ring A is a 5-membered monocyclic heteroaryl; R 1 The R is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L3-(C3-C6 carbocykyl), or -L3-(4-10 member heterocyclyl), and the alkyl, alkenyl, alkynyl, carbocykyl, and heterocyclyl independently have 0, 1, 2, 3, or 4 R 1A It is replaced by; each R1A These 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 Alkilen)-SR 1B or two R's that appeared 1A However, together they form =O; each R 1B R is independently hydrogen, a C1-C4 alkyl, or a C1-C4 haloalkyl, wherein the alkyl and the haloalkyl independently contain 0, 1, 2, 3, or 4 R 1D It is replaced by; each R 1C These are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -OR 1F and; each R 1D These are, independently, halogen, -OR 1F , or -N(R 1F )2; each R 1F These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, where the alkylene independently has 0, 1, 2, 3 or 4 R 1E It is replaced by; each R 1E These are independently -(C1-C3 alkylene)-OR 1B , or -OR 1B or two R's that appeared 1E However, together they form the O symbol; R 2 is hydrogen, or 0, 1, 2, 3 or 4 R 2A It is a C1-C6 alkyl substituted with, and each R 2A These are, independently, halogen, -OR 2B , or -N(R 2B )2, and each R 2B These are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; Alternatively, R 1 and R2 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 1A It forms a 6-membered or 7-membered heterocycline substituted with; R 3 C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkinyl, C3-C 10 The molecule is a carbocyclyl or a 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl independently have 0, 1, 2, 3, or 4 R groups. 3A It has been replaced with; Alternatively, R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4-10 member heterocycline that is substituted with; Each R 3A These 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-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3A The groups, together with the atoms to which they are bonded, form a C6 aryl, a 5-6 membered heteroaryl, a C3-C6 carbocykyl, or a 4-6 membered heterocycline, and the alkyl, alkenyl, alkynyl, carbocykyl, heterocycline, aryl, and heteroaryl independently have 0, 1, 2, 3, or 4 R groups. 3DIt has been replaced with; Each R 3B Each is independently hydrogen, a C1-C3 alkyl group, a C3-C6 carbocyryl group, or a 4-6 membered heterocycline, wherein the alkyl group, the carbocyryl group, and the heterocycline group independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3C These are independently C1-C3 alkyl or C1-C3 haloalkyl; Each R 3D These are, independently, halogen, -OR 3E It is -CN, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E These are independently hydrogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; Each R 4 These 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 These are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or -C(=O)R 4C And R 4C These are C1-C6 alkyl or C1-C6 haloalkyl; Each L1 and L2 is independently a bond, a C1-C3 alkylene, or a C1-C3 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 The alkyl, alkenyl, and alkynyl groups are C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and each alkyl, alkenyl, and alkynyl group independently has 0, 1, 2, 3, or 4 R groups. 1A It is replaced by; each R 1A However, independently, halogen, -OR 1B, or -N(R 1B )2; each R 1B However, independently, these are hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 2 However, hydrogen, or 0, 1, 2, 3 or 4 R 2A It is a C1-C6 alkyl substituted with, and each R 2A However, independently, halogen, -OR 2B , or -N(R 2B )2, and each R 2B However, independently, these are hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 3 However, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkinyl, C3-C 10 The molecule is a carbocyclyl or a 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl independently have 0, 1, 2, 3, or 4 R groups. 3A It has been replaced with; Alternatively, R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4-10 member heterocycline that is substituted with; Each R 3A However, 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-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3AThe groups, together with the atoms to which they are bonded, form a C6 aryl, a 5-6 membered heteroaryl, a C3-C6 carbocykyl, or a 4-6 membered heterocycline, and the alkyl, alkenyl, alkynyl, carbocykyl, heterocycline, aryl, and heteroaryl independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3B However, independently, these are hydrogen, a C1-C3 alkyl group, a C3-C6 carbocyryl group, or a 4-6 membered heterocycline, and the alkyl group, the carbocyryl group, and the heterocycline group independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3C However, they are independently C1-C3 alkyl or C1-C3 haloalkyl; Each R 3D However, independently, halogen, -OR 3E , C1-C3 alkyl, or C1-C3 haloalkyl; Each R 3E However, independently, these are hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 4 However, 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 However, independently, these are hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; Each L1 and L2 is independently a bond, a C1-C3 alkylene, or a C1-C3 haloalkylene; m is 0, 1, or 2. The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0481] Embodiment 3. The amino portion [ka] However, the basis 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 It is alkynylene; Ring B is C3-C 10 They are carbocyclyls, or 4- to 10-membered heterocyclyls; Ring C is a 5-10 membered heterocyclyl; p is 0, 1, 2, or 3. The compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

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

[0483] Embodiment 5. The compound is of formula (I''): [ka] [In the formula, ring B is C3-C 10 [Carbocyclyl, or 4- to 10-membered heterocyclyl, where p is 0, 1, 2, or 3] The compound according to Embodiment 1 or 2, having or a pharmaceutically acceptable salt thereof.

[0484] Embodiment 6. The compound is of formula (I'''): [ka] [In the formula, ring C is a 5- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.] The compound according to Embodiment 1 or 2, having or a pharmaceutically acceptable salt thereof.

[0485] Embodiment 7. The compound is of formula (I''''): [ka] [In the formula, the nitrogen atom of heteroaryl ring A is directly bonded to the thiadiazole moiety.] The compound according to Embodiment 1 or 2, having or a pharmaceutically acceptable salt thereof.

[0486] Embodiment 8. R 1 However, 0, 1, 2, 3 or 4 R 1A A compound according to any one of Embodiments 1 to 7, which is a C1-C6 alkyl substituted with, or a pharmaceutically acceptable salt thereof.

[0487] Embodiment 9. R 1 is -CH3, -CH2-C(CH3)2-CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, [ka] The compound described in Embodiment 8, or a pharmaceutically acceptable salt thereof.

[0488] Embodiment 10. R 2 A compound according to any one of Embodiments 1 to 9, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0489] Embodiment 11. R 3 However, 0, 1, 2, 3 or 4 R 3A C1-C replaced by 10 A compound according to any one of Embodiments 1 to 10, which is alkyl, or a pharmaceutically acceptable salt thereof.

[0490] Embodiment 12. R 3 However, 0, 1, 2, 3 or 4 R 3A C3-C replaced by 10 A compound according to any one of Embodiments 1 to 10, which is a carbocyclyl, or a pharmaceutically acceptable salt thereof.

[0491] Embodiment 13. R 3 However, 0, 1, 2, 3 or 4 R 3A A compound according to any one of Embodiments 1 to 10, which is a 4- to 10-membered heterocycline substituted with, or a pharmaceutically acceptable salt thereof.

[0492] Embodiment 14. R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A A compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, forming a 4- to 10-membered heterocycline substituted with .

[0493] Embodiment 15. R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A A compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, forming a 4- to 10-membered heterocycline substituted with .

[0494] Embodiment 16. [ka] but, [ka] [ka] [ka] [ka] [ka] A compound according to any one of Embodiments 1 to 15, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

[0495] Embodiment 17. [ka] but, [ka] A compound according to Embodiment 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

[0496] Embodiment 18. [ka] but, [ka] A compound according to Embodiment 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

[0497] Embodiment 19. [ka] but, [ka] A compound according to Embodiment 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

[0498] Embodiment 20. Ring A is [ka] The compound described in any one of Embodiments 1 to 19, or a pharmaceutically acceptable salt thereof.

[0499] Embodiment 21. Ring A is [ka] The compound described in Embodiment 20, or a pharmaceutically acceptable salt thereof.

[0500] Embodiment 22. Each R 4 However, independently, halogen, -CN, -L2-OR 4A -L2-N(R 4B )2. A compound according to any one of Embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, which is a C1-C6 alkyl or C1-C6 haloalkyl.

[0501] Embodiment 23. Each R 4 The compounds described in Embodiment 22, or pharmaceutically acceptable salts thereof, wherein the compounds are independently -CH3, -CH2CH3, -CHF2, -CF3, -Cl, -CN, -NH2, or -CH2OH.

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

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

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

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

[0506] Embodiment 28. Ring A is [ka] The compound described in Embodiment 20, or a pharmaceutically acceptable salt thereof.

[0507] Embodiment 29. Ring A is [ka] The compound described in Embodiment 28, or a pharmaceutically acceptable salt thereof.

[0508] Embodiment 30. The compound is of 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] [In the equation, x is 0, 1, 2, 3, or 4] The compound according to Embodiment 1 or 2, having or a pharmaceutically acceptable salt thereof.

[0509] Embodiment 31. R 1 However, 0, 1, 2, 3 or 4 R 1A It is a C1-C6 alkyl substituted with, and each R 1A However, independently -OR 1B And each R 1B However, independently, they are hydrogen or C1-C3 alkyl; R 2 However, hydrogen, or 0, 1, 2, 3 or 4 R 2A It is a C1-C6 alkyl substituted with, and each R 2A However, independently -OR 2B And each R 2B However, independently, they are hydrogen or C1-C3 alkyl; R 3However, C1-C 10 Alkyl, C3-C 10 The alkyl group is a carbocyclyl, or a 4-10 membered heterocyclyl, wherein the alkyl group, the carbocyclyl group, and the heterocyclyl group independently have 0, 1, 2, 3, or 4 R groups. 3A It has been replaced with; Alternatively, R 2 and R 3 These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. 3A It forms a 4-10 member heterocycline that is substituted with; Each R 3A However, independently, C1-C3 alkyl, halogen, =O, -L1-CN, -L1-SO2R 3C , -L1-OR 3B -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4-6 member heterocyclyl), -L1-(C 6-10 It is either an aryl, or -L1- (5-10 member heteroaryl), or two R 3A The groups, together with the atoms to which they are bonded, form a C6 aryl, a 5-6 membered heteroaryl, a C3-C6 carbocykryl, or a 4-6 membered heterocycline, and the alkyl, the carbocykryl, the heterocycline, the aryl, and the heteroaryl independently have 0, 1, 2, 3, or 4 R groups. 3D It has been replaced with; Each R 3C However, they are independently C1-C3 alkyl groups; Each R 3D However, independently, halogen or -OR 3E and; R 3E However, it is a C1-C3 alkyl group; Each R 4 However, independently, halogen, -CN, -L2-OR 4A -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl; Each L1 and L2 is independently bonded or a C1-C3 alkylene; m is 1 or 2. The compound described in Embodiment 2, or a pharmaceutically acceptable salt thereof.

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

[0511] Embodiment 33. The compound according to 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. 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 method for preparing a salt thereof, comprising a compound of formula (H-1) or a salt thereof, and 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 [It is a haloalkyl] The method comprising performing peptide coupling to obtain a compound of formula (I) or a salt thereof.

[0513] Embodiment 35. A compound of formula (H-1) or a salt thereof, of formula (H-2): [ka] A compound having, or a salt thereof, wherein the method is a compound of formula (I''''): [ka] The method according to embodiment 34, which yields a salt thereof.

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

[0515] Embodiment 37. 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 method for preparing a salt thereof, comprising an amine of formula (K) or a salt thereof and a compound of formula (J-1) or a salt thereof: [ka] [In the formula, X is Cl, Br, or I] The method comprising performing a cross-coupling of to obtain a compound of formula (I) or a salt thereof.

[0516] Embodiment 38. A compound of formula (J-1) or a salt thereof, of formula (J-2): [ka] A compound having, or a salt thereof, wherein the method is a compound of formula (I''''): [ka] The method according to embodiment 37, which yields a salt thereof.

[0517] Embodiment 39. A compound of formula (H-1) or a salt thereof, and a compound of formula (D) or a salt thereof: [ka] The method according to Embodiment 37, further comprising performing peptide coupling to obtain a compound of formula (J-1) or a salt thereof.

[0518] Embodiment 40. A compound of formula (H-2) or a salt thereof, and a compound of formula (D) or a salt thereof: [ka] The method according to Embodiment 38, further comprising performing peptide coupling to obtain a compound of formula (J-2) or a salt thereof.

[0519] Embodiment 41. A hydrazinecarbothioamide of formula (G) or a salt thereof, 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] The method according to embodiment 33 or 39, further comprising carrying out the reaction to obtain a compound of formula (H-1) or a salt thereof.

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

[0521] Embodiment 43. (a) Protect the compound of formula (A) or a salt thereof to form an alkyl ester of formula (B): [ka] [In the formula, R a C 1-6 Alkyl, or C 1-6 [It is a haloalkyl] To bring forth the salt of that salt; (b) Compound (B) or a salt thereof is halogenated to obtain compound (C): [ka] [In the formula, X is Cl, Br, or I] To bring forth the salt of that salt; (c) Protecting the hydroxyl group of a compound of formula (C) or a salt thereof to form a compound of formula (D): [ka] [In the formula, R 1 This is defined in Embodiment 1. or to bring forth its salt; and (d) Selectively deprotect the compound of formula (D) or its salt, R a This yields a carboxylic acid of formula (D) with hydrogen as the atom. The method according to any one of embodiments 36, 39, and 40, further comprising:

[0522] Embodiment 44. 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 method for preparing a salt thereof, comprising a compound of formula (P-1): [ka] [In the formula, LG is a leaving group.] The method comprising cyclizing a salt thereof.

[0523] Embodiment 45. A compound of formula (I-BC-a) or a salt thereof, of formula (I-BC-b): [ka] A compound having, or a salt thereof; a compound of formula (P-1), formula (P-2): [ka] The method according to Embodiment 44, wherein the person having or a salt thereof.

[0524] Embodiment 46. A compound of formula (P-1) or a salt thereof, or a compound of formula (P-2) or a salt thereof, which is formula (IX-1) or formula (IX-2): [ka] The method according to embodiment 44 or 45, which is prepared by converting the terminal -OH group to a leaving group.

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

[0526] Embodiment 48. A method for 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 according to Embodiment 48, wherein the disease or disorder is inflammation, autoimmune disease, cancer, infectious disease, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disorder, graft-versus-host disease, allodynia, or cGAS-related disease in a subject determined to have germline or somatic nonsilent mutations in cGAS.

[0528] Embodiment 50. A method for regulating cGAS activity, comprising contacting cells with 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. [Examples]

[0529] To allow for a more detailed understanding of this disclosure, the following examples are provided. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting this disclosure in any way.

[0530] Analysis method Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as shown and at 300.3 K unless otherwise specified, and chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16, or 32 scans. Typical NMR solvents include deuterated dimethyl sulfoxide (DMSO-d6) and deuterated methanol (CD3OD).

[0531] Liquid chromatography-mass spectrometry (LCMS) chromatograms and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7–8.0 μl, and flow rates were typically 0.8 or 1.2 mL / min. Detection methods included diode array (DAD) or evaporative light scattering (ELSD), and cation electron spray 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 = electron spray ionization; m / z = mass / charge; RT = retention time (min).

[0532] Purification / separation methods. The synthesis methods describe the chromatographic methods used for purification and / or separation of the exemplified compounds. Rf = retention factor; RT = retention time (minutes); preparative HPLC = preparative high-performance liquid chromatography.

[0533] The star next to the compound number (#) * ) indicates that an arbitrary stereochemistry has been assigned. The future tense expression ("may be prepared / synthesized") indicates an example that is going to be done.

[0534] Synthesis method Example 1: 4-((1,3-dimethoxypropan-2-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-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-oxopyrane-2-carboxylic acid (180 g, 1153 mmol, 1 equivalent) in methanol (MeOH) (2000 mL), H2SO4 (10 mL, 56 mmol) at room temperature was added. The resulting mixture was then stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate ( Depositphotos) (1000 mL), 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 obtain methyl 5-hydroxy-6-oxopyrane-2-carboxylic acid (85 g, yield 43%). LCMS (ES, m / z) = 171[M+1]+.

[0535] Step 2: To a solution of methyl 5-hydroxy-6-oxopyran-2-carboxylate (1.0 g, 5.9 mmol, 1.0 equivalent) in acetic acid (AcOH) (25 mL, 323 mmol) under stirring, N-bromosuccinimide (NBS) (1.25 g, 7.02 mmol, 1.19 equivalents) was added 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 ( Depositphotos) (3 × 70 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (PE / Depositphotos) (3:7) to obtain methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (800 mg, yield 55%). LCMS(ES, m / z) = 247[M-1]-.

[0536] Step 3: Diisopropylethylamine (DIEA) (11.0 g, 85.1 mmol, 5.30 equivalents) and methyl trifluoromethanesulfonate (TfOMe) (13.0 g, 79.2 mmol, 4.93 equivalents) were added dropwise to a solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (4.0 g, 16 mmol, 1.0 equivalent) in dichloromethane (DCM) (50 mL) under stirring 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 using petroleum ether / ethyl acetate (PE / siRNA) (3:2) to obtain methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (3.0 g, 71% yield). LCMS (ES, m / z) = 263[M+1]+.

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

[0538] Example 1 - Part B: Preparation of 5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-amine [ka] Step 1: A mixture containing 5-bromo-1,3,4-thiadiazole-2-amine (200 g, 1110 mmol, 1.0 equivalent), diisopropylethylamine (DIEA) (431 g, 3333 mmol, 3.0 equivalents), and pyrazole (90.76 g, 1333 mmol, 1.2 equivalents) in 1,4-dioxane was stirred at 80°C for 3 hours. The resulting mixture was concentrated under vacuum, and the residue was dissolved in tetrahydrofuran (THF). The mixture was filtered, and the filtrate was washed with tetrahydrofuran (THF). The filtrate was concentrated under reduced pressure to obtain 5-(pyrazole-1-yl)-1,3,4-thiadiazole-2-amine (100 g, 54% yield), which was used directly in the next step without further purification.

[0539] Step 2: A mixture containing 5-(pyrazole-1-yl)-1,3,4-thiadiazole-2-amine (100 g, 598 mmol, 1.0 equivalent), tosylic acid (TsOH) (20.60 g, 119.6 mmol, 0.2 equivalents), and 2,5-hexanedione (102 g, 897 mmol, 1.5 equivalents) in toluene was stirred at 110°C for 2 hours. The resulting mixture was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (PE / SiO) (9:1) to obtain 2-(2,5-dimethylpyrrole-1-yl)-5-(pyrazole-1-yl)-1,3,4-thiadiazole (90.3 g, yield 61%). LCMS (ES, m / z) = 246.1[M+1]+.

[0540] Step 3: A THF solution of 2-(2,5-dimethylpyrrole-1-yl)-5-(pyrazole-1-yl)-1,3,4-thiadiazole (50.0 g, 204 mmol, 1.0 equivalent) was treated with n-butyllithium (n-BuLi) (97.8 mL, 245 mmol, 1.2 equivalents) under N2 (nitrogen gas) at -78°C for 1 hour, and then methyl iodide (CH3I) (34.7 g, 245 mmol, 1.2 equivalents) was added dropwise at -78°C. The resulting mixture was stirred under N2 at room temperature for 2 hours. The reaction was stopped with saturated NH4Cl (aqueous solution) at 0°C. The resulting mixture was extracted with ELISA. 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 eluted with petroleum ether / ethyl acetate (PE / SiO) (9:1) to obtain 2-(2,5-dimethylpyrrole-1-yl)-5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole (40 g, yield 76%). LCMS(ES, m / z) = 260.0[M+1]+.

[0541] Step 4: 2-(2,5-dimethylpyrrole-1-yl)-5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole (7.0 g, 27 mmol, 1.0 equivalent) was added to a room temperature solution containing tetrahydrofuran (THF) (14 mL) and H2O (28 mL), to which trifluoroacetic acid (TFA) (28 mL) was added. 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 (water with acetonitrile (MeCN), gradient from 10% to 20% in 10 minutes; wavelength: 254 nm) to obtain 5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-amine (also called 5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-amine) (3.0 g, yield 58%). 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide) [ka] Step 1: To a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4 of Part A of Example 1) (12.0 g, 48.2 mmol, 1.00 equivalent) in N,N-dimethylformamide (DMF) (150 mL) under stirring, hydroxybenzotriazole (HOBt) (13.02 g, 96.38 mmol, 2.00 equivalent), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (27.81 g, 145.05 mmol, 3.01 equivalent), and 5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-amine (product of Step 4 of Part B of Example 1) (9.00 g, 49.7 mmol, 1.03 equivalent) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour, and then the reaction was stopped by adding water (70 mL). The precipitated solid was collected by filtration and washed with acetonitrile (5 × 3 mL) to obtain 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (11.0 g, yield 55%). LCMS(ES, m / z) = 412[M+1]+.

[0543] Step 2: N,N-dimethylform of 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (also known herein as 4-bromo-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide) (100 mg, 0.243 mmol, 1.00 equivalent) ("Halopyrone Reagent") under stirring To a 3.5 mL solution of amide (DMF) at room temperature, 1,3-dimethoxypropan-2-amine ("Amine Reagent") (60 mg, 0.50 mmol, 2.1 equivalents), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (40 mg, 0.086 mmol, 0.35 equivalents), (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 equivalents), and Cs2CO3 (240 mg, 0.737 mmol, 3.04 equivalents) were added. The resulting mixture was stirred at 100°C for 3 hours under N2 (nitrogen gas). The resulting mixture was filtered, the filter cake was washed with acetonitrile (1 × 3 mL), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by C18 reverse-phase flash chromatography (water with acetonitrile (MeCN), gradient from 10% to 50% over 10 minutes; wavelength: 254 nm), and then further purified 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)) over 10 minutes to 39%, holding at 39% for 2 minutes); wavelength: 254 nm) to obtain 4-((1,3-dimethoxypropan-2-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 3) * ), and 3-methoxy-4-(((1S,2S)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 4 * ) [ka] According to step 2 of part C of Example 1, trans-2-methoxycyclopentan-1-amine hydrochloride as the "amine reagent" and 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (the product of step 1 of part C of Example 1, referred to as the "halopyrone reagent") were used to prepare a racemic trans-3-methoxy-4-((-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide. Separation of the constituent enantiomers of the racemic trans-3-methoxy-4-((-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide was performed using preparative chiral HPLC (Conditions: Column: Chiral ART). By performing the test using 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: from 60% B to 60% B in 10 mins; wavelength: 220 / 254 nm; RT1 (min): 6.99; RT2 (min): 9.03; sample solvent: MeOH), two enantiomers with arbitrarily assigned stereochemistry were obtained: 3-methoxy-4-(((1R,2R)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 3) * ), the first elution 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 .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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 4 * ), the second elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 23a) * ), and 4-(((1R,2S)-2-hydroxycyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 23b)* ) [ka] 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (100 mg, 0.243 mmol, 1 equivalent) (product of step 1 of part C of Example 1; "Halopyrone Reagent") is mixed with N,N-dimethylformamide (DMF) (1.5 mL) at room temperature, and cis-2-aminocyclopentan-1-ol hydrochloride (81 mg, 0.59 mmol, 2.45 equivalents) ("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 equivalents), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphan (tBuxphos) (32 mg, 0.075 mmol, 0.31 equivalents), and cesium carbonate (230 mg, 0.71 mmol, 2.91 equivalents) were added. The resulting mixture was stirred at 100°C for 1 hour under N2 (nitrogen gas). The resulting mixture was filtered, and the filtrate 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: water containing MeCN, gradient from 10% to 50% over 10 minutes; wavelength: 254 nm). Further purification was performed 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 over 8 mins; wavelength: 254 nm) to obtain the title compound (compound 23a). * and compound 23b * A racemic mixture (7.2 mg, yield 6.8%) was obtained. 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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 136) [ka] Step 1: Thiosemicarbazide (257 mg, 2.82 mmol, 1.50 equivalent) was added at room temperature to a solution of 4-chlorothiophene-3-carbonitrile (270 mg, 1.88 mmol, 1.00 equivalent) in trifluoroacetic acid (TFA) (3.00 mL) under stirring. 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) / H2O=3:2) to obtain 5-(4-chlorothiophene-3-yl)-1,3,4-thiadiazole-2-amine (260 mg, yield 64%). LCMS (ES, m / z) = 218.0 [M+1]+.

[0547] Step 2: To a stirred solution containing 5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazole-2-amine (200 mg, 0.92 mmol, 1.00 equivalent) and 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4 of Part A of Example 1) (343 mg, 1.38 mmol, 1.50 equivalents) in acetonitrile (MeCN) (2.00 mL), N-methylimidazole (NMI) (377 mg, 4.60 mmol, 5.00 equivalents) and chloro-N,N,N',N'-tetramethylformamidinium hexafluoride phosphate (TCFH) (335 mg, 1.20 mmol, 1.3 equivalents) were added at room temperature. 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 obtain 4-bromo-N-[5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (80 mg, yield 18%). LCMS (ES, m / z) = 448.0[M+1]+.

[0548] Step 3: Following the procedure outlined in Example 3 for the preparation of compound 23, N-(5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazole-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-thiadiazole-2-yl]-5-methoxy-6-oxopyrran-2-carboxamide as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". LCMS(ES, m / z) = 443.0[M+1]+. 1 ¹H NMR (400MHz, 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-thiadiazole-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-thiadiazole-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-thiadiazole-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, 4-bromo-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide was prepared by using 3-chlorothiophen-2-carbonitriel instead of 4-chlorothiophen-3-carbonitriel. LCMS(ES, m / z) = 448.0[M+1]+.

[0550] Step 3: Following Step 2 of Part C of Example 1, using cis-2-aminocyclopentan-1-ol hydrochloride as the "amine reagent" and 4-bromo-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent", N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazole-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-thiadiazole-2-yl)-4-(((1R,2S)-2-hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 7b) * The mixture 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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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 equivalent) in acetic acid (AcOH) (300 mL), N-iodosuccinimide (NIS) (39.0 g, 173 mmol, 1.18 equivalents) was added in small amounts at room temperature. The resulting mixture was stirred at 80°C for 20 hours, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (siRNA) (1 L), washed with water (3 × 100 mL), and dried over anhydrous sodium SiO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (PE / siRNA) (3:2) to obtain methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (20.0 g, yield 46%). LCMS (ESI, m / z) = 295[M-1]-.

[0552] Step 2: Diisopropylethylamine (DIEA) (26.0 g, 201 mmol, 2.98 equivalents) was added at room temperature to a solution of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (20.0 g, 67.6 mmol, 1.00 equivalent) in dichloromethane (DCM) (250 mL). Triflate ester (33.0 g, 201 mmol, 2.98 equivalents) was added dropwise to the above mixture 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 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 using petroleum ether / ethyl acetate (PE / siRNA) (4:1) to obtain 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-oxopyrane-2-carboxylate (5.0 g, 16 mmol, 1.0 equivalent) in HCl (6 M) (100 mL) was stirred at 80°C for 4 hours. The resulting mixture was then concentrated under reduced pressure to obtain 4-iodo-5-methoxy-6-oxopyrane-2-carboxylic acid (3.8 g, 80% yield). LCMS (ESI, m / z) = 295[M-1]-.

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

[0555] Step 5: Prepare the "halopyrone reagent" as 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (100 mg, 0.218 mmol, 1 equivalent) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle) A mixture containing Gen3) (37 mg, 0.044 mmol, 0.20 equivalents), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)(RuPhos) (20 mg, 0.043 mmol, 0.20 equivalents), Cs2CO3 (212 mg, 0.651 mmol, 2.99 equivalents), and 1-cyclopropyl-2-methoxyethaneamine (25 mg, 0.217 mmol, 1.00 equivalent) as an "amine reagent" in N,N-dimethylformamide (DMF) (5.0 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The residue was purified directly by reverse-phase flash chromatography (C18 silica gel; mobile phase: water containing MeCN (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector: UV 254 nm), and then dried under reduced pressure in a furnace to obtain 140 mg of crude material. The crude substance was further purified by preparative HPLC under 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: from 25% B to 30% B in 8 mins, 30% B; wavelength: 254 nm; RT1 (min): 8), and then dried under reduced pressure in a furnace to obtain 70 mg of racemic 4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide).The separation of its constituent enantiomers is performed under the following conditions: (CHIRALPAK Chiral preparative HPLC was performed using IF, 2×25cm, 5μm; 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: from 70% B to 70% B in 17 mins; wavelength: 254 / 220 nm; RT1 (min): 7.81; RT2 (min): 12.17; sample solvent: MeOH:DCM = 1:1) to obtain two enantiomers with arbitrarily assigned stereochemistry: (R)-4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 21). * ), the first elution 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 .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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 22 * ), the second elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 26a * ), and 4-(((1R,2S)-2-hydroxycycloheptyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 26b) * ) [ka] 4-iodo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (50 mg, 0.11 mmol, 1.00 equivalent) (product of step 4 of Example 6; "Halopyrone Reagent") is mixed with N,N-dimethylformamide (DMF) (1.25 mL) at room temperature, and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (rac-BINAP) (10 mg, 0.016 mmol, 0.15 equivalent), rac-BINAP-Pd-G3([1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphan Methanesulfonic acid, palladium, 2-phenylaniline (15 mg, 0.015 mmol, 0.14 equivalents), cesium carbonate (174 mg, 0.534 mmol, 4.90 equivalents), and cis-2-aminocycloheptan-1-ol hydrochloride (20 mg, 0.121 mmol, 1.11 equivalents) ("Amine Reagent") were added. The resulting mixture was stirred at 100°C for 1 hour under N2 (nitrogen gas). The mixture was then purified as is by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN) (5 mmol / L NH4HCO3), gradient from 20% to 50% over 15 minutes; detector, UV254 nm). Subsequently, the crude product (20 mg) was 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) (from 23% MeCN to 31% in 8 mins)) to obtain the title compound (compound 26a). * and compound 26b * A racemic mixture (3.9 mg, yield 7.6%) was obtained. 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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 28b) * ) [ka] 4-iodo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (product of step 4 of Example 6) (200 mg, 0.436 mmol, 1 equivalent) ("Halopyrone Reagent") is dissolved in N,N-dimethylformamide (DMF) (2.5 mL) at room temperature and CuI(20 The following were added: (mg, 0.105 mmol, 0.24 equivalents), N,N-diethyl-2-hydroxybenzamide (20 mg, 0.103 mmol, 0.24 equivalents), K2CO3 (120 mg, 0.868 mmol, 1.99 equivalents), and cis-1-amino-2,3-dihydro-1H-inden-2-ol (80 mg, 0.536 mmol, 1.23 equivalents) ("Amine Reagent"). The resulting mixture was stirred at 80°C for 40 minutes under N2 (nitrogen gas). The mixture was then purified as is by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN) (5 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV254 nm). Subsequently, the crude product (40 mg) was 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) (from 31% MeCN to 41% in 10 mins)) to obtain 4-(((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 28b) * A racemic mixture (3.4 mg, yield 1.6%) was obtained with ). 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 29) [ka] 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (product of step 1 of part C of Example 1; "Halopyron Reagent") (100 mg, 0.24 mmol, 1.00 equivalent) ("Halopyron Reagent") and 4-aminotetrahydro-2H-thiopyran-1,1-dioxide (125 mg, 0.84 mmol, 3.45 equivalents) ("Amine Reagent") are mixed with N,N-dimethylmethylphosphate. To a stirred solution contained in lumamide (DMF) (5 mL), tris(dibenzylideneacetone)dipalladium(0)dibenzylideneacetone (Pd2(dba)3) (20 mg, 0.04 mmol, 0.14 equivalents), (±)-2,2'-bis(diphenylphosphin)-1,1'-binaphthalene (rac-BINAP) (32 mg, 0.05 mmol, 0.21 equivalents), and cesium carbonate (240 mg, 0.74 mmol, 3.04 equivalents) were added at room temperature under N2 (nitrogen gas). The resulting mixture was stirred under N2 at 120°C for 2 hours. The resulting mixture was diluted with water (40 mL) and extracted with ethyl acetate (SiO) (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: 8 min from 53% B to 58% B, 58% B; wavelength: 254 nm) to obtain 4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 29) (10.6 mg, yield 9.0%). 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-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-(isopropylamino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 131) [ka] Step 1: In a 250 mL round-bottom flask, methyl 3-chloro-1H-pyrrole-2-carboxylate (2.40 g, 15.0 mmol, 1.00 equivalent) and tetrahydrofuran (THF) (20 mL, 247 mmol, 16.4 equivalents) were added at room temperature. NaH (1.44 g, 60.0 mmol, 3.99 equivalents) was added to the mixture in small amounts at 0°C. The resulting mixture was stirred at 0°C for a further 1 hour. Then, methyl iodide (MeI) (6.48 g, 45.6 mmol, 3.04 equivalents) was added dropwise to the mixture at 0°C. The resulting mixture was then stirred at room temperature overnight. The reaction was then stopped by adding HCl (1N) (40 mL) at 0°C. The resulting mixture was extracted with ethyl acetate (SiO) (3 × 40 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with petroleum ether / ethyl acetate (PE / SiO4) (1:1) and purified by silica gel column chromatography to obtain methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylate (1.7 g, yield 71%). LCMS (ESI, m / z) = 173.85[M+1]+.

[0560] Step 2: Methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylic acid (750 mg, 4.32 mmol, 1.00 equivalent) and methanol (MeOH) (4.0 mL, 99 mmol, 23 equivalents) were added to a 40 mL vial at room temperature. To the above mixture, H2O (4.0 mL, 222 mmol, 51.4 equivalents) containing NaOH (330 mg, 8.25 mmol, 1.91 equivalents) at room temperature was added. The resulting mixture was stirred at 50°C for a further 2 hours. The mixture was then acidified to pH 6 with HCl (3 M). The resulting mixture was extracted with ethyl acetate ( Depositphotos) (3 × 30 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 3-chloro-1-methylpyrrole-2-carboxylic acid (580 mg, yield 80%). LCMS(ESI, m / z)=160.00[M+1]+.

[0561] Step 3: In a 40 mL vial, 3-chloro-1-methylpyrrole-2-carboxylic acid (2.20 g, 13.8 mmol, 1.00 equivalent), N,N-dimethylformamide (DMF) (20 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoride phosphate (15.7 g, 41.4 mmol, 3.00 equivalent), diisopropylethylamine (DIEA) (5.42 g, 41.9 mmol, 3.04 equivalent), and NH4Cl (2.97 g, 55.6 mmol, 4.03 equivalent) were added at room temperature. The resulting mixture was stirred at 80°C for 3 hours. The reaction was then stopped with water at room temperature, and the aqueous layer was extracted with ethyl acetate (SiO) (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 (water containing acetonitrile (MeCN), gradient from 20% to 50% over 10 minutes; detector, UV 254 nm) to obtain 3-chloro-1-methylpyrrole-2-carboxamide (1.47 g, yield 60%). LCMS (ESI, m / z) = 159.05[M+1]+.

[0562] Step 4: 3-chloro-1-methylpyrrole-2-carboxamide (1.40 g, 8.83 mmol, 1.00 equivalent), dichloroethane (DCE) (20 mL), and methyl N-(triethylammonium sulfonyl)carbamate (Burgess reagent) (6.29 g, 26.4 mmol, 2.99 equivalents) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 50°C for 2 hours. The reaction was then stopped with water at room temperature and extracted with dichloromethane (DCM) (3 × 20 mL). The combined organic layer was washed with water (3 × 20 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (PE / Â) (70:30) to obtain 3-chloro-1-methylpyrrole-2-carbonitrile (940 mg, yield 68%). 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 containing 3-chloro-1-methylpyrrole-2-carbonitrile (100 mg, 0.71 mmol, 1.00 equivalent) and thiosemicarbazide (200 mg, 2.19 mmol, 3.09 equivalents) in trifluoroacetic acid (TFA) (5.00 mL, 67.3 mmol, 94.6 equivalents) was stirred at 80°C for 16 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by C18 reverse-phase flash chromatography (water with acetonitrile (MeCN), gradient from 30% to 40% over 10 minutes; detector, UV 254 nm) to obtain 5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-amine (45 mg, yield 26%). LCMS (ESI, m / z) = 215.00 [M+1]+.

[0564] Step 6: To a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4 of Part A of Example 1) (770 mg, 3.09 mmol, 1.00 equivalent) in acetonitrile (MeCN) (20 mL) at room temperature, chloro-N,N,N',N'-tetramethylformamidinium hexafluoride phosphate (TCFH) (960 mg, 3.42 mmol, 1.11 equivalents), N-methylimidazole (NMI) (900 mg, 11.0 mmol, 3.54 equivalents), and 5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-amine (616 mg, 2.87 mmol, 0.93 equivalents) were added. 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 obtain 4-bromo-N-[5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-6-oxopyrran-2-carboxamide (also known herein as 4-bromo-N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide) (910 mg, yield 65%). 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-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-(isopropylamino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 131) was prepared using 4-bromo-N-[5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-(isopropylamino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 131) 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-pyrrole-2-yl)-1,3,4-thiadiazole-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-pyrrole-2-yl)-1,3,4-thiadiazole-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-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-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-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (product of step 6 of Example 10) as the "halopyrone reagent" and (1,2-cis)-2-aminocyclobutan-1-ol as the "amine reagent". Separation of the constituent enantiomers of the racemic N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-(((1,2-cis)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide was performed using 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) By performing the test using the following method ( / min; gradient: 21.5 min from 50% B to 50% B; wavelength: 220 / 254 nm; RT1 (min): 10.66; RT2 (min): 13.55; sample solvent: MeOH:DCM = 1:1), two enantiomers with arbitrarily assigned stereochemistry were obtained: N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-(((1S,2R)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 53) * ), the first elution 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-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-(((1R,2S)-2-hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 54) * ), the second elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 73) * ), and 4-(((1S,2R)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 74) * ) [ka] According to step 2 of part C of Example 1, racemic 4-(((1,2-cis)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 4 of Example 6) as the "halopyrone reagent" and (1,2-cis)-2-aminocyclopentan-1-carbonitride 2,2,2-trifluoroacetate as the "amine reagent". Separation of the constituent enantiomers of the racemic 4-(((1,2-cis)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide was performed using preparative chiral HPLC (column: CHIRALPAK). By performing the procedure using ID, 2×25cm, 5μm; mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: methanol (MeOH):dichloromethane (DCM) = 1:1; flow rate: 20 mL / min; gradient: from 90% B to 90% B in 17 mins; wavelength: 220 / 254 nm; RT1 (min): 6.85; RT2 (min): 10.82; sample solvent: MeOH:DCM = 1:1), two enantiomers with arbitrarily assigned stereochemistry were obtained: 4-(((1R,2S)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 73) * ), the first elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 74) * ), the second elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 75) [ka] According to step 2 of part C of Example 1, 3-methoxy-4-((2-methoxyethyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 75) was prepared using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 75) as the "halopyrone reagent" and 2-methoxyethane-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 80 * ) [ka] According to step 2 of part C of Example 1, racemic 3-methoxy-4-(((1,2-cis)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 4 of Example 6) as the "halopyrone reagent" and cis-2-(methoxymethyl)cyclopentanamine as the "amine reagent". Separation of the constituent enantiomers of the racemic 3-methoxy-4-(((1,2-cis)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide was performed by preparative chiral HPLC (conditions: chiral ART). By performing the experiment using 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: from 50% B to 50% B in 9.5 mins; RT1 (min): 7.14; RT2 (min): 8.71; sample solvent: ethanol / dichloromethane (EtOH:DCM) = 1:1), two enantiomers with arbitrarily assigned stereochemistry were obtained: 3-methoxy-4-(((1S,2R)-2-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 79) * ), the first elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 80 * ), the second elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 200) [ka] Step 1: To a stirred solution containing methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2 of Part A of Example 1) (5.0 g, 20 mmol, 1.0 equivalent) and 2-methoxyethanol (2.0 g, 26 mmol, 1.3 equivalents) in tetrahydrofuran (THF), triphenylphosphine (PPh3) (8.0 g, 30 mmol, 1.5 equivalents) was added in small amounts at room temperature. The resulting mixture was stirred at 0°C for 10 minutes. Then, di-tert-butyl azodicarboxylate (DBAD) (7.0 g, 30 mmol, 1.5 equivalents) was added dropwise at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was then diluted with ethyl acetate (siRNA) (600 mL), washed with water (3 × 200 mL), and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (PE / Â) (1:3) to obtain methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyrane-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-oxopyrane-2-carboxylate (1700 mg, 5.54 mmol, 1.00 equivalent) in HCl (6M) (30 mL) was stirred at 80°C for 3 hours. The resulting mixture was then concentrated under reduced pressure, diluted with ethyl acetate ( Depositphotos) (200 mL), washed with brine (3 × 10 mL), and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 4-bromo-5-(2-methoxyethoxy)-6-oxopyrane-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 equivalent) and 5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-amine (also called 5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-amine) (production of Step 4 of Part B of Example 1) To a stirred solution containing (820 mg, 4.52 mmol, 1.11 equivalents) of (a substance) in N,N-dimethylformamide (DMF) (21 mL), hydroxybenzotriazole (HOBT) (1110 mg, 8.22 mmol, 2.01 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2355 mg, 12.3 mmol, 3.00 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour, and then diluted with water (40 mL). The precipitated solid was recovered by filtration to obtain 4-bromo-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (also known herein as 4-bromo-5-(2-methoxyethoxy)-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide) (1.3 g, yield 70%). 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 200) was prepared using 4-bromo-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 200) using 4-bromo-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 200) as the "halopyrone reagent" and (R)-2-methoxy-1-phenylethane-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-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-((2-methoxy-1-phenylethyl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (compound 201) [ka] Following steps 3-4 of Example 15, 4-bromo-N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-amine was used as the "halopyrone reagent" by substituting 5-(5-methyl-1H-pyrrole-1-yl)-1,3,4-thiadiazole-2-amine with 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid (the product of step 2 of Example 15). Azole-2-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide was obtained, and then coupled with (R)-2-methoxy-1-phenylethane-1-amine as the "amine reagent" to prepare (R)-N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-((2-methoxy-1-phenylethyl)amino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (compound 201). 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)pyrrolidine-1-yl)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 87) [ka] 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (product of step 1 of part C of Example 1; "halopyrone reagent") (50 mg, 0.12 mmol, 1.0 equivalent) and (3S)-3-(methoxymethyl)pyrrolidine (27 mg, 0.24 mmol, 2.00 equivalent) ("amine reagent") are mixed in N,N-dimethylformamide (DMF) (0.5 mL). To the mixture contained in [the original compound], 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (26 mg, 0.048 mmol, 0.40 equivalents), [(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 equivalents), and K2CO3 (50 mg, 0.36 mmol, 3.0 equivalents) were added. The resulting mixture was stirred at 100°C for 1 hour under N2 (nitrogen gas). The mixture was then purified by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN) (0.1% trifluoroacetic acid (TFA)), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to obtain (S)-3-methoxy-4-(3-(methoxymethyl)pyrrolidine-1-yl)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 87) (20 mg, yield 38%). 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-thiadiazole-2-yl)-3-methoxy-4-((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 94) [ka] According to step 2 of part C of Example 1, (R)-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 94) was prepared using 4-bromo-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 94) 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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 101 * ) [ka] According to step 2 of part C of Example 1, racemic 3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide was prepared using 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 4 of Example 6) as the "halopyrone reagent" and 3-(methoxymethyl)tetrahydrofuran-3-amine as the "amine reagent". Separation of the constituent enantiomers of the racemic 3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide was performed using 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) The process was carried out using a solvent (methanol (MeOH):DCM=1:1) from 50% B to 50% B in 9.5 minutes; wavelength: 220 / 254 nm; RT1 (min): 7.15; RT2 (min): 9.27; sample solvent: methanol (MeOH):DCM=1:1) to obtain two enantiomers with arbitrarily assigned stereochemistry: (S)-3-methoxy-4-((3-(methoxymethyl)tetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 100) *), first elution peak, LCMS(ESI, m / z) = 463.1[M+1]+, 1H NMR (400MHz, 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=9.6Hz, 1H), 3.53 (d, J=9.6Hz, 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 101) * ), second elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 108, rac-108), 3-Methoxy-4-(((trans)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyran Zol-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 108a) *), and 3-methoxy-4-(((1R,3S)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 108b) * ), as well as 3-methoxy-4-(((1S,3S)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 109a) * ), and 3-methoxy-4-(((1R,3R)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 109b) * ) [ka] 3-methoxy-4-((3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-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-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent". Diastereoisomers were separated 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: 8 min from 15% B to 20% B, 20% B; wavelength: 254 nm), yielding two pairs of enantiomers with arbitrarily assigned stereochemistry that are diastereomers: 3-methoxy-4-(((1S,3R)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (compound 126-OMe) was prepared using 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (compound 126-OMe) 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-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (compound 126-OMe) (80 mg, 0.180 mmol, 1.00 equivalent) in dichloromethane (DCM) (3 mL), a solution of BBr3 (0.80 mL, 0.80 mmol, 4.44 equivalents) in DCM (1 M) was added. The resulting mixture was stirred at 0 °C for 30 minutes. The reaction was stopped with methanol (MeOH) at 0°C, and then purified by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to obtain 4-({3-hydroxybicyclo[1.1.1]pentan-1-yl}amino)-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (compound 126) (12 mg, yield 15%). 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-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-4-((2-hydroxyethyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 129), and N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 129-OMe) [ka] Step 1: Following Step 7 of Example 10, N-[5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 129-OMe) was prepared using 4-bromo-N-(5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (product of Step 6 of Example 10) as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". 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-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyrran-2-carboxamide (compound 129-OMe) (180 mg, 0.41 mmol, 1.00 equivalent) in acetonitrile (MeCN) (3 mL) at room temperature, NaI (307 mg, 2.04 mmol, 5.00 equivalent) and trimethylsilyl chloride (TMSCl) (222 mg, 2.04 mmol, 5.00 equivalent) were added. The resulting mixture was stirred overnight at 80°C, and then purified directly by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to obtain the crude product (40 mg). This 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 (from 15% MeCN to 25% over 10 minutes); detector, UV 254 nm) to obtain N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 130) [ka] Step 1: 4-bromo-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyrane-2-carboxamide (product of Step 1 of Part C of Example 1; "halopyrone reagent") (200 mg, 0.485 mmol, 1.00 equivalent) and (2-aminoethoxy)(tert-butyl)dimethylsilane ("amine reagent") (851 mg, 4.85 mmol, 10.0 equivalent) To a stirred mixture containing (amount) and (5 mL) of dioxane, bis(tri-tert-butylphosphine)palladium(0)(Pd(t-Bu3P)2) (37 mg, 0.073 mmol, 0.15 equivalents), tri-tert-butylphosphonium tetrafluoroborate(t-Bu3P-HBF4) (21 mg, 0.073 mmol, 0.15 equivalents), and cesium carbonate (316 mg, 0.97 mmol, 2.0 equivalents) were added at room temperature. The resulting mixture was stirred at 120°C for 4 hours under N2 (nitrogen gas). The mixture was then poured into water and extracted with ethyl acetate (SiO) (3 × 10 mL). The combined organic layers were washed with water and brine (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 (water (10 mmol / L NH4HCO3) containing acetonitrile (MeCN), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to obtain 4-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-5-methoxy-N-[5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (48 mg, yield 19%). 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-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-6-oxopyran-2-carboxamide (30 mg, 0.059 mmol, 1.00 equivalent) 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 (NH4HCO3 at 10 mmol / L) and acetonitrile (MeCN) (from 8% MeCN to 20% in 10 mins); detector, UV 254 nm) to obtain 4-((2-hydroxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 130) (9.3 mg, yield 40%). LC-MS (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-pyrrole-2-yl)-1,3,4-thiadiazole-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-pyrrole-2-yl)-1,3,4-thiadiazole-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 of Example 6) (150 mg, 0.51 mmol, 1.00 equivalent) in acetonitrile (MeCN) (2 mL) at room temperature, chloro-N,N,N',N'-tetramethylformamidinium hexafluoride phosphate (TCFH) (200 mg, 0.713 mmol, 1.41 equivalent) and N-methylimidazole (NMI) (166 mg, 2.02 mmol, 3.99 equivalent) were added. 5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-amine (product of Step 5 of Example 10) (109 mg, 0.51 mmol, 1 equivalent) was added to the mixture, and the resulting mixture was stirred at room temperature for 0.5 hours, after which it was concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase flash chromatography (eluting with acetonitrile / water (5:1)) to obtain N-[5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide (120 mg, yield 47%).

[0586] Step 2: Following Example 14, use N-[5-(3-chloro-1-methylpyrrole-2-yl)-1,3,4-thiadiazole-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" to form a racemic N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy -4-(((1,2-cis)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide was prepared, and its constituent enantiomers were separated to obtain two enantiomers with arbitrarily assigned stereochemistry: N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-(((1R,2S)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 132) * ), the first elution peak, LCMS(ESI, m / z) = 466.05[M+1]+, 1 ¹H NMR (400MHz, DMSO-d6) δ 7.20 (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); and N-(5-(3-chloro-1-methyl-1H-pyrrole-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-(((1S,2R)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 133) * ), second elution 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-5-methoxy-4-(2-methoxyethylamino)-6-oxo-6H-pyran-2-carboxamide (compound 134) [ka] Step 1: Diisopropylethylamine (DIEA) (29.8 g, 231 mmol, 3.01 equivalents) was added to a stirred solution containing 5-bromo-1,3,4-thiadiazole-2-amine (13.8 g, 76.6 mmol, 1.00 equivalent) and 4-fluoro-1H-pyrazole (7.96 g, 92.5 mmol, 1.21 equivalents) in dioxane (80 mL) at room temperature. The resulting mixture was stirred overnight at 80 °C. The mixture was then diluted with water and extracted with ethyl acetate (SiO2) (3 × 1 L). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous sodium 2 SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), the precipitated solid was collected by filtration, and washed with ethyl acetate (3 × 10 mL) to obtain 5-(4-fluoropyrazole-1-yl)-1,3,4-thiadiazole-2-amine (5.0 g, yield 35%). LCMS (ESI, m / z) = 186[M+1]+.

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

[0589] Step 3: To a tetrahydrofuran (THF) (5 mL) solution of 2-(2,5-dimethylpyrrole-1-yl)-5-(4-fluoropyrazole-1-yl)-1,3,4-thiadiazole (1.0 g, 3.8 mmol, 1.0 equivalent) under stirring, lithium diisopropylamide (LDA) (3.80 mL, 3.80 mmol, 1.00 equivalent) at -78°C was added under N2 (nitrogen gas). After 30 minutes, THF (2 mL) at -78°C containing hexachloroethane (900 mg, 3.80 mmol, 1.00 equivalent) was added to the above mixture under N2. The resulting mixture was stirred under N2 at -78°C for 2 hours. The mixture was then stopped with saturated NH4Cl and extracted with ethyl acetate (RINKAN) (3 × 100 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN) (0.1% trifluoroacetic acid (TFA)), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to obtain 2-(5-chloro-4-fluoropyrazole-1-yl)-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (600 mg, yield 53%). LCMS (ESI, m / z) = 298[M+1]+.

[0590] Step 4: Trifluoroacetic acid (TFA) (2 mL) was added dropwise to a solution of 2-(5-chloro-4-fluoropyrazole-1-yl)-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (200 mg, 0.672 mmol, 1.00 equivalent) in H2O / THF (2:1, 3 mL) under stirring. The resulting mixture was stirred at 50°C for 2 hours and then concentrated under vacuum. The resulting residue was purified by C18 reverse-phase flash chromatography (water with acetonitrile (MeCN), gradient from 0% to 100% over 10 minutes; detector, UV 254 nm) to obtain 5-(5-chloro-4-fluoropyrazole-1-yl)-1,3,4-thiadiazole-2-amine (70 mg, yield 47%). 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 of Part A of Example 1) (113 mg, 0.45 mmol, 1.00 equivalent) and 5-(5-chloro-4-fluoro-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-amine (100 mg, 0.45 mmol, 1.00 equivalent) are mixed with N,N-dimethylformamide (DMF) (1 To a stirred solution contained in 0 mL, 1-((dimethylamino)(dimethylimino)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluoride phosphate (V) (HATU) (258 mg, 0.68 mmol, 1.50 equivalents) and diisopropylethylamine (DIEA) (176 mg, 1.36 mmol, 3.00 equivalents) were added under N2 (nitrogen gas) at 0°C. The resulting mixture was stirred under N2 at room temperature for 16 hours. The mixture was then diluted with water, extracted with ethyl acetate (SiO) (3 × 50 mL), and the combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluting with methanol / dichloromethane (MeOH / DCM) (1:4) to obtain 4-bromo-N-(5-(5-chloro-4-fluoro-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (80 mg, yield 29%). LCMS (ESI, m / z) = 450.1[M+1]+.

[0592] Step 6: Following Step 2 of Part C of Example 1, N-(5-(5-chloro-4-fluoro-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 134) was prepared using 4-bromo-N-(5-(5-chloro-4-fluoro-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-5-methoxy-4-(2-methoxyethylamino)-6-oxo-6H-pyran-2-carboxamide (compound 134) as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". 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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 135) [ka] Step 1: Carbonyl diimidazole (CDI) (1.50 g, 9.22 mmol, 1.5 equivalents) was added in small amounts to a solution of 2-chlorothiophene-3-carboxylic acid (1.0 g, 6.15 mmol, 1.0 equivalent) in tetrahydrofuran (THF) (10 mL) under stirring at room temperature. The resulting mixture was stirred at room temperature for 1 hour. A methanol solution of ammonia (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 a further 30 minutes, and then concentrated under reduced pressure. The residue was then purified by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN) (0.1% trifluoroacetic acid (TFA)), gradient from 10% to 50% in 10 minutes) to obtain 2-chlorothiophene-3-carboxamide (770 mg, yield 77%). LCMS (ESI, m / z) = 162 [M+1] + .

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

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

[0596] Step 4: To a 3 mL solution of 5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazole-2-amine (100 mg, 0.46 mmol, 1.0 equivalent) in acetonitrile at room temperature, chloro-N,N,N',N'-tetramethylformamidinium hexafluoride phosphate (TCFH) (385 mg, 1.37 mmol, 2.99 equivalents), N-methylimidazole (NMI) (376 mg, 4.58 mmol, 9.97 equivalents), and 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product from Step 4 of Part A of Example 1) (137 mg, 0.55 mmol, 1.20 equivalents) were added. 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 (water containing MeCN, gradient from 10% to 50% over 10 minutes) to obtain 4-bromo-N-[5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (70 mg, yield 34%). LCMS (ESI, m / z) = 448[M+1]+.

[0597] Step 5: Mix 4-bromo-N-[5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-6-oxopyran-2-carboxamide ("Halopyrone Reagent") (160 mg, 0.357 mmol, 1.00 equivalent) and 2-methoxyethane-1-amine ("Amine Reagent") (32 mg, 0.43 mmol, 1.19 equivalents) in N,N-dimethylformamide (DMF) (4 mL) at room temperature, then add CF3COONa (160 mg, 1.18 mmol, 3.30 equivalents) were added, along with 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (63 mg, 0.14 mmol, 0.38 equivalents), 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU) (160 mg, 1.05 mmol, 2.95 equivalents), 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 equivalents). The resulting mixture was stirred at 100°C for 1 hour under N2 (nitrogen gas). The resulting solid was filtered and washed with acetonitrile (MeCN) (10 × 3 mL). Subsequently, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by C18 reverse-phase flash chromatography (water containing MeCN, gradient from 10% to 50% in 10 minutes) to obtain the crude product, which was then preparatively 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, 28% B over 8 mins; wavelength: 220 nm; RT1 (min): 6.58) to obtain N-(5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 135) (4.4 mg, yield 2.8%). 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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 137) [ka] Step 1: To a stirred solution containing 5-bromo-1,3,4-thiadiazole-2-amine (10.0 g, 55.5 mmol, 1.00 equivalent) and 2,5-hexanedione (8.93 g, 78.2 mmol, 1.41 equivalents) in toluene (100 mL), tosylic acid (TsOH) (1.92 g, 11.15 mmol, 0.20 equivalent) was added at room temperature. The resulting mixture was stirred at 120 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and diluted with water (300 mL). The mixture was extracted with ethyl acetate (SiO) (3 × 400 mL), the combined organic layer was washed with water (3 × 100 mL), and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (PE / siRNA) (5:1) to obtain 2-bromo-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (6.0 g, yield 42%).

[0599] Step 2: To a stirred solution containing 2-bromo-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (1.00 g, 3.87 mmol, 1.00 equivalent) and 4-methylthiophene-3-ylboronic acid (0.83 g, 5.81 mmol, 1.50 equivalent) in dioxane (10 mL), [(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 equivalent) and K2CO3 (1.07 g, 7.75 mmol, 2.00 equivalent) were added at room temperature. The resulting mixture was stirred overnight at 80°C under N2 (nitrogen gas), and then concentrated under vacuum. The resulting residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN):H2O=1:1) to obtain 2-(2,5-dimethylpyrrole-1-yl)-5-(4-methylthiophen-3-yl)-1,3,4-thiadiazole (460 mg, yield 39%). LCMS (ESI, m / z) = 276.0[M+1]+.

[0600] Step 3: To a 60 mL solution of tetrahydrofuran (THF) containing 2-(2,5-dimethylpyrrole-1-yl)-5-(4-methylthiophen-3-yl)-1,3,4-thiadiazole (400 mg, 1.45 mmol, 1.00 equivalent) under stirring, a 2.5 M solution of n-butyllithium (nBuLi) (0.87 mL, 2.18 mmol, 1.50 equivalent) in THF (2.5 M) was added dropwise at -78°C under N2 (nitrogen gas). The reaction mixture was stirred at -78°C for 1 hour, then a solution containing I2 (184 mg, 0.73 mmol, 0.50 equivalent) in 2 mL of THF was added dropwise, and the mixture was stirred for another hour. The reaction was then stopped by adding saturated NH4Cl (aqueous solution) (10 mL) at 0°C, and the mixture was extracted with ethyl acetate (RINKAN) (3 × 50 mL). The resulting mixture was concentrated under vacuum, and the residue was purified by C18 reverse-phase flash chromatography (acetonitrile (MeCN):H2O=9:1) to obtain 2-(2,5-dimethylpyrrole-1-yl)-5-(2-iodo-4-methylthiophen-3-yl)-1,3,4-thiadiazole (160 mg, yield 25%). LCMS (ESI, m / z) = 402.0[M+1]+.

[0601] Step 4: To a 3 mL solution of 2-(2,5-dimethylpyrrole-1-yl)-5-(2-iodo-4-methylthiophen-3-yl)-1,3,4-thiadiazole (120 mg, 0.31 mmol, 1.00 equivalent) in N,N-dimethylacetamide (DMAC) at room temperature, Zn(CN)2 (72 mg, 0.61 mmol, 2.00 equivalent), XantPhos (266 mg, 0.46 mmol, 1.50 equivalent), PdCl2 (82 mg, 0.46 mmol, 1.50 equivalent), and diisopropylethylamine (DIEA) (79 mg, 0.61 mmol, 2.00 equivalent) were added. The resulting mixture was stirred overnight at 100°C under N2 (nitrogen gas). The mixture was then diluted with water and extracted with ethyl acetate (siRNA) (3 × 20 mL). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (Â1 / PE) (3:1) to obtain 3-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]-4-methylthiophene-2-carbonitrile (80 mg, 78% yield). LCMS (ESI, m / z) = 301.0[M+1]+.

[0602] Step 5: Trifluoroacetic acid (TFA) (0.7 mL) was added to a solution of 3-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]-4-methylthiophene-2-carbonitrile (50 mg, 0.17 mmol, 1.00 equivalent) in H2O (0.7 mL) under stirring. The resulting mixture was stirred overnight at room temperature under an air atmosphere. The mixture was then concentrated under reduced pressure to obtain 3-(5-amino-1,3,4-thiadiazole-2-yl)-4-methylthiophene-2-carbonitrile (50 mg, 95% yield). LCMS(ESI, m / z) = 223[M+1]+.

[0603] Step 6: To a stirred solution containing 3-(5-amino-1,3,4-thiadiazole-2-yl)-4-methylthiophen-2-carbonitrile (35 mg, 0.16 mmol, 1.00 equivalent) and 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4 of Part A of Example 1) (118 mg, 0.47 mmol, 3.00 equivalent) in acetonitrile (MeCN) (1 mL), N-methylimidazole (NMI) (65 mg, 0.79 mmol, 5.00 equivalent) and chloro-N,N,N',N'-tetramethylformamidinium hexafluoride phosphate (TCFH) (53 mg, 0.19 mmol, 1.20 equivalent) were added. The resulting mixture was stirred overnight at room temperature under an air atmosphere, and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (MeCN:H2O=1:1) to obtain 4-bromo-N-[5-(2-cyano-4-methylthiophen-3-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (30 mg, yield 38%). 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-thiadiazole-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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 137) as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". LCMS(ESI, m / z)=448[M+1]+; 1 ¹H 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-thiadiazole-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (compound 138) [ka] Step 1: To a stirred solution containing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile (210 mg, 0.89 mmol, 1.00 equivalent) in dioxane (1.4 mL) and water (7 mL), 2-bromo-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (product of Step 1 of Example 27) (272 mg, 1.05 mmol, 1.18 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (65 mg, 0.089 mmol, 0.10 equivalents), and potassium carbonate (378 mg, 2.74 mmol, 3.06 equivalents) were added at room temperature. The resulting mixture was stirred under nitrogen (N2) at 90°C for 3 hours, then cooled to room temperature and diluted with water (200 mL). The mixture was extracted with ethyl acetate ( Depositphotos) (3 × 200 mL), the combined organic layers were washed with water (100 mL), and dried over anhydrous sodium (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 / Depositphotos) (5:1) to obtain 4-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]thiophene-3-carbonitrile (128 mg, yield 38%). LCMS (ESI, m / z) = 287[M+1]+.

[0606] Step 2: To a solution of 4-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]thiophene-3-carbonitrile (120 mg, 0.419 mmol, 1.00 equivalent) in dichloromethane (DCM) (0.24 mL) under stirring, water (0.24 mL) and trifluoroacetaldehyde (0.6 mL) were added 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 obtain 4-(5-amino-1,3,4-thiadiazole-2-yl)thiophene-3-carbonitrile (32 mg, yield 36%). LCMS (ESI, m / z) = 209[M+1]+.

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

[0608] Step 4: Following Step 2 of Part C of Example 1, N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (compound 138) was prepared using 4-bromo-N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (compound 138) as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". 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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 139) [ka] Step 1: Thiosemicarbazide (540 mg, 5.926 mmol, 1.62 equivalents) was added at room temperature to a POCl3 (5 mL) solution of 4-chloroisothiazole-5-carboxylic acid (600 mg, 3.67 mmol, 1.00 equivalent). The resulting mixture was stirred at room temperature for 5 hours, then concentrated under vacuum and diluted with ethyl acetate (RINKAN) (200 mL). The resulting solution was neutralized to pH 8 with NaOH (aqueous solution, 1 M) and extracted with ethyl acetate (RINKAN) (3 × 30 mL). The combined organic layers were washed with water and brine (3 × 5 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 using petroleum ether / ethyl acetate (PE / Â) (5:1) to obtain 5-(4-chloro-1,2-thiazole-5-yl)-1,3,4-thiadiazole-2-amine (200 mg, yield 25%). LCMS (ESI, m / z) = 218.9[M+1]+.

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

[0611] Step 3: Following Step 2 of Part C of Example 1, N-(5-(4-chloroisothiazol-5-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 139) was prepared using 4-bromo-N-[5-(4-chloroisothiazol-5-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 139) as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". LCMS(ESI, m / z) = 444.00[M+1]+. 1 H NMR (400MHz, DMSO-d6) δ 8.65 (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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 140) [ka] Step 1: 2-bromo-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (product of Step 1 of Example 27) (2.50 g, 9.68 mmol, 1.00 equivalent) and 2-methylthiophene-3-ylboronic acid (1.66 g, 11.7 mmol, 1.21 equivalents) were mixed in 18 mL of dioxane to a stirred solution. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (0.80 g, 1.09 mmol, 0.11 equivalents), H2O (3 mL), and K2CO3 (2.70 g, 19.5 mmol, 2.02 equivalents) were added dropwise at room temperature under nitrogen (N2). The resulting mixture was stirred under N2 at 80°C for 4 hours. The mixture was then diluted with water and extracted with ethyl acetate ( Depositphotos) (3 × 30 mL). The combined organic layers were washed with water and brine (3 × 5 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / Depositphotos (5:1) to obtain 2-(2,5-dimethylpyrrole-1-yl)-5-(2-methylthiophen-3-yl)-1,3,4-thiadiazole (1.5 g, yield 56%). LCMS (ESI, m / z) = 276[M+1]+.

[0613] Step 2: 2-(2,5-dimethylpyrrole-1-yl)-5-(2-methylthiophen-3-yl)-1,3,4-thiadiazole (1.50 g, 5.45 mmol, 1.00 equivalent) was mixed in H2O (2 mL) and tetrahydrofuran (THF) (1 mL) in a stirred solution. Trifluoroacetic acid (TFA) (2 mL) was added dropwise at room temperature. The resulting mixture was stirred at 50 °C for 5 hours and then concentrated under vacuum. The residue was then purified by C18 reverse-phase flash chromatography (water with acetonitrile (MeCN), gradient from 0% to 100% over 10 minutes; detector, UV 254 nm) to obtain 5-(2-methylthiophen-3-yl)-1,3,4-thiadiazole-2-amine (600 mg, yield 56%). LCMS (ESI, m / z) = 198[M+1]+.

[0614] Step 3: To a solution of 5-(2-methylthiophen-3-yl)-1,3,4-thiadiazole-2-amine (500 mg, 2.54 mmol, 1.00 equivalent) in trifluoroacetic acid (TFA) (20 mL) under stirring, Br2 (3.0 g, 19 mmol, 7.4 equivalents) was added dropwise at room temperature. The resulting mixture was stirred overnight at 80°C. The mixture was then stopped with saturated NaHSO3 and extracted with ethyl acetate (RINKAN) (3 × 30 mL). The combined organic layers were washed with water and brine (3 × 5 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 / RINKAN) (5:1) to obtain 5-(4,5-dibromo-2-methylthiophen-3-yl)-1,3,4-thiadiazole-2-amine (800 mg, yield 89%). LCMS(ESI, m / z) = 355[M+1] + .

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

[0616] Step 5: 2-(4,5-dibromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (600 mg, 1.38 mmol, 1.00 equivalent) was added to a stirred solution containing acetic acid (AcOH) (5 mL) and H2O (5 mL) at room temperature, to which Zn (540 mg, 8.26 mmol, 5.96 equivalents) was added. The resulting mixture was stirred at room temperature for 3 hours. The mixture was then diluted with water and extracted with ethyl acetate ( Depositphotos) (3 × 50 mL). The combined organic layers were washed with water and brine (3 × 5 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (PE / siRNA) (5:1) to obtain 2-(4-bromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (440 mg, 90% yield). LCMS (ESI, m / z) = 355[M+1]+.

[0617] Step 6: CuCN (230 mg, 2.57 mmol, 2.07 equivalents) was added to a 5 mL NMP solution of 2-(4-bromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (440 mg, 1.24 mmol, 1.00 equivalent) at room temperature. The resulting mixture was stirred at 150°C for 3 hours. The mixture was then extracted with RINKAN (3 × 30 mL). The combined organic layers were washed with water and brine (3 × 5 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (PE / Â) (5:1) to obtain 4-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]-5-methylthiophene-3-carbonitrile (300 mg, yield 80%). LCMS(ESI, m / z) = 301[M+1]+.

[0618] Step 7: 300 mg, 0.99 mmol, 1.00 equivalent of 4-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]-5-methylthiophene-3-carbonitrile (300 mg, 0.99 mmol, 1.00 equivalent) was added dropwise to a stirred solution containing 2 mL of H2O and 1 mL of tetrahydrofuran (THF) at room temperature, to which 2 mL of trifluoroacetic acid (TFA) was added. The resulting mixture was stirred at 50°C for 2 hours and then concentrated under vacuum. The resulting residue was then purified by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN), gradient from 0% to 100% over 10 minutes; detector, UV 254 nm) to obtain 130 mg, 58% yield of 4-(5-amino-1,3,4-thiadiazole-2-yl)-5-methylthiophene-3-carbonitrile (130 mg, yield 58%). LCMS(ESI, m / z) = 222[M+1] + .

[0619] Step 8: 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 3 of Example 6) (192 mg, 0.649 mmol, 1.07 equivalents) and 4-(5-amino-1,3,4-thiadiazole-2-yl)-5-methylthiophene-3-carbonitrile (120 mg, 0.608 mmol, 1.00 equivalent) were mixed in N,N-dimethylformamide (DMF) (5 mL) and hydroxybenzotriazole (HOBT) (102 mg, 0.755 mmol, 1.24 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (141 mg, 0.736 mmol, 1.21 equivalents) were added at room temperature to a stirred solution. The resulting mixture was stirred at 50°C for 3 hours. The obtained solid was collected by filtration and washed with DMF (3 × 1 mL) to obtain N-[5-(4-cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazole-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide (200 mg, yield 69%). 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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 140) was prepared using 2-methoxyethane-1-amine as the "amine reagent" and N-[5-(4-cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazole-2-yl]-4-iodo-5-methoxy-6-oxopyrane-2-carboxamide as the "halopyrane 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 141) [ka] Step 1: To a solution of tetrahydrofuran (THF) (150 mL) of 2-(2,5-dimethylpyrrole-1-yl)-5-(pyrazole-1-yl)-1,3,4-thiadiazole (product of Step 2 of Part B of Example 1) (6.0 g, 24 mmol, 1.0 equivalent) was added dropwise to hexane (2.5 M) containing n-butyllithium (n-BuLi) (12 mL, 30 mmol, 1.2 equivalents) over 15 minutes at -78°C under N2 (nitrogen gas). The resulting mixture was stirred for a further 1.5 hours at -78°C. Then, ethyl iodide (4500 mg, 28.85 mmol, 1.18 equivalents) was added dropwise to the mixture over -78°C under N2. The resulting mixture was stirred for a further 1.5 hours at room temperature. The reaction was then stopped with saturated NH4Cl (aqueous solution) at 0°C. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 300 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (PE / Depositphotos) (9:1) to obtain 2-(2,5-dimethylpyrrole-1-yl)-5-(5-ethylpyrazole-1-yl)-1,3,4-thiadiazole (5100 mg, yield 72%). LCMS (ESI, m / z) = 274.0[M+1]+.

[0622] Step 2: To a solution of 2-(2,5-dimethylpyrrole-1-yl)-5-(5-ethylpyrazole-1-yl)-1,3,4-thiadiazole (5000 mg, 19.28 mmol, 1.00 equivalent) in THF (10 mL), H2O (20 mL) and trifluoroacetic acid (TFA) (20 mL) were added at room temperature. The resulting mixture was stirred at 60°C for 4 hours and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (water with acetonitrile (MeCN), gradient from 10% to 50% over 15 minutes, detector, UV 254 nm) to obtain 5-(5-ethylpyrazole-1-yl)-1,3,4-thiadiazole-2-amine (3000 mg, yield 82%). LCMS (ESI, m / z) = 196.0[M+1]+.

[0623] Step 3: To a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Step 4 of Part A of Example 1) (200 mg, 0.80 mmol, 1.00 equivalent) in acetonitrile (MeCN) (5 mL) at room temperature, chloro-N,N,N',N'-tetramethylformamidinium hexafluoride phosphate (TCFH) (270 mg, 0.96 mmol, 1.20 equivalent), N-methylimidazole (NMI) (132 mg, 1.61 mmol, 2.00 equivalent), and 5-(5-ethylpyrazole-1-yl)-1,3,4-thiadiazole-2-amine (157 mg, 0.80 mmol, 1.0 equivalent) were added. The resulting mixture was stirred overnight at room temperature. The resulting solid was collected by filtration and washed with acetonitrile. Subsequently, the solid was purified by grinding with acetonitrile and water (15 mL) to obtain 4-bromo-N-[5-(5-ethylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-6-oxopyran-2-carboxamide (150 mg, yield 39%). 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 141) was prepared using 2-methoxyethane-1-amine as the "amine reagent" and 4-bromo-N-[5-(5-ethylpyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 141) 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-pyrazole-1-yl)-1,3,4-thiadiazole-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 tetrahydrofuran (THF) (100 mL) containing 2-(2,5-dimethylpyrrole-1-yl)-5-(pyrazole-1-yl)-1,3,4-thiadiazole (product of Step 2 of Part B of Example 1) (5.0 g, 20 mmol, 1.0 equivalent) was added dropwise with n-butyllithium (n-BuLi) (8.97 mL, 22.4 mmol, 1.10 equivalent) over 5 minutes at -78°C. The resulting mixture was stirred at -78°C for 1 hour. Then, ethyl fumarate (4.53 g, 61.1 mmol, 3.00 equivalent) was added dropwise to the mixture over 5 minutes at -78°C. The mixture was stirred for a further 1 hour at -78°C, and then the reaction was stopped with saturated NH4Cl (aqueous solution) at 0°C. The aqueous layer was extracted with ethyl acetate ( Depositphotos) (3 × 100 mL). The resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (PE / siRNA) (8:1) to obtain 2-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]pyrazole-3-carboaldehyde (3.5 g, yield 56%). LCMS (ESI, m / z) = 274.2[M+1]+.

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

[0627] Step 3: To a solution of {2-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]pyrazole-3-yl}methanol (3.3 g, 12 mmol, 1.0 equivalent) in tetrahydrofuran (THF) (16 mL), H2O (16 mL) and trifluoroacetic acid (TFA) (20 mL) were added at room temperature. The resulting mixture was stirred at 60 °C for 5 hours, and then concentrated under reduced pressure. The residue was then purified by C18 reverse-phase flash chromatography (water with acetonitrile (MeCN), gradient from 10% to 50% over 10 mins; detector, UV 254 nm) to obtain [2-(5-amino-1,3,4-thiadiazole-2-yl)pyrazole-3-yl]methanol (1.5 g, yield 57%). 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 Step 3, Example 6) (2.25 g, 7.61 mmol, 1.00 equivalent) in N,N-dimethylformamide (DMF) (20 mL) at room temperature, hydroxybenzotriazole (HOBT) (1.54 g, 11.4 mmol, 1.50 equivalent), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.92 g, 15.2 mmol, 2.00 equivalent), and [2-(5-amino-1,3,4-thiadiazole-2-yl)pyrazole-3-yl]methanol (1.5 g, 7.6 mmol, 1.0 equivalent) were added. The resulting mixture was stirred at room temperature for 1 hour. The reaction was then stopped with water at room temperature. The resulting solid was collected by filtration and washed with water. The filtrate was concentrated under reduced pressure to obtain N-{5-[5-(hydroxymethyl)pyrazole-1-yl]-1,3,4-thiadiazole-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)-1-methoxypropan-2-amine was used as the "amine reagent" and N-{5-[5-(hydroxymethyl)pyrazole-1-yl]-1,3,4-thiadiazole-2-yl}-4-iodo-5-methoxy-6-oxopyran-2-carboxamide was used as the "halopyron reagent" to prepare (R)-N-(5-(5-(hydroxymethyl)-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 142). 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 144) [ka] Step 1: Diethylaminosulfur trifluoride (DAST) (826 mg, 5.12 mmol, 2.00 equivalent) was added at 0°C to a solution of 2-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole-2-yl]pyrazole-3-carboaldehyde (product from Step 1 of Example 32) (700 mg, 2.56 mmol, 1.00 equivalent) in dichloromethane (DCM) (5 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The reaction was then stopped by adding water (2 mL) at room temperature, and the mixture was extracted with ethyl acetate (Â) (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 / Â) (5:1) to obtain 2-[5-(difluoromethyl)pyrazole-1-yl]-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (300 mg, 40% yield).

[0631] Step 2: A solution containing 2-[5-(difluoromethyl)pyrazole-1-yl]-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (300 mg, 1.02 mmol, 1.00 equivalent) in tetrahydrofuran (THF) (1 mL) and H2O (0.5 mL) was prepared, to which trifluoroacetic acid (TFA) (0.5 mL) at 0°C was added. The resulting mixture was stirred at 60°C for 2 hours under an air atmosphere. 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 / SiO) (5:1) to obtain 5-[5-(difluoromethyl)pyrazole-1-yl]-1,3,4-thiadiazole-2-amine (190 mg, yield 86%). LCMS (ESI, m / z) = 218.0[M+1]+.

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

[0633] Step 4: Following Step 2 of Part C of Example 1, N-(5-(5-(difluoromethyl)-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 144) was prepared using 4-bromo-N-{5-[5-(difluoromethyl)-1H-pyrazole-1-yl]-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 144) as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". 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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 145) [ka] Step 1: A solution containing thiophene-3-carbonitride (500 mg, 4.58 mmol, 1.00 equivalent), 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) (123 mg, 0.458 mmol, 0.10 equivalent), and bis(1,5-cyclooctadiene)dimu-methoxydiiridium(I)[Ir(OMe)(COD)]2 (304 mg, 0.458 mmol, 0.10 equivalent) in hexane (2 mL) was stirred at room temperature under N2 (nitrogen gas) for 2 minutes. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (586 mg, 4.58 mmol, 1.00 equivalent) was added dropwise to the mixture over 2 minutes at 0°C. The resulting mixture was stirred further at room temperature for 48 hours, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography using petroleum ether / ethyl acetate (PE / siRNA) (1:1) to obtain 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile (220 mg, yield 20%).

[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-carbonitride was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitride to obtain 2-(5-amino-1,3,4-thiadiazole-2-yl)thiophene-3-carbonitride (the product of step 3 of this example), and then 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid and a capri By coupling with 2-methoxyethane-1-amine, the compound N-(5-(3-cyanothiophen-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide was obtained as the "halopyrone reagent," and then coupled with 2-methoxyethane-1-amine, the "amine reagent," to prepare N-(5-(3-cyanothiophen-2-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (compound 145). 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-chloropyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-5-methoxy-4-[(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (compound 148) [ka] Step 1: To a solution of tetrahydrofuran (THF) containing 2-(2,5-dimethylpyrrole-1-yl)-5-(pyrazole-1-yl)-1,3,4-thiadiazole (product of Step 2 of Part B of Example 1) (1000 mg, 4.077 mmol, 1.00 equivalent), n-butyllithium (n-BuLi) (2.4 mL, 6.0 mmol, 1.5 equivalent) was added dropwise at -78°C under N2 (nitrogen gas). The solution was stirred at -78°C for 1 hour, and then hexachloroethane (C2Cl6) (1000 mg, 4.22 mmol, 1.04 equivalent) was added dropwise at -78°C. The resulting mixture was stirred at room temperature under N2 (nitrogen gas) for 2 hours, and then the reaction was stopped with saturated NH4Cl (aqueous solution) at 0°C. The aqueous layer was extracted with ethyl acetate (siRNA) (3 × 30 mL). The extract was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (PE / Â) (9:1) to obtain 2-(5-chloropyrazole-1-yl)-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (880 mg, yield 76%). LCMS (ESI, m / z) = 280.0[M+1]+.

[0637] Step 2: 2-(5-chloropyrazole-1-yl)-5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazole (880 mg, 3.15 mmol, 1.00 equivalent) was dissolved in THF (1 mL) and H2O (2 mL). Trifluoroacetic acid (TFA) (2 mL, 27 mmol, 8.6 equivalents) was added at room temperature. The resulting mixture was stirred at 60°C for 3 hours and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (water with acetonitrile (MeCN), gradient from 10% to 30% over 7 mins; detector, UV 254 nm) to obtain 5-(5-chloropyrazole-1-yl)-1,3,4-thiadiazole-2-amine (390 mg, yield 61%). LCMS (ESI, m / z) = 202.0[M+1]+.

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

[0639] Step 4: Following Step 2 of Part C of Example 1, N-[5-(5-chloropyrazole-1-yl)-1,3,4-thiadiazole-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide (compound 148) was prepared using 4-bromo-N-(5-(5-chloro-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the "halopyrone reagent" and 2-methoxyethane-1-amine as the "amine reagent". 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 149) [ka] Step 1: To a solution of 2,2-dimethylpropane-1,3-diol (10.0 g, 96.0 mmol, 1.00 equivalent) in tetrahydrofuran (THF) (100 mL) under stirring, NaH (3.60 g, 150 mmol, 1.56 equivalents) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, and then methyl iodide (CH3I) (16.0 g, 113 mmol, 1.17 equivalents) was added at 0°C. The resulting mixture was stirred overnight at room temperature, and then the reaction was stopped with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was poured into water and extracted with ethyl acetate (SiO) (3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL) and brine (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 using petroleum ether / ethyl acetate (PE / siRNA) (4:1) to obtain 3-methoxy-2,2-dimethylpropan-1-ol (2.9 g, yield 25%). LCMS(ES, m / z) = 119[M+1]+.

[0641] Step 2: Triphenylphosphine (PPh3) (800 mg, 3.05 mmol, 1.52 equivalents) was added to a stirred solution containing 3-methoxy-2,2-dimethylpropan-1-ol (479 mg, 4.06 mmol, 2.02 equivalents) and 4-bromo-3-hydroxy-2-oxo-2H-pyran-6-carboxylate methyl (product of Step 4 of Part A of Example 1) (500 mg, 2.01 mmol, 1.00 equivalent) in THF (5 mL) at room temperature. DBAD (700 mg, 3.04 mmol, 1.51 equivalents) was added to the above mixture at 0 °C. The resulting mixture was stirred further at 60 °C for 1 hour, then poured into water and extracted with  (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL) and brine (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 eluted with petroleum ether / ethyl acetate (PE / siRNA) (85:15) to obtain methyl 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-2-oxo-2H-pyran-6-carboxylate (544 mg, yield 77%). 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 equivalent), 10 mL of room temperature water containing HCl (6 M) was added. The resulting mixture was stirred overnight at 80°C and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN), gradient from 0% to 100% in 10 minutes (H2O:MeCN=1:1)) to obtain 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-2-oxo-2H-pyran-6-carboxylic acid (370 mg, yield 71%). 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 equivalent), 5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-amine (product of Step 4 of Part B of Example 1) (260 mg, 1.44 mmol, 1.55 equivalent), and N,N-dimethyl To a stirred solution containing formamide (DMF) (3 mL), 1-((dimethylamino)(dimethylimino)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluoride phosphate (V) (HATU) (530 mg, 1.39 mmol, 1.51 equivalents) and diisopropylethylamine (DIEA) (180 mg, 1.39 mmol, 1.51 equivalents) were 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 obtain 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (310 mg, yield 67%). 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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 149) 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-oxopyrrolidine-1-yl)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 150) [ka] Step 1: A stirring solution containing (3R)-3-hydroxypyrrolidine-2-one (390 mg, 3.86 mmol, 1.99 equivalents) and methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (product of Step 2 in Example 6) (600 mg, 1.94 mmol, 1.00 equivalent) in dioxane (9 mL) is prepared. Add [(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 equivalents), 2'-(dicyclohexylphosphanyl)-N 2 ,N 2 ,N 6 ,N 6-Tetramethyl[1,1'-biphenyl]-2,6-diamine (CPhos) (172 mg, 0.394 mmol, 0.20 equivalents) and cesium carbonate (1880 mg, 5.77 mmol, 2.98 equivalents) were added at room temperature under N2 (nitrogen gas). The resulting mixture was stirred at 100°C for 1 hour under N2 (nitrogen gas), and then purified by silica gel column chromatography (yield 50%~100%) using petroleum ether / ethyl acetate (PE / siRNA) to obtain methyl 4-[(3R)-3-hydroxy-2-oxopyrrolidine-1-yl]-5-methoxy-6-oxopyrran-2-carboxylate (90 mg, yield 13%). LCMS (ES, m / z) = 284[M+1]+.

[0646] Step 2: To a solution of methyl 4-[(3R)-3-hydroxy-2-oxopyrrolidine-1-yl]-5-methoxy-6-oxopyrran-2-carboxylate (50 mg, 0.18 mmol, 1.0 equivalent) in dichloromethane (DCM) (0.6 mL) under stirring, Ag2O (50 mg, 0.22 mmol, 1.22 equivalents) and MeI (0.6 mL) were added at room temperature. The resulting mixture was stirred at 50°C for 2 hours. The resulting mixture was then filtered, and the filtrate was washed with dichloromethane (DCM) (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain methyl 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidine-1-yl]-6-oxopyrran-2-carboxylate (40 mg, yield 61%). LCMS(ES, m / z) = 298[M+1]+.

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

[0648] Step 4: To a solution of 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidine-1-yl]-6-oxopyrran-2-carboxylic acid ("Aminopyrone Reagent") (80 mg, 0.28 mmol, 1.0 equivalent) in N,N-dimethylformamide (DMF) (2 mL) under stirring, hydroxybenzotriazole (HOBT) (60 mg, 0.44 mmol, 1.57 equivalents), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (108 mg, 0.56 mmol, 1.99 equivalents), and 5-(5-methylpyrazole-1-yl)-1,3,4-thiadiazole-2-amine (product of Step 4 of Part B of Example 1; "ADT Amine Reagent") (50 mg, 0.28 mmol, 0.98 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours, and then purified directly by C18 reverse-phase flash chromatography (water containing acetonitrile (MeCN) (0.1% trifluoroacetic acid (TFA)), gradient from 20% to 40% over 10 minutes; detector: UV 254 nm) to obtain the crude product, which was then subjected to chiral preparative HPLC (SHIMADZU: column, Xselect CSH C18 OBD column 30 × 150 mm). Further purification by mobile phase, water (0.05% TFA), and MeCN (from 29% MeCN to 39% in 10 mins) was performed to obtain (R)-3-methoxy-4-(3-methoxy-2-oxopyrrolidine-1-yl)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 150) (7.4 mg, yield 5.8%). 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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 152) [ka] Step 1: Following Step 5 of Example 6, methyl 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6-carboxylate was prepared using methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (product of Step 2 of Example 6) and 1-(methoxymethyl)cyclopentan-1-amine. 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-oxopyrrolidine-1-yl]-6-oxopyrran-2-carboxylate as the "aminopyrone reagent" 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6-carboxylate A methyl amine was obtained, and then coupled with 5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-amine (product of step 4 of part B of Example 1) as the "ADT amine reagent" to prepare 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 153b) * ) [ka] Step 1: Rac-5-methoxy-4-{[cis-2-methoxycyclopentyl]amino}-6-oxopyran-2-carboxylic acid ester was prepared according to Step 5 of Example 6 using methyl 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylate and (1,2-cis)-2-methoxycyclopentane-1-amine hydrochloride. LCMS(ES, m / z) = 298[M+1]+.

[0652] Step 2: Methyl iodide (360 mg, 2.54 mmol, 9.31 equivalents) and tert-butoxypotassium (122 mg, 1.09 mmol, 3.99 equivalents) were added at 0°C to a dimethylformamide (DMF) (5 mL) solution of rac-5-methoxy-4-{[cis-2-methoxycyclopentyl]amino}-6-oxopyrane-2-carboxylate methyl (81 mg, 0.27 mmol, 1.0 equivalent) 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 ( Depositphotos) (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using petroleum ether / ethyl acetate (PE / siRNA) (1:1) to obtain rac-5-methoxy-4-{[cis-2-methoxycyclopentyl](methyl)amino}-6-oxopyrane-2-carboxylate methyl (63 mg, yield 66%). LCMS(ES, m / z) = 312[M+1]+.

[0653] Steps 3-4: Following steps 3-4 of Example 37, rac-5-methoxy-4-{[cis-2-methoxycyclopentyl](methyl)amino}-6-oxopyrran-2-carboxylate methyl was used in place of 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidine-1-yl]-6-oxopyrran-2-carboxylate 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 as the "ADTamine reagent" By coupling with -(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-2-amine (product of step 4 of part B of Example 1), rac-5-methoxy-4-{[cis-2-methoxycyclopentyl](methyl)amino}-6-oxopyran-2-carboxylate methyl is converted to 3-methoxy-4-(((1S,2R)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H-pyrazole-1-yl)-1,3,4-thiadiazole-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-pyrazole-1-yl)-1,3,4-thiadiazole-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-thiadiazole-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 156) [ka] Step 1: A mixture containing (2-methoxyethyl)[(4-methoxyphenyl)methyl]amine (1000 mg, 5.12 mmol, 1.00 equivalent) and methyl 4-iodo-5-methoxy-6-oxopyrane-2-carboxylate (product of Step 2 in Example 6) (1000 mg, 3.22 mmol, 0.63 equivalents) in N,N-dimethylformamide (DMF) (10 mL) was mixed with CuI (205 mg, 1.08 mmol, 0.21 equivalents), N,N-diethyl-2-hydroxybenzamide (198 mg, 1.02 mmol, 0.20 equivalents), and K2CO3 (1000 mg, 7.24 mmol, 1.41 equivalents). The resulting mixture was stirred at 100°C for 1 hour under N2 (nitrogen gas), and then diluted with water (50 mL). The mixture was extracted with ethyl acetate ( Depositphotos) (3 × 150 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (PE / Depositphotos) (1:2) to obtain methyl 5-methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-carboxylate (600 mg, yield 31%). LCMS (ES, m / z) = 378.0[M+1]+.

[0655] Step 2: A mixture containing methyl 5-methoxy-4-[(2-methoxyethyl)[(4-methoxyphenyl)methyl]amino]-6-oxopyran-2-c...

Claims

1. Compound of formula (I): 【Chemistry 1】 [During the ceremony, Ring A is a five-membered monocyclic heteroaryl; R ３ is C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, -L ３ -(C ３ -C ６ carbocyclic), or -L ３ -(4- to 10-membered heterocyclyl), and the alkyl, the alkenyl, the alkynyl, the carbocyclic and the heterocyclyl are each independently substituted with 0, 1, 2, 3 or 4 R １Ａ ; each R １Ａ is 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 that appear together form =O; each R １Ｂ is independently hydrogen, C １ -C ４ alkyl, or C １ -C ４ haloalkyl, and the alkyl and the haloalkyl are each independently substituted with 0, 1, 2, 3 or 4 R １Ｄ ; each R １Ｃ is independently hydrogen, C １ -C ３ alkyl, C １ -C ３ haloalkyl, or -OR １Ｆ ; each R １Ｄ is independently halogen, -OR １Ｆ , or -N(R １Ｄ )([[]] ２ [[]]); each R １Ｆ is independently hydrogen, C １Ｆ ), or -N(R ２ ); each R １Ｆ is independently hydrogen, C １ -C ３ Alkyl, or C １ -C ３ It is a haloalkyl; group R １ L ３ C １ -C ３ Alkylene, or -(C １ -C ３ The alkylene is -O-, and the alkylene independently has 0, 1, 2, 3 or 4 R １Ｅ It is replaced by; each R １Ｅ Independently, -(C １ -C ３ Alkylene) - OR １Ｂ , or -OR １Ｂ or two R's that appeared １Ｅ However, together they form the O; R ２ This is hydrogen, or 0, 1, 2, 3 or 4 R atoms. ２Ａ C replaced by １ -C ６ It is alkyl, and each R ２Ａ These are, independently, halogen, -OR ２Ｂ , or -N(R ２Ｂ ) ２ And each R ２Ｂ These are, independently, hydrogen and C １ -C ３ Alkyl, or C １ -C ３ It is a haloalkyl; Alternatively, R １ and R ２ These atoms, along with the atoms they are bonded to, independently form 0, 1, 2, 3, or 4 R atoms. １Ａ It forms a six- or seven-membered heterocycline that is substituted with; R ３ C １ -C １０ Alkyl, C ２ -C １０ Alkenil, C ２ -C １０ Alkinyl, C ３ -C １０ The molecule is a carbocyclyl or a 4- to 10-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl each independently have 0, 1, 2, 3, or 4 R groups. ３Ａ It has been replaced with; Alternatively, R ２ and R ３ together with the atoms to which they are attached are attached to form, independently, a 4- to 10-membered heterocyclyl substituted with 0, 1, 2, 3 or 4 R ３Ａ ; Each R ３Ａ is independently C 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 carbocyclic), -L １ -(4- to 6-membered heterocyclic), -L １ -(C ６－１０ aryl), or -L １ -(5- to 10-membered heteroaryl), or two R ３Ａ groups are attached together with the atoms to which they are attached to form C ６ aryl, 5- to 6-membered heteroaryl, C ３ -C ６ carbocyclic, or 4- to 6-membered heterocyclic, and the alkyl, the alkenyl, the alkynyl, the carbocyclic, the heterocyclic, the aryl and the heteroaryl are each independently substituted with 0, 1, 2, 3 or 4 R ３Ｄ ; Each R ３Ｂ These are, independently, hydrogen and C １ -C ３ Alkyl, C ３ -C ６ The alkyl group is a carbocyclyl, or a 4-6 membered heterocyclyl, wherein the alkyl group, the carbocyclyl, and the heterocyclyl independently have 0, 1, 2, 3, or 4 R groups. ３Ｄ It has been replaced with; Each R ３Ｃ Independently, C １ -C ３ Alkyl, or C １ -C ３ It is a haloalkyl; Each R ３Ｄ These are, independently, halogen, -OR ３Ｅ ,-CN,C １ -C ３ Alkyl, or C １ -C ３ It is a haloalkyl; Each R ３Ｅ These are, independently, hydrogen and C １ -C ４ Alkyl, or C １ -C ４ It is a haloalkyl; Each R ４ These are, independently, halogen, -CN, and -L ２ -OR ４Ａ , -L ２ -N(R) ４Ｂ ) ２ , C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, and each R ４Ａ and R ４Ｂ These are, independently, hydrogen and C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or -C(=O)R ４Ｃ And R ４Ｃ C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl; Each L １ and L ２ Independently, combined, C １ -C ３ Alkylene, or C １ -C ３ It is a haloalkylene; m is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

2. (i) Amino portion 【Chemistry 2】 is the formula 【Transformation 3】 It is a base of and the compound is of formula (I'): 【Chemistry 4】 [In the formula, L ３ C １ -C １０ Alkylene, C ２ -C １０ Alkenylene, or C ２ -C １０ It is an alkynylene, and p is 0, 1, 2, or 3. Having or a pharmaceutically acceptable salt thereof; or (ii) Amino portion 【Transformation 5】 is the formula 【Transformation 6】 It is a base of and the compound is of formula (I''): 【Transformation 7】 [In the formula, ring B is C ３ -C １０ It is a carbocyclyl or a 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3. Having or a pharmaceutically acceptable salt thereof; or (iii) Amino portion 【Transformation 8】 is the formula 【Chemistry 9】 The compound is of formula (I'''): 【Chemistry 10】 [In the formula, ring C is a 5- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.] The compound according to claim 1, having or a pharmaceutically acceptable salt thereof.

3. The aforementioned compound is of formula (I''''): 【Chemistry 11】 [In the formula, the nitrogen atom of heteroaryl ring A is directly bonded to the thiadiazole moiety.] The compound according to claim 1, having or a pharmaceutically acceptable salt thereof.

4. R １ However, 0, 1, 2, 3 or 4 R １Ａ C replaced by １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which 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】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

7. R ３ However, 0, 1, 2, 3 or 4 R ３Ａ C replaced by １ -C １０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

8. amino acid portion 【Chemistry 13】 but, 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

9. Ring A is 【Chemistry 19】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. Each R ４ However, independently, -CH ３ ien-CH ２ CH ３ ,-CHF ２ , -CF ３ , -Cl, -CN, -NH ２ , or -CH ２ The compound according to claim 9, or a pharmaceutically acceptable salt thereof, which is an OH group.

11. Ring A is 【Chemistry 20】 The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound is of the formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-a-1), (I-a-2), (I-a-3), (I-f-1), (I-f-2), (I-f-3), (I-BC-a), or (I-BC-b): 【Chemistry 20】 【Chemistry 20】 【Chemistry 20】 [In the equation, x is 0, 1, 2, 3, or 4] The compound according to claim 1, having or a pharmaceutically acceptable salt thereof.

13. The aforementioned compound is as follows: 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 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. The aforementioned compound 【Chemistry 21】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. The aforementioned compound 【Chemistry 22】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

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

17. Compound 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 method for preparing the salt thereof, (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 [It is a haloalkyl] This includes performing peptide coupling of to obtain 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】 [In the formula, X is Cl, Br, or I] This involves performing a cross-coupling operation to obtain a compound of formula (I) or a salt thereof. The aforementioned 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 method for preparing a salt thereof, comprising a compound of formula (P-1): 【Chemistry 27】 [In the formula, LG is a leaving group.] The method comprising cyclizing 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. A pharmaceutical composition according to claim 19 for treating a disease or disorder in a person in need thereof, wherein the disease or disorder is inflammation, autoimmune disease, cancer, disease or disorder of the central nervous system, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, rheumatic disease, or psychological disorder.

21. The pharmaceutical composition according to claim 20, wherein the disease or disorder is systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), frostbite-like lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), scleroderma, Ecardi-Goutier syndrome, dermatomyositis, systemic sclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, or Sjögren's syndrome (SS).

22. A pharmaceutical composition according to claim 19 for regulating cGAS activity in cells.

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