KR20240022938A - Novel compounds as nlrp3 inhibitor and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a compound represented by Formula 1 as an NLRP3 inhibitor, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound as an active ingredient, the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Possible salts and pharmaceutical compositions containing them as active ingredients can be usefully used in the prevention or treatment of diseases related to NLRP3 activity.
[Formula 1]

Description

Novel compounds as NLRP3 inhibitors and pharmaceutical compositions containing the same {NOVEL COMPOUNDS AS NLRP3 INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}

The present invention relates to compounds as NLRP3 inhibitors, stereoisomers thereof, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same, and methods for preventing or treating diseases related to NLRP3 activity using the compounds, and their uses.

NOD-like receptor protein 3 (NLRP3) is a protein-coding gene that encodes a nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR). ) belongs to the family. NLRP3 encodes a protein containing a pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. NLRP3 responds to sterile inflammatory danger signals by interacting with adapter proteins, apoptosis-associated speck-like protein (ASC) and pro-caspase-1. Forms the NLRP3 inflammasome. NLRP3 inflammasome activation can then lead to the release of inflammatory cytokines IL-1β and IL-18, thereby triggering a number of related diseases.

Activating cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to stereotype immune responses to infection and injury. For example, IL-1β signaling induces secretion of proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by γδ T cells and memory CD4 Th17 cells in the absence of T cell receptor engagement. IL-18 and IL-12 also act synergistically to induce IFN-γ production from memory T cells and NK cells, promoting Th1 responses.

NLRP3 inflammasome activation is associated with various inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases and autoinflammatory diseases, such as autoinflammatory febrile syndrome, such as cryopyrin associated periodic syndrome. syndrome; CAPS) (Mortimer et al., Nature Immunol. 2016, 17(10), 1176-1188); sickle cell disease; systemic lupus erythematosus (SLE); Liver-related diseases/disorders, such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH, Hugh Thomas Nature Reviews Gastroenterology & Hepatology 2017:14, 197), alcoholic steatohepatitis and alcoholic liver disease (Petrasek) et al., J. Clin. Invest.2012, 122, 3476-89; Petrasek et al., Nat. Rev. Gastroenterol. Hepatol.2015, 12, 387-400; Mridha et al., J. Hepatol. 2017, 66, 1037-46); Inflammatory arthritis-related disorders such as gout, pseudogout (chondrocalcinosis), osteoarthritis (Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31) and rheumatoid arthritis (Mathews et al., Ann. Rheum. Dis.2014, 73, 1202-10), acute or chronic arthropathy; Kidney-related diseases, such as hyperoxaluria (Knauf et al., Kidney Int. 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al., Br. J. Pharmacol.2016, 173, 752 -65), diabetic nephropathy, also called hemodialysis-related inflammation and diabetic kidney disease, which is a kidney-related complication of diabetes mellitus (type 1, type 2, and diabetes mellitus) (Shahzad et al., Kidney It is known that it can contribute to the invention and progress of [Int. 2015, 87, 74-84]).

Additionally, the involvement of increased production of IL-1β and IL-18 by the NLRP3 inflammasome has been implicated in a variety of diseases, such as neuroinflammation-related disorders such as brain infections, acute injury, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases. (hao et al., Front. Pharmacol.2015, 6, 262); Cardiovascular/metabolic disorders/disease, e.g. cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications (e.g. nephropathy, retinopathy), peripheral Peripheral artery disease (PAD), acute heart failure, and hypertension (Ridker et al., N. Engl. J. Med.2017, 377, 1119-31); wound healing and scar formation; Inflammatory skin diseases such as acne, hidradenitis suppurativa (Sweeney et al., Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age-related macular degeneration; Cancer-related diseases/disorders, such as myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer (Ridker et al., Lancet 2017, 390, 1833-42) It has been shown that it may contribute to the onset and progression. Immune or inflammatory diseases/disorders are generally difficult to diagnose or treat efficiently. Most treatments involve treating symptoms, slowing the progression of the disease/disorder, lifestyle changes, and surgery as a last resort (eg, open heart surgery for advanced forms of atherosclerosis). Recent studies have shown that mitochondrial dysfunction and NLRP3 activation are related to neuroinflammation-related diseases such as Parkinson's disease (Sarkar et al., npj Parkinson's disease 2017, 3:30; Zhou et al., Nature, 2011, 469, 221) . One of the major problems associated with mitochondrial regulators is their poor metabolic stability; Therefore, a selective and stable inhibitor is needed for neuroinflammation of this nature (Lee et al., Eur J. Org. Chem. 2017, 141, 240).

These inflammasome-related diseases/disorders and others, such as autoinflammatory febrile syndrome cryophyrin-related periodic syndrome (e.g. CAPS), sickle cell disease, chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, Hyperoxaluria, pseudogout (chondrocalcinosis), type I/type II diabetes and related complications (e.g. nephropathy, retinopathy), neuroinflammation-related disorders (e.g. multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scarring, and cancer (e.g. colon cancer) There is a need for inhibitors of the NLRP3 inflammasome pathway to provide new and/or alternative treatments for lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis).

International Public Patent WO 2016131098 International Public Patent WO 2020021447 International Public Patent WO 2020234715

A critical role for the NLRP3 inflammasome in NASH, Hugh Thomas Nature Reviews Gastroenterology & Hepatology 2017:14, 197 NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice, Mridha, A. R. et al. J. Hepatol. 2017:66, 1037 Mortimer et al., Nature Immunol. 2016, 17(10), 1176-1188 Petrasek et al., J. Clin. Invest.2012, 122, 3476-89 Petrasek et al., Nat. Rev. Gastroenterol. Hepatol.2015, 12, 387-400 Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31 Mathews et al., Ann. Rheum. Dis.2014, 73, 1202-10 Knauf et al., Kidney Int. 2013, 84, 895-901 Krishnan et al., Br. J. Pharmacol.2016, 173, 752-65 Shahzad et al., Kidney Int. 2015, 87, 74-84 hao et al.,Front. Pharmacol.2015, 6, 262 Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31 Ridker et al., Lancet 2017, 390, 1833-42 Sarkar et al., npj Parkinson's disease 2017, 3:30 Zhou et al., Nature, 2011, 469, 221 Lee et al., Eur J. Org. Chem.2017, 141, 240)

The purpose of the present invention is to provide a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an NLRP3 inhibitor.

Another object of the present invention is to provide a pharmaceutical composition containing a compound as an NLRP3 inhibitor, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a composition for the prevention or treatment of diseases related to NLRP3 activity, comprising a compound as an NLRP3 inhibitor, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preventing or treating diseases related to NLRP3 activity, comprising administering the compound in a therapeutically effective amount.

Another object of the present invention is to provide the use of the compound for the prevention or treatment of NLRP3 activity-related diseases, or for the preparation of a medicament for the prevention or treatment of NLRP3 activity-related diseases.

Another object of the present invention is to provide a use of the compound for the prevention or treatment of NLRP3 activity-related diseases, or for the prevention or treatment of NLRP3 activity-related diseases.

Hereinafter, the present invention will be described in more detail. All combinations of the various elements disclosed herein fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered limited by the specific description below.

Compound represented by formula 1

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ₁ is H, O, S, C _1-6 alkyl, cycloalkyl, or -NR ₇ R ₈ , where one or more H of the C _1-6 alkyl or cycloalkyl is each independently substituted with halogen, or OH. It can be,

A is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, aryl, heteroaryl, or , where one or more H of A may each independently be substituted with R ₂ ,

X _1, X ₂ and X ₃ are each independently CH, N, O, S or S(=O) ₂ ,

W ₁ is CR ₃ or N,

W ₂ is O or S,

W ₃ is N or NH,

R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen, where one or more H of the C _1-6 alkyl may be substituted with halogen, OH,

R ₄ is H, O, S, or C _1-6 alkyl,

L is CR ₉ , -C(=O)- or -S(=O) ₂ -,

In each of R ₅ and R ₆ , R ₅ and R ₆ are each independently selected from H, C _1-6 alkyl, -C _1-6 alkyl-C(=O)-NH ₂ , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring with N,

Here, one or more H of R ₅ and R ₆ are each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C= O)-(C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl can be substituted with halogen, OH, or C _3-8 cycloalkyl,

Here, the ring in which R ₅ and R ₆ are connected to each other and formed together with N is a 5- to 12-membered heteroaryl containing at least one N, and herein is a 5- to 12-membered heteroaryl containing at least one N. Heteroaryl may further include 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, and at least one H of the 5- to 12-membered heteroaryl containing at least one N is may be substituted with halogen, OH, or NH ₂ ,

R ₇ and R ₈ are each independently H, C _1-6 alkyl, or C _3-8 cycloalkyl,

R ₉ is H, C _1-6 alkyl or halogen, where one or more H of the C _1-6 alkyl may be substituted with halogen, OH,

are each independently a single bond or a double bond.

In one embodiment, in Formula 1, when R ₁ is H, C _1-6 alkyl, cycloalkyl, or -NR ₇ R ₈ , at is a single bond, W ₃ is N, at is a double bond.

In another example, in Formula 1, when R ₁ is O or S, at is a double bond, W ₃ is NH, at is a single bond.

In the present invention, the fact that one or more H may be substituted means that H may not be substituted and one or more H may be substituted.

In one embodiment, the compound represented by Formula 1 may be represented by Formula 1a or Formula 1b below.

[Formula 1a]

[Formula 1b]

In formula 1a, R ₁ is H, C _1-6 alkyl, C _3-8 cycloalkyl, or -NR ₇ R ₈ , where at least one H of the C _1-6 alkyl or C _3-8 cycloalkyl is may each independently be substituted with halogen or OH,

In Formula 1b, R ₁ is O or S,

_{In each of Formulas 1a and 1b , A , _ _ _} , and Each is the same as defined in Formula 1 above.

In one embodiment, in Formula 1b, R ₁ may be O.

In one embodiment, in Formula 1, Formula 1a, or Formula 1b, respectively

A has 1 to 3 heteroatoms independently selected from the group consisting of C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _8-10 cycloalkynyl, N, O and S in the ring. 3- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 12-membered ring containing 1 to 5 heteroatoms independently selected from the group consisting of N, O and S. heteroaryl, or , where one or more H of A may each independently be substituted with R ₂ ,

X _1, X ₂ and X ₃ are each independently CH, N, O, S or S(=O) ₂ ,

W ₁ is CR ₃ or N,

W ₂ is O,

R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen,

R ₄ is H, O, or C _1-6 alkyl,

L is CR ₉ , -C(=O)- or -S(=O) ₂ -,

In each of R ₅ and R ₆ , R ₅ is H, R ₆ is H, C _1-6 alkyl, -C _1-6 alkyl-C(=O)-NH ₂ , C _3-8 cycloalkyl, N, 3- to 8-membered heterocycloalkyl containing in the ring 1 to 3 heteroatoms independently selected from the group consisting of O and S, 1 to 5 heteroatoms independently selected from the group consisting of N, O and S 5- to 12-membered heteroaryl containing atoms in the ring, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring with N,

Here, one or more H of R ₆ are each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C=O)- (C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl can be substituted with halogen, OH, or C _3-8 cycloalkyl,

Here, the ring in which R ₅ and R ₆ are connected to each other and formed together with N is a 5- to 12-membered heteroaryl containing at least one N, and herein is a 5- to 12-membered heteroaryl containing at least one N. Heteroaryl may further include 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, and at least one H of the 5- to 12-membered heteroaryl containing at least one N is may be substituted with halogen, OH, or NH ₂ ,

R ₇ and R ₈ are each independently H or C _1-6 alkyl,

R ₉ is H, or C _1-6 alkyl, where one or more H of the C _1-6 alkyl may each independently be substituted with halogen or OH,

may each independently be a single bond or a double bond.

In one embodiment, in Formula 1, Formula 1a, or Formula 1b, respectively

A is , , , , or and one or more H of A may each be independently substituted with R ₂ ,

X ₁ is O, S or S(=O) ₂ ,

X ₂ and X ₃ are each independently CR ₁₀ or N,

Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently CR ₁₁ or N,

W ₁ is CR ₃ or N,

W ₂ is O,

R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen,

R ₄ is H, O, or C _1-6 alkyl,

L is CR ₉ , -C(=O)- or -S(=O) ₂ -,

In each of R ₅ and R ₆ , R ₅ is H, R ₆ is H, C _1-6 alkyl, -C _1-6 alkyl-C(=O)-NH ₂ , C _3-8 cycloalkyl, N, 3- to 8-membered heterocycloalkyl containing in the ring 1 to 3 heteroatoms independently selected from the group consisting of O and S, 1 to 5 heteroatoms independently selected from the group consisting of N, O and S 5- to 12-membered heteroaryl containing atoms in the ring, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring with N,

One or more H of R ₆ is each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C=O)-( C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl can be substituted with halogen, OH, or C _3-8 cycloalkyl,

The ring in which R ₅ and R ₆ are linked together and formed together with N is a 5- to 12-membered heteroaryl containing at least one N, and in this case, a 5- to 12-membered heteroaryl containing at least one N. One or more H of the aryl may be substituted with halogen, OH, or NH ₂ ,

R ₇ and R ₈ are each independently H or C _1-6 alkyl,

R _9, R ₁₀ and R ₁₁ are each independently H, or C _1-6 alkyl, where one or more H of the C _1-6 alkyl may each independently be substituted with halogen or OH,

may each independently be a single bond or a double bond.

In the present invention, defined in A A resonance structure such as It can be seen as the same as the structure expressed as. In the above, the resonance structure defined in A is described as an example, but is not limited thereto.

In one embodiment, in each of Formula 1 or Formula 1a,

R ₁ is H, C _1-6 alkyl, or -NR ₇ R ₈ , where one or more H of the C _1-6 alkyl may each independently be substituted with OH,

A is , , , , or and one or more H of A may each be independently substituted with R ₂ ,

X ₁ is O, S or S(=O) ₂ ,

X ₂ and X ₃ are each independently CH or N,

Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently CH or N,

W ₁ is CR ₃ or N,

W ₂ is O,

R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen,

R ₄ is H or C _1-6 alkyl,

L is -C(=O)- or -S(=O) ₂ -,

In each of R ₅ and R ₆ , R ₅ is H and R ₆ is heterocycloalkyl selected from the group consisting of C _1-6 alkyl, C _3-8 cycloalkyl, piperidinyl, pyrrolidinyl, and azepanyl. , pyrimidinyl, pyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, purinyl, thiazolyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, Hetero selected from the group consisting of indazolyl, isoxazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl and benzoxadiazolyl. aryl, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring with N,

One or more H of R ₆ is each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C=O)-( C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl may be substituted with OH, or C _3-8 cycloalkyl,

The ring in which R ₅ and R ₆ are connected to each other and formed together with N is pyrazolopyridine, and one or more H of the ring may be substituted with NH ₂ ,

R ₇ and R ₈ may each independently be H or C _1-6 alkyl.

At this time, in Formula 1, may each independently be a single bond or a double bond, and in Formula 1a, may be a single bond.

In the present invention, "Cm-Cn" (where m and n are each independently an integer of 1 or more) refers to the number of carbons, and for example, 'C1-C5alkyl' represents alkyl having 1 to 5 carbon atoms.

In the present invention, “alkyl” refers to a straight-chain or branched saturated hydrocarbon group. In the present invention, alkyl may have 1 to 5 carbon atoms. In one embodiment, alkyl can have 1 to 3 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neo-pentyl, etc. can be mentioned. In the present invention, alkyl may mean unsubstituted, or may mean that one or more H of alkyl is optionally substituted. The substituent on which one or more H of the alkyl may be substituted may include without limitation any functional group capable of substituting one or more H of the alkyl. For example, the substituent may be defined in the compounds represented by Formula 1, 1a, and/or 1b of the present invention, but is not necessarily limited thereto.

In the present invention, “cycloalkyl” refers to a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic ring structures. Cycloalkyl may be a saturated hydrocarbon ring having 3 to 12 carbon atoms. Examples of cycloalkyl may be one or more selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, but are not limited thereto. In the present invention, cycloalkyl may mean unsubstituted, or may mean that one or more H of cycloalkyl is optionally substituted. The substituent on which one or more H of the cycloalkyl may be substituted may include without limitation any functional group capable of substituting one or more H on the cycloalkyl. For example, the substituent may be defined in the compounds represented by Formula 1, 1a, and/or 1b of the present invention, but is not necessarily limited thereto.

In the present invention, “cycloalkenyl” refers to an unsaturated hydrocarbon ring having 3 or more carbon atoms including one or more double bonds, and the hydrocarbon ring includes both monocyclic and polycyclic ring structures. That is, in the present invention, cycloalkenyl Alkenyl may refer to a ring structure containing one or more carbon-carbon double bonds in a cycloalkyl ring.In the present invention, cycloalkenyl may be an unsaturated hydrocarbon ring having a carbon number of 3 to 12. Cycloalkenyl Examples of may include, but are not limited to, one or more selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. In the present invention, cycloalkyl Kenyl may mean unsubstituted, or may mean that one or more H of the cycloalkenyl is optionally substituted. The substituent on which one or more H of the cycloalkenyl may be substituted may be one or more H of the cycloalkenyl. It may include without limitation any functional group capable of substituting H. For example, the substituent may be defined in the compounds represented by Formulas 1, 1a, and/or 1b of the present invention, but is not necessarily limited thereto.

In the present invention, “cycloalkynyl” refers to an unsaturated hydrocarbon ring containing a triple bond, and a monohydrocarbon ring includes both monocyclic and polycyclic ring structures. That is, in the present invention, cycloalkynyl may mean a ring structure containing a triple bond in the cycloalkyl ring. Examples of cycloalkynyl include, but are not limited to, cyclooctynyl. In the present invention, cycloalkynyl may mean unsubstituted, or may mean that one or more H of cycloalkynyl is optionally substituted. The substituent that can substitute one or more H of the cycloalkynyl may include without limitation any functional group that can substitute one or more H of the cycloalkynyl. For example, the substituent may be defined in the compounds represented by Formula 1, 1a, and/or 1b of the present invention, but is not necessarily limited thereto.

In the present invention, “heterocycloalkyl” refers to a cyclic functional group in which at least one carbon atom forming the ring is replaced with a heteroatom. Examples of the heteroatom may be nitrogen (N), oxygen (O), or sulfur (S). At this time, the heteroatoms included in the heterocycloalkyl ring may be one or two or more types, one or more types of heteroatoms may be included, and two or more types of heteroatoms may be included at least one each. . Heterocycloalkyl can be a 3- to 12-membered ring. Examples of heterocycloalkyl include oxiranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, and tetrahydrothiopyran. Examples include, but are not limited to, days and days. In the present invention, heterocycloalkyl may mean unsubstituted, or may mean that one or more H of heterocycloalkyl is optionally substituted. The substituent on which one or more H of heterocycloalkyl may be substituted may include without limitation any functional group capable of substituting one or more H on heterocycloalkyl. For example, the substituent may be defined in the compounds represented by Formula 1, 1a, and/or 1b of the present invention, but is not necessarily limited thereto.

In the present invention, “aryl” includes monoaromatic or polycyclic aromatics and means aromatic hydrocarbons having 6 or more carbon atoms. Aryl may have 6 to 20 carbon atoms. For example, aryl can be phenyl, biphenyl, naphthalenyl, etc. In the present invention, aryl may mean unsubstituted, or may mean that one or more H of aryl is optionally substituted. The substituent that can substitute one or more H of the aryl may include without limitation any functional group that can substitute one or more H of the aryl. For example, the substituent may be defined in the compounds represented by Formula 1, 1a, and/or 1b of the present invention, but is not necessarily limited thereto.

In the present invention, “heteroaryl” refers to a mono- or polycyclic hetero ring in which at least one carbon atom in the aryl is substituted with heteroatoms such as nitrogen (N), oxygen (O), or sulfur (S). For example, in the present invention, heteroaryl may have 5 to 12 members, but is not limited thereto. When heteroaryl contains two or more heteroatoms, the types of heteroatoms may be the same or different from each other. For example, if heteroaryl contains two or more heteroatoms selected from nitrogen, oxygen and sulfur, if it contains two nitrogens, if it contains one nitrogen and one oxygen, if it contains two oxygens and one nitrogen It means various combinations, such as cases containing . For example, heteroaryl is pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl. , pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzoimidazolyl, Dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridinyl. It may include dajinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazole and isomers thereof. In the present invention, heteroaryl may mean unsubstituted, or may mean that one or more H of heteroaryl is optionally substituted. The substituent on which one or more H of heteroaryl may be substituted may include without limitation any functional group capable of substituting one or more H on heteroaryl. For example, the substituent may be defined in the compounds represented by Formula 1, 1a, and/or 1b of the present invention, but is not necessarily limited thereto.

In the present invention, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycloalkyl refer to all monovalent substituents or divalent or more multivalent substituents of the chemical structure according to each definition. For example, “alkyl” can include monovalent alkyl or divalent alkyl (alkylene), and “aryl” can include monovalent aryl or divalent aryl (arylene).

In the present invention, in the definitions of alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycloalkyl, "may be substituted" means the alkyl, aryl, heteroaryl, cycloalkyl, This means that each of cycloalkenyl, cycloalkynyl, and heterocycloalkyl may be unsubstituted or substituted. Specifically, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycloalkyl may be substituted with alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and Heterocycloalkyl may be unsubstituted or one or more H of alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycloalkyl may each independently be substituted with a substituent, and the substituent may be substituted with one or more substituents. Any functional group capable of substituting H may be possible without limitation. For example, the substituents in each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycloalkyl of the present invention may be selected from the compounds represented by Formula 1, 1a, and/or 1b of the present invention. It may be a substituent defined in the definitions of alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycloalkyl, but is not necessarily limited thereto.

In the present invention, “halogen” may be F, Cl, Br or I.

The compound according to the present invention, its stereoisomer or its pharmaceutically acceptable salt may be a compound listed in Table 1 below.

[Table 1]

Additionally, the compound according to the present invention, its stereoisomer or its pharmaceutically acceptable salt may be a compound listed in Table 2 below.

[Table 2]

In the present invention, “pharmaceutically acceptable salt” refers to a salt commonly used in the pharmaceutical industry, and can be prepared by conventional methods known to those skilled in the art.

Pharmaceutically acceptable salts in the present invention include, for example, inorganic ionic salts made of calcium, potassium, sodium, or magnesium; Inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, or sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid. Organic acid salts made from acids, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; Sulfonic acid salts made from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, amino acid salts made from glycine, arginine, lysine, etc.; Alternatively, there are amine salts made from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are not limited by these salts listed. In one embodiment of the present invention, the salt may be hydrochloride.

In the present invention, “stereoisomer” includes diastereomers and optical isomers, and optical isomers include not only enantiomers but also mixtures of enantiomers and racemates. These isomers can be separated by resolution using conventional techniques, such as column chromatography or HPLC. Alternatively, each stereoisomer of the compound represented by Formula 1 can be stereospecifically synthesized using a known array of optically pure starting materials and/or reagents.

In the present invention, “prevention” refers to any act of suppressing or delaying the onset of a disease by administering a compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In the present invention, “treatment” refers to any action that improves or beneficially changes the symptoms of an individual suspected or affected by a disease by administering a compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. .

In the present invention, “NLRP3” refers to nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, and variants. , derivatives, splice variants, alleles, other species, and active fragments thereof.

The compound represented by Formula 1 of the present invention, its stereoisomer, or its pharmaceutically acceptable salt can be usefully used for the prevention or treatment of diseases related to NLRP3 activity.

The compound represented by Formula 1 of the present invention, its stereoisomer, or its pharmaceutically acceptable salt can inhibit NLRP3 or the NLRP3 inflammasome pathway, which induces the production of IL-1β. This may include reduced capacity of the ramasome pathway.

The compound represented by Formula 1 of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof has NLRP3 activity at a level similar to, substantially the same as, or superior to, conventionally known drugs for the prevention or treatment of diseases related to NLRP3 activity. It may have a preventive or therapeutic effect on activity-related diseases.

A composition comprising a compound represented by Formula 1

The present invention provides a pharmaceutical composition comprising the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases related to NLRP3 activity, comprising the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

That is, a pharmaceutical composition containing the compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully used for the prevention or treatment of diseases related to NLRP3 activity.

The diseases related to NLRP3 activity include inflammation, autoimmune disease, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease, lymphatic condition, psychological disorder, and graft disease. This may include host disease, allodynia, wounds, scars, etc.

Inflammation refers to inflammation that occurs as a result of an inflammatory disorder, such as an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of an infection, or inflammation that occurs as a result of an infection or inflammation secondary to injury or autoimmunity. It may include etc.

Autoimmune diseases include acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase antibody syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune infection, and autoimmune oophoritis. , autoimmune glandular dysfunction, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture syndrome, Grave's disease, Galan-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenia , reductive purpura, Kawasaki disease, lupus erythematosus, including systemic lupus erythematosus (SLE), primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and Multiple sclerosis (MS), including relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Oud's thyroiditis, pemphigus, pernicious anemia, Polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, intractable gouty arthritis, Reiter's syndrome, Sjögren's syndrome, multiple sclerosis, systemic connective tissue disorder, Takayasu's arteritis, temporal Arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Behcet's disease, Chagas disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromuscular dystonia, psoriasis, sarcoid These may include idosis, scleroderma, congestive colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo, or vulvodynia.

Cancers include lung cancer, pancreatic cancer, stomach cancer, myelodysplastic syndrome, leukemia including acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML), adrenal cancer, anal cancer, and basal squamous cell skin cancer. , biliary tract cancer, bladder cancer, bone cancer, cerebrospinal tumor, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing tumor. , including eye cancer, gallbladder cancer, gastrointestinal carcinoid, gastrointestinal stromal tumour (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, hypopharyngeal cancer, liver cancer, lung carcinoid, and cutaneous T-cell lymphoma. Lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, Pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, thyroid cancer, including undifferentiated thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, This may include Waltenstrom's macroglobulinemia, Wilms' tumor, etc.

Infections include viral infections (e.g., influenza virus, human immunodeficiency virus (HIV), alphavirus (e.g., Chikungunya and Ross River virus), flavivirus (e.g., dengue virus and Zika virus) viruses), herpes viruses (e.g., Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (e.g., vaccinia virus (modified vaccinia virus Ankara) and myxoma virus) , adenovirus (e.g., adenovirus 5), or papillomavirus), bacterial infection (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis , bordatel) Bordatella pertussis , Burkholderia pseudomallei , Corynebacterium diptheriae, Clostridium tetani , Clostridium botulinum , Streptococcus pneumoniae Streptococcus pneumoniae , Streptococcus pyogenes, Listeria monocytogenes , Hemophilus influenzae , Pasteurella multicida , Shigella dysenteriae dysenteriae ), Mycobacterium tuberculosis , Mycobacterium leprae , Mycoplasma pneumoniae , Mycoplasma hominis , Neisseria meningitidis ( Neisseria meningitidis ), Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila , Klebsiella pneumoniae , Pseudomonas aerugi Pseudomonas aeruginosa , Propionibacterium acnes , Treponema pallidum , Chlamydia trachomatis , Vibrio cholerae , Salmonella typhimurium , Salmonella typhi , Borrelia burgdorferi or Yersinia pestis , fungal infections (e.g. from Candida species or Aspergillus species), protozoa Infections (e.g. from malaria parasites, Babesia, Giardia, Entamoeba, Leishmania or Trypanosome), helminth infections (e.g. Schistosomes, Roundworms, may include tapeworm or trematode origin), prion infection, etc.

Central nervous system diseases may include Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, cerebral aneurysm, traumatic brain injury and amyotrophic axonal sclerosis.

Metabolic diseases may include type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudogout, etc.

Cardiovascular disease includes hypertension, ischemia, reperfusion injury, including ischemic reperfusion injury after MI, stroke, including ischemic stroke, transient ischemic attack, myocardial infarction, including recurrent myocardial infarction, congestive heart failure, and heart failure with preserved ejection fraction. These may include renal failure, embolism, aneurysms, including abdominal aortic aneurysm, or pericarditis, including Dressler syndrome.

Respiratory diseases may include chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, idiopathic pulmonary fibrosis, and the like.

Liver disease includes non-alcoholic fatty liver disease (NAFLD), including advanced fibrosis stages F3 and F4, non-alcoholic steatohepatitis (NASH), and alcoholic fatty liver disease. disease: AFLD) and alcoholic steatohepatitis (ASH).

Kidney disease may include chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, diabetic nephropathy, etc.

Ocular diseases may include ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve damage, dry eye, glaucoma, etc. .

Skin diseases may include dermatitis, such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin diseases, acne clusters, and the like.

Lymphatic conditions may include lymphangitis, Castleman disease, etc.

Psychological disorders may include depression, psychological stress, etc.

The pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable carriers are those commonly used in the art, specifically lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, It may be, but is not limited to, polyvinylpyrrolidine, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzonate, propyl hydroxybenzonate, talc, magnesium stearate, minerals, or oil. In addition to the above components, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, dispersants, stabilizers, etc. In addition, the pharmaceutical composition of the present invention can be formulated into oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral solutions, emulsions, syrups, external preparations, and suppositories using pharmaceutically acceptable carriers and excipients. Alternatively, it may be formulated in the form of a sterile injectable solution and manufactured in unit dosage form, or may be manufactured by placing it in a multi-dose container. The preparation can be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and can be formulated into various preparations depending on each disease or ingredient.

Non-limiting examples of preparations for oral administration using the pharmaceutical composition of the present invention include tablets, troches, lozenges, aqueous suspensions, oily suspensions, preparation powders, granules, emulsions, hard capsules, and soft capsules. Capsules, syrups, or elixirs may be used. In order to formulate the pharmaceutical composition of the present invention for oral administration, binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax can be used, and sweeteners, fragrances, syrups, etc. can also be used. Furthermore, in the case of capsules, in addition to the above-mentioned substances, a liquid carrier such as fatty oil can be additionally used.

Non-limiting examples of parenteral preparations using the pharmaceutical composition of the present invention include injections, suppositories, powders for respiratory inhalation, aerosols for sprays, ointments, powders for application, oils, creams, etc. To prepare the pharmaceutical composition of the present invention for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, topical preparations, etc. can be used. Examples of the non-aqueous solvents and suspensions include propylene glycol and polyethylene. Glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, etc. may be used, but are not limited thereto.

The present invention provides a method for preventing or treating diseases related to NLRP3 activity, comprising administering to a subject a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In the present invention, “administration” means introducing a predetermined substance into an individual by an appropriate method.

In the present invention, “individual” refers to all animals such as rats, mice, and livestock, including humans, that have or may develop a disease related to NLRP3 activity, and may specifically be mammals, including humans, but are not limited thereto. no.

The method for preventing or treating diseases related to NLRP3 activity of the present invention may be administering the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.

In the present invention, “therapeutically effective amount” refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, which refers to the patient's gender, age, weight, and health. Factors including the condition, type and severity of the disease, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, excretion rate, duration of treatment, drugs combined or used simultaneously, and other factors well known in the field of medicine. It can be determined by a person skilled in the art accordingly. The specific therapeutically effective amount for a particular patient will depend on the type and degree of response to be achieved, the specific composition, including whether other agents are used as the case may be, the patient's age, weight, general health, gender and diet, and time of administration. , it is desirable to apply it differently depending on various factors including the route of administration, secretion rate of the composition, treatment period, drugs used together or simultaneously with the specific composition, and similar factors well known in the medical field.

The present invention provides the use of the compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a composition containing the same for the prevention or treatment of diseases related to NLRP3 activity.

The present invention provides the use of the compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a composition containing the same for the manufacture of a drug for the prevention or treatment of diseases related to NLRP3 activity.

For the manufacture of drugs, the compound represented by Formula 1, its stereoisomer, or its pharmaceutically acceptable salt can be mixed with pharmaceutically acceptable auxiliaries, diluents, carriers, etc., and can be prepared as a complex preparation with other active agents. It can also be manufactured to have a synergistic effect.

Matters mentioned in the compounds, pharmaceutical compositions, treatment methods and uses of the present invention apply equally unless contradictory to each other.

Compounds represented by Formula 1 of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof; And a pharmaceutical composition containing the same as an active ingredient can be usefully used in the prevention or treatment of diseases related to NLRP3 activity.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.

Preparation of a compound represented by Formula 1

The compound represented by Formula 1 of the present invention can be prepared through the method described below. Unless otherwise stated, starting materials are commercially available or can be prepared by known methods. Any examples, or use of exemplary language, provided herein are intended to better illustrate the invention only and are not intended to limit the scope of the invention as claimed.

<Example>

Example 1: Synthesis of Compound 1, 2-(2-chloro-5-isopropyl-8-oxofuro[2',3':4,5]pyrrolo[1,2-d][1,2 ,4]triazine-7(8H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide

[Step 1] Synthesis of Compound A1

Under nitrogen atmosphere, 5-chlorofuran-2-carbaldehyde (5 g, 38.3 mmol) and ethyl-2-azidoacetate (13 ml, 11.49 mmol) were added to sodium methoxide (13.5 ml, 11.49 mmol, 28% in MeOH). ), a solution of ethanol (76 ml) was slowly added at -10°C. Afterwards, the reaction was stirred at room temperature (15 to 25°C) for 4 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried using magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound A1 (4.4 g, 47%) as a maroon liquid.

^1H NMR (400MHz, CDCl ₃ ) δ 7.07 (d, J = 3.6Hz, 1H), 6.75 (s, 1H), 6.30 (d, J = 3.6Hz, 1H), 4.33 (q, J = 7.2Hz, 2H), 1.37 (t, J = 7.2Hz, 3H). LC/MS: m/z 242.0 (M+H)+(ES).

[Step 2] Synthesis of Compound A2

Compound A1 (8.8 g, 36.36 mmol) was added to xylene (91 ml), and then the reaction was stirred at 160°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound A2 (6.42 g, 83%) as an ivory solid.

^1H NMR (400MHz, CDCl ₃ ) δ 8.67 (br, 1H), 6.75 (s, 1H), 6.32 (s, 1H), 4.34 (q, J = 7.2Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). LC/MS: m/z 214.0 (M+H)+(ES).

[Step 3] Synthesis of Compound A3

Compound A2 (6.42 mg, 30.05 mmol) was dissolved in ethanol (44 ml), and then hydrazine monohydrate (15 ml, 29.96 mmol) was added. The reaction was then stirred at 110°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with water and ethanol and filtered to obtain Compound A3 (5.27 g, 88%) as an ivory solid.

^1H NMR (400MHz, DMSO-d ₆ ) δ 11.47 (br, 1H), 9.36 (s, 1H), 6.77 (s, 1H), 6.65 (s, 1H), 4.35 (br, 2H). LC/MS: m/z 200.0 (M+H)+(ES).

[Step 4] Synthesis of Compound A4

Compound A3 (5.27 g, 26.43 mmol) was dissolved in acetonitrile (MeCN (also referred to as ACN), 83 ml), then aluminum isopropoxide (540 mg, 2.64 mmol) and 1,1,1 -Trimethoxy-2-methylpropane (6.5 ml, 39.64 mmol) was added. The reaction was then stirred at 100°C for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound A4 (6.66 g, 99%) as a white solid.

^1H NMR (400MHz, CDCl ₃ ) δ 9.05 (br, 1H), 7.15 (s, 1H), 6.59 (s, 1H), 3.21 (sixt, J = 6.8, 13.6 Hz, 1H), 1.40 (d, J = 6.8Hz, 6H). LC/MS: m/z 251.9 (M+H)+(ES).

[Step 5] Synthesis of Compound A5

Compound A4 (5.63 mg, 22.37 mmol) was dissolved in acetonitrile (MeCN, 112 ml), then 18-Crown-6 (295.4 mg, 1.12 mmol), potassium iodide (445.6 mg, 2.68 mmol), Potassium carbonate (4.63 g, 33.55 mmol) and methyl-2-chloroacetate (3.7 ml, 33.55 mmol) were added. The reaction was then stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried using magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound A5 (5.93 g, 82%) as a white solid.

^1H NMR (400MHz, CDCl ₃ ) δ 7.12 (s, 1H), 6.57 (s, 1H), 4.80 (s, 2H), 3.77 (s, 3H), 3.19 (hepet, J = 6.8Hz, 1H), 1.39 (d, J = 6.8Hz, 3H). LC/MS: m/z 324.0 (M+H)+(ES).

[Step 6] Synthesis of Compound A6

Compound A5 (5.93 g, 18.30 mmol) was dissolved in tetrahydrofuran (THF, 61 ml), and then lithium hydroxide monohydrate (1.54 g, 36.60 mmol) was dissolved in water (18 ml) and added. Afterwards, the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the pH of the reaction mixture was adjusted to 2-3 with 1 N HCl (aq.), and the organic layer was extracted using ethyl acetate. The organic layer was dried using magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound A6 (5.65 g, 99%) as an ivory solid.

^1H NMR (400MHz, DMSO-d ₆ ) δ 13.04 (br, 1H), 7.42 (s, 1H), 7.25 (s, 1H), 4.64 (s, 2H), 3.46-3.38 (m, 1H), 1.29 (d, J = 6.8Hz, 6H). LC/MS: m/z 310.0 (M+H)+(ES).

[Step 7] Synthesis of Compound A7

Compound A6 (40 mg, 0.13 mmol) was dissolved in dichloromethane (DCM, 1.3 ml), then 5-fluoropyrimidin-4-amine (26 mg, 0.23 mmol), HATU (1-[bis(dimethyl Amino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate) (73.6 mg, 0.19 mmol), triethylamine (TEA, 0.054 ml, 0.38 mmol) was added. The reaction was then stirred at room temperature for 3 days. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM) to obtain the target compound A7 ( Compound 1 ) (10.7 mg, 20%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 7.17 (s, 1H), 6.59 (s, 1H), 5.25 (s, 2H), 3.22 (sept, J = 6.8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 6H); LC/MS: m/z 405.1 (M+H)+(ES).

Examples 2 to 33, 61, 66, 68, and 69: Synthesis of compounds 2 to 33, 61, 66, 68, and 69

Examples in Table 4 below were obtained through substantially the same synthetic method as the compound synthesis method in Example 1, except that the amines in Table 3 below were used instead of the 5-fluoropyrimidin-4-amine in Example 1. Compounds 2 33 and 61, 66, 68, and 69 ( compounds 2 to 33 and 61, 66, 68, and 69 ) were synthesized, respectively.

Here, Example 3 uses EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 2.0 eq.) and HOBt (hydroxybenzotriazole, 2.0 eq.) instead of HATU used in Step 7 of Example 1. ) was used, and in examples except Example 3 (Examples 2, 4 to 33 and 61, 66, 68, and 69), propylphosphonic acid was used instead of HATU used in step 7 of Example 1. anhydride (T3P), 0.19 mL, 0.32 mmol) was used, and in Examples 27 and 28, 80°C conditions in tetrahydrofuran were used instead of the room temperature conditions in dichloromethane in Step 7 of Example 1.

[Table 3]

[Table 4]

Example 37: Synthesis of compound 37, N-(1H-indazol-6-yl)-2-(6-isopropyl-9-oxopyrido[2',3':4,5]pyrrolo[1 ,2-d][1,2,4]triazine-8(9H)-yl)acetamide

[Step 1] Synthesis of Compound B1

Ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2 g, 10.51 mmol) was dissolved in ethanol (15 ml), and then hydrazine monohydrate (5.1 ml, 105.1 mmol) was added. . The reaction was then stirred at 75°C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with water and ethanol and filtered to obtain Compound B1 (1.7 g, 92%) as a light brown solid.

^1H NMR (400MHz, DMSO- _d6 ) δ 11.83 (s, 1H), 9.94 (s, 1H), 8.37 (dd, J = 4.4Hz, 1.2Hz, 1H), 7.78 (m, 1H), 7.22 ( s, 1H), 7.7.17 (dd, J = 8Hz, 4.4Hz, 1H), 4.57 (br. 2H). LC/MS: m/z 177.0 (M+H)+(ES).

[Step 2] Synthesis of Compound B2

Compound B1 (1.2 g, 6.81 mmol) was dissolved in acetonitrile (MeCN, 21.3 ml), then aluminum isopropoxide (139 mg, 0.681 mmol) and 1,1,1-trimethoxy-2- Methylpropane (1.55 ml, 10.22 mmol) was added. The reaction was then stirred at 80°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain Compound B2 (1.8 g, 98%) as a white solid. The obtained compound B2 was used in the next reaction without further purification.

[Step 3] Synthesis of Compound B3

Compound B2 (1.8 g, 6.81 mmol) was dissolved in ethanol (68 ml), and then potassium hydroxide (458 mg, 8.17 mmol) was added. The reaction was then stirred at reflux temperature (90°C) for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography to obtain Compound B3 (123 mg, 8%) as a white solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 12.06 (s, 1H), 8.73 (dd, J = 1.1, 4.4 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.55-7.52 (m , 1H), 7.50 (s, 1H), 3.83 (sixt, J = 6.6, 13.2 Hz, 1H), 1.36 (d, J = 8.4 Hz, 6H). LC/MS: m/z 229.1 (M+H)+(ES).

[Step 4] Synthesis of Compound B4

Compound B3 (123 mg, 0.539 mmol) was dissolved in acetonitrile (MeCN, 4.2 ml), then 18-Crown-6 (7 mg, 0.03 mmol), potassium iodide (11 mg, 0.07 mmol), Potassium carbonate (112 mg, 0.809 mmol) and methyl-2-chloroacetate (0.07 mL, 0.808 mmol) were added. The reaction was then stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography to obtain compound B4 (150 mg, 93%) as a red solid. It was used in the next reaction without further purification.

[Step 5] Synthesis of Compound B5

Compound B4 (150 mg, 0.5 mmol) was dissolved in tetrahydrofuran (THF, 1.8 ml), and then lithium hydroxide monohydrate (63 mg, 1.5 mmol) was dissolved in water (2.5 mL) and added. Afterwards, the reaction was stirred at room temperature for 10 minutes. After completion of the reaction, the reaction mixture was washed with diethyl ether, and the inorganic layer was extracted with water. The pH of the inorganic layer was adjusted to 2-3 with 1N HCl (aq.) and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography to obtain compound B5 (74 mg, 52%) as a white solid. The obtained compound B5 was used in the next reaction without further purification.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.12 (br, 1H), 8.76 (dd, J = 1.2, 4.4 Hz, 1H), 8.53 (d, J = 9.2 Hz, 1H), 7.58-7.55 (m , 2H), 4.68 (s, 2H), 3.86 (sixt, J = 6.7, 13.3 Hz, 1H), 1.36 (d, J = 8.8 Hz, 6H). LC/MS: m/z 287.1 (M+H)+(ES).

[Step 6] Synthesis of Compound B6

Compound B5 (34 mg, 0.12 mmol) was dissolved in dichloromethane (DCM, 1.2 ml), then 1H-indazol-6-amine (28 mg, 0.21 mmol) and propylphosphonic anhydride (0.14 mL, 0.24 mmol) and triethylamine (0.03 mL, 0.24 mmol) were added. The reaction was stirred at room temperature for 16 hours. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target compound B6 ( Compound 37 ) (14 mg, 29%) as a white solid.

^1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 10.34 (s, 1H), 8.77 (dd, J = 1.0, 4.6 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H) ), 8.07 (s, 1H), 7.97 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59-7.56 (m, 2H), 7.13 (dd, J = 1.6, 8.8 Hz, 1H) , 4.86 (s, 2H), 3.91-3.85 (m, 1H), 1.37 (d, J = 6.4 Hz, 6H), 1.22 (s, 3H); LC/MS: m/z 402.2 (M+H)+(ES).

Examples 34 to 36, 38 to 45, 60, 62, 63, 64, 67 and 405: Synthesis of compounds 34 to 36, 39 to 45, 60, 62, 63, 64, 67 and 405

The compound synthesis method of Example 37 was substantially the same as that of Example 37, except that the carboxylate and amine shown in Table 5 below were used instead of the ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate of Example 37, respectively. Through the same synthesis method, the compounds of Examples 34 to 36, 38 to 45, 60, 62, 63, 64, 67 and 405 in Table 6 ( Compounds 34 to 36, 38 to 45, 60, 62, 63, 64, 67 and 405 ) were synthesized, respectively.

Here, Examples 41 to 43 used HATU (1.5 eq.) instead of T3P used in step 6 of Example 37, and Example 45 used tetrahydrofuran instead of room temperature conditions in dichloromethane in step 6 of Example 37. Conditions of 80°C were used.

[Table 5]

[Table 6]

Example 46: Synthesis of compound 46, 2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2 ,4]triazine-6(5H)-yl)-N-(1,3,5-triazine-2-yl)acetamide

[Step 1] Synthesis of Compound C1

Sodium ethoxide (5.6 ml, 20% ethanol solution, 16.5 mmol), thiophene-3-carbaldehyde (615 mg, 5.5 mmol), and ethyl-2-azidoacetate (1.91 ml, 16.5 mmol) were dissolved in ethanol (11). The mixture dissolved in ml) was added dropwise at 0°C using an ice bath. Afterwards, the reaction was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound C1 (424 mg, 35%) as a light yellow liquid.

^1H NMR (400MHz, CDCl ₃ ) δ 7.87 (s, 1H), 7.50 - 7.48 (m, 1H), 7.33 - 7.31 (m, 1H), 6.96 (s, 1H), 4.36 (q, J = 7.2 Hz) , 2H), 1.39 (t, J = 7.2 Hz, 3H).

[Step 2] Synthesis of Compound C2

Compound C1 (424 mg, 1.90 mmol) was dissolved in toluene (26 ml), and the reaction was stirred at 120°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA/Hexane) to obtain Compound C1 (335 mg, 90%) as a light yellow solid.

^1H NMR (400MHz, CDCl ₃ ) δ 9.17 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.00 - 6.99 (m, 1H), 6.92 (d, J = 5.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H).

[Step 3] Synthesis of Compound C3

Compound C2 (335 mg, 1.72 mmol) was dissolved in ethanol (3.4 ml), and then hydrazine monohydrate (1.25 ml, 25.8 mmol) was added. The reaction was then stirred at 95°C for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with water and ethanol, and filtered to obtain Compound C3 (335 mg, 67%) as a white solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.88 (s, 1H), 9.44 (s, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.99 (d, J = 5.6 Hz, 1H), 6.98 (s, 1H), 4.36 (s, 2H).

[Step 4] Synthesis of compounds C4 and C5

Compound C3 (517 mg, 2.86 mmol) was dissolved in acetonitrile (MeCN, 9.5 ml), then aluminum isopropoxide (58 mg, 0.286 mmol) and 1,1,1-trimethoxy-2- Methylpropane (0.7 ml, 4.29 mmol) was added. The reaction was then stirred at 80°C for 7 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain Compound C4 as a white solid. The obtained compound C4 was used in the next reaction without further purification.

Compound C4 was dissolved in ethanol (29 ml), and then potassium hydroxide (192 mg, 3.43 mmol) was added. The reaction was then stirred at 95°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography to obtain Compound C5 (397 mg, 60%) as a white solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 7.57 (d, J = 5.2 Hz, 1H), 7.34 (s, 1H), 7.31 (d, J = 5.6 Hz, 1H), 3.38 (sixt, J = 6.8 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[Step 5] Synthesis of Compound C6

Compound C5 (50 mg, 0.214 mmol) was dissolved in acetonitrile (MeCN, 1 ml), then 18-Crown-6 (3 mg, 0.011 mmol), potassium iodide (4 mg, 0.0026 mmol), Potassium carbonate (44 mg, 0.321 mmol) and methyl 2-chloroacetate (0.028 mL, 0.321 mmol) were added. The reaction was then stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography to obtain Compound C6 (62 mg, 95%) as a colorless liquid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (d, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 5.6 Hz, 1H), 4.78 (s, 2H), 3.70 (s, 3H), 3.40 (sept, J = 6.8 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[Step 6] Synthesis of Compound C7

Compound C6 (30 mg, 0.1 mmol) was dissolved in tetrahydrofuran (THF, 0.5 ml), and then N -chlorosuccinimide (NCS, 21 mg, 0.15 mmol) was added. The reaction was then stirred at 55°C for 22 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound C7 (18 mg, 53%) as a light yellow liquid.

^1H NMR (400MHz, CDCl ₃ ) δ 7.35 (s, 1H), 7.11 (s, 1H), 4.81 (s, 2H), 3.78 (s, 3H), 3.18 (sept, J = 6.8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 6H).

[Step 7] Synthesis of Compound C8

Compound C7 (18 mg, 0.053 mmol) was dissolved in methanol (MeOH, 0.8 ml), and then lithium hydroxide monohydrate (7 mg, 0.159 mmol) was dissolved in water (0.2 ml) and added. Afterwards, the reaction was stirred at room temperature for 30 minutes. After completion of the reaction, the pH of the reaction mixture was adjusted to 2-3 with a 2 N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to obtain ivory-colored liquid compound C8 (17 mg, 99%). The obtained compound B5 was used in the next reaction without further purification.

^1H NMR (400MHz, CDCl ₃ ) δ 7.37 (s, 1H), 7.11 (s, 1H), 4.86 (s, 2H), 3.18 (sept, J = 6.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 6H).

[Step 8] Synthesis of Compound C9

Compound C8 (50 mg, 0.153 mmol) was dissolved in tetrahydrofuran (THF, 1 ml), then 1,3,5-triazine-2-amine (29 mg, 0.306 mmol) and propylphosphonic anhydride ( T3P, 0.195 mL, 0.306 mmol) and triethylamine (TEA, 0.064 ml, 0.459 mmol) were added. The reaction was stirred at 80°C for 18 hours. After completion of the reaction, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate, and the organic layer was extracted using dichloromethane (DCM). The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed using silica gel column chromatography (EA/hexane) to obtain the target compound C9 ( Compound 46 ) (7 mg, 11%) as a light yellow solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.41 (s, 1H), 9.04 (s, 2H), 7.51 (s, 1H), 7.38 (s, 1H), 5.08 (s, 2H), 3.29- 3.12 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H); LC/MS: m/z 403.5 (M+H)+(ES).

Example 404: Synthesis of Compound 404, N-(1H-benzo[d][1,2,3]triazol-6-yl)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4, 5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1,3,5-triazin-2-yl)acetamide

In the synthesis method of Example 46, except that 1H-benzo[d][1,2,3]triazol-6-amine was used instead of 1,3,5-triazin-2-amine. Example 404 ( compound 404 ) (52.1 mg, 77%) was synthesized through a synthetic method substantially the same as that of compound 46.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.48 (s, 1H), 8.28 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.41-7.38 (m , 2H), 4.85 (s, 2H), 3.27-3.22 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H); LC/MS: m/z 441.3 (M+H)+(ES).

Example 7: Synthesis of Compound 7, N-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-(2-chloro-5-isopropyl-8- Oxofuro[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7(8H)-yl)acetamide

Compound 7 was also synthesized using the following synthesis method.

[Step 1] Synthesis of Compound D1

Compound A5 (50 mg, 0.154 mmol) was dissolved in dimethylformamide (DMF, 0.8 ml) under nitrogen conditions, and then 1M LiHMDS (0.34 mL, 0.339 mmol in THF) was slowly added at 0 ^o C. After 5 minutes, 1,2,4-triazolo[4,3-b]pyridazin-6-amine (25 mg, 0.185 mmol) was dissolved in dimethylformamide (DMF, 0.74 ml) and then added. The reaction was stirred at room temperature for 16 hours. The reaction product was washed with an aqueous ammonium chloride solution, and the organic layer was extracted using ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reduced pressure concentrate was purified by silica gel column chromatography to obtain the target compound D1 ( compound 7 ) (47 mg, 70%) as a beige solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 9.52 (s, 1H), 8.35 (dd, J = 0.8, 10.0 Hz, 1H), 7.92 (d, J = 10.0 Hz, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 4.92 (s, 2H), 3.47-3.38 (m, 1H), 1.30 (d, J = 6.4 Hz, 6H); LC/MS: m/z 427.1 (M+H)+(ES).

Examples 49 to 52: Synthesis of Compounds 49 to 52

Compound A5 of Example 7 (ethyl methyl 2-(2-chloro-5-isopropyl-8-oxofuro[2`,3`:4,5]pyrrolo[1,2-d]triazine- Example 7, except that the acetates and amines in Table 7 below were used instead of 7(8H)-yl)acetate) and 1,2,4-triazolo[4,3-b]pyridazin-6-amine, respectively. Each of the compounds (compounds 49 to 52) of Examples 49 to 52 in Table 8 below was synthesized through a synthetic method substantially the same as the compound synthesis method of.

[Table 7]

[Table 8]

Example 53: Synthesis of compound 53, (R)-2-(2-chloro-5-isopropyl-8-oxofuro[2',3':4,5]pyrrolo[1,2-d ][1,2,4]triazine-7(8H)-yl)-N-(1-cyclobutylpyrrolidin-3-yl)acetamide

[Step 1] Synthesis of Compound E1

Compound A6 (100 mg, 0.32 mmol) was dissolved in dichloromethane (DCM, 3.2 ml), then tert-butyl R-3-aminopyrrolidine-1-carboxylate (0.098 ml, 0.56 mmol), propyl Phosphonic anhydride (0.38 ml, 0.64 mmol) and triethylamine (0.09 ml, 0.64 mmol) were added. The reaction was then stirred at room temperature for 2 days. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM) to obtain the target compound E1 (134 mg, 87%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.13 (s, 1H), 6.59 (s, 1H), 6.38 (d, J = 6.8 Hz, 1H), 4.71 (s, 2H), 4.48-4.44 (m, 1H), 3.63-3.60 (m, 1H), 3.39 (brs, 2H), 3.24-3.15 (m, 2H), 2.18-2.09 (m, 1H), 1.86-1.82 (m, 1H), 1.43 (s, 9H), 1.40 (d, J = 6.8 Hz, 6H); LC/MS: m/z 478.1 (M+H)+(ES).

[Step 2] Synthesis of Compound E2

Compound E1 (134 mg, 0.28 mmol) was dissolved in 4 N HCl (in dioxane, 1.4 ml), and the reaction was stirred at room temperature for 3 hours. The reaction product was concentrated under reduced pressure, washed with normal-hexane, and filtered to obtain the target compound E2 (94.3 mg, 81%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ +MeOD d ₄ ) δ 8.39 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 6.66 (s, 1H), 4.70 (s, 2H), 4.65 ( m, 1H), 3.54-3.47 (m, 1H), 3.37-3.19 (m, 4H), 2.10-2.30 (m, 2H), 1.39 (d, J = 6.8 Hz, 6H); LC/MS: m/z 378.0 (M+H)+(ES).

[Step 3] Synthesis of Compound E3

Compound E2 (14.6 mg, 0.038 mmol) was dissolved in dichloromethane (DCM, 0.19 ml), followed by cyclobutanone (0.003 ml, 0.042 mmol) and sodium triacetoxyborohydride (0.012 mg, 0.058 mmol). was added. Afterwards, the reaction was stirred at room temperature for 16 hours. After the reaction mixture was terminated using a saturated aqueous sodium carbonate solution, the organic layer was extracted using dichloromethane. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM) to obtain the target compound E3 ( Compound 53 ) (6.2 mg, 37%) as a light yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.11 (s, 1H), 6.57 (s, 1H), 4.71, (m, 3H), 3.24-3.19 (m, 1H), 3.16-2.93 (m, 2H) , 2.63-2.61 (m, 1H), 2.38-2.34 (m, 2H), 2.14-2.06 (m, 4H), 1.80-1.65 (m, 4H), 1.41 (d, J = 6.8 Hz, 6H); LC/MS: m/z 432.1 (M+H)+(ES).

Example 54: Synthesis of compound 54, 2-(2-chloro-5-isopropyl-8-oxofuro[2',3':4,5]pyrrolo[1,2-d][1,2 ,4]triazine-7(8H)-yl)-N-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5yl)acetamide

[Step 1] Synthesis of Compound F1

Compound A6 (50 mg, 0.154 mmol) was dissolved in acetonitrile (ACN, 1.3 ml) and then dissolved in 5-amino-1,3-dihydro-1-methyl-2H-benzimidazol-2-one ( 34 mg, 0.21 mmol), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate) (54 mg, 0.193 mmol), 1-methylimidazole (NMI, 0.05 mL, 0.564 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction product was washed with water, and the organic layer was extracted using ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reduced pressure concentrate was purified by silica gel column chromatography to obtain the target compound F1 ( compound 54 ) (8 mg, 11%) as a brown solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 2H), 10.07 (s, 1H), 7.46 (s, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.27 (s, 1H), 7.11 (dd, J = 1.6, 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.76 (s, 2H), 3.46-3.34 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H); LC/MS: m/z 455.1 (M+H)+(ES).

Examples 47 and 55-58: Synthesis of compounds 47 and 55-58

Compound A6 of Example 54 (2-(2-chloro-5-isopropyl-8-oxofuro[2',3':4,5]pyrrolo[1,2-d][1,2, Instead of 4]triazin-7(8H)-yl)acetic acid) and 5-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one, acetic acid and Except for using an amine, the compounds of Examples 47 and 55 to 58 ( Compounds 47 and 55 to 58 ) of Table 10 below were synthesized through a synthetic method substantially the same as that of Example 54.

[Table 9]

[Table 10]

Example 65: Synthesis of Compound 65, N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(8-isopropyl-1,1-dioxido-5-oxothieno [3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide

[Step 1] Synthesis of Compound G1

Compound C6 (1 g, 3.28 mmol) was dissolved in methanol (MeOH, 12 ml), and then lithium hydroxide monohydrate (413 mg, 9.83 mmol) was dissolved in water (4 ml) and added. Afterwards, the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the pH of the reaction mixture was adjusted to 2-3 with a 2 N aqueous hydrochloric acid solution, water was added, filtered, and washed several times with water. The filtered solid was dried to obtain white solid Compound G1 (910 mg, 95%).

^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (d, J = 5.6 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 5.6 Hz, 1H), 4.66 (s, 2H), 3.43 - 3.37 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[Step 2] Synthesis of Compound G2

Compound G1 (100 mg, 0.343 mmol) was dissolved in dichloromethane (DCM, 3.4 ml), then cis-3-amino-1-methylcyclobutan-1-ol hydrochloride (71 mg, 0.519 mmol), Propylphosphonic anhydride (0.436 mL, 0.69 mmol, 50% in ethyl acetate) and triethylamine (0.143 ml, 1.03 mmol) were added. The reaction was stirred at room temperature for 16 hours. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target compound G2 (92 mg, 71%) as a white solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 5.4 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 5.4 Hz, 1H), 4.96 (s, 1H), 4.52 (s, 2H), 3.84 - 3.74 (m, 1H). 3.49 - 3.32 (m, 1H), 2.25 - 2.20 (m, 2H), 1.97 - 1.92 (m, 2H), 1.35 (d, J = 6.7 Hz, 6H), 1.22 (s, 3H); LC/MS: m/z 375.2 (M+H) ⁺ (ES).

[Step 3] Synthesis of Compound G3

G2 (92 mg, 0.246 mmol) was dissolved in dichloromethane (2.1 ml) under nitrogen conditions, and then metachloroperoxybenzoic acid (mCPBA, 170 mg, 0.983 mmol) was dissolved in dichloromethane (2.0 ml) and added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reactant was washed with aqueous sodium bicarbonate solution and extracted using dichloromethane. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane) to obtain Compound G3 ( Compound 65 ) (9 mg, 17%) as a white solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.17 (s, 1H), 4.98 (s, 1H), 4.52 (s, 2H), 3.84-3.75 (m, 1H), 3.26-3.18 (m, 1H), 2.24-2.19 (m, 2H), 1.96-1.91 (m, 2H), 1.35 (d, J = 6.8 Hz, 6H), 1.22 (s,3H); LC/MS: m/z 407.1 (M+H)+(ES).

<Intermediate>

Below, a method for synthesizing intermediate compounds for preparing the compounds of Examples 1 to 69, 404, and 405 will be described. Intermediates omitted below are commercially available or can be prepared by known methods.

(1) Synthesis of carboxylate intermediate

Synthesis of Inter-1 to 4

Except that the aldehydes shown in Table 11 below were used instead of 5-chlorofuran-2-carbaldehyde in the A2 synthesis method of Example 1, respectively, through a synthetic method substantially the same as the method of synthesizing compound A2 of Example 1, as shown in the table below. Each of the carboxylate intermediates of 11 (compounds of Inter-1 to 4) was synthesized.

[Table 11]

(2) Amine intermediate synthesis

Inter-6: (R)-1-cyclobutylpiperidin-3-amine hydrochloride

[Step 1] Synthesis of compound Inter-5

After dissolving tert-butyl (R)-piperidin-3-yl-carbamate (700 mg, 3.5 mmol) in dichloromethane (DCM, 17 ml), cyclobutanone (283 μL, 3.85 ml) was added thereto. mmol) and sodium triacetoxyborohydride (1.11 g, 5.25 mmol) were added and dissolved. Afterwards, the reaction was stirred at room temperature for 16 hours. After completion of the reaction, sodium carbonate was added to the reaction mixture, and the organic layer was extracted with dichloromethane (DCM). The extracted organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The next step was performed without additional purification (893 mg, quantitative).

^1H NMR (400MHz, CDCl ₃ ) δ 4.95 (s, 1H), 3.72 (s, 1H), 2.70-2.62 (m, 1H), 2.32-2.29 (m, 2H), 2.17-2.13 (m, 2H) , 2.02-1.99 (m, 2H), 1.88-1.75 (m, 2H), 1.72-1.47 (m, 6H), 1.45 (s, 9H).

[Step 2] Synthesis of compound Inter-6

Inter-5 (893 mg, 3.5 mmol) was dissolved by adding 4 N hydrochloric acid (1,4-dioxane solution, 15 ml). Afterwards, the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and co-evaporated three times with acetonitrile to obtain compound Inter-6 (692 mg, 87%) as a white solid.

^1H NMR (400MHz, DMSO-d ₆ ) δ 11.73 (s, 1H), 8.39 (s, 3H), 3.73-3.67 (m, 1H), 3.64-3.62 (m, 1H), 3.50-3.37 (m, 1H), 3.32-3.22 (m, 1H), 2.69- 2.59 (m, 2H), 2.48-2.32 (m, 2H), 2.26-2.12 (m, 2H), 2.11-2.03 (m, 1H), 1.94 - 1.81 (m, 2H), 1.81-1.63 (m, 2H), 1.56-1.52 (m, 1H).

Inter-8: (R)-1-cyclopropylpiperidin-3-amine hydrochloride

[Step 1] Synthesis of compound Inter-7

Tert-butyl (R)-piperidin-3-yl-carbamate (200 mg, 1 mmol) was dissolved in methanol (8 mL), then 1-(ethylcyclopropyl)trimethylsilane (302 μL, 1.5 mmol), sodium cyanoborohydride (251 mg, 4 mmol), and acetic acid (570 μL, 10 mmol) were added and dissolved. Afterwards, the reaction was boiled at room temperature for 16 hours. After completion of the reaction, sodium carbonate was added to the reaction mixture, and the organic layer was extracted with ethyl acetate (EA). The extracted organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM) to obtain Inter-7 (211 mg, 88%).

^1H NMR (400 MHz, DMSO-d ₆ ) δ 6.63 (brs, 1H), 2.87-2.85 (m, 1H), 2.77-2.71 (m, 1H), 2.07-2.01 (m, 1H), 1.95-1.88 (m, 1H), 1.69-1.62 (m, 1H), 1.61-1.52 (m, 2H), 1.41-1.33 (m, 10H), 1.20-1.09 (m, 1H), 0.41-0.32 (m, 2H) , 0.28-0.21 (m, 2H).

[Step 2] Synthesis of compound Inter-8

4 N hydrochloric acid (1,4-dioxane solution, 15 ml) was added to Inter 7 and dissolved. Afterwards, the reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and co-evaporated three times with acetonitrile to synthesize compound Inter-8 (189 mg, quantitative) as a white solid.

^1H NMR (400MHz, DMSO-d ₆ ) δ 11.40 (s, 1H), 8.50 (s, 3H), 3.70-3.59 (m, 1H), 3.19-3.00 (m, 2H), 2.99-2.78 (m, 1H), 2.20-2.01 (m, 1H), 2.00-1.82 (m, 2H), 1.63-1.42 (m, 1H), 1.27-1.02 (m, 2H), 0.92-0.75 (m, 2H).

Inter-10: (R)-1-(2-hydroxyethyl)piperidin-3-amine hydrochloride

[Step 1] Synthesis of compound Inter-9

After dissolving tert-butyl (R)-piperidin-3-yl-carbamate (200 mg, 1 mmol) in acetonitrile (2 mL), 2-bromoethane-1-ol (92 μL, 1.3 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added and dissolved. Afterwards, the reaction was stirred at 90°C for 16 hours. After completion of the reaction, sodium carbonate was added to the reaction mixture, and the organic layer was extracted with ethyl acetate (EA). The extracted organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM) to obtain Inter-9 (178 mg, 73%).

^1H NMR (400 MHz, DMSO-d ₆ ) δ 6.67 (s, 1H), 4.35 (t, J = 5.2 Hz, 1H), 3.50-3.43 (m, 2H), 3.41-3.33 (m, 1H), 2.74 -2.65 (m, 1H), 2.61-2.53 (m, 1H), 1.99-1.89 (m, 1H), 1.87-1.79 (m, 1H), 1.72-1.60 (m, 2H), 1.48-1.34 (m, 10H), 1.19-1.11 (m, 1H).

[Step 2] Synthesis of compound Inter-10

The white solid compound Inter-10 (160 mg, quantitative) was synthesized through a synthetic method substantially the same as the Inter-8 compound synthesis method, except that Inter-9 was used instead of Inter-7.

^1H NMR (400MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 8.45 (s, 3H), 5.38 (s, 1H), 3.88-3.77 (m, 2H), 3.76-3.66 (m, 1H) , 3.58-3.46 (m, 2H), 3.28-3.19 (m, 2H), 3.14-2.82 (m, 2H), 2.12-2.04 (m, 1H), 1.93-1.72 (m, 2H), 1.49-1.41 ( m, 1H).

Inter-11: (R)-1-(cyclopropylmethyl)piperidin-3-amine hydrochloride

Except that cyclopropanecarboxaldehyde was used instead of cyclobutanone in [Step 1] of the Inter-6 intermediate synthesis method, a white solid compound Inter was produced through a synthetic method substantially the same as the Inter-6 compound synthesis method. -11 (162 mg, 95%) was synthesized.

^1H NMR (400MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 8.54 (s, 3H), 3.73-3.67 (m, 2H), 3.62-3.48 (m, 1H), 3.14-3.04 (m, 1H), 3.05-2.93 (m, 1H), 2.91-2.78 (m, 2H), 2.11-2.04 (m, 1H), 2.01-1.82 (m, 2H), 1.61-1.48 (m, 1H), 1.17- 1.07 (m, 1H), 0.69-0.55 (m, 2H), 0.49-0.38 (m, 2H).

Inter-12: (R)-1-Isobutylpiperidin-3-amine hydrochloride

The white solid compound Inter-12 (144 mg, quantitative) was synthesized.

^1H NMR (400MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.53 (s, 3H), 3.79-3.67 (m, 1H), 3.67-3.59 (m, 1H), 3.52-3.44 (m, 1H), 3.02-2.94 (m, 2H), 2.91- 2.77 (m, 1H), 2.12-1.97 (m, 3H), 1.93-1.78 (m, 1H), 1.59-1.46 (m, 1H), 1.05 ( d, J = 5.6 Hz, 6H), 0.92-0.84 (m, 1H).

Inter-13: (R)-1-(cyclopropylmethyl)piperidin-3-amine hydrochloride

Except that acetone was used instead of cyclobutanone in [Step 1] of the Inter-6 intermediate synthesis method, a white solid compound Inter-13 (259 mg, 96%) was synthesized.

^1H NMR (400MHz, DMSO-d ₆ ) δ 11.38 (s, 1H), 8.60 (s, 3H), 3.71-3.61 (m, 1H), 3.58-3.47 (m, 1H), 3.49-3.32 (m, 2H), 2.98-2.77 (m, 2H), 2.13- 2.03 (m, 1H), 2.01-1.83 (m, 2H), 1.64-1.53 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H) .

Inter-14: (R)-1-(cyclobutylmethyl)piperidin-3-amine hydrochloride

Except that (bromomethyl)cyclobutane was used instead of 2-bromoethane-1-ol in [Step 1] of the Inter-10 intermediate synthesis method, the synthesis method was substantially the same as the Inter-10 compound synthesis method. Compound Inter-14 (437 mg, 92%) was obtained as a white solid.

^1H NMR (400MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 8.34 (s, 3H), 3.56-3.43 (m, 2H), 3.24-3.15 (m, 2H), 3.83-3.72 (m, 3H), 2.17-2.01 (m, 3H), 1.94-1.73 (m, 7H), 1.51-1.40 (m, 1H).

Inter-16: (R)-1-acetylpiperidin-3-amine hydrochloride

[Step 1] Synthesis of compound Inter-15

Tert-butyl (R)-piperidin-3-yl-carbamate (400 mg, 2 mmol) was dissolved in dichloromethane (DCM, 10 mL), triethylamine (502 μL, 3.6 mmol), Acetic anhydride (265 μL, 2.8 mmol) was added and dissolved. Afterwards, the reaction was stirred at room temperature for 16 hours. After completion of the reaction, methanol was added to the reaction mixture, the aqueous solution was acidified with 0.5 N HCl, and the organic layer was extracted with dichloromethane (DCM). The extracted organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. Inter-15 (475 mg, 98%) was obtained by purification by silica gel column chromatography (MeOH/DCM).

^1H NMR (400MHz, CDCl ₃ ) δ 4.56 (s, 1H), 4.80-3.54 (m, 3H), 3.52-3.24 (m, 2H), 2.09 (s, 3H), 1.98-1.82 (m, 1H) , 1.77-1.52 (m, 8H), 1.49-1.38 (m, 10H).

[Step 2] Synthesis of compound Inter-16

Inter-15 (73 mg, 0.3 mmol) was dissolved in dichloromethane (1 ml), and then trifluoroacetic acid (0.5 ml) was added. Afterwards, the reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and co-evaporated with toluene three times to obtain a white gummy compound Inter-16 (71 mg, 99%).

^1H NMR (400MHz, DMSO-d ₆ ) δ 8.20-7.70 (m, 3H), 4.17-4.03 (m, 1H), 3.90-3.72 (m, 1H), 3.62-3.50 (m, 1H), 3.32- 3.14 (m, 2H), 3.13-2.92 (m, 2H), 2.02 (s, 3H), 2.00-1.91 (m, 1H), 1.78-1.60 (m, 1H), 1.59-1.38 (m, 2H).

Inter-19: (S)-1-((R)-3-aminopiperidin-1-yl)propan-2-ol hydrochloride

[Step 1] Synthesis of compound Inter-17

Dissolve (R)-ethyl 2-((tert-butyldimethylsilyl)oxy)propanoate (330 μL, 1.0 mmol) in dichloromethane (DCM, 5 ml), then lower the temperature to -78°C. gave. DIBAL (diisobutylaluminum hydride) (1.2 ml, 1 M in toluene, 1.2 mmol) was slowly added dropwise at -78°C. Afterwards, the reaction was stirred at -78°C for 3 hours. After completion of the reaction, methanol was added to the reaction mixture, Rochelle's salt was added, and the mixture was stirred for 1.5 hours. Afterwards, the organic layer was extracted with hexane. The extracted organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained Inter-17 was used in the next process without further purification.

[Step 2] Synthesis of compound Inter-18

The compound Inter-18 (65 mg, 76%) as a white solid was obtained through a synthetic method substantially the same as the Inter-5 intermediate synthesis method, except that Inter-17 was used instead of cyclobutanone in the Inter-5 intermediate synthesis method. was synthesized.

^1H NMR (400MHz, CDCl ₃ ) δ 5.02 (brs, 1H), 3.93-3.81 (m, 1H), 3.715 (brs, 1H), 2.50 (brs, 2H), 2.49-2.22 (m, 3H), 2.19 -2.12 (m, 1H), 1.83-1.61 (m, 1H), 1.52-1.48 (m, 2H), 1.45 (s, 9H), 1.13 (d, J = 6.0 Hz, 3H), 0.89 (s, 9H) ), 0.07 (m, 6H).

[Step 3] Synthesis of compound Inter-19

Inter-18 (70 mg, 0.19 mmol) was dissolved in tetrahydrofuran (THF, 0.8 ml), then 1 M n-tetrabutylammonium fluoride (TBAF, 290 μL, 0.29 mmol) was added. gave. After stirring for 16 hours, water was added, and the organic layer was extracted with dichloromethane (DCM), dried over sodium sulfate, filtered, and concentrated. Silicone by-products were removed through column chromatography (MeOH/DCM). After concentrating the purified compound, 4 N hydrochloric acid (1,4-dioxane solution, 1.6 ml) was added and stirred at room temperature for 2 hours. After completion of the reaction, it was concentrated and co-evaporated three times with toluene to obtain Inter-19 (43 mg, quantitative).

^1H NMR (400MHz, DMSO-d ₆ ) δ 10.18 (s, 1H), 8.42 (s, 3H), 5.50 (s, 1H), 4.29-4.11 (m, 1H), 3.79-3.59 (m, 2H) , 3.21-3.05 (m, 1H), 3.06-2.73 (m, 4H), 2.05-1.99 (m, 1H), 1.98-1.87 (m, 1H), 1.82-1.70 (m, 1H), 1.57-1.40 ( m, 1H), 1.12 (s, 3H).

Inter-20: (R)-1-((R)-3-aminopiperidin-1-yl)propan-2-ol hydrochloride

Instead of ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate in the Inter-19 intermediate synthesis method, (R)-2-((tert-butyldimethylsilyl)oxy)propanoate is used. Except for using, the compound Inter-20 (70 mg, Quantitative) as a white solid was obtained through a synthesis method substantially the same as the method for synthesizing the Inter-19 compound.

^1H NMR (400MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.42 (s, 3H), 5.48 (s, 1H), 4.11 (brs, 1H), 3.73-3.60 (m, 1H), 3.58 -3.44 (m, 2H), 3.23-3.09 (m, 1H), 3.07-2.82 (m, 3H), 2.09-2.00 (m, 1H), 1.95-1.82 (m, 2H), 1.62-1.41 (m, 1H), 1.13 (s, 3H).

<Experimental example>

Experimental Example 1: ELISA for interleukin-1β (IL-1β)

Mouse cell line J774A.1 (ATCC) was cultured in DMEM medium [DMEM (Hyclone) + 10% Fetal Bovine Serum (Hyclone) + 1% Penicillin-Streptomycin (Hyclone)]. J774A.1 cells were seeded at a concentration of 100,000 cells/well in a 96-well plate (Tissue culture plate, 96 well, Falcon) and then treated with LPS (sigma), compounds, and ATP (sigma) to induce inflammasomes. IL-1β was measured using an ELISA kit (invitrogen) according to the manufacturer's instructions, and absorbance was measured at 450 nm using a spectrophotometer microplate reader.

[Table 12] IC ₅₀ : less than 10nM (A), 10nM or more to less than 100nM (B), 100nM or more to less than 500nM (C), 500nM or more to less than 1μM (D), 1μM or more (E)

As can be seen in Table 12 above, it was confirmed that the example compounds or salts thereof can inhibit the release of IL-1β induced by NLRP3 inflammasome activity. In other words, the compound of the present invention provides an inflammasome-related mechanism and can therefore be usefully used in the treatment of diseases caused by overactivity of the NLRP3 inflammasome.

Having described the present invention in detail, it will be clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

A compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is H, O, S, C _1-6 alkyl, cycloalkyl, or -NR ₇ R ₈ , where one or more H of the C _1-6 alkyl or cycloalkyl is each independently substituted with halogen, or OH. It can be,
A is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, aryl, heteroaryl, or , where one or more H of A may each independently be substituted with R ₂ ,
X _1, X ₂ and X ₃ are each independently CH, N, O, S or S(=O) ₂ ,
W ₁ is CR ₃ or N,
W ₂ is O or S,
W ₃ is N or NH,
R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen, where one or more H of the C _1-6 alkyl may be substituted with halogen, OH,
R ₄ is H, O, S, or C _1-6 alkyl,
L is CR ₉ , -C(=O)- or -S(=O) ₂ -,
In each of R ₅ and R ₆ , R ₅ and R ₆ are each independently selected from H, C _1-6 alkyl, -C _1-6 alkyl-C(=O)-NH ₂ , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring with N,
Here, one or more H of R ₅ and R ₆ are each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C= O)-(C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl can be substituted with halogen, OH, or C _3-8 cycloalkyl,
Here, the ring in which R ₅ and R ₆ are connected to each other and formed together with N is a 5- to 12-membered heteroaryl containing at least one N, and herein is a 5- to 12-membered heteroaryl containing at least one N. Heteroaryl may further include 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, and at least one H of the 5- to 12-membered heteroaryl containing at least one N is may be substituted with halogen, OH, or NH ₂ ,
R ₇ and R ₈ are each independently H, C _1-6 alkyl, or C _3-8 cycloalkyl,
R ₉ is H, C _1-6 alkyl or halogen, where one or more H of the C _1-6 alkyl may be substituted with halogen, OH,
are each independently a single bond or a double bond.
According to paragraph 1,
The compound represented by Formula 1 is a compound represented by Formula 1a or Formula 1b below,
A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1a]

[Formula 1b]

In formula 1a, R ₁ is H, C _1-6 alkyl, C _3-8 cycloalkyl, or -NR ₇ R ₈ , where at least one H of the C _1-6 alkyl or C _3-8 cycloalkyl is may each independently be substituted with halogen or OH,
In Formula 1b, R ₁ is O or S,
_{In each of Formula 1a and Formula 1b , A , _} R ₉ , and Each is the same as defined in Formula 1 above.
According to claim 1 or 2,
In each of Formula 1, Formula 1a, or Formula 1b,
A has 1 to 3 heteroatoms independently selected from the group consisting of C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _8-10 cycloalkynyl, N, O and S in the ring. 3- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 12-membered ring containing 1 to 5 heteroatoms independently selected from the group consisting of N, O and S. heteroaryl, or , where one or more H of A may each independently be substituted with R ₂ ,
X _1, X ₂ and X ₃ are each independently CH, N, O, S or S(=O) ₂ ,
W ₁ is CR ₃ or N,
W ₂ is O,
R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen,
R ₄ is H, O, or C _1-6 alkyl,
L is CR ₉ , -C(=O)- or -S(=O) ₂ -,
In each of R ₅ and R ₆ , R ₅ is H, R ₆ is H, C _1-6 alkyl, -C _1-6 alkyl-C(=O)-NH ₂ , C _3-8 cycloalkyl, N, 3- to 8-membered heterocycloalkyl containing in the ring 1 to 3 heteroatoms independently selected from the group consisting of O and S, 1 to 5 heteroatoms independently selected from the group consisting of N, O and S 5- to 12-membered heteroaryl containing atoms in the ring, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring with N,
Here, one or more H of R ₆ are each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C=O)- (C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl can be substituted with halogen, OH, or C _3-8 cycloalkyl,
Here, the ring in which R ₅ and R ₆ are connected to each other and formed together with N is a 5- to 12-membered heteroaryl containing at least one N, and herein is a 5- to 12-membered heteroaryl containing at least one N. Heteroaryl may further include 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, and at least one H of the 5- to 12-membered heteroaryl containing at least one N is may be substituted with halogen, OH, or NH ₂ ,
R ₇ and R ₈ are each independently H or C _1-6 alkyl,
R ₉ is H, or C _1-6 alkyl, where one or more H of the C _1-6 alkyl may each independently be substituted with halogen or OH,
are each independently a single bond or a double bond,
A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1 or 2,
In each of Formula 1, Formula 1a, or Formula 1b,
A is , , , , or and one or more H of A may each be independently substituted with R ₂ ,
X ₁ is O, S or S(=O) ₂ ,
X ₂ and X ₃ are each independently CR ₁₀ or N,
Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently CR ₁₁ or N,
W ₁ is CR ₃ or N,
W ₂ is O,
R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen,
R ₄ is H, O, or C _1-6 alkyl,
L is CR ₉ , -C(=O)- or -S(=O) ₂ -,
In each of R ₅ and R ₆ , R ₅ is H, R ₆ is H, C _1-6 alkyl, -C _1-6 alkyl-C(=O)-NH ₂ , C _3-8 cycloalkyl, N, 3- to 8-membered heterocycloalkyl containing in the ring 1 to 3 heteroatoms independently selected from the group consisting of O and S, 1 to 5 heteroatoms independently selected from the group consisting of N, O and S 5- to 12-membered heteroaryl containing atoms in the ring, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring with N,
Here, one or more H of R ₆ are each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C=O)- (C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl can be substituted with halogen, OH, or C _3-8 cycloalkyl,
Here, the ring formed by linking R ₅ and R ₆ together with N is a 5- to 12-membered heteroaryl containing at least one N, and in this case, the ring is a 5- to 12-membered heteroaryl containing at least one N. One or more H of the heteroaryl may be substituted with halogen, OH, or NH ₂ ,
R ₇ and R ₈ are each independently H or C _1-6 alkyl,
R _9, R ₁₀ and R ₁₁ are each independently H, or C _1-6 alkyl, where one or more H of the C _1-6 alkyl may each independently be substituted with halogen or OH,
are each independently a single bond or a double bond,
A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1 or 2,
In each of Formula 1 or Formula 1a,
R ₁ is H, C _1-6 alkyl, or -NR ₇ R ₈ , where one or more H of the C _1-6 alkyl may each independently be substituted with OH,
A is , , , , or and one or more H of A may each be independently substituted with R ₂ ,
X ₁ is O, S or S(=O) ₂ ,
X ₂ and X ₃ are each independently CH or N,
Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently CH or N,
W ₁ is CR ₃ or N,
W ₂ is O,
R ₂ and R ₃ are each independently H, C _1-6 alkyl or halogen,
R ₄ is H or C _1-6 alkyl,
L is -C(=O)- or -S(=O) ₂ -,
In each of R ₅ and R ₆ , R ₅ is H and R ₆ is heterocycloalkyl selected from the group consisting of C _1-6 alkyl, C _3-8 cycloalkyl, piperidinyl, pyrrolidinyl, and azepanyl. , pyrimidinyl, pyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, purinyl, thiazolyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, Hetero selected from the group consisting of indazolyl, isoxazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl and benzoxadiazolyl. aryl, , , , or Or, R ₅ and R ₆ are connected to each other to form a ring together with N,
Here, one or more H of R ₆ are each independently C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, CH ₂ F, CHF ₂ , CF ₃ , halogen, -(C=O)- (C _1-6 alkyl) or OH, where one or more H of the C _1-6 alkyl can be substituted with OH, or C _3-8 cycloalkyl,
where R ₅ and R ₆ are connected to each other and the ring formed with N is pyrazolopyridine, and one or more H of the ring may be substituted with NH ₂ ,
R ₇ and R ₈ are each independently H or C _1-6 alkyl,
are each independently a single bond or a double bond,
A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Compounds listed in the table below, stereoisomers thereof or pharmaceutically acceptable salts thereof:

Comprising a compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
Pharmaceutical composition for the treatment or prevention of diseases related to NLRP3 activity.
In clause 7,
The diseases related to NLRP3 activity are
Inflammation, autoimmune diseases, cancer, infections, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic conditions, psychological disorders, graft-versus-host disease, allodynia, wounds and Containing one or more diseases selected from scars,
Pharmaceutical composition.