Heterocyclic compound and use thereof

Abstract

The present invention relates to a heterocyclic compound and the use thereof. Specifically, the present invention relates to a compound represented by formula (I), a pharmaceutical composition comprising the compound represented by formula (I), and the use thereof as a cGAS inhibitor in the treatment of related diseases, such as autoimmune diseases.

Description

A heterocyclic compound and its uses Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a novel class of cyclic GMP-AMP synthase (cGAS) inhibitors, their preparation methods, and their pharmaceutical uses.

[0002] Specifically, the present invention provides a class of novel compounds and their pharmaceutically acceptable salts, stereoisomers, tautomers or solvates, said compounds having inhibitory activity against cyclic GMP-AMP synthase (cGAS); the present invention also provides pharmaceutical compositions comprising the above compounds, and the use of said compounds or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of diseases or conditions associated with cyclic GMP-AMP synthase. Background Technology

[0003] Abnormal accumulation of DNA in the cytoplasm can trigger a series of immune responses, including the production of type I interferon and other cytokines. While these factors play an important role in antibacterial defense, overactivation may lead to autoimmune diseases.

[0004] Existing technologies indicate that cytoplasmic DNA signaling pathways include multiple signaling molecules such as interferon gene-stimulating factor (STING), transcription factor NF-κB, and IRF3. Studies have found that a circular GMP-AMP molecule (cGAMP) synthesized from ATP and GTP exists in mammalian cytoplasm. cGAMP production can be induced when mammalian cells undergo DNA transfection or DNA viral infection. cGAMP, upon binding to STING, can activate IRF3 and induce the production of type I interferon (IFN-β), thus confirming that cGAMP plays a crucial role as an endogenous second messenger in cytoplasmic DNA responses.

[0005] Circular GMP-AMP synthase (cGAS) is a nucleotide transferase that regulates the synthesis of circular cGAMP. Previous studies have shown that overexpression of cGAS can activate the transcription factor IRF3 via a STING-dependent pathway and induce the production of type I interferon; conversely, the absence of cGAS can inhibit the activation of IRF3 and the production of type I interferon. These findings suggest that cGAS, as a cytoplasmic DNA sensor, mediates interferon production by generating the second messenger cGAMP (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)).

[0006] Furthermore, existing research has revealed that cGAS plays an important role in various biological processes such as cellular senescence and micronucleus monitoring. Therefore, developing therapeutics targeting cGAS has significant clinical implications.

[0007] Although cGAS plays an important role in immune responses and disease development, no drugs targeting cGAS have been approved for marketing globally. As our understanding of the mechanisms by which cGAS plays a role in disease development and progression deepens, its importance as a therapeutic target is becoming increasingly apparent. The lack of effective inhibitors for cGAS in current technologies severely limits treatment options for related diseases. Therefore, developing highly effective and selective small-molecule inhibitors of cGAS has significant clinical application value for treating autoimmune diseases and related conditions (Gao et al., PNAS 112, E5699-E5705 (2015), Pisetsky et al., Nat. Rev. Rheumatol. 12, 102-110 (2016)).

[0008] In view of this, the present invention provides a novel class of small molecule cGAS inhibitors that can effectively inhibit cGAS activity, offering a new treatment option for autoimmune diseases. The technical solution of the present invention not only solves the technical problem of the lack of effective cGAS inhibitors in the prior art, but also provides a new treatment method for related diseases. Summary of the Invention

[0009] To address the aforementioned problems, this invention provides a small molecule inhibitor for the treatment of autoimmune diseases.

[0010] In a first aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, solvate, prodrug, deuterated derivative, or pharmaceutically acceptable salt thereof:

[0011] in,

[0012] Indicates a single bond or a double bond;

[0013] Y is selected from S or Se;

[0014] R1 is selected from -OR a -N(R) a )2、-C(O)R a -SR a -S(O)R a -S(O)2R a -CN, nitro, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein, the R a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more R b Replaced;

[0015] R2 is selected from non-existent, hydrogen, deuterium, -OR a -N(R) a )2、-C(O)R a -SR a -S(O)R a -S(O)2R a -CN, nitro, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein, the R a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more R b Replaced;

[0016] R3 is selected from O, -OR a NR a 、N(R a )2、-C(O)R a -C(=NR) a )R a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein, the R a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more Rb Replaced;

[0017] R4 is selected from non-existent, O, or NR. c ;

[0018] R5 is selected from -OR a -N(R) a )2、-C(O)R a -C(=NR) a )R a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein, the R a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more R b Replaced;

[0019] R6 and R7 are selected from hydrogen, deuterium, and -OR. a -N(R) a )2、-C(O)R a -SR a -S(O)R a -S(O)2R a -CN, nitro, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein, the R a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more R b Replaced; or

[0020] R1 and R2, R1 and R3, R2 and R5, R3 and R5 and / or R5 and R c Together with the atoms to which they are attached, they form 3-14 membered heterocyclic groups; wherein, the 3-14 membered heterocyclic groups are optionally surrounded by one or more R b Replaced;

[0021] Ring A is selected from C 6-10 Aryl, 3-14 membered heterocyclic or 5-14 membered heteroaryl;

[0022] Each R a R c Same or different, independent selection - OR b -N(R) b )2、-C(O)R b -SR b -S(O)R b -S(O)2R b Hydrogen, deuterium, -CN, nitro, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 10 Aryl or 5-10 heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. b Replaced;

[0023] Each R b The same or different, independently selected from hydrogen, deuterium, oxo, -OH, halogen, nitro, -CN, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 3-14 cycloalkyl, -OC 3-14 Heterocyclic groups, -SC 3-14 Heterocyclic groups, -SC 3-14 cycloalkyl, -SC 1-6 Alkyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 2-6 alkenyl), -N(C) 2-6 alkenyl)2, -NH(C 2-6 alkynyl group), -N(C 2-6 ynyl group)2, -CONH2, -CONH(C 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-CONH(C2-6 alkenyl), -CON(C) 2-6 alkenyl)2, -CONH(C 2-6 alkynyl group), -CON(C) 2-6 2-S(O)-C (alkynyl group) 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 alkenyl, -S(O)2-C 2-6 alkenyl, -S(O)-C 2-6 alkynyl group, -S(O)2-C 2-6 alkynyl group, -S(O)-C 3-14 cycloalkyl, -S(O)2-C 3-14 Heterocyclic groups, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1- 6-alkyl)2, -CHO, -COOH, -C(O)-C 1-6 Alkyl, -C(O)-C 2-6 alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 alkylene-5-14-membered heteroaryl, -C 0-6 Alkylene-C 3-14 carbonyl group, or -C 0-6 Alkylene-3-14-membered heterocyclic group; wherein, the C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkylene, C 3- 14 cycloalkyl, C 3-14 Heterocyclic group, C 6-14 Aryl, 5-14 quinone heteroaryl and C 3-14 The carbocyclic group may optionally be substituted by one or more substituents selected from the following: hydrogen, deuterium, halogen, -CN, -OH, thiol, nitro, NH2, -CHO, -COOH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COO(C 1-6Alkyl), -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-OCO(C 1- 6-alkyl), -NHCO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CONH(C 1-6 alkyl), -N(C) 1- 6-alkyl)-CON(C 1-6 Alkyl)2, -C 0-6 Alkylene-NHC(=O)C 1-6 Alkyl, -C 0-6 Alkylene-C(=O)NH-C 1-6 Alkyl, -C 0-6 Alkylene-C(=O)N(C) 1-6 Alkyl)2, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2- 6-Alkenyl, substituted or unsubstituted -C 0-6 Alkylene-C 3-14 Carbocyclic group, substituted or substituted -C 0-6 Alkylene-3-14-membered heterocyclic group, substituted or unsubstituted -C 0-6 Alkylene-C 6-14 aryl, and substituted or unsubstituted -C 0-6 alkylene-5-14-membered heteroaryl;

[0024] n is selected from 0, 1, 2, 3, 4, 5 or 6.

[0025] In some implementations, Y in formula (I) is selected from S.

[0026] In some implementations, Y in formula (I) is selected from Se.

[0027] In some embodiments, ring A in formula (I) is selected from 5-membered monocyclic heteroaryl groups.

[0028] In some implementations, in equation (I), if If there is a double bond between them, then There is a single bond between them, and R2 is selected from those that do not exist.

[0029] In some implementations, in equation (I), if If there is a single bond between them, then There is a double bond between them.

[0030] In some implementations, in formula (I) Selected from the following structures:

[0031] In some implementations, R1 in equation (I) is selected from -OR a .

[0032] In some implementations, R1 in equation (I) is selected from -OR a ;where R a Selected from H, -CH3,

[0033] In some implementations, R1 in formula (I) is selected from...

[0034] In some embodiments, R1 and R2 in formula (I), together with the atoms to which they are attached, form a 3-11 membered heterocyclic group; wherein the 3-11 membered heterocyclic group is optionally surrounded by one or more R... b What it replaced.

[0035] In some embodiments, R3 and R5 in formula (I), together with the atoms to which they are attached, form a 3-11 member heterocyclic group (preferably a 3-6 member heterocyclic group); wherein the 3-11 member heterocyclic group (preferably a 3-6 member heterocyclic group) is optionally surrounded by one or more R b What it replaced.

[0036] In some implementations, R5 and R in equation (I) c Together with the atoms to which they are attached, they form 3-11 membered heterocyclic groups (preferably 3-6 membered heterocyclic groups); wherein, the 3-11 membered heterocyclic group (preferably 3-6 membered heterocyclic group) is optionally surrounded by one or more R b What it replaced.

[0037] In some embodiments, R2 and R5 in formula (I), together with the atoms to which they are attached, form a 3-11 member heterocyclic group (preferably a 3-6 member heterocyclic group); wherein the 3-11 member heterocyclic group (preferably a 3-6 member heterocyclic group) is optionally surrounded by one or more R b What it replaced.

[0038] In some embodiments, R2 in formula (I) is selected from hydrogen, deuterium, or C. 1-6 alkyl.

[0039] In some implementations, in formula (I) Selected from

[0040] In some implementations, in formula (I) Selected from

[0041] In some embodiments, R4 in formula (I) is selected from O, NH or NCH3.

[0042] In some embodiments, the formula (I) Selected from -CH3, -CH2CH3, -CH2CH2CH3, O = 、 NH=、CH3N=、

[0043] In some embodiments, R5 in formula (I) is selected from -CH3, -CH2CH3, -CH2CH2CH3, -N(CH3)2、

[0044] In some embodiments, R3 and R5 in formula (I), together with the atoms they are attached to, form the following structure:

[0045] In some embodiments, formula (I) is selected from the structure of formula (II) shown below:

[0046] Among them, R1, R3, R5, R6, Y, ring A and n are defined as in equation (I) above.

[0047] In some embodiments, formula (I) is selected from the structure of formula (III) shown below:

[0048] Among them, R1, R3, R5, R6, R c The definitions of Y, ring A and n are as described above for equation (I).

[0049] In some embodiments, formula (I) is selected from the structure of formula (IV) shown below:

[0050] Among them, R1, R2, R5, R6, R c The definitions of Y, ring A and n are as described above for equation (I).

[0051] In some embodiments, formula (I) is selected from the structure of formula (V) shown below:

[0052] Among them, R1, R2, R5, R6, Y, ring A and n are defined as in equation (I) above.

[0053] In some embodiments, formula (I) is selected from the following compounds:

[0054] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl))(oxo)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0055] 4-(((3-aminophenyl)(methyl)(oxo)-λ 6 -Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0056] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl))(oxo)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0057] N-(5-(2-chlorophenyl)-1,3,4-selenodiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0058] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2-hydroxyethyl)(3-nitrophenyl))(oxo)-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0059] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((2-methoxyethyl)(3-nitrophenyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0060] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((3-nitrophenyl)(oxetane-2-ylmethyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0061] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2,2-difluoro-3-methoxypropoxy)-4-((methyl(3-nitrophenyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0062] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((2-methoxyethyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0063] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(thiazol)-2-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0064] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((4-fluorophenyl)(methyl)(oxo))-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0065] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0066] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((4-cyanophenyl)(methyl)(oxo))-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0067] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-tetrahydro-1λ) 6 -Thiophene-1-methylene)amino)-2-oxo-2H-pyran-6-carboxamide;

[0068] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(pyridine)-4-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0069] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(pyridine)-2-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0070] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((dimethyl(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0071] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(phenyl))-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0072] N-(5-(5-amino-1H-pyrazole-1-yl)-1,3,4-selenodiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0073] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(methylsulfonylamino)-2-oxo-2H-pyran-6-carboxamide;

[0074] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(phenylsulfonamido)-2H-pyran-6-carboxamide;

[0075] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((3-methoxyphenyl)sulfonamido)-2-oxo-2H-pyran-6-carboxamide;

[0076] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((3-nitrophenyl)sulfonamido)-2-oxo-2H-pyran-6-carboxamide;

[0077] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(2-(methylamino))-2-oxoethyl)(oxo)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0078] N-(5-(5-chloro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(oxo))-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0079] N-(5-(5-cyano-1H-pyrazole-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(oxo))-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0080] N-(5-(5-(difluoromethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0081] N-(5-(3-cyanothiophene-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(oxo)-λ) 6 -sulfinyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0082] N-(5-(3-chlorothiophene-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(oxo)-λ) 6 -sulfinyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0083] 3-Methoxy-4-(((4-Methoxyphenyl)(methyl)(oxo)-λ 6 -thionyl)amino)-N-(5-(1-methyl-1H-imidazol-2-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide;

[0084] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(cyanomethoxy)-4-((methyl(oxo))(thiazol-2-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0085] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2-(2,2-difluoroethoxy)ethoxy)-4-((methyl(oxo)(thiazol-2-yl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0086] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(2-methylbutyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0087] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2,2-difluoroethyl)(4-methoxyphenyl)(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0088] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2-fluoropropyl)(4-methoxyphenyl))(oxo)-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0089] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(oxo)(3,3,3-trifluoropropyl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0090] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((imino(4-methoxyphenyl)(methyl)-)-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0091] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(methylimino)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0092] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(benzenesulfonamide amido)-2H-pyran-6-carboxamide;

[0093] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(N'-methylphenylsulfonamido)-2-oxo-2H-pyran-6-carboxamide;

[0094] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)sulfonamido)-2-oxo-2H-pyran-6-carboxamide;

[0095] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-((tetrahydrofuran)-3-sulfonamido)-2H-pyran-6-carboxamide;

[0096] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-methylpyrrolidin)-3-sulfonamido)-2-oxo-2H-pyran-6-carboxamide;

[0097] N-[5-(3-chloro-1-methylpyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-{[methyl(methylazinyl)(oxo)-λ] 6 [-thioalkyl]amino}-6-oxopyran-2-carboxamide;

[0098] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-(thiophen-2-sulfonamido)-2H-pyran-6-carboxamide;

[0099] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(furan-2-sulfonamido)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0100] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((3-methoxyphenyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0101] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((2-methoxyphenyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0102] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((3-fluoro-4-methoxyphenyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0103] 4-((benzo[d][1,3]dioxacyclopenten-5-yl(methyl)(oxo)-λ) 6 -Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0104] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(4-(methylthio))phenyl)(oxo)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0105] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2-fluorophenyl)(methyl)(oxo))-λ 6-Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0106] (E)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-((methoxyimino)methyl)phenyl)(methyl)(oxo)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0107] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((2-methoxyethyl)(4-methoxyphenyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0108] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((6-methoxypyridin-3-yl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0109] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(4-(methylamino))phenyl)(oxo)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0110] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(methyl)(oxo)-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0111] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxyfuran-2-yl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0112] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((4-methoxythiophen-2-yl)(methyl)(oxo)-λ) 6-Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0113] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((3-methoxythiophen-2-yl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0114] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(thiophene)-3-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0115] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((5-methoxythiophene-3-yl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0116] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((2-methoxyfuran-3-yl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0117] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(tetrahydrofuran)-3-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0118] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(tetrahydrofuran)-2-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0119] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(1-methylpyrrolidin-3-yl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0120] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(tetrahydro)-1H-furano[3,4-c]pyrrolo-5(3H)-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0121] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(morpholino)(oxo))-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0122] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((dimethylamino)(methyl)(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0123] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(1-methylpiperidin-4-yl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0124] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(tetrahydro)-2H-thiaran-3-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0125] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2-hydroxyethyl)(methyl)(oxo))-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0126] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((2-methoxyethyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0127] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2-fluorocyclopropyl)(methyl)(oxo))-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0128] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((2-methoxycyclopropyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0129] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2-(dimethylamino)cyclopropyl)(methyl)(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0130] 4-((benzo[b]thiophene-6-yl(methyl)(oxo)-λ) 6 -Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0131] 4-((benzo[b]thiophene-5-yl(methyl)(oxo)-λ) 6 -Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0132] 4-((benzofuran-5-yl(methyl)(oxo)-λ) 6 -Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0133] 4-(((1H-indole-5-yl)(methyl)(oxo)-λ 6 -Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0134] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(difluoromethoxy)-4-((methyl(oxo))(thiazol-2-yl)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0135] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(methoxy-d3)-4-((methyl(oxo)(thiazol-2-yl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0136] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((methyl(oxo)(thiazol-2-yl))-λ 6 -Thionyl)amino)-2-oxo-3-(trifluoromethoxy)-2H-pyran-6-carboxamide;

[0137] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((methyl(oxo)(thiazol-2-yl))-λ 6 -Thionyl)amino)-3-(oxetane-2-ylmethoxy)-2-oxo-2H-pyran-6-carboxamide;

[0138] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((methyl(oxo)(thiazol-2-yl))-λ 6 -Thionyl)amino)-3-(3-morpholinopropoxy)-2-oxo-2H-pyran-6-carboxamide;

[0139] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxy-2-(methoxymethyl)propoxy)-4-((methyl(oxo)(thiazol-2-yl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0140] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2-(difluoromethoxy)ethoxy)-4-((methyl(oxo)(thiazol-2-yl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0141] 3-(2-(tert-butoxy)ethoxy)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((methyl(oxo)(thiazol-2-yl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0142] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((methyl(oxo)(thiazol-2-yl))-λ 6 -Thionyl)amino)-2-oxo-3-((tetrahydrofuran-2-yl)methoxy)-2H-pyran-6-carboxamide;

[0143] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((4-chlorophenyl)(methyl)(oxo))-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0144] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-((oxodiphenyl-λ) 6 -Thionyl)amino)-2H-pyran-6-carboxamide;

[0145] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((4-oxy-1,4-λ) 6 -Thiaoxacyclohexane-4-thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0146] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-4-((4-oxo-1,4-oxathiacyclohexane-λ) 6 -4-methylene)amino)-2H-pyran-6-carboxamide;

[0147] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0148] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(p-tolyl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0149] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxo)(p-tolyl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0150] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiazepine-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0151] (R)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxy)(phenyl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0152] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiaza-2-yl)-3-methoxy-4-((4-oxy-1,4-λ) 6 -Thiohetero-4-thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0153] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((cyclopropyl(methyl)(oxy)-λ6-thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0154] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((cyclopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0155] N-(5-bromo-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0156] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiazepine-2-yl)-3-methoxy-4-(((4-methoxyphenyl)(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0157] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(3-chlorophenyl)-4-(((4-methoxyphenyl)(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0158] N-(5-(1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0159] N-(5-(5-iodo-1H-pyrazole-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0160] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxy)(thiazol-2-yl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0161] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-tetrahydro-2H-1-λ) 6 -Thiopyran-1-thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0162] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0163] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(difluoromethoxy)-4-((methyl(3-nitrophenyl)(oxy)-λ)6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0164] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(oxy)(thiophen-2-yl)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0165] N-(5-(5-acetamido-1H-pyrazole-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0166] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((3-methoxyphenyl)(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0167] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((3-fluorophenyl)(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0168] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((4-methoxyphenyl)sulfonamide)-2-oxo-2H-pyran-6-carboxamide;

[0169] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(methoxy-d3)-4-((methyl(3-nitrophenyl)(oxy)-λ) 6 -Thionyl))amino)-2-oxo-2H-pyran-6-carboxamide;

[0170] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-((3,3-difluorocyclobutyl)methoxy)-4-((methyl(3-nitrophenyl)(oxy)-λ) 6 (thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0171] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-3-vinyl-2H-pyran-6-carboxamide;

[0172] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-cyclopropyl-4-((isopropyl(methyl)(oxy)-λ) 6 (thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0173] 6-((5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)carboxamide)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-3-yldimethylcarbamate;

[0174] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((6-hydroxyhexyl)(oxy)(phenyl)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0175] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2,2-difluoroethoxy)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0176] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-3-(2-(prop-2-yn-1-yloxy)ethoxy)-2H-pyran-6-carboxamide;

[0177] N-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0178] 4-((isopropyl(methyl)(oxy)-λ) 6-Thionyl)amino)-3-methoxy-2-oxo-N-(5-(thien-2-yl)-1,3,4-thiadiazol-2-yl)-2H-pyran-6-carboxamide;

[0179] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-(3-morphopyroxy)-2-oxo-2H-pyran-6-carboxamide;

[0180] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(cyclopropylethynyl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0181] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiaza-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0182] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-(oxoethane-2-ylmethoxy)-2-oxo-2H-pyran-6-carboxamide;

[0183] 4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-N-(5-(4-methoxypyridin-2-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide;

[0184] 4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-N-(5-(1-methyl-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide;

[0185] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)(methyl)(oxy)-λ 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0186] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-3-hydroxy-2-oxo-2H-pyran-6-carboxamide;

[0187] 6-((5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)carboxamide)-4-((diisopropyl(oxy)-λ 6 -Thionyl)amino)-2-oxo-2H-pyran-3-yltrifluoromethanesulfonate;

[0188] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((hex-5-en-1-yl(isopropyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0189] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((3,3-dimethoxy-1-oxo-1-λ) 6 -Thioalkyl-1-thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0190] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((3-hydroxy-3-methoxy-1-oxo-1-λ) 6 -Thioene-1-methylene)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0191] 3-(2-(tert-butoxy)ethoxy)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0192] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(cyclopropylmethoxy)-N-(cyclopropylmethyl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0193] 3-(2-(tert-butoxy)ethoxy)-N-(2-(tert-butoxy)ethyl)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0194] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-2-oxo-3-((tetrahydrofuran-2-yl)methoxy)-2H-pyran-6-carboxamide;

[0195] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(cyclopropylmethoxy)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0196] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(3,5-difluorophenyl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0197] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-ethynyl-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0198] 3-(azacyclopropane-1-yl)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0199] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-3-(2-oxoazacyclopropane-1-yl)-2H-pyran-6-carboxamide;

[0200] 3-Acetyl-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0201] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-cyano-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0202] (E)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2-ethoxyvinyl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0203] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 (-thionyl)amino)-2-oxo-3-(prop-1-en-2-yl)-2H-pyran-6-carboxamide;

[0204] N-(5-(5-cyano-4-methylthiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0205] N-(5-(5-acetylthiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0206] 4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-N-(5-(thiazolyl-5-yl)-1,3,4-thiadiazol-2-yl)-2H-pyran-6-carboxamide;

[0207] N-(5-(2-(dimethylamino)thiazolyl-5-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0208] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-3-hydroxy-2-oxo-2H-pyran-6-carboxamide;

[0209] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-hydroxy-4-(((2-hydroxyethyl)(3-nitrophenyl)-oxy-λ) 6 -Thionyl)amino)-2-oxo-2H-pyran-6-carboxamide;

[0210] (R)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0211] (S)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxo)-λ) 6 -Thionyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0212] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-3-(methylamino)-2-oxo-2H-pyran-6-carboxamide;

[0213] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-3-(methylamino)-2-oxo-2H-pyran-6-carboxamide;

[0214] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thionyl)amino)-3-(1-hydroxyethyl)-2-oxo-2H-pyran-6-carboxamide;

[0215] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ)6 -Thionyl)amino)-3-ethyl-2-oxo-2H-pyran-6-carboxamide;

[0216] N-[5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0217] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-(1-hydroxyethyl)-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-2H-pyran-6-carboxamide;

[0218] N-[5-(5-ethynyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0219] 4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-N-[5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-2-oxo-2H-pyran-6-carboxamide;

[0220] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-3-(methylamino)-2-oxo-2H-pyran-6-carboxamide;

[0221] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-2-oxo-3-(2-oxoazacyclobutan-1-yl)-2H-pyran-6-carboxamide;

[0222] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(oxo)(propyl)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0223] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(ethyl(isopropyl)(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0224] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0225] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(4-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0226] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluorothiophen-2-yl)-1,3,4-thiadiazol-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0227] N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-3-(methylamino)-2-oxo-2H-pyran-6-carboxamide;

[0228] N-[5-(3-chloro-1-(trifluoromethyl)-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0229] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-2-oxo-3-(2-oxoazacyclobutane-1-yl)-2H-pyran-6-carboxamide;

[0230] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(diethyl(oxo)-λ] 6[-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide;

[0231] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-(dimethylamino)-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-2H-pyran-6-carboxamide;

[0232] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-3-(methylamino)-2-oxo-2H-pyran-6-carboxamide;

[0233] 3-(difluoromethoxy)-N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-2H-pyran-6-carboxamide;

[0234] 3-(difluoromethoxy)-4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-2-oxo-2H-pyran-6-carboxamide;

[0235] N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-3-vinyl-2H-pyran-6-carboxamide;

[0236] N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-3-(prop-1-en-2-yl)-2H-pyran-6-carboxamide;

[0237] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-isopropyl-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-2H-pyran-6-carboxamide;

[0238] N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-ethyl-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-2H-pyran-6-carboxamide;

[0239] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-N-[5-(1,3,5-trimethyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-2H-pyran-6-carboxamide;

[0240] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-N-[5-(thiazo-2-yl)-1,3,4-thiadiazol-2-yl]-2H-pyran-6-carboxamide;

[0241] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoropyridin-2-yl)-1,3,4-thiadiazol-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide; or

[0242] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoro-1-isopropyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide.

[0243] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, tautomer, solvate, prodrug, deuterated derivative, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0244] In another aspect, the present invention provides a method for treating and modulating cGAS-related diseases or disorders, wherein the method comprises administering to a patient in need a compound of formula (I), or a stereoisomer, tautomer, solvate, prodrug, deuterated form, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0245] In another aspect, the present invention provides a method for inhibiting cGAS, wherein the method comprises administering to a patient in need a compound of formula (I), or a stereoisomer, tautomer, solvate, prodrug, deuterated form, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0246] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, labeled isotopic variant or tautomer stereoisomer, tautomer, solvate, prodrug, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preparing a drug for inhibiting cGAS.

[0247] In another aspect, the present invention provides the use of a compound of formula (I), or a stereoisomer, tautomer, solvate, prodrug, deuterated form or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, in the preparation of a medicament for treating and / or preventing a disease or disorder, wherein the disease or disorder is a disease or disorder related to cGAS.

[0248] In some implementations, the aforementioned administration to a patient in need is a therapeutically effective amount of the compound represented by formula (I), or its stereoisomers, tautomers, solvates, prodrugs, deuterates, or pharmaceutically acceptable salts, or the aforementioned pharmaceutical composition.

[0249] In some implementations, the aforementioned patients in need are preferably mammals; the mammals are preferably humans.

[0250] In some embodiments, the administration methods during the aforementioned treatment process include oral, mucosal, sublingual, ocular, local, parenteral, rectal, cisternae dorsalis, vaginal, peritoneal, bladder, and nasal administration.

[0251] In some implementations, the aforementioned treatment and / or prevention of diseases or disorders related to cGAS include, but are not limited to, inflammation, autoimmune diseases, infections, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, mental diseases, graft-versus-host disease, or abnormal pain.

[0252] In some implementations, the aforementioned treatment and / or prevention of cGAS-related diseases or disorders are cGAS-related diseases in subjects who have been identified as carrying germline or somatic non-silent mutations in cGAS.

[0253] In some implementations, the aforementioned diseases or disorders of the central nervous system are Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0254] In some implementations, the aforementioned kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

[0255] In some implementations, the aforementioned skin condition is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0256] In some implementations, the aforementioned rheumatic disease is dermatomyositis Still's disease or juvenile idiopathic arthritis.

[0257] In some implementations, the aforementioned cGAS-related disease in subjects who have been identified as carrying germline or somatic non-silent mutations in cGAS is a cold pyridine-related autoinflammatory syndrome.

[0258] In some implementations, the aforementioned cold pyridine-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or a neonatal multisystem inflammatory disease.

[0259] In another aspect, the present invention provides intermediates as described herein, which are suitable for use in methods of preparing compounds as described herein (e.g., the intermediates are selected from those described in the examples).

[0260] Definitions and Explanations

[0261] Unless otherwise specified, the terms used in this invention have their usual meanings.

[0262] Unless otherwise stated, the term “and / or” is used in this disclosure to mean “and” or “or”.

[0263] Unless otherwise stated, in cases where the name of a compound differs from its corresponding chemical structural formula in this document, the chemical structural formula shall prevail.

[0264] Unless otherwise stated, the terms "halogenated" and "halogen" as used in this invention refer to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include fluorine, chlorine, and bromine.

[0265] In this invention, unless otherwise stated, the term "alkyl" includes a straight-chain or branched monovalent saturated hydrocarbon group. The alkyl group used herein may optionally be substituted with one or more substituents. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms.

[0266] The term "alkenyl" refers to a straight-chain or branched alkenyl group containing at least one double bond. Similarly, "C 2-6 "Alkenyl" refers to alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched form, such as vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, n-pentenyl, 2-pentenyl, n-hexenyl, 2-hexenyl, etc.

[0267] The term "alkynyl" refers to a straight-chain or branched alkynyl group containing at least one triple bond. "C" 2-6 "Alynyl" refers to an alkynyl group containing 2, 3, 4, 5, or 6 carbon atoms arranged in a straight chain or branched chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0268] The term "alkylene" refers to an alkyl group as defined above, which is a divalent group. For example, "C 0-6 "alkylene" refers to the absence of this group or its presence as methylene, ethylene, propylene, butylene, pentylene, or hexylene, etc.

[0269] The term "alkoxy" refers to -O-alkyl, wherein the alkyl group is as defined above for alkyl.

[0270] The term "halogenated alkyl" refers to the aforementioned "alkyl" that has been replaced by one or more halogens.

[0271] The term "haloalkoxy" refers to a group consisting of -O-haloalkyl groups.

[0272] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0273] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the composition comprises "one or more" pharmaceutically acceptable excipients.

[0274] In this invention, unless otherwise stated, the terms "aromatic ring", "aromatic ring" or "aromatic heterocycle" refer to a carbon ring or heterocycle with aromatic characteristics (having (4n+2) non-localized π electrons, where n is an integer) of polyunsaturated ring.

[0275] The term "aryl" in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic, fused, or cyclic aromatic group consisting of carbon and hydrogen atoms, preferably a C4 group. 6-14 Aryl, the C 6-14 The aryl group is further preferably C 6- 10 Aryl groups. Examples of these aromatic rings include, but are not limited to, phenyl and naphthyl groups.

[0276] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom ring member (e.g., 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms), wherein the heteroatom is selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatom may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The linkage site of the heteroaryl group can be on any heteroatom or carbon atom, as long as a stable structure can be formed. The heteroaryl group is preferably a 5-14 membered heteroaryl group, more preferably a 5-10 membered heteroaryl group or a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, quinazolinyl, quinoxolinyl, or isoquinolinyl.

[0277] The term "carbocyclic group" refers to a saturated or unsaturated cyclic group that is not aromatic. Depending on its degree of saturation, it may include "cycloalkyl," "cycloalkenyl," or "cycloynyl." Monocyclic carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, or cyclohexene groups; polycyclic carbocyclic groups include carbocyclic groups that form spirocyclic, fused, or bridged rings. The carbocyclic group is preferably C10. 3-14 Carbocyclic group, the C 3-14 The carbocyclic group is further preferably C 3-10 carbonyl group or C 3-8 Carbocyclic group, the C 3-8 The carbocyclic group is further preferably C 3-6 Carbocyclic group, the C 3-8 The carbocyclic group is further preferably C 5-6 Carbon cyclic group.

[0278] The term "cycloalkyl" refers to a saturated monocyclic and polycyclic system containing only carbon and hydrogen atoms in the ring, and may optionally be substituted with one or more substituents. "Cycloalkyl" can have cyclic systems including bridged rings, fused rings, and spirocyclic rings. Non-limiting examples of cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.4]octyl, bicyclo[2.2.1]heptane, etc. The cycloalkyl is preferably C14. 3-14 cycloalkyl, the C 3-14 Cycloalkyl groups are further preferably C14-24-3 ... 3-10 carbonyl group or C 3-8 cycloalkyl, the C 3-8 Cycloalkyl groups are further preferred to be C14. 3-6 cycloalkyl, the C 3-8 Cycloalkyl groups are further preferred to be C14.5-6 Cycloalkyl.

[0279] The term "heterocyclic group," in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic and polycyclic system consisting of a carbon atom and 1-3 heteroatoms selected from N, O, or S, including saturated or unsaturated cyclic systems and polycyclic systems having unsaturated and / or aromatic moieties. The nitrogen or sulfur heteroatoms may be selectively oxidized, and the nitrogen heteroatoms may be selectively quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that polycyclic heterocyclic alkyl groups may have cyclic systems including fused rings, bridged rings, and spirocyclic rings. The heterocyclic group is preferably a 3-14 membered heterocyclic group, more preferably a 3-10 membered heterocyclic group, a 3-8 membered heterocyclic group, or a 5-10 membered heterocyclic group, more preferably a 3-6 membered heterocyclic group, and more preferably a 5-6 membered heterocyclic group. The heterocyclic alkyl groups used herein may optionally be substituted with one or more substituents. Examples of these heterocyclic groups include, but are not limited to, azircyclic butyl, azircyclic pentanyl, azircyclic hexyl, azircyclic heptyl, oxacyclic butyl, oxacyclic pentanyl, oxacyclic hexyl, oxacyclic heptyl, thiocyclic butyl, thiocyclic pentanyl, thiocyclic hexyl, thiocyclic heptyl, diazacyclic butyl, diazacyclic pentanyl, diazacyclic hexyl, diazacyclic heptyl, dioxacyclic butyl, dioxacyclic pentanyl, dioxacyclic hexyl, and dioxacyclic heptane. The group includes: dithiohexacyclobutane, dithiohexacyclopentane, dithiohexacyclohexane, dithiohexacycloheptane, 1,4-oxathiohexacyclohexane, pyrroleyl, imidazoyl, thiazoyl, thiadiazolyl, triazolyl, piperidinyl, piperazinyl, oxoperazinyl, oxoperidinyl, tetrahydrofuranyl, dioxopentaneyl, tetrahydroimidazoyl, tetrahydrothiazoyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl.

[0280] However, in any case, the scope of heterocyclic groups and carbocyclic groups does not overlap or contain each other. Therefore, according to the above definition, if at least one carbocyclic group fuses with a heterocyclic group to form a bi-, poly-, or spiro-ring, it will still be defined as a heterocyclic group.

[0281] In addition, if a heteroaryl group fuses with a heterocyclic group to form a di-, poly-, or spiro-cycle, it will be defined as a heterocyclic group rather than a heteroaryl group.

[0282] The term "substituted" refers to a group in which one or more hydrogen atoms are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogens (F, Cl, Br, or I), oxo groups, and C groups. 1-8 Alkyl, C 1-8Haloalkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR 2x -SR 2x =O, =S, -C(O)R 2x -C(S)R 2x =NR 2x -C(O)OR 2x -C(S)OR 2x -NR 2x R 2x -C(O)NR 2x R 2x , cyano, nitro, -S(O)2R 2x -OS(O2)OR 2x -OS(O)2R 2x -OP(O)(OR) 2x (OR) 2x ); where R 2x Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl; wherein, the C 6-10 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl groups and 3-12 membered heterocyclic groups can be further reacted with H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, cyano, nitro, NH2, NHC 1-6 Alkyl, NHC 1- 6-Hydroalkyl, N(C) 1-6 Alkyl)2, N(C) 1-6 (Haloalkyl)2-substituted. In some embodiments, the typical substituents are independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -C(OCH3), cyano, nitro, -CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl groups.

[0283] The term "pharmaceutically acceptable salt" refers to a salt prepared with a pharmaceutically acceptable base or acid. "Pharmaceutically acceptable salt" means those addition salts of organic or inorganic acids or bases of the compounds of this application that are suitable for contact with patient tissues within the bounds of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) the zwitterionic forms of the compounds of this application.

[0284] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0285] The base addition salt of acidic compounds can be formed by contacting the free acid form with a sufficient amount of the required base in a conventional manner. The free acid can then be regenerated by contacting the salt form with the acid in a conventional manner and then separating the free acid. The free acid form may differ from its respective salt form in some physical properties, such as its solubility in polar solvents.

[0286] Pharmaceutically acceptable salts can be those prepared from inorganic or organic acids, including, for example: hydrochlorides, hydrobroms, hydroiodates, sulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, toluenesulfonates, citrates, maleates, fumarates, succinates, tartrates, naphthates, methanesulfonates, glucono-p-ethyl, lactobionates, laurylsulfonates, and hydroxyethanesulfonates. Pharmaceutically acceptable salts can also be those prepared from, for example, aliphatic mono- or dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, octanoate, sebacic acid salt, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, etc.

[0287] Pharmaceutically acceptable salts include salts formed with inorganic or organic bases, such as cations of alkali and alkaline earth metals, such as lithium, sodium, potassium, calcium, and magnesium, as well as non-toxic organic amines, quaternary ammonium and amine cations, including but not limited to salts formed with ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Salts of amino acids are also included, such as arginine salts, gluconates, and galacturons; see, for example, Berge S. et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66:1-19, which is incorporated herein by reference.

[0288] The term "deuterated compound" as used herein refers to a compound or group formed when a hydrogen atom in the structure of a compound or chemical group is partially or completely replaced by its isotope deuterium. Any position specifically designated as "D" or "deuterium" is understood to have a deuterium enrichment of 50%, 80%, 90%, 95%, 98%, or 99%. "Deuterium enrichment" is a molar percentage determined by dividing the number of deuterium-containing compounds at the indicated position by the total number of all compounds. When a position is designated as "H" or "hydrogen," that position has a natural abundance of hydrogen. When a position is silencing the presence of hydrogen or deuterium, the hydrogen at that position is at its natural abundance. A specific alternative embodiment relates to compounds of this disclosure having a deuterium enrichment of at least 5%, 10%, 25%, 50%, 80%, 90%, 95%, 98%, or 99% at one or more positions not specifically designated as "D" or "deuterium." In some embodiments, one or more hydrogen atoms of any compound described herein may be substituted with deuterium to provide a corresponding labeled or enriched compound.

[0289] The "deuterated C" described in this invention 1-6 "alkyl" or "C" 1-6 "Deuterated alkyl" refers to "C 1-6 "Alkyl" refers to a group obtained by partially or completely replacing the hydrogen atoms in an alkyl structure with its isotope deuterium; "deuterated methyl" refers to a group obtained by partially or completely replacing the hydrogen atoms in a methyl structure with its isotope deuterium. CD3 is a group obtained by completely replacing the hydrogen atoms in a methyl structure with its isotope deuterium. The deuterated C 1-6 The alkyl group is preferably a deuterated C. 1-3 Alkyl group; the deuterated C 1-3 The alkyl group is preferably a deuterated methyl group.

[0290] Since the compound represented by formula (I) of the present invention will be used as a pharmaceutical, it is preferable to use a certain purity, for example, at least 60% purity, more suitable purity is at least 75% purity, and particularly suitable purity is at least 98% purity (% is by weight).

[0291] Prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a prodrug refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of this application, which, upon administration to a receptor, can directly or indirectly provide the compound of this application or its pharmaceutically active metabolites or residues. Particularly preferred derivatives or prodrugs are those compounds that, when administered to a patient, can improve the bioavailability of the compounds of this application (e.g., make orally administered compounds more readily absorbed into the bloodstream), or those compounds that facilitate the delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system). Therefore, the terms "administration" or "application" in the treatment methods provided by this invention refer to the administration of a compound disclosed in this invention that can treat various diseases, or, although not explicitly disclosed, can be converted into a compound disclosed in this invention in vivo upon administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985).

[0292] Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of other positions in the molecule. It is readily understood that those skilled in the art can select the substituents or substitution forms of the compounds of this invention using existing techniques and the methods described in this invention to obtain chemically stable and easily synthesized compounds.

[0293] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, substantially pure enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0294] Although the compounds represented by formula (I) do not precisely define the stereostructure at a particular position, this invention includes all stereoisomers of the compounds represented by formula (I) and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and specific isolated stereoisomers are also included in this invention. In the synthesis of such compounds, or in the use of racemic or epimerization processes known to those skilled in the art, the resulting products may be mixtures of stereoisomers.

[0295] When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0296] The present invention includes any possible solvates and polymorphs when the compound represented by formula (I) and its pharmaceutically acceptable salt are present in a solvate or polymorph. There are no particular limitations on the type of solvent used to form the solvate, provided that the solvent is pharmaceutically acceptable.

[0297] The term "composition" in this invention refers to a product comprising specified amounts of each of the specified ingredients, and any product produced directly or indirectly from a combination of specified amounts of the specified ingredients. Therefore, pharmaceutical compositions containing compounds of this invention as active ingredients, and methods for preparing the compounds of this invention, are also part of this invention.

[0298] Furthermore, some crystalline forms of the compounds can exist in polymorphic forms, and such polymorphisms are included in this invention. Additionally, some compounds can form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of this invention.

[0299] The pharmaceutical compositions provided by this invention comprise a compound of formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, one or more pharmaceutically acceptable excipients, and other optional therapeutic components or excipients. Although the most suitable route of administration of the active ingredient in any given case depends on the specific individual receiving the drug, their individual characteristics, and the severity of their condition, the pharmaceutical compositions of this invention include those suitable for oral, rectal, topical, and non-enteric administration (including subcutaneous, intramuscular, and intravenous administration). The pharmaceutical compositions of this invention can be readily prepared in unit dosage forms known in the art and by any method of preparation known in the pharmaceutical field.

[0300] The pharmaceutical compositions of the present invention can be prepared using any pharmaceutical method. Generally, such methods involve associating the active ingredient with a carrier comprising one or more essential components. Typically, the pharmaceutical composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely fractionated solid carrier, or a mixture of both. Furthermore, the product can be readily prepared to the desired appearance.

[0301] Therefore, the pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier and a compound of formula (I), or a stereoisomer, tautomer, polymorph, solvate, pharmaceutically acceptable salt thereof, or a prodrug thereof. The compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other compounds having therapeutic activity is also included in embodiments of the pharmaceutical compositions of the present invention.

[0302] The drug carrier used in this invention can be, for example, a solid carrier, a liquid carrier, or a gaseous carrier.

[0303] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0304] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure. Detailed Implementation

[0305] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0306] Unless otherwise stated, all proportions and percentages in this invention are by weight, and all temperatures refer to degrees Celsius.

[0307] The following abbreviations were used in the examples:

[0308] DCM: Dichloromethane;

[0309] DCE: 1,2-Dichloroethane;

[0310] PhI(OAc)2: Iodophenylacetic acid;

[0311] Pd(OAc)2: Palladium acetate;

[0312] (TfO)2: Trifluoromethanesulfonic anhydride;

[0313] MeOTf: Methyl trifluoromethanesulfonate;

[0314] p-TsOH: p-Toluenesulfonic acid;

[0315] DMF: N,N-dimethylformamide;

[0316] EA: Ethyl acetate;

[0317] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate;

[0318] THF: Tetrahydrofuran;

[0319] PE: Petroleum ether;

[0320] PLC: Preparative Liquid Chromatography;

[0321] mCPBA: m-chloroperoxybenzoic acid;

[0322] TFA: Trifluoroacetic acid;

[0323] ETOH: Ethanol;

[0324] MEOH: Methanol;

[0325] Dioxane: 1,4-Dioxane;

[0326] X-phos: 2-Bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl

[0327] Xantphos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene

[0328] NMI: N-methylimidazole;

[0329] TCFH: N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate;

[0330] h: hour;

[0331] ml / mL: milliliters;

[0332] OTf: Trifluoromethanesulfonyl

[0333] TEA: Triethylamine

[0334] FA: Formic acid

[0335] TCL: Thin Layer Chromatography

[0336] T4P: 50% ethyl acetate solution of 1-butylphosphine anhydride;

[0337] ACN: Acetonitrile;

[0338] Xantphos Pd G3: (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2-amino-1,1'-biphenyl-2-yl)palladium(II);

[0339] Pd(dppf)Cl2CH2Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex;

[0340] Gphos: (3-(tert-butoxy)-2',6'-diisopropyl-6-methoxy-[1,1'-biphenyl]-2-yl)dicyclohexylphosphine;

[0341] Gphos Pd G6: [2-(dicyclohexylphosphine)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl)palladium bromide;

[0342] Ruphos: 2-Dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl;

[0343] Ruphos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II);

[0344] Pd2(dBa)3: Tris(dibenzylacetone)dipalladium;

[0345] TBAF: Tetra-n-Butylammonium Fluoride

[0346] LC-MS / LCMS: Liquid Chromatography-Mass Spectrometry

[0347] The raw materials and reagents used in the examples can be obtained from commercial sources or prepared by conventional methods in the art.

[0348] Synthesis of intermediate compound A01:

[0349] Step 1: Synthesis of Compound 1-A1

[0350] Compound 1-A0 (10 g) was added to THF (200 mL) and cooled to 0 °C in an ice-water bath. NaH (6.1 g, 60%) was added in portions to the reaction solution, and the reaction was carried out at room temperature for 2 hours. Then, iodomethane (13 g) was added at 0 °C, and the reaction was carried out overnight at room temperature. The reaction was quenched with ice water, acidified with 2 M dilute hydrochloric acid, extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 11.1 g of compound 1-A1 as a brown solid.

[0351] Step 2: Synthesis of Compound 1-A2

[0352] Compound 1-A1 (11 g) was dissolved in methanol (50 mL), and sodium hydroxide (5 g) was dissolved in water (50 mL). These were then added sequentially to a 500 mL single-necked flask containing THF (50 mL). The mixture was reacted at 50 °C for 1.5 hours. The reaction solution was concentrated to remove methanol and tetrahydrofuran. The aqueous phase was acidified with 2 M hydrochloric acid, and a solid precipitated. The solid was then extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated to obtain 11 g of compound 1-A2 as a pale purple solid.

[0353] Step 3: Synthesis of Compound 1-A3

[0354] Compound 1-A2 (11 g), NH4Cl (13.5 g), HATU (35 g), and DIEA (25 g) were added to a 500 mL single-necked flask containing DMF (200 mL) at room temperature, and then reacted at 80 °C for 2.5 h. The reaction was quenched with water, extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 9 g of compound 1-A3 as a yellow solid.

[0355] Step 4: Synthesis of Compound 1-A4

[0356] Compound 1-A3 (9 g) and Burgess reagent (18 g) were added to a 500 mL single-necked flask containing DCE (150 mL) at room temperature, and the reaction was carried out overnight at 50 °C. After cooling, the reaction solution was concentrated and purified by normal phase column chromatography (ethyl acetate: petroleum ether = 1:25), yielding 7 g of compound 1-A4 as a yellow solid.

[0357] Step 4: Synthesis of Compound A01

[0358] Compound 1-A4 (7 g) and aminothiourea (15 g) were added to trifluoroacetic acid (30 mL) and reacted overnight at 80 °C. After the reaction was completed, the mixture was cooled, and dichloromethane was added for concentration. This process was repeated 6 times. After concentration, a small amount of dichloromethane was added to dissolve the mixture, and the mixture was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 1:1). The organic phases were combined and concentrated to obtain 7 g of solid compound A01.

[0359] 1 H NMR (400MHz, DMSO-d6) δ7.34 (s, 2H), 7.02 (d, J = 2.9 Hz, 1H), 6.22 (d, J = 2.9 Hz, 1H), 3.83 (s, 3H).

[0360] Synthesis of intermediate compound A02

[0361] Step 1: Synthesis of compound A02-2

[0362] A02-1 (5.00 g) was dissolved in EtOH (50.00 mL), and MeI (5.123 mL) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the mixture was recrystallized by cooling to obtain compound A02-2 (5.2 g) as a white solid.

[0363] Step 2: Synthesis of compound A02-4

[0364] Anhydrous ethanol was slowly added to a mixture of selenium powder (A02-3 / 4.00 g) and NaBH4 (4.67 g) under nitrogen protection, and the reaction was maintained at 0 °C for 3 h. After the black color disappeared, the reaction was complete, and crude compound A02-4 was obtained (for later use).

[0365] Step 3: Synthesis of compound A02-5

[0366] Dissolve A02-2 (5.20 g) in ethanol (50.00 mL) and add it dropwise to the crude reaction solution of A02-4 while maintaining the temperature at 0 °C. Nitrogen protection was maintained throughout the process. After the addition was completed, the temperature was slowly raised to room temperature and stirred overnight at room temperature. The product was separated by filtration and the solid was slurryed to obtain compound A02-5 (4.0 g).

[0367] Step 4: Synthesis of compound A02

[0368] A02-5 (1500 mg) and 1-A4 (610.98 mg) were dissolved in TFA (20.00 mL). The reaction mixture was stirred at 80 °C for 16 hours. At 0 °C, the reaction mixture was added dropwise to a saturated NaHCO3 aqueous solution, and extracted with DCM:MeOH = 10:1. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane: methanol = 20:10:10:1) to give compound A02 (500.00 mg) as a yellow solid.

[0369] Synthesis of intermediate compound A03

[0370] Step 1:

[0371] Compound A03-00 (1.00 g) was added to DMF (20 mL), and the mixture was cooled to 0 °C in an ice-water bath. NaH (305.45 mg, 60%) was added in portions to the reaction solution, and the mixture was stirred for 15 min. Then, iodomethane (0.436 mL) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 1 h. The reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain compound A03-01 (950 mg).

[0372] Step Two:

[0373] Compound A03-01 (470 mg) and sodium hydroxide (219.66 mg) were added sequentially to a mixed solution of methanol (5 mL) and water (5 mL). The reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated to remove methanol. The aqueous phase was acidified with 1 N hydrochloric acid, and a solid precipitated. The solid was collected by filtration. The remaining filtrate was then extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, concentrated, and dried to obtain compound A03-02 (350 mg).

[0374] Step 3:

[0375] At room temperature, compounds A03-02 (340 mg), NH4Cl (508.30 mg), HATU (1354.99 mg), and DIEA (921.17 mg) were added to a reaction flask containing 10 mL of DMF, and reacted at 80 °C for 3 hours. The reaction was quenched with water, extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by normal-phase chromatography and concentrated to obtain compound A03-03 (220 mg).

[0376] Step Four:

[0377] At room temperature, compound A03-03 (210 mg) and Burgess reagent (352.08 mg) were added to a reaction flask containing DCE (4 mL), and the reaction was carried out at 50 °C for 4 h. After cooling, the reaction solution was stirred with silica gel, and the crude product was purified by normal phase chromatography (ethyl acetate: petroleum ether = 1:25), and concentrated to obtain compound A03-04 (177 mg).

[0378] Step 5:

[0379] Compound A03-04 (158 mg) and aminothiourea (127.61 mg) were added to trifluoroacetic acid (4 mL) and reacted overnight at 80 °C. After the reaction was complete, the mixture was cooled and concentrated under reduced pressure to obtain a crude product. The pH was then adjusted to 8 with dilute sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic phase was collected, dried, and purified by normal phase chromatography (ethyl acetate: petroleum ether = 1:1). The organic phase was concentrated to obtain compound A03 (140 mg).

[0380] 1 H NMR (400MHz, DMSO-d6) δ7.61 (s, 2H), 6.94–6.85 (m, 1H), 6.05 (d, J = 3.1Hz, 1H), 3.84 (s, 3H).

[0381] Synthesis of intermediate compound A04

[0382] Step 1:

[0383] Step 1:

[0384] A04-0 (24 g), pyrazole (11.2 g), and DIEA (54 g) were dissolved sequentially in a redistilled dioxane (200 mL) reaction flask, and then stirred at 80 °C for 3 h. After cooling, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was mixed with silica gel (100-200 mesh), and eluted by normal phase chromatography (PE:EA = 12:1). The desired fraction was collected and concentrated under reduced pressure to obtain compound A04-1 (12 g).

[0385] Step Two:

[0386] A04-1 (12 g), 2,5-hexanedione (15.4 mL), and p-toluenesulfonic acid (2.6 g) were dissolved sequentially in a xylene (200 mL) reaction flask and reacted at 110 °C for 1.5 hours. The mixture was then cooled and concentrated under reduced pressure to obtain a crude product. The crude product was mixed with silica gel (100-200 mesh) and eluted by normal-phase chromatography (PE:EA = 12:1). The desired fraction was collected and concentrated under reduced pressure to obtain compound A04-2 (13 g).

[0387] Step 3:

[0388] 10 g of raw material A04-2 was dissolved in 200 mL of anhydrous THF in a dry three-necked flask (500 mL). The mixture was purged with nitrogen three times. The reaction system was cooled to -78 °C and maintained at this temperature. 16.5 mL of 2.5 M n-hexane solution of n-butyllithium was slowly added dropwise with stirring. After the addition was complete, the reaction mixture was stirred for 1 h at -78 °C. Then, the reaction temperature was slowly raised to -65 °C, and 15.5 g of iodine dissolved in 100 mL of THF was added at this temperature. After the addition was complete, the mixture was stirred for 1 h at -65 °C. The reaction was monitored for completion by TLC (PE / EA = 10:1). The reaction mixture was added to 500 mL of water and extracted with EA (500 mL * 3). The organic phase was washed with saturated sodium thiosulfate solution (500 mL * 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal phase chromatography (mobile phase: PE / EA, gradient 5%-15%), and the desired fraction was collected and concentrated to obtain compound A04-3 (11g).

[0389] Step Four:

[0390] A04-3 (4.00 g), TFA (30 mL), and water (15 mL) were dissolved sequentially in a reaction flask containing THF (15 mL), and the reaction was carried out at room temperature for 48 hours. The reaction solution was added dropwise to a saturated sodium bicarbonate aqueous solution at 0 °C. After the addition was complete, the pH was adjusted and the solution was added dropwise. The reaction mixture was added to 100 mL of water and extracted with EA (100 mL * 3). The organic phase was washed with saturated brine (50 mL * 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was transferred to a 20 mL reaction flask (PE:EA = 3:1), stirred at room temperature for 10 minutes, and then filtered. The solid was washed with PE:EA = 5:1 (20 mL) and dried to obtain compound A04 (2.20 g).

[0391] Synthesis of intermediate compound B01

[0392] 4-Iodo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid

[0393] Step 1: Synthesis of compound B01-2

[0394] Viscous acid (B01-1) (30g) was dissolved in propionic anhydride (150ml) and added to a 500ml single-necked flask. Pyridine (11.3g) was then added, and the mixture was reacted at 90℃ for 16 hours. The reaction solution was evaporated to dryness, and 30ml of DCM was added. The solid was collected and washed three times with 5ml of DCM. The solid was dissolved in 100ml of acetonitrile and 40ml of water. The mixture was prepared by reverse-phase column chromatography (acetonitrile / water). The system was concentrated to obtain 10g of brown solid compound B01-2.

[0395] Step 2: Synthesis of compound B01-3

[0396] Compound B01-2 (10g) was added to a 250ml single-necked flask, followed by 50ml of 20% hydrochloric acid. The mixture was then stirred at 50℃ for 4h. Finally, the reaction solution was concentrated to obtain a brown solid of compound B01-3 (6.5g).

[0397] Step 3: Synthesis of compound B01-4

[0398] Compound B01-3 (6.5 g) was dissolved in 55 ml of methanol and added to a 250 ml single-necked flask. Then, 1.5 ml of concentrated sulfuric acid was slowly added, the temperature was raised to 80 °C and stirred for 3 h. After the reaction was completed, the reaction solution was concentrated, 10 ml of water was added and stirred, filtered, the solid was collected and washed with 1 ml of water, and finally 5.5 g of compound B01-4 was obtained, which was a brown solid.

[0399] 1 H NMR (400MHz, DMSO-d6) δ 11.18 (s, 1H), 7.18 (d, J = 7.4Hz, 1H), 6.69 (d, J = 7.4Hz, 1H), 3.80 (s, 3H).

[0400] Step 4: Synthesis of compound B01-5

[0401] Compound B01-4 (1 g), NIS (1.45 g), p-toluenesulfonic acid (101 mg), and acetonitrile (12 ml) were added sequentially to a 100 ml single-necked flask and stirred under reflux at 80 °C for 1 h. After the reaction was completed, 1 ml of water was added to quench the reaction, the reaction solution was evaporated to dryness, 10 ml of dichloromethane was added to dissolve the solution, silica gel was added to mix the sample, and then eluted with DCM / MeOH = 10 / 1 to obtain 1.1 g of compound B01-5, which was a brownish-yellow solid.

[0402] Step 5: Synthesis of compound B01-6

[0403] Compound B01-5 (1.1 g), DIEA (2.39 g), and dichloromethane (12 ml) were added sequentially to a 100 ml single-necked flask. The temperature was lowered to 0 °C, and methyl trifluoromethanesulfonate (3.04 g) was slowly added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred overnight at room temperature. Once the reaction was complete, the reaction solution was concentrated, and 5 ml of dichloromethane was added to dissolve it. The mixture was then loaded onto the flask using a wet method. Elution with PE / EA = 3 / 1 yielded 1.1 g of compound B01-6, which was a white solid.

[0404] Step Six: Synthesis of Compound B01

[0405] Compound B01-6 (1.1 g) and 20% hydrochloric acid (10 ml) were added to a 100 ml single-necked flask, heated to 80 °C and stirred for 5 h. The reaction solution was concentrated to obtain 960 mg of compound B01, which was a pale yellow solid.

[0406] 1 H NMR (400MHz, DMSO-d6) δ7.36 (s, 1H), 3.91 (s, 3H).

[0407] Synthesis of intermediate compound B02

[0408] Step 1: Synthesis of compound B02

[0409] Compound BO1 (950 mg), compound A01 (687 mg), TCFH (1.08 g), NMI (1.05 g), and acetonitrile were added sequentially to a 100 mL single-necked flask and reacted at 50 °C for 16 h. After the reaction was complete, the mixture was filtered, the filter cake was collected, washed with 2 mL of acetonitrile, and dried to give 650 mg of compound BO2 as a yellow solid.

[0410] Synthesis of intermediate compound B03

[0411] Step 1: Synthesis of compound B03

[0412] Compound BO1 (100 mg), compound A02 (167 mg), TCFH (160 mg), NMI (78 mg g), and acetonitrile were added sequentially to a 100 mL single-necked flask and reacted at 80 °C for 2 h. After the reaction was complete, the mixture was filtered, the filter cake was collected, washed with 2 mL of acetonitrile, and dried to obtain 30 mg of compound BO3 as a yellow solid.

[0413] Synthesis of intermediate compound B04

[0414] Step 1:

[0415] Compound B01-6 (2.0 g), compound 105-01 (1.05 g), potassium carbonate (1.33 g), Xantphos (373.26 mg), and Xantphos Pd G3 (305.88 mg) were added sequentially to a 30 mL anhydrous DMF flask. The reaction was carried out at 80 °C for 2 hours under nitrogen protection. The mixture was cooled, filtered, and the filter cake was washed with 50 mL of methanol. The filtrate was collected and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (mobile phase: PE / (DCM:EA:MeOH = 10:10:1), and concentrated to obtain compound B04-01 (1.20 g).

[0416] 1 H NMR (400MHz, CDCl3) δ7.41 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.65–3.50 (m, 2H), 1.46 (dd, J = 17.9, 6.8Hz, 12H).

[0417] Step Two:

[0418] 1.2 g of BO4-1 was added to a reaction flask containing 20 mL of tetrahydrofuran and 20 mL of methanol. The mixture was cooled to 0 °C, and then 20 mL of 0.5 M K2CO3 was slowly added. The reaction mixture was reacted at room temperature for 1 hour. The pH of the reaction solution was adjusted to 5 with 1 M HCl at 0 °C. The crude product was concentrated under reduced pressure and purified by reversed-phase chromatography (mobile phase: H2O (0.05% FA) / ACN, gradient 15%-25%). The desired fraction was collected and concentrated to obtain compound BO4 (750 mg).

[0419] Example 1: Synthesis of Compound 1

[0420] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl))(oxo)-λ 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0421] Step 1: Synthesis of Compound 1-S1

[0422] 1-S0 (500 mg), iodophenyl diacetic acid (2873.35 mg), and ammonium acetate (911.12 mg) were dissolved in EtOH (10 mL) and stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was concentrated and purified by normal phase column chromatography (PE / EA) to obtain compound 1-S1 (591 mg).

[0423] Step 2: Synthesis of Compound 1

[0424] Compound BO2 (150 mg), compound 1-S1 (67.05 mg), XantPhos Pd G3 (28.90 mg), Xantphos (35.23 mg), Cs2CO3 (297.60 mg), and TEA (0.042 mL) were dissolved in DMF (2.5 mL) and dioxane (2.50 mL). After purging with nitrogen, the mixture was stirred at 100 °C for 3 hours. The reaction solution was cooled to room temperature and purified by reversed-phase column chromatography with water (0.05% FA) and acetonitrile, followed by rotary evaporation to dryness to obtain compound 1 (159 mg).

[0425] Example 2: Synthesis of Compound 1A

[0426] 4-(((3-aminophenyl)(methyl)(oxo)-λ 6 -Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0427] Step 1: Synthesis of Compound 1A

[0428] Compound 1 (150 mg), Fe (74.13 mg), and NH4Cl (71.01 mg) were dissolved in EtOH (2 mL) and H2O (2 mL) and stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. After purification by reverse-phase column chromatography with water (0.05% FA) and acetonitrile, the filtrate was lyophilized to obtain compound 1A (11 mg).

[0429] Example 3: Synthesis of Compound 2

[0430] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiazol-2-yl)-3-methoxy-4-((methyl(3-nitrophenyl))(oxo)-λ 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0431] Step 1: Synthesis of Compound 2

[0432] Compound BO3 (50 mg), compound 1-S1 (18.05 mg), XantPhos Pd G3 (8.90 mg), Xantphos (10.23 mg), Cs2CO3 (67.60 mg), and TEA (0.01 mL) were dissolved in DMF (2.5 mL), purged with nitrogen, and stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, purified by column chromatography (dichloromethane:ethyl acetate:methanol = 10:10:1), and then evaporated to dryness to give compound 2 (18.9 mg).

[0433] Example 4: Synthesis of Compound 92

[0434] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxo)-λ) 6 -Thiono)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0435] Step 1: Synthesis of Compound 92-01

[0436] Compound 92-SM (50 mg) and ammonium carbonate (79 mg) were dissolved in methanol (1 mL) at room temperature and transferred to the corresponding reaction flask. Iodophenyl diacetic acid (359.01 mg) was then added in portions. The reaction system was magnetically stirred at room temperature (25 °C) for 2 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (pre-coated silica gel plate, developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) to finally obtain the target compound 92-01 (60 mg).

[0437] Step 2: Synthesis of Compound 92

[0438] At room temperature, compound B02 (50 mg), compound 92-01 (24 mg), cesium carbonate (66 mg), Xantphos (11 mg), and XantPhos Pd G3 (9 mg) were added sequentially to a dry reaction flask, followed by dissolution in anhydrous DMF (1 mL). The system was purged with nitrogen three times and then heated to 100 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 2 mL of methanol. The filtrate was collected and evaporated to dryness. The mixture was dissolved in 1 mL of DCM and 0.1 mL of methanol, and purified by TLC (developing solvent: DCM / MeOH = 20 / 1) to obtain 7.4 mg of compound 92.

[0439] 1H NMR (400MHz, DMSO-d6) δ13.35(s,1H),7.28(s,1H),7.17(d,J=2.9Hz,1H),6.34(d,J=2 .9Hz,1H),3.95(s,3H),3.73(s,3H),3.71–3.58(m,1H),1.40(dd,J=14.5,6.7Hz,6H).

[0440] Example 5: Synthesis of Compound 123

[0441] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(cyclopropylethynyl)-4-((isopropyl(methyl)(oxy)-λ) 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0442] Step 1: Synthesis of Compound 123-01

[0443] Compound 92 (300 mg) was added to the appropriate reaction flask at room temperature and diluted with 5 mL of dichloromethane. After the system was cooled to 0 °C, boron tribromide (1.5 mL, 0.617 mmol) was slowly added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred for 1.5 hours. The reaction solution was slowly quenched in ice water and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give 240 mg of compound 123-01.

[0444] Step 2: Synthesis of Compound 123-02

[0445] Compound 123-01 (610 mg) was added to the appropriate reaction flask and diluted with dichloromethane (10 mL). Triethylamine (0.539 mL) was added, and after the system was cooled to 0 °C, trifluoromethanesulfonic anhydride (407.22 mg) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1.5 hours. The reaction solution was then directly loaded onto a column for column chromatography using wet chromatography (eluent DCM / MeOH = 30:1), finally yielding 530 mg of compound 123-02.

[0446] Step 3: Synthesis of Compound 123

[0447] Compound 123-02 (15 mg), cyclopropylacetylene (10 mg), TBAF (13 mg), XPHOS (2 mg), and Pd(OAc)2 (0.56 mg) were added to the corresponding reaction flasks, diluted with acetonitrile (0.5 mL), purged three times with nitrogen, and stirred at 65 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was dissolved in DCM / MeOH (1 mL / 0.1 mL). The residue was purified by preparative thin-layer chromatography (developing solvent DCM:MeOH = 20:1) to finally obtain 5 mg of compound 123.

[0448] Example 6: Synthesis of Compound 114

[0449] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 (-Thiono)amino)-2-oxo-3-vinyl-2H-pyran-6-carboxamide

[0450] Step 1: Synthesis of Compound 114

[0451] At room temperature, compound 123-02 (10 mg), compound 114-SM1 (30 mg), potassium phosphate (20.5 mg), and 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (1.25 mg) were added to the corresponding reaction flasks and diluted with dioxane:water (1 mL:0.1 mL). After stirring the system at 80 °C for 5 hours, it was purified directly by preparative thin-layer chromatography (DCM:MeOH = 30:1) to finally obtain 4.2 mg of compound 114.

[0452] 1 H NMR (400MHz, DMSO-d6) δ13.51(s,1H),7.47(s,1H),7.17(d,J=2.9Hz,1H),6.95(dd,J=17.7,11.9Hz,1H),6.35(dd, J=13.6,3.0Hz,2H),5.37–5.30(m,1H),3.95(s,3H),3.79–3.72(m,1H),3.42(s,3H),1.40(dd,J=15.0,6.8Hz,6H).

[0453] Example 7: Synthesis of Compound 115

[0454] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-cyclopropyl-4-((isopropyl(methyl)(oxy)-λ) 6(thionyl)amino)-2-oxo-2H-pyran-6-carboxamide

[0455] Step 1:

[0456] Compound 123-02 (10 mg), compound 115-SM1 (18 mg), potassium carbonate (25 mg), and 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (1.25 mg) were added to the corresponding reaction flasks and diluted with dioxane:water (1 mL:0.1 mL). The system was heated to 80 °C and stirred for 5 hours under nitrogen protection. The mixture was then purified directly by preparative thin-layer chromatography (DCM:MeOH = 30:1) to obtain 2.5 mg of compound 115.

[0457] Example 8: Synthesis of Compound 140

[0458] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-ethynyl-4-((isopropyl(methyl)(oxy)-λ) 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0459] Step 1: Synthesis of Compound 140-01

[0460] Compound 123-02 (50 mg), triethylamine (0.115 mL), XPHOS (7 mg), and Pd(OAc)2 (5 mg) were added to the corresponding reaction flasks, diluted with acetonitrile (1 mL), and trimethylsilylacetylene (162 mg) was added. After purging with nitrogen three times, the mixture was stirred at 55 °C for 3 hours. The mixture was then directly purified by preparative thin-layer chromatography (developing solvent DCM:MeOH = 30:1) to obtain 30 mg of compound 140-01.

[0461] Step 2: Synthesis of Compound 140

[0462] Compound 140-01 (25 mg) was dissolved in methanol (2 mL), K2CO3 (30 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then purified by preparative thin-layer chromatography (DCM:MeOH = 30:1) to obtain 7.2 mg of compound 140.

[0463] Example 9: Synthesis of Compound 145

[0464] (E)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2-ethoxyvinyl)-4-((isopropyl(methyl)(oxy)-λ) 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0465] Step 1:

[0466] Compound 123-02 (50 mg) was added to the corresponding reaction flask along with compound 145-SM1 (81 mg), Cs2CO3 (53 mg), XPHOS (12 mg), and Pd(OAc)2 (5 mg). The mixture was diluted with dioxane (1 mL) and water (0.1 mL), heated to 73 °C and stirred for 15 hours under nitrogen protection. The mixture was then purified directly by preparative thin-layer chromatography (developing solvent DCM:MeOH = 30:1) to obtain 6.3 mg of compound 145.

[0467] Example 10: Synthesis of Compound 146

[0468] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 (-thiono)amino)-2-oxo-3-(prop-1-en-2-yl)-2H-pyran-6-carboxamide

[0469] Step 1:

[0470] Compound 123-02 (50.05 mg), compound 146-SM1 (69.56 mg), Cs2CO3 (53 mg), XPHOS (12 mg), and Pd(OAc)2 (5 mg) were added to the corresponding reaction flasks, diluted with dioxane (1 mL) and water (0.1 mL), and stirred at 78 °C for 16 hours. The reaction solution was directly purified by preparative thin-layer chromatography (DCM:MeOH = 30:1) to obtain 4.5 mg of compound 146.

[0471] Example 11: Synthesis of Compound 142

[0472] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thionyl)amino)-2-oxo-3-(2-oxozadicyclopropane-1-yl)-2H-pyran-6-carboxamide

[0473] Step 1:

[0474] In a reaction flask, compound 123-02 (50.00 mg) and compound 142-SM1 (9.79 mg) were dissolved in dioxane (1.00 mL), followed by the sequential addition of potassium carbonate (34.32 mg), GPhos (8.89 mg), and GPhos Pd G6 (7.82 mg). The mixture was purged with nitrogen and stirred at 100 °C under a nitrogen atmosphere for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (3 × 5 mL), and the organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by normal column chromatography (PE:EA:DCM:MeOH = 20:10:10:1) to obtain 11.2 mg of compound 142.

[0475] Example 12: Synthesis of Compound 143

[0476] 3-Acetyl-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0477] Step 1:

[0478] 123-02 (52.0 mg), 4-hydroxybutylvinyl ether (18.0 mg), palladium acetate (2.5 mg), 1,3-bis(diphenylphosphine)propane (dppp, 6.0 mg), and triethylamine (26.0 mg) were added sequentially to a reaction flask and dispersed in anhydrous DMF (2 mL). The reaction mixture was stirred at 80 °C for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into ice water (20 mL), and 2 M HCl aqueous solution (2 mL) was added. The mixture was stirred for 5 minutes and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (2 × 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography yielded 1.3 mg of compound 143.

[0479] Example 13: Synthesis of Compound 144

[0480] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-cyano-4-((isopropyl(methyl)(oxy)-λ) 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0481] Step 1:

[0482] 123-02 (59.0 mg), zinc cyanide (23.0 mg), and Pd(PPh3)4 (12.0 mg) were dispersed in anhydrous DMF (1.0 mL). The reaction mixture was stirred at 80 °C for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature and slowly poured into ice water (10 mL), then extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over anhydrous Na2SO4. After concentration under reduced pressure, the solution was purified by column chromatography to give 3.9 mg of compound 144.

[0483] Example 14: Synthesis of Compound 96

[0484] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-selenodiaza-2-yl)-3-methoxy-4-((4-oxy-1,4-λ) 6 -Thiohetero-4-thionyl)amino)-2-oxo-2H-pyran-6-carboxamide

[0485] Step 1:

[0486] Compound B03 (50 mg), compound 96-SM1 (13.78 mg), Cs2CO3 (60 mg), Xantphos Pd G3 (8.8 mg), and Xantphos (10.7 mg) were added to the corresponding reaction flasks, dissolved and diluted with DMF (1 mL), and purged with nitrogen. The mixture was reacted at 100 °C for 2 hours, and the reaction was monitored by LC-MS to indicate completion. The crude product was extracted with ethyl acetate (3 × 5 mL), dried over anhydrous Na2SO4, and the organic phase was concentrated by rotary evaporation. The purified product was obtained by silica gel plate (EA / DCM / MeOH = 10:10:1) to give 19.2 mg of compound 96.

[0487] Example 15: Synthesis of Compound 118

[0488] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2,2-difluoroethoxy)-4-((isopropyl(methyl)(oxy)-λ) 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0489] Step 1:

[0490] Compound 123-01 (20 mg), compound 118-SM1 (9.8 mg), and K2CO3 (17.6 mg) were added to the corresponding reaction flasks and dispersed and dissolved with DMF (1 mL). The mixture was stirred at 80 °C for 30 minutes. The mixture was cooled to 0 °C, and the reaction solution was quenched dropwise with saturated NH4Cl aqueous solution. The mixture was extracted with ethyl acetate (3 × 5 mL), and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and rotary evaporated to obtain the crude product. The crude product was purified by preparative plate separation (EA / DCM / MeOH = 10:10:1) to obtain 8.5 mg of compound 118.

[0491] Example 16: Synthesis of Compound 105

[0492] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thiono)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0493] Step 1: Synthesis of Compound 105-01

[0494] At room temperature, compound 105-SM1 (50 mg), ammonium carbonate (79 mg), and iodophenyl diacetic acid (359 mg) were added to the corresponding reaction flasks, dissolved and diluted with methanol (1 mL), and stirred at room temperature for 2 h. The reaction solution was directly purified by pre-TLC plate (PE / EA = 2 / 1) to obtain 50 mg of compound 105-01.

[0495] Step 2: Synthesis of Compound 105

[0496] Compound B02 (50 mg), compound 105-01 (22.72 mg), Cs2CO3 (66 mg), Xantphos (11 mg), and XantPhos Pd G3 (9 mg) were added sequentially to a reaction flask and dissolved in DMF (1 mL). Nitrogen gas was introduced, and the mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with methanol (2 mL). The combined filtrates were concentrated under reduced pressure, and the crude product was redissolved in DCM (1 mL) and methanol (0.1 mL). The product was purified by preparative thin-layer chromatography (developing solvent: DCM / MeOH = 20:1) to obtain 16.1 mg of compound 105.

[0497] 1H NMR (400MHz, DMSO-d6) δ13.37(s,1H),7.49(s,1H),7.16(d,J=2.9Hz,1H),6.33(d,J=2 .9Hz,1H),3.95(s,3H),3.86–3.78(m,2H),3.72(s,3H),1.35(dd,J=11.6,6.7Hz,12H).

[0498] Example 17: Synthesis of Compound 129

[0499] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ6-thionyl)amino)-3-hydroxy-2-oxo-2H-pyran-6-carboxamide

[0500] Step 1:

[0501] Compound 105 (140.01 mg) was dissolved in DCM (3 mL) in a 20 mL sample vial. The system was cooled to 0 °C, and a DCM solution of BBr3 (0.272 mL, 0.545 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature, and stirring was continued for 30 minutes. The reaction solution was quenched in ice water (10 mL), and extracted with EA (20 mL). The organic phase was collected and concentrated under reduced pressure. The crude product was washed three times with a DCM / MeOH mixed solvent (10:1, 10 mL) to obtain 100 mg of compound 129.

[0502] 1 H NMR (400MHz, DMSO-d6) δ7.39(s,1H),7.02(d,J=2.9Hz,1H),6.23(d,J=2.9Hz,1H),3.87(s,3H),3.76–3.66(m,2H),1.33(dd,J=17.8,6.7Hz,12H).

[0503] Example 18: Synthesis of Compound 137

[0504] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((diisopropyl(oxy)-λ) 6 -Thiono)amino)-2-oxo-3-((tetrahydrofuran-2-yl)methoxy)-2H-pyran-6-carboxamide

[0505] Step 1:

[0506] Compound 129 (50.00 mg) was dissolved in DMF (1.00 mL), and potassium carbonate (41.46 mg) and compound 137-SM1 (12.72 mg) were added sequentially. The reaction mixture was stirred at 80 °C for 60 min. The reaction solution was cooled to 0 °C and quenched by slow dropwise addition to a saturated NH4Cl aqueous solution. Extraction was performed with a DCM / MeOH mixed solvent (10:1), and the organic phase was washed sequentially with saturated brine (3 times) and dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and purified by C18 reversed-phase column chromatography (mobile phase A: 0.05% formic acid aqueous solution, mobile phase B: acetonitrile; gradient: 40% B → 70% B) to obtain 14.9 mg of compound 137.

[0507] 1 H NMR (400MHz, DMSO-d6) δ13.38(s,1H),7.50(s,1H),7.16(d,J=2.9Hz,1H),6.33(d,J=2.9Hz,1H),4. 14–4.02(m,1H),3.94(s,3H),3.93–3.60(m,6H),2.04–1.73(m,4H),1.35(dd,J=12.5,6.6Hz,12H).

[0508] Example 19: Synthesis of Compound 119

[0509] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thiono)amino)-2-oxo-3-(2-(prop-2-yn-1-yloxy)ethoxy)-2H-pyran-6-carboxamide

[0510] Step 1:

[0511] Compound B01-6 (3.0 g) and compound 92-01 (1.17 g) were dissolved in DMF (30 mL), and cesium carbonate (2.01 g), Xantphos (1.12 g), and Xantphos Pd G3 (0.92 g) were added sequentially. The reaction was carried out under N2 protection and stirred at 100 °C for 2 hours. LC-MS monitoring showed that the target product was formed. After cooling, the mixture was extracted three times with ethyl acetate (3 × 100 mL), and the combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate:dichloromethane:methanol = 30:10:10:1) to give 2.01 g of compound 119-01.

[0512] Step Two:

[0513] Compound 119-01 (2.00 g) was dissolved in dichloromethane (20 mL) and cooled to 0°C in an ice bath. Boron tribromide (6.59 mL, 13.19 mmol) was slowly added dropwise, and the mixture was allowed to warm to room temperature and stirred for 1 hour after the addition was complete. The reaction solution was cooled to 0°C in an ice bath and quenched by slowly adding methanol (50 mL). The solution was concentrated under reduced pressure to obtain the crude product. After purification by slurrying in dichloromethane, 1.51 g of compound 119-02 was obtained.

[0514] Step 3:

[0515] Compound 119-02 (100 mg) was dissolved in DMF (2 mL), and potassium carbonate (143 mg) and compound 119-03-SM1 (72.6 mg) were added sequentially. The reaction mixture was stirred at 75 °C for 1 hour. After cooling to 0 °C in an ice bath, the mixture was quenched by slowly adding 30 mL of saturated NH4Cl aqueous solution. Extraction was performed with DCM / MeOH (10:1, 3 × 20 mL), and the combined organic phases were washed with saturated brine (3 × 10 mL) and dried over anhydrous Na2SO4. After concentration under reduced pressure, the mixture was purified by thin-layer chromatography (DCM:MeOH = 50:1) to obtain 80 mg of compound 119-03.

[0516] Step Four:

[0517] Compound 119-03 (80 mg) was dissolved in a THF / MeOH mixed solvent (1 mL each), and 0.86 mL (0.43 mmol) of 0.5 mol / L K2CO3 aqueous solution was added. The reaction solution was stirred at 25 °C for 1 hour. The solution was then purified directly by C18 reversed-phase chromatography [mobile phase A: 0.05% formic acid aqueous solution; mobile phase B: acetonitrile; gradient: 20% → 30% B (10 min), flow rate 15 mL / min], and lyophilized to obtain 60.2 mg of compound 119-04.

[0518] Step 5:

[0519] Compound 119-04 (60 mg) and compound A01 (36.0 mg) were dissolved in ethyl acetate (2 mL), and T4P (145 mg) and N,N-diisopropylethylamine (DIEA, 43.4 mg) were added sequentially. The reaction mixture was stirred at 80 °C for 1 hour. The mixture was cooled to 0 °C in an ice bath, and the reaction was quenched by slowly adding saturated NH4Cl aqueous solution (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate:dichloromethane:methanol = 20:10:10:1) to give 14.1 mg of compound 119.

[0520] Example 20: Synthesis of Compound 147

[0521] N-(5-(5-cyano-4-methylthiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thiono)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0522] Step 1:

[0523] Compound 119-01 (1.60 g) was dissolved in a methanol / THF mixed solvent (20 mL each) and cooled to 0 °C in an ice bath. A 0.5 mol / L K₂CO₃ aqueous solution (21.1 mL) was slowly added dropwise, and the mixture was heated to 25 °C and stirred for 1 hour after the addition was complete. The pH was adjusted to 5 with 4 M HCl aqueous solution, and the solution was purified by C18 reversed-phase chromatography (mobile phase A: 0.05% formic acid aqueous solution; mobile phase B: acetonitrile; gradient: 20% → 30% B). After lyophilization, 1.4 g of compound 147-01 was obtained.

[0524] Step Two:

[0525] Compound 147-01 (1.40 g) and compound 147-SM1 (871 mg) were dissolved in ethyl acetate (20 mL), and N,N-diisopropylethylamine (1.25 g) and T4P (2.09 g) were added sequentially. The reaction mixture was stirred at 80 °C for 1 hour. The mixture was cooled to 0 °C in an ice bath, and the reaction was quenched by slowly adding saturated NH4Cl aqueous solution (30 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (3 × 20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give 1.21 g of compound 147-02.

[0526] Step 3:

[0527] Compound 147-02 (60.0 mg) and compound 147-SM2 (33.3 mg) were dissolved in a 1,4-dioxane / water mixed solvent (2.0 mL / 0.2 mL), and sodium tert-butoxide (25.6 mg) was added. Tris(dibenzylacetone)dipalladium (24.4 mg) and n-butylbis(1-adamantyl)phosphine (19.1 mg) were added sequentially. The reaction mixture was stirred at 100 °C for 2 hours under N2 protection, and LC-MS monitoring showed the formation of the target product. After cooling, the mixture was extracted with ethyl acetate (3 × 5 mL), and the combined organic phases were dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography to give 6.2 mg of compound 147.

[0528] Example 21: Synthesis of Compound 152

[0529] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-hydroxy-4-(((2-hydroxyethyl)(3-nitrophenyl)-oxy-λ) 6 (-thiono)amino)-2-oxo-2H-pyran-6-carboxamide

[0530] Step 1:

[0531] Compound 152-SM1 (1.50 g), 2-mercaptoethoxyethanol (0.733 g), Xantphos (0.694 g), N,N-diisopropylethylamine (2.33 g), and tris(dibenzylacetone)dipalladium(0) (Pd2(dba)3, 0.549 g) were sequentially added to a reaction flask containing anhydrous 1,4-dioxane (30 mL). The system was stirred at 100 °C for 16 hours under N2 protection. The reaction solution was cooled to room temperature, poured into ice water (150 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with 5% sodium thiosulfate solution (2 × 20 mL), washed with saturated brine (1 × 30 mL), and dried over anhydrous Na2SO4. After concentration under reduced pressure, the solution was purified by silica gel column chromatography to give 1.38 g of compound 152-01.

[0532] Step Two:

[0533] Compound 152-01 (1.38 g), iodophenyl diacetic acid (5.49 g), and ammonium carbonate (1.09 g) were dissolved in anhydrous ethanol (40 mL). The reaction mixture was stirred at 25 °C for 3 hours, and TLC (developing solvent: dichloromethane / methanol = 10:1) showed complete conversion of the starting material. The reaction system was directly concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (3:1 → 1:1 gradient)) to give 1.16 g of compound 152-03.

[0534] Step 3:

[0535] Compound 152-03 (520 mg), compound BO2 (840 mg), Xantphos (219 mg), Xantphos Pd G3 (90 mg), and sodium bicarbonate (479 mg) were added sequentially to a reaction flask and dispersed in anhydrous DMF (30 mL). The reaction mixture was stirred at 100 °C for 3 hours under N2 protection, and LC-MS monitoring showed the formation of the main product. The reaction solution was cooled to room temperature and poured into ice water (200 mL), and the pH was adjusted to 3.5 with 1 M HCl aqueous solution. Extraction was performed with ethyl acetate (2 × 100 mL), and the combined organic phases were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After concentration under reduced pressure, the mixture was purified by reversed-phase silica gel column chromatography [eluent: acetonitrile / water (containing 0.1% formic acid) = 40% → 70%, gradient], and lyophilized to give 270 mg of compound 152-04.

[0536] Step Four:

[0537] Compound 152-04 (65.0 mg) was dissolved in anhydrous dichloromethane (3.0 mL) and cooled to 0 °C in an ice bath. A dichloromethane solution of boron tribromide (2.0 M, 0.15 mL, 0.30 mmol) was slowly added dropwise while stirring at 0 °C for 10 minutes. The temperature was then raised to 25 °C and the reaction was continued for 1 hour. The reaction was quenched with methanol (1.0 mL) and concentrated to dryness under reduced pressure. The residue was dissolved in DMF (2.0 mL), purified by preparative HPLC [mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: acetonitrile; gradient: 30% → 70% B], and lyophilized to give 55 mg of compound 152.

[0538] Example 22: Synthesis of Compound 49

[0539] 4-((benzo[d][1,3]dioxacyclopenten-5-yl(methyl)(oxo)-λ) 6-Thionyl)amino)-N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0540] Step 1:

[0541] At room temperature, compound 49-SM1 (1000 mg) was dissolved in 2 mL of THF and transferred to the corresponding reaction flask, then cooled to -78 °C. A solution of n-butyllithium / hexane (2.189 mL, 5.472 mmol) was slowly added dropwise, and the mixture was stirred at -78 °C for 1 h after the addition was complete. Compound 49-SM2 (0.882 mL) was then added, and the mixture was heated to room temperature and stirred for another 12 h. The reaction mixture was poured into 20 mL of saturated NH4Cl solution and extracted with EtOAc (20 mL × 2). The combined organic phases were concentrated. The crude product was dissolved in DCM, stirred with silica gel, and eluted with petroleum ether (100%) to give 760 mg of compound 49-01.

[0542] Step Two:

[0543] Compound 49-01 (100 mg) was dissolved in 1.5 mL of methanol at room temperature and transferred to the appropriate reaction flask. Ammonium carbonate (85 mg) and iodophenyl diacetic acid (423 mg) were added sequentially, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until complete, and purified by column chromatography with DCM / MeOH = 30 / 1 elution to give 87 mg of compound 49-02.

[0544] Step 3:

[0545] At room temperature, compound 49-02 (16 mg), compound BO2 (50 mg), cesium carbonate (66.13 mg), Xantphos (11.74 mg), and XantPhos Pd G3 (9.63 mg) were dissolved sequentially in 1.3 mL of DMF and transferred to the respective reaction flasks under nitrogen protection. The mixture was heated to 100 °C and stirred for 2 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was evaporated to dryness. The residue was dissolved in 1 mL of DCM and 0.1 mL of MeOH and purified by TLC (DCM / MeOH = 30 / 1) to give 8.9 mg of compound 49.

[0546] Example 23: Synthesis of Compound 150

[0547] N-(5-(2-(dimethylamino)thiazolyl-5-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6-Thiono)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0548] Step 1:

[0549] Compound 147-02 (50.0 mg) and compound 150-SM2 (42.2 mg) were dissolved in 1,4-dioxane / water (2.0 mL / 0.2 mL), and sodium tert-butoxide (21.3 mg) was added. Tris(dibenzylacetone)dipalladium (10.2 mg) and n-butylbis(1-adamantyl)phosphine (7.9 mg) were added sequentially. The reaction mixture was stirred at 100 °C for 2 hours under N2 protection, and the formation of the target product was confirmed by LC-MS. After cooling to room temperature, the mixture was extracted with ethyl acetate (3 × 5 mL), and the combined organic phases were dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography to give 3.5 mg of compound 150.

[0550] Example 24: Synthesis of Compound 111

[0551] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((4-methoxyphenyl)sulfonamide)-2-oxo-2H-pyran-6-carboxamide

[0552] Step 1:

[0553] Compound B01-6 (900 mg), tert-butyl carbamate (400 mg), PEPPSI-IPr catalyst (116 mg), and cesium carbonate (2.22 g) were suspended in anhydrous 1,4-dioxane (50 mL). The reaction mixture was stirred at 90 °C for 2 hours under N2 protection. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with water (2 × 20 mL) and dried over anhydrous Na2SO4. After concentration under reduced pressure, the solution was purified by silica gel column chromatography to give 360 ​​mg of compound 111-01.

[0554] Step Two:

[0555] Compound 111-01 (355 mg) was dispersed in anhydrous tetrahydrofuran (10 mL), and an equal volume of 0.1 mol / L lithium hydroxide aqueous solution (10 mL) was added. The mixture was stirred at room temperature for 3 minutes, and TLC monitoring showed complete conversion of the starting material. The pH was adjusted to 3.0 with 1 M HCl aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with water (2 × 10 mL) and dried over anhydrous Na₂SO₄. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography to give 115.1 mg of compound 111-02.

[0556] Step 3:

[0557] Compound 111-02 (70 mg) and compound A01 (53 mg) were dissolved in DCM (5 mL), and propylphosphonic anhydride (T3P, 116 mg) and N,N-diisopropylethylamine (DIEA, 63 mg) were added sequentially. The reaction mixture was stirred at room temperature for 3 hours, and TLC monitoring showed that the reaction was complete. The mixture was extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography to give 60.1 mg of compound 111-03.

[0558] Step Four:

[0559] Compound 111-03 (60 mg) was dissolved in 2 mL of 4 M HCl solution of 1,4-dioxane and reacted with stirring at 25 °C for 30 minutes. After concentration under reduced pressure, 46 mg of compound 111-04 was obtained.

[0560] Step 5:

[0561] Compound 111-04 (46.0 mg), compound 111-SM2 (25.0 mg), and triethylamine (24.0 mg) were dissolved in dichloromethane (3 mL). The mixture was stirred at room temperature for 3 hours, and TLC monitoring showed that the starting material disappeared. The reaction was quenched with ice water (5 mL), and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine (2 × 5 mL) and dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and purified by column chromatography to obtain 5.6 mg of compound 111.

[0562] Example 25: Synthesis of Compound 153

[0563] N-(5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl)-4-((isopropyl(methyl)(oxy)-λ) 6 -Thiono)amino)-3-(methylamino)-2-oxo-2H-pyran-6-carboxamide

[0564] Step 1:

[0565] Compound 123-02 (100.0 mg), methylamine hydrochloride (111.2 mg), cesium carbonate (107.1 mg), Gphos (17 mg), and Gphos Pd G6 (7 mg) were dispersed in dioxane (3 mL). The reaction was carried out under nitrogen protection at 80 °C with stirring for 15 hours. After the reaction was complete, the mixture was cooled and concentrated to dryness under reduced pressure. Purification was performed by preparative reversed-phase chromatography (mobile phase A: 0.05% vol formic acid aqueous solution; mobile phase B: acetonitrile; gradient: 25% → 45% B; flow rate: 60 mL / min). The target fraction was collected and lyophilized to give 9.38 mg of compound 153.

[0566] Example 26: Synthesis of Compound 158

[0567] N-[5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0568] Step 1:

[0569] Compound 147-01 (1.60 g), compound A04 (1.62 g), T4P (5.18 g), and DIEA (1.6 g) were added to a 100 mL single-necked flask containing EtOAc (20 mL) at room temperature. The mixture was then reacted at 80°C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by reversed-phase chromatography (mobile phase: A: H2O (0.05% FA) / B: ACN, gradient 40%-60%). The desired fraction was collected and concentrated to obtain compound 158-01 (2.20 g), which was a yellow solid.

[0570] Step Two:

[0571] Compound 158-01 (40.00 mg) and benzophenone imine (30.55 mg) were dissolved in DMF (1.00 mL), and cesium carbonate (140.28 mg) was added. Xantphos (8.20 mg) and Xantphos Pd G3 (1.68 mg) were then added under nitrogen protection. The mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. After the reaction was complete, the mixture was kept at 0 °C and added dropwise to an aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3 × 50 mL) and dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure. Compound 158-02 (18.00 mg) was purified by silica gel plate (DCM:MeOH:=10:1) as a yellow solid.

[0572] Step 3:

[0573] Compound 158-02 (30.00 mg) was dissolved in DCM (3 mL), and TFA (1.00 mL) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to a saturated sodium bicarbonate aqueous solution at 0 °C, and extracted with DCM:MeOH = (10:1). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 30 mg of crude product as a yellow oil. The crude product was purified by reversed-phase chromatography (mobile phase: A:H2O (0.05% FA) / B:ACN, gradient 20%-30%), and the desired fraction was collected and concentrated to obtain compound 158 (8.1 mg).

[0574] Example 27: Synthesis of Compound 159

[0575] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-(1-hydroxyethyl)-4-[(isopropyl(methyl)(oxo)-λ] 6 [-thionyl)amino]-2-oxo-2H-pyran-6-carboxamide

[0576] Step 1:

[0577] Compound 143 (42 mg) was added to an 8 mL sample vial containing 3 mL of THF and stirred at 0 °C for 10 min. Then, sodium borohydride (3.19 mg) was added, and the mixture was stirred at 0 °C for 30 min. After the reaction was complete, the reaction solution was extracted with a dilute hydrochloric acid solution (0.1 N) / EA system. After separation, the solution was dried over anhydrous sodium sulfate. The crude product was purified by Pre-TLC to obtain compound 159 (11.3 mg).

[0578] Example 28: Synthesis of Compound 160

[0579] Step 1:

[0580] Compound 158-01 (100.00 mg), compound trimethylsilylacetylene (34.81 mg), PPh3 (69.71 mg), palladium acetate (8.87 mg), and triethylamine (0.074 mL) were dissolved in DMF (1.00 mL) and stirred at 90 °C for 3 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by TLC (DCM:MeOH = 20:1) to give compound 160-01 (50.00 mg).

[0581] Step Two:

[0582] Compound 160-01 (50.00 mg) was dissolved in methanol (3 mL), and then potassium carbonate (19.39 mg) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was filtered, and the filter cake was washed three times with methanol (5 mL). The filtrate was collected and distilled under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase chromatography (mobile phase: A: H2O (0.05% FA) / B: ACN, gradient 30%-45%). The desired fraction was collected and concentrated to obtain compound 160 (12 mg).

[0583] Example 29: Synthesis of Compound 164

[0584] N-[5-(3-chloro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-4-[(isopropyl(oxo)(propyl)-λ] 6 [-thionyl)amino]-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0585] Step 1:

[0586] Compound 164-SM1 (100 mg) and ammonium carbonate (121.90 mg) were dissolved in methanol (2 mL) and added to a reaction flask, followed by the addition of iodophenyl diacetic acid (548.23 mg). The mixture was stirred at room temperature for 2 h. The reaction solution was purified by Pre-TLC (evolving solvent: PE / EA = 2 / 1) to obtain compound 164-01 (105 mg).

[0587] Step Two:

[0588] Compound B02 (50 mg), compound 164-01 (29.52 mg), Cs2CO3 (66.13 mg), Xantphos (5.87 mg), and XantPhos Pd G3 (4.82 mg) were added sequentially to a reaction flask containing 1 mL of DMF. The mixture was purged with nitrogen and stirred at 100 °C for 2 h. The mixture was then cooled, filtered, and the filter cake was washed with 2 mL of methanol. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-TLC (developing solvent: DCM / MeOH = 20 / 1) to obtain compound 164 (12.22 mg).

[0589] 1 H NMR (400MHz, DMSO-d6) δ7.33(s,1H),7.12(d,J=2.9Hz,1H),6.30(d,J=2.9Hz,1H),3.93(s,3H),3.71(s, 4H), 3.71–3.61 (m, 1H), 3.56–3.40 (m, 3H), 1.87–1.70 (m, 2H), 1.47–1.31 (m, 6H), 1.03 (t, J = 7.4Hz, 3H).

[0590] Example 30: Synthesis of Compound 166

[0591] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0592] Step 1:

[0593] Compound B04 (48.03 mg), compound A03 (30 mg), T4P (109.05 mg), and TEA (0.063 mL) were sequentially added to a reaction flask containing ethyl acetate (2 mL), and the mixture was heated at 70 °C for 1.5 h. After the reaction was complete, the reaction solution was added to brine, and then extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-TLC to obtain compound 166 (15.5 mg).

[0594] 1H NMR (400MHz, DMSO-d6) δ13.35(s,1H),7.48(s,1H),7.01(dd,J=5.5,3.1Hz,1H),6.14(d,J =3.1Hz,1H),3.94(s,3H),3.87–3.78(m,2H),3.71(s,3H),1.35(dd,J=11.8,6.7Hz,12H).

[0595] Example 31: Synthesis of Compound 168

[0596] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluorothiophen-2-yl)-1,3,4-thiadiazol-2-yl]-3-methoxy-2-oxo-2H-pyran-6-carboxamide

[0597] Step 1:

[0598] Compound 168-00 (500 mg) was dissolved in DMF (5 mL), and DIEA (2.21 g), HATU (1.95 g), and ammonium chloride (915.06 mg) were added. The mixture was reacted at 80 °C for 3 h under a sealed environment. The resulting mixture was extracted with ethyl acetate (3 × 5 mL) and dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure. Compound 168-01 (480 mg) was obtained as a white solid by forward purification (EA:PE = 3:1).

[0599] Step Two:

[0600] Compound 168-01 (480 mg) was added to DCE (5 mL), stirred until dissolved, and then Burgess reagent (1.56 g) was added. The reaction was carried out at 50°C for 1.5 h. LCMS showed that the reaction was basically complete. The mixture was stirred with silica gel, purified in normal phase, and the product was obtained from 8% EA:92% PE. The organic phase was concentrated by vacuum distillation to obtain compound 168-02 (260 mg).

[0601] Step 3:

[0602] Compound 168-02 (260 mg) was added to TFA (5.00 mL) and stirred until dissolved. Then, thiourea (223 mg) was added, and the mixture was reacted at 80 °C for 16 h. LC-MS showed that the reaction was essentially complete. The reaction solution was added dropwise to a saturated sodium bicarbonate aqueous solution at 0 °C, and extracted with DCM:MeOH (10:1). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product. This crude product was purified using silica gel plates (DCM:MeOH = 20:1) to obtain compound 168-03 (200 mg).

[0603] Step Four:

[0604] Compound B04 (50 mg) was dissolved in ACN (1.5 mL), and NMI (30 mg), TCFH (57 mg), and 168-03 (38.05 mg) were added sequentially. The mixture was stirred at 80 °C for 0.5 hours. The crude product was purified by Pre-TLC (DCM:MeOH = 15:1) to obtain compound 168 (45.3 mg).

[0605] 1 H NMR (400MHz, DMSO-d6) δ13.56(s,1H),7.86–7.81(m,1H),7.49(s,1H),7.24(d,J=5.6Hz,1H),3.86–3.78(m,2H),3.71(s,3H),1.38–1.32(m,12H).

[0606] Example 32: Synthesis of Compound 176

[0607] 3-(difluoromethoxy)-4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-2-oxo-2H-pyran-6-carboxamide

[0608] Step 1:

[0609] At room temperature, compound B04-01 (1000 mg) was dissolved in a 20.00 mL DCM reaction flask. The mixture was cooled to 0 °C, and boron tribromide (2.263 mL, 4.526 mmol, 1.5 eq.) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 30 min. The reaction solution was quenched directly in 120 mL of ice water, and then extracted with 150 mL of EA. The organic phase was washed three times with 120 mL of water, collected, and dried over anhydrous sodium sulfate. The organic phase was then evaporated to dryness to give compound 176-1 (150.00 mg).

[0610] Step Two:

[0611] At room temperature, compound 176-1 (150.00 mg) was dissolved in a reaction flask containing 3.00 mL of DMF. K2CO3 (130.65 mg) and sodium difluorochloroacetate (108.09 mg) were added, and the mixture was heated to 80 °C and stirred for 30 min. The reaction solution was quenched directly in 20 mL of ice water, and then extracted with 50 mL of EA. The organic phase was washed three times with 20 mL of water, collected, and dried over anhydrous sodium sulfate. The organic phase was distilled under reduced pressure to obtain the crude product, which was purified by forward purification (EA:PE = 3:1) to obtain compound 176-2 (80.00 mg).

[0612] Step Four:

[0613] Compound 176-2 (80.00 mg) was dissolved in THF (1.00 mL) and MeOH (1.00 mL) at room temperature. The temperature was lowered to 0 °C, and K2CO3 (0.5 M aq. 0.871 mL) was slowly added dropwise. After the addition was complete, the temperature was restored to room temperature and stirring was continued for 30 min. The pH was adjusted to 5 with 1 M hydrochloric acid, and DCM:MeOH (10:1) was added for extraction. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 176-3 (80.00 mg).

[0614] Step 5:

[0615] Compound 176-3 (80.00 mg) and compound A03 (53.86 mg) were dissolved in ACN (2.00 mL), and NMI (42.75 mg) and TCFH (82.58 mg) were added. The mixture was stirred at 80 °C for 0.5 hours. Compound 176 (15.10 mg) was purified by silica gel plate (DCM:MeOH = 20:1).

[0616] Example 33: Synthesis of Compound 171

[0617] 4-[(diisopropyl(oxo)-λ] 6 [-thionyl)amino]-N-[5-(3-fluoro-1-methyl-1H-pyrrolo-2-yl)-1,3,4-thiadiazol-2-yl]-2-oxo-3-(2-oxoazapyridine-1-yl)-2H-pyran-6-carboxamide

[0618] Step 1:

[0619] Compound 166 (630.00 mg) was dissolved in 1,2-dichloroethane (12 mL) in the corresponding reaction flask. The system was cooled to 0 °C, and a DCM solution of BBr3 (1.361 mL, 2 M) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature, and stirring was continued for 30 minutes. The reaction solution was quenched in ice water (10 mL), and extracted with EA (20 mL). The organic phase was collected and concentrated under reduced pressure. The crude product was washed three times with a DCM / MeOH mixed solvent (10:1, 10 mL) to obtain compound 171-01 (120.00 mg).

[0620] Step Two:

[0621] Compound 171-01 (100.00 mg) was dissolved in a 2.00 mL DCM flask at room temperature, followed by the addition of 0.10 mL TEA. The temperature was lowered to 0 °C, and trifluoromethanesulfonic anhydride (87.52 mg) was added dropwise to the flask. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction solution was then purified by vacuum distillation using normal phase (DCM / MEOH = 50 / 1) to obtain compound 171-02 (50.00 mg).

[0622] Step 3:

[0623] Compound 171-02 (50.00 mg) and 2-azacyclobutanone (8.66 mg) were dissolved in dioxane (2.00 mL), followed by the addition of potassium carbonate (33.68 mg). Under nitrogen protection, Gphos (8.72 mg) and Gphos Pd G3 (7.47 mg) were added. The mixture was stirred at 70 °C under nitrogen atmosphere for 2 h. The reaction was then complete. The resulting mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. Compound 171 (16.85 mg) was purified by TLC (EA:DCM:MeOH = 10:10:1) to obtain compound 171.

[0624] 1H NMR(400MHz,DMSO-d6)δ13.47(s,1H),7.50(s,1H),7.05–6.98(m,1H),6.14(d,J=3.1Hz,1H),3.9 4(s,3H),3.90–3.76(m,2H),3.53(t,J=4.4Hz,2H),3.00(t,J=4.4Hz,2H),1.34(d,J=6.7Hz,12H).

[0625] Other compounds in Table 1 below were prepared using a similar method to that used to synthesize the above-described end products:

[0626] Table 1

[0627] Pharmacological test

[0628] Pharmacological Example A: Inhibitory activity of the compound on human cGAS enzyme activity

[0629] cGAS is an innate immune sensor of double-stranded DNA (dsDNA). The allosteric binding of cGAS to dsDNA activates its catalytic activity, catalyzing the production of cGAMP by consuming substrates such as ATP and GTP, and further activating STING and downstream pathways. The Kinase-Glo assay was used to assess cGAS enzyme activity by measuring ATP consumption in 384-well plates (revvity), evaluating the inhibitory activity of compounds against cGAS. 1X Enzyme Buffer (10mM MgCl2, 200μM MnCl2, 20mM Tris-HCl, pH 7.5, 0.01% Brij) was prepared. TM-35°C solution, 1 mM DTT, 0.1 mg / ml BAS). Prepare stock solutions of the target compounds with DMSO to the corresponding concentrations, then dilute with 1X Enzyme Buffer to prepare 5X working stock solutions. Pipette 8 μL of the 2.5X Substrates (250 μM ATP, 250 μM GTP, 3 μg / ml dsDNA) mixture into a 384-well plate and centrifuge at 1000 rpm for 1 min. Add 4 μL of the 5X compound working stock solution and centrifuge at 1000 rpm for 1 min. Transfer 8 μL of 2.5X cGAS Enzyme (250 nM) working solution to the 384-well plate, centrifuge at 1000 rpm, and incubate at 37°C for 2 h. Add 20 μL of Kinase-Glo Max reagent to each well to terminate the enzyme reaction, incubate at room temperature for 10 min, and read the Luminescence value on a microplate reader. Negative wells (enzyme-free) contained only 8 μL of 2.5X Substrates mixture and 12 μL of 1X Enzyme Buffer, while positive wells (enzyme-containing) contained DMSO. The inhibition percentage of the test compound was calculated as (1 - (experimental well value - negative well value) / (positive well value - negative well value)) * 100. The IC was calculated using GraphPad Prism 8 software. 50 (Half-maximal inhibitory concentration). Experimental results are shown in the table below; "A" represents the IC50 value. 50 <50nM; "B" represents 50nM <IC 50 <200nM; "C" represents 200nM <IC 50 <1μM; "D" represents >1μM.

[0630] Table 2

[0631] Pharmacological Example B: Inhibitory effect of the compound on ISRE-luciferase activity in the THP-1Reporter cell line

[0632] ISRE-Luc / NFκB-SEAP / THP-1 cells are derived from the THP1 mononuclear cell line. ISRE-Luc / NFκB-SEAP / THP-1 cells stably express two inducible reporter genes: one is an interferon-stimulated response element (ISRE) connected to a secretory luciferase reporter gene, which can catalyze the generation of chemiluminescent signals upon substrate stimulation, and this reporter gene can assess the IRF pathway; the other is the NF-κB pathway, downstream of which is a secretory embryonic alkaline phosphatase (SEAP) reporter gene, which can respond to some NF-κB-related stimuli.

[0633] ISRE-Luc / NFκB-SEAP / THP-1 cells in the logarithmic growth phase were collected, centrifuged at 1200 rpm, and resuspended for cell counting. The cells were then prepared into a cell suspension with a density of 6*10^5 cells / mL. An appropriate volume of PMA stimulation mixture (Invitrogen, 500X) was added to the cell suspension to a final concentration of 1X. Cells were cultured at 37°C in a 5% CO2 incubator for 6 h. Cells were then collected, resuspended in culture medium, counted, and plated (3.4*10^4 cells / well). Cells were incubated overnight at 37°C in a 5% CO2 incubator to ensure full cell adhesion. Different concentrations of the compound were added, with DMSO wells serving as negative controls, and pre-incubated for 1 h. ISD-naked (InvivoGen) cells were then analyzed using Opti-MEM. TM I-reduced serum culture medium was prepared to a working solution with a concentration of 10 μg / ml. Lipo2000 stock solution was then used with Opti-MEM. TM I. Dilute the culture medium (add an appropriate amount of PEG2000 and incubate at room temperature for 5 min for PEGylation) to prepare a working solution with a concentration of 10 μl / ml. Mix ISD Naked working solution and Lipo2000 working solution at a 1:1 volume ratio to obtain the transfection complex. Add the transfection complex to the cell suspension in the corresponding wells, and incubate the cells at 37℃, 5% CO2 for 24 h. Transfer 20 μl of cell culture supernatant to a new 96-well plate, and add 50 μl of QUANTI-Luc to each well. TM Reagent (InvivoGen), gently tap to mix, and immediately read the Luminescence value on a microplate reader. Control wells (containing DMSO and ISD Naked stimulation), blank wells (containing cells only, without DMSO and ISD Naked stimulation); Inhibition% = (Value) control -Value test ) / (Value control -Value blank )*100. Calculate IC using GraphPad Prism 8 software. 50 (Half-maximal inhibitory concentration). Experimental results are shown in the table below; "A" represents the IC50 value. 50 <500nM; "B" represents 500nM <IC 50 <2000nM; "C" represents 2000nM <IC 50 <10μM; "D" represents >10μM.

[0634] Table 3

[0635] While the invention has been fully described through its embodiments, it is worth noting that various changes and modifications to these embodiments will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims.

[0636] Implementation Plan

[0637] The following clauses describe other embodiments of the invention.

[0638] 1. A compound of formula (I'), or a stereoisomer, tautomer, solvate, prodrug, pharmaceutically acceptable salt, or deuterated derivative thereof:

[0639] in,

[0640] Y' is either S or Se;

[0641] X'1 is independent of O and NR' b or R' b ;

[0642] X'2 is independent of O or NR' c Or X'2 does not exist;

[0643] Indicates a single bond or a double bond;

[0644] Z' is -OR'1, CN, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 5-10 heteroaryl, or C 3-10 Heterocyclic group, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by one or more R'1;

[0645] R'1 is independently selected from H, deuterium, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -C0-6 alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 alkylene-3-14-membered heterocyclic group or -C 0-6 Alkylene-5-14-membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -C 0-6 Alkylene-C 3-14 Carbocyclic group, -C0-6 Alkylene-C 6-14 Aryl, -C 0-6 alkylene-3-14-membered heterocyclic groups and -C 0-6 Each of the alkylene-5-14 heteroaryl groups is optionally substituted by one or more substituents selected from the following: hydrogen, deuterium, halogen, CN, oxo, hydroxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne group, -OR' h -NR' h R' f Substituted or unsubstituted -C 0-6 Alkylene-C 3-14 Carbocyclic group, substituted or unsubstituted -C 0-6 Alkylene-3-14-membered heterocyclic group, substituted or unsubstituted -C 0-6 Alkylene-C 6-14 aryl, substituted or unsubstituted -C 0-6 alkylene-5-14-membered heteroaryl, -C(O)OR' h -C 0-6 Alkylene-C(O)OR' h -OC(O)R' h -C0-6 alkylene-OC(O)R' h -C(O)NR' h R' f -C 0-6 Alkylene-C(O)NR' h R' f -NR' h C(O)R' f -C 0-6 Alkylene-NR' h C(O)R' f -NR' h C(O)-NR' h R' f 、 and -C 0-6 Alkylene-NR' h C(O)-NR' h R' f ;

[0646] Ring A' is C 6-10Aryl, 3-14-membered heterocyclic or 5-14-membered heteroaryl, preferably 5-10-membered heteroaryl, wherein the aryl, heterocyclic or heteroaryl is optionally substituted by one or more R'2;

[0647] Each R'2 is independently hydrogen, halogen, hydroxyl, -CN, or -L'2-OR'. 4a -L'2-N(R' 4b )2, C1-C6 alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0648] Each R' 4a and R' 4b Hydrogen and C are independent. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, C1-C6 deuterated alkyl, -C 0-6 Alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-3-14-membered heterocyclic group or -C 0-6 alkylene-5-14-membered heteroaryl or -C 0-6 Alkylene-(C=O)R' 4c ;where R' 4c It is a C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl;

[0649] L'2 is a bond, a C1-C6 alkylene group, or a C1-C6 haloalkylene group;

[0650] n' is an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0651] R' e It does not exist, or R' e As defined by R'1;

[0652] R' a 、R' b 、R' c 、R' h 、R' f Selected independently from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 3-14 cycloalkyl, -OC3-14 Heterocyclic groups, -SC 3-14 Heterocyclic groups, -SC 3-14 cycloalkyl, -SC 1-6 Alkyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 2-6 alkenyl), -N(C) 2-6 alkenyl)2, -NH(C 2-6 alkynyl group), -N(C 2-6 ynyl group)2, -CONH2, -CONH(C 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-CONH(C 2-6 alkenyl), -CON(C) 2- 6-Alkenyl)2, -CONH(C 2-6 alkynyl group), -CON(C) 2-6 2-S(O)-C (alkynyl group) 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 alkenyl, -S(O)2-C 2-6 alkenyl, -S(O)-C 2-6 alkynyl group, -S(O)2-C 2-6 alkynyl group, -S(O)-C 3-14 cycloalkyl, -S(O)2-C 3-14 Heterocyclic groups, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl group 2, -CHO, -C(O)-C 1-6 Alkyl, -C(O)-C 2-6 alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 alkylene-5-14-membered heteroaryl, -C 0-6 Alkylene-C 3-14 carbonyl group, or -C 0- 6-alkylene-3-14-membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkylene, C 3-14 cycloalkyl, C 3-14 Heterocyclic group, C 6-14The aryl group and the 5-14 heteroaryl group are each optionally substituted by one or more substituents selected from the following: hydrogen, deuterium, halogen, CN, OH, thiol group, nitro group, NH2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COO(C 1-6 Alkyl), -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-OCO(C 1- 6-alkyl), -NHCO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CONH(C 1-6 alkyl), -N(C) 1-6 alkyl)-CON(C 1-6 Alkyl)2, -C 0-6 Alkylene-NHC(=O)C 1-6 Alkyl, -C 0-6 Alkylene-C(=O)NH-C 1-6 Alkyl, -C 0-6 Alkylene-C(=O)N(C) 1-6 Alkyl)2, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl, substituted or unsubstituted -C 0-6 Alkylene-C 3-14 Carbocyclic group, substituted or substituted -C 0-6 Alkylene-3-14-membered heterocyclic group, substituted or unsubstituted -C 0-6 Alkylene-C 6-14 aryl, and substituted or unsubstituted -C 0-6 alkylene-5-14-membered heteroaryl;

[0653] Or, R' a and R' b 、R' a and R' c 、R' a and R' e 、or R'h and R' f Together with the atoms they are attached to, they form 3-14 membered heterocyclic groups, which are optionally substituted by one or more substituents selected from the following: hydrogen, deuterium, halogen, CN, oxo, hydroxyl, thiol, nitro, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)OH, -C(O)O(C 1-6 Alkyl), -C 0-6 Alkylene -C(O)OH, -C 0-6 Alkylene-C(O)O(C) 1-6 Alkyl), -OC(O)-(C 1-6 Alkyl), -C 0-6 Alkylene-OC(O)-(C 1-6 Alkyl), -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2, -C 0-6 Alkylene-C(O)NH-C 1-6 Alkyl, -C 0-6 Alkylene-C(O)N(C) 1-6 Alkyl)2、-NHC(O)-C 1-6 Alkyl, -N(C) 1-6 Alkyl)C(O)-C 1-6 Alkyl, -C 0-6 Alkylene-NHC(O)-C 1-6 Alkyl and -C 0-6 Alkylene-N(C) 1-6 Alkyl)C(O)-C 1-6 alkyl.

[0654] 2. The compound according to embodiment 1, wherein in formula (I'), Y' is an S atom.

[0655] 3. The compound according to embodiment 1, wherein in formula (I'), Y' is a Se atom.

[0656] 4. The compound according to any one of embodiments 1-3, wherein ring A' in formula (I') is a 5-membered monocyclic heteroaryl group.

[0657] 5. The compound according to any one of embodiments 1-4, wherein in formula (I'), if If there is a double bond between them, then There is a single bond between them, and R' e Missing.

[0658] 6. The compound according to any one of embodiments 1-4, wherein in formula (I'), if If there is a single bond between them, then There is a double bond between them.

[0659] 7. The compound according to any one of embodiments 1-6, wherein the group in formula (I') Selected from the following structures:

[0660] 8. The compound according to any one of embodiments 1-7, wherein in formula (I'), Z' is -OR'1, and R'1 is independently selected from H, deuterium, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -C 0-6 Alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 alkylene-3-14-membered heterocyclic group or -C 0-6 Alkylene-5-14-membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -C 0-6 Alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-C 6-14 Aryl, -C0-6 alkylene-3-14 membered heterocyclic, -C 0-6 The alkylene-5-14-membered heteroaryl group is optionally surrounded by one or more hydrogens, deuteriums, halogens, CN, oxo groups, or C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Halogenated alkyl groups, -NH(C 1-6 (halogenated alkyl), or -N(C) 1-6 (Halogenated alkyl)2-substituted.

[0661] 9. The compound according to any one of embodiments 1-7, wherein in formula (I'), Z' is -OR'1, and R'1 is selected from...

[0662] 10. The compound according to embodiment 1, wherein in the compound of formula (I'), R' a and R' b Together with the attached atoms, they form substituted or unsubstituted 3-11 member heterocyclic groups, preferably 3-6 member heterocyclic groups.

[0663] 11. The compound according to embodiment 1, wherein in the compound of formula (I'), R' a and R' c Together with the attached atoms, they form substituted or unsubstituted 4-11 member heterocyclic groups, preferably 3-6 member heterocyclic groups.

[0664] 12. The compound according to embodiment 1, wherein in the compound of formula (I'), R' a and R' e Together with the attached atoms, they form substituted or unsubstituted 5-11 member heterocyclic groups.

[0665] 13. The compound according to any one of embodiments 1-12, wherein in formula (I'), R' e It is hydrogen, deuterium or C 1-6 alkyl.

[0666] 14. The compound according to any one of embodiments 1-13, wherein in formula (I'), for

[0667] 15. The compound according to any one of embodiments 1-14, wherein in formula (I'), for

[0668] 16. The compound according to any one of embodiments 1-15, wherein the compound of formula (I') is a compound of formula (II)' as shown below:

[0669] Among them, Y', Z', R' a 、R' b The definitions of R'2, ring A' and n' are as defined in any of the aforementioned implementation schemes 1-15 for equation (I').

[0670] 17. The compound according to embodiment 16, wherein R' in the compound of formula (II') a and R'b Together with the atoms to which they are attached, they form substituted or unsubstituted 3-11 membered heterocyclic groups, preferably 3-6 membered rings.

[0671] 18. The compound according to any one of embodiments 1-15, wherein the compound of formula (I') is a compound of formula (III') as shown below:

[0672] Among them, Y', Z', R' a 、R' b 、R' c The definitions of R'2, ring A' and n' are as defined in any of the aforementioned implementation schemes 1-15 for equation (I').

[0673] 19. The compound according to embodiment 18, wherein R' in the compound of formula (III') a and R' b Together with the atoms to which they are attached, they form substituted or unsubstituted 3-11 member heterocyclic groups, preferably 3-6 member heterocyclic groups.

[0674] 20. The compound according to embodiment 18, wherein R' in the compound of formula (III') a and R' c Together with the atoms to which they are attached, they form substituted or unsubstituted 3-11 member heterocyclic groups, preferably 3-6 member heterocyclic groups.

[0675] 21. The compound according to any one of embodiments 1-15, wherein the compound of formula (I') is a compound of formula (IV') as shown below:

[0676] Among them, Y', Z', R' a 、R' e 、R' c The definitions of R'2, ring A' and n' are as defined in any of the aforementioned implementation schemes 1-15 for equation (I').

[0677] 22. The compound according to embodiment 21, wherein R' in the compound of formula (Ⅳ') a and R' c Together with the atoms to which they are attached, they form substituted or unsubstituted 3-11 member heterocyclic groups, preferably 3-6 member heterocyclic groups.

[0678] 23. The compound according to any one of embodiments 1-15, wherein the compound of formula (I') is selected from the compounds of formula (V') shown below:

[0679] Among them, Y', Z', R' a、R' e The definitions of R'2, ring A' and n' are as defined in any of the aforementioned implementation schemes 1-15 for equation (I').

[0680] 24. The compound according to embodiment 23, wherein R' in the compound of formula (V') a and R' e Together with the atoms they are attached to, they form substituted or unsubstituted 5-11 member heterocyclic groups.

[0681] 25. A pharmaceutical composition comprising the compound of any one of embodiments 1-24 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, labeled isotopic variant or tautomer thereof and a pharmaceutically acceptable carrier, preferably, the pharmaceutically acceptable carrier may further comprise an excipient, a diluent or a surfactant.

[0682] 26. A method for treating cGAS-related diseases or disorders, the method comprising administering to a subject a compound of any one of embodiments 1-24.

[0683] 27. A method for modulating cGAS, the method comprising administering to the subject a compound of any one of embodiments 1-24.

[0684] 28. A compound according to any one of embodiments 1-24, used for the treatment of cGAS-related diseases or disorders.

[0685] 29. Use of the compound of any one of embodiments 1-24 in the preparation of a medicament for treating cGAS-related diseases or disorders.

[0686] 30. The method, compound, or use of any one of embodiments 26-29, wherein the subject is a human being.

[0687] 31. The method, compound, or use of any one of embodiments 26-30, wherein the cGAS-related disease or disorder is inflammation, autoimmune disease, 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, mental illness, graft-versus-host disease, abnormal pain, or cGAS-related disease in a subject who has been identified as carrying a germline or somatic non-silent mutation in cGAS.

[0688] 32. The method, compound, or use of any one of embodiments 26-31, wherein the disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0689] 33. The method, compound, or use of any one of embodiments 26-31, wherein the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

[0690] 34. The method, compound, or use of any one of embodiments 26-31, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0691] 35. The method, compound, or use of any one of embodiments 26-31, wherein the rheumatic disease is dermatomyositis Still's disease or juvenile idiopathic arthritis.

[0692] 36. The method, compound, or use of any one of embodiments 26-31, wherein the cGAS-related disease in a subject who has been identified as carrying a germline or somatic non-silent mutation in cGAS is a cold pyridine-associated autoinflammatory syndrome.

[0693] 37. The method, compound, or use of any one of embodiments 26-31, wherein the cold pyridine-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or a neonatal multisystem inflammatory disease.

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