WO2025046419A1 - Novel compound as nlrp3 inhibitor and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention relates to a compound as an NLRP3 inhibitor, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising same as an active ingredient. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprising same as an active ingredient can be advantageously used for preventing or treating NLRP3 activity-related diseases.

Description

【Description of the invention】

【Title of invention】

Novel compound as NLRP3 inhibitor and pharmaceutical composition comprising same

【Technical Field】 The present invention relates to a compound as an NLRP3 inhibitor, a stereoisomer thereof, a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the same, and a method for preventing or treating a disease associated with NLRP3 activity using the compound and a use thereof.

【Background Technology】

NOD-like receptor 3 (NLRP3) is a protein-coding gene that belongs to the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family. NLRP3 encodes a protein containing a pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with the adaptor protein, apoptosis-associated speck-like protein (ASC), and pro-caspase-1 to form the NLRP3 inflammasome. Subsequent NLRP3 inflammasome activation can induce a number of related diseases by leading to the release of the inflammatory cytokines IL-1P and IL-18. Activated cytokines resulting from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to format immune responses to infection and injury. For example, IL-1P signaling induces secretion of the proinflammatory cytokines IL-6 and TNF. IL-1P and IL-18 synergize with IL-23 to induce IL-17 production by x8 T cells and memory CD4 Th17 cells in the absence of T cell receptor engagement. IL-18 and IL-12 also synergize to induce IFN-x production from memory T cells and NK cells that promote Th1 responses.

NLRP3 inflammasome activation is associated with various inflammasome-associated diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases and autoinflammatory diseases, for example, autoinflammatory febrile syndromes, such as cryopyrin-associated periodic syndrome (CAPS) (Mor timer 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, nonalcoholic steatohepatitis (NASH, Hugh Thomas Nature Reviews Gastroenterology & Hepatology 2017： 14, 197), alcoholic steatohepatitis and alcoholic liver disease (Petrasek et al. , J. Cl in. Invest . 2012, 122, 3476—89; Petrasek et al. , Nat . Rev. Gastroenterol . Hepatol . 2015, 12, 387—400; Mr i dha , AR 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; renal 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-associated inflammation and diabetic kidney disease, which is a kidney-related complication of diabetes (type 1, type 2 and diabetes mellitus) (Shahzad et al., Kidney Int. 2015, 87, 74- 84). Furthermore, the involvement of increased production of IL-1P and IL- 18 by NLRP3 inflammasome has been suggested in various diseases, such as neuroinflammation-related disorders, such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases (hao et al. , Front. Pharmacol. 2015, 6, 262); cardiovascular/metabolic disorders/diseases, such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications (e.g. nephropathy, retinopathy), 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; It has been shown that it may contribute to the onset and progression of inflammatory skin diseases, such as acne, hidradenitis suppurativa (Sweeney et al. , Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age-related macular degeneration; and cancer-related diseases/disorders, such as myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis, lung cancer, and colon cancer (Ridker et al. , Lancet 2017, 390, 1833- 42). Inherently immune or inflammatory diseases/disorders are generally difficult to effectively diagnose or treat. Most treatments include treatment of symptoms, slowing the progression of the disease/disorder, lifestyle changes, and surgery as a last resort (e.g., open heart surgery for advanced forms of atherosclerosis). Recent studies have linked mitochondrial dysfunction and NLRP3 activation in neuroinflammatory 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, selective and stable inhibitors for this type of neuroinflammation are needed（Lee et al., Eur J. Org. Chem.2017, 141, 240）. To provide new and/or alternative treatments for these inflammasome-related diseases/disorders and others, such as autoinflammatory febrile syndrome cryopyrin-associated periodic syndrome (e.g. CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (chondrocalcinosis), type I/II diabetes and related complications (e.g. nephropathy, retinopathy), neuroinflammation-related disorders (e.g. multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis). Inhibitors of the NLRP3 inflammasome pathway are needed. [Prior art literature] [Patent literature]

(Patent Document 1) International Publication No. W0 2016131098

(Patent Document 2) International Publication No. W0 2020021447

(Patent Document 3) International Publication No. W0 2020234715 [Non-patent Document]

(Non-patent Document 1) A critical role for the NLRP3 inf lammasome in NASH, Hugh Thomas Nature Reviews Gastroenterology & Hepatology 2017： 14, 197 (Non-patent Document 2) NLRP3 inf lammasome blockade reduces 1 iver inflammation and fibrosis in experimental NASH in mice, Mr i dha , AR et al. ,

J. Hepatol. 2017, 66, 1037-46

(Non-patent literature Mortimer et al., Nature Immunol. 2016, 17(10), 1176 -

1188

(Non-patent literature 4) Petrasek et al., J. Clin. Invest.2012, 122, 3476-89

(Non-patent literature 5) Petrasek et al., Nat. Rev. Gastroenterol. Hepatol.2015,

387-400

(Non-patent literature 6) Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31

(Non-patent document 7) Mathews et al., Ann. Rheum. Dis.2014, 73, 1202-10

(Non-patent literature 8) Knauf et al., Kidney Int. 2013, 84, 895-901

(Non-patent literature 9) Kr i shnan et al . , Br . J . Pharmacol . 2016, 173 , 752-65

(Non-patent document 10) Shahzad et al. , Kidney Int. 2015, 87, 74—84

(Non-patent literature hao et al., Front. Pharmacol.2015, 6, 262

(Non-patent document 12) Ridker et al., N. Engl. J. Med.2017, 377, 1119-31

(Non-patent literature 13) Ridker et al., Lancet 2017, 390, 1833-42

(Non-patent literature 14) Sarkar et al., npj Parkinson’s disease 2017, 3: 30

(Non-patent literature 15) Zhou et al., Nature, 2011, 469, 221

(Non-patent literature 16) Lee et al., Eur J. Org. Chem.2017, 141, 240

【Contents of the invention】

【Technical Challenges】 An object of the present invention is to provide 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 pharmaceutical composition 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 pharmaceutical composition for the prevention or treatment of a disease associated with 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 the prevention or treatment of a disease associated with NLRP3 activity, comprising a step of administering a therapeutically effective amount of a compound as an NLRP3 inhibitor. Another object of the present invention is to provide the use of a compound as an NLRP3 inhibitor for the prevention or treatment of a disease associated with NLRP3 activity. Another object of the present invention is to provide the use of a compound as an NLRP3 inhibitor for the manufacture of a medicament for the prevention or treatment of a disease associated with NLRP3 activity.

【Technical Solution】 The present invention is described in more detail below. All combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention cannot be considered limited by the following specific description. Compound The present invention provides a compound according to any one of the following (1) to (19), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

상기 화학식 1에서, R₁내지 R₄는이들중서로 인접한둘은 이들이 부착된 원자와함께 고리를 형성하고, 나머지 둘은각각독립적으로 H, 할로겐, C1-C5알킬, 0- (Cl- C5알킬), C1-C5 할로알킬 또는 CN이고, 여기서 고리는사이클로알킬 , 헤테로사이클로알킬 또는 헤테로아릴이고, 사이클로알킬, 헤테로사이클로알킬 또는 헤테로아릴의 하나 이상의 보는 각각 독립적으로 할로겐, C1-C5알킬, C1-C5할로알킬, OH, 0-CC1-C5알킬)또는 CN으로 치환될 수 있고, 여기서 R₁ 및 R₂가 고리를 형성하는 경우 고리는 N 및 S로 이루어진 군으로부터 독립적으로 선택된 하나 이상의 헤테로원자를 포함하는 헤테로사이클로알킬 또는 헤테로아릴이고 , (1) A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1]

In the above chemical formula 1, two of R ₁ to R ₄ , which are adjacent to each other, form a ring together with the atoms to which they are attached, and the remaining two are each independently H, halogen, C1-C5 alkyl, 0-(Cl-C5 alkyl), C1-C5 haloalkyl or CN, wherein the ring is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of the groups of cycloalkyl, heterocycloalkyl or heteroaryl may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or CN, and wherein, when R ₁ and R ₂ form a ring, the ring is heterocycloalkyl or heteroaryl including one or more heteroatoms independently selected from the group consisting of N and S,

R ₅ is H, C1-C5 alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, Heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)-cycloalkenyl, (C1-C5 alkyl)-cycloalkynyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkenyl, (C1-C5 alkyl)-heterocycloalkynyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)-N（R _x ）（R _y ）, (C1-C5 alkyl)-CN or (C1-C5 alkyl)-O（R _Z ）, and

One or more hydrogens of R ₅ may be independently substituted with R _A , and R _A is selected from the group consisting of halogen, OH, CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)-cycloalkenyl, (C1-C5 alkyl)-cycloalkynyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkenyl, (C1-C5 alkyl)-heterocycloalkynyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)-N(R _x )(R _y ), (C1-C5 alkyl)-CN, (C1-C5 alkyl)-O(R _Z ), C(=O)R ₁ or (C1-C5 alkyl)-C(=O)R _m ,

One or more hydrogens of R _A can be independently substituted with R _B , wherein R _B is halogen, CN, C1-C5 alkyl, C1-C5 haloalkyl, N（R _x ）（R _y ）, O（R _Z ）, C（=O）R ₁ or S（=0） ₂ R _n , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, and R ₁ , R m and R _n are each independently H, OH, C1-C5 alkyl, 0-（Cl- C5 alkyl）, N（R _a ）（R _b ） or (C1-C5 alkyl） - N（R _c ）（R _d ）, wherein R _a , R _b , R _c and R _d are each Independently H, C1-C5 alkyl or C1-C5 haloalkyl,

R ₆ is H, OH, 0-CC1-C5 alkyl) or C1-C5 haloalkyl,

R ₇ is H, C1-C5 alkyl or C1-C5 haloalkyl, and halogen is F, Cl, Br or I.

(2) In the above (1), in the above chemical formula 1, two of R ₁ to R ₄ , which are adjacent to each other, form a ring together with the atoms to which they are attached, and the remaining two are each independently H, halogen, C1-C5 alkyl, 0-(Cl-C5 alkyl), C1-C5 haloalkyl or CN, wherein the ring is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of the groups of cycloalkyl, heterocycloalkyl or heteroaryl may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or CN, and wherein, when R ₁ and R ₂ form a ring, the ring is heterocycloalkyl or heteroaryl including one or more heteroatoms independently selected from the group consisting of N and S,

R ₅ is H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)-N (R _x ) (R _y ) or (C1-C5 alkyl)-0 (R _z ),

One or more hydrogens of R ₅ may be independently substituted with R _A , and R _A is halogen, OH, CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 haloalkyl, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl) - N(R _x )(R _y ), (C1-C5 alkyl)- O(R _Z ), C(=O)R ₁ or (C1-C5 alkyl) - C(=O)R _m ,

One or more hydrogens of R _A can be independently substituted with R _B , wherein R _B is halogen, CN, C1-C5 alkyl, C1-C5 haloalkyl, N(R _x )(R _y ), O(R _Z ), C(=O)R ₁ or S(=0) ₂ R _n , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, R ₁ , R _m and R _n are each independently H, OH, C1-C5 alkyl, 0- (Cl- C5 alkyl), N(R _a )(R _b ) or (C1-C5 alkyl) - N(R _c )(R _d ), wherein R _a , R _b , R _c and R _d are each independently H, C1-C5 alkyl or C1-C5 haloalkyl,

R ₆ is H, 0H or 0-CC1-C5 alkyl),

R ₇ is H, C1-C5 alkyl or C1-C5 haloalkyl, and halogen can be F or C1.

(3) In the above (1) or (2), in the above chemical formula 1, two of R ₁ to R ₄ , which are adjacent to each other, form a ring together with the atoms to which they are attached, and the remaining two are each independently H, halogen or C1-C5 alkyl, wherein the ring is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of the groups of cycloalkyl, heterocycloalkyl or heteroaryl may be each independently substituted with halogen, C1-C5 haloalkyl or 0-CC1-C5 alkyl, When R ₁ and R ₂ form a ring, the ring is a heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and S,

R ₅ is C1-C5 alkyl, cycloalkyl, heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)- N(R _x )(R _y ) or (C1-C5 alkyl)- O(R _Z ),

One or more hydrogens of R ₅ may be independently substituted with R _A , wherein R _A is halogen, OH, C1-C5 alkyl, C2-C5 alkynyl, C1-C5 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)- O(R _Z ), C(=O)R ₁ or (C1-C5 alkyl) - C(=O)R _m ,

One or more hydrogens of R _A can be independently substituted with R _B , wherein R _B is halogen, CN, C1-C5 alkyl, O(R _Z ), C(=O)R ₁ or S(=OhR _n , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, and R ₁ , R _m and R _n are each independently OH, C1-C5 alkyl, 0-CC1-C5 alkyl) or N(R _a )(R _b ), wherein R _a and R _b are each independently H or C1-C5 alkyl,

R ₆ is H, 0H or 0-CC1-C5 alkyl),

R ₇ is C1-C5 alkyl or C1-C5 haloalkyl, and halogen can be F or C1.

(4) In any one of the above (1) to (3), in the chemical formula 1, two adjacent ones of R ₁ to R ₃ form a ring together with the atoms to which they are attached. forming, and the other one is shown, wherein the ring is a heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and S,

R ₄ is visible,

R ₅ is C1-C5 alkyl, cycloalkyl, heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)- N(R _x )(R _y ) or (C1-C5 alkyl)- O(R _Z ),

One or more hydrogens of R ₅ may be independently substituted with R _A , wherein R _A is halogen, OH, C1-C5 alkyl, C1-C5 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)- O(R _Z ), C(=O)R ₁ or (C1-C5 alkyl) - C(=O)R _m ,

One or more hydrogens of R _A may be independently substituted with R _B , wherein R _B is halogen, C1-C5 alkyl, O(R _Z ) or C(=O)R ₁ , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, and R ₁ , R _m and R _n are each independently OH, C1-C5 alkyl, 0-CC1-C5 alkyl) or N(R _a )(R _b ), wherein R _a and R _b are each independently C1-C5 alkyl,

R ₆ is H, 0H or 0- (Cl- C5 alkyl),

R ₇ is C1-C5 alkyl and halogen can be F.

(5) In the above (1) or (2), the compound represented by the chemical formula 1 It can be represented by the following chemical formula 1a.

상기 화학식 1a에서, A는 N 및 으로 이루어진 군으로부터 독립적으로 선택된 하나 이상의 헤테로원자를 포함하는 헤테로사이클로알킬 또는 헤테로아릴이고, A의 하나 이상의 보는 각각독립적으로 할로겐, C1-C5 알킬, C1-C5 할로알킬, OH, 0-CC1-C5 알킬) 또는으시으로치환될 수 있고, [Chemical formula 1a]

In the above chemical formula 1a, A is a heterocycloalkyl or heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and , and one or more groups of A may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or ,

R ₃ and R ₄ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl), C1- C5 haloalkyl or CN,

R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(6) In any one of the above (1) to (3), the compound represented by the chemical formula 1 may be represented by the following chemical formula 1a. [Chemical formula 1a]

상기 화학식 1a에서 ,

In the above chemical formula 1a,

A is a heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and , and one or more of A's groups may be independently substituted with halogen, C1-C5 haloalkyl or 0-CC1-C5 alkyl,

Rs and R ₄ are each independently H, halogen or C1-C5 alkyl, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(7) In any one of the above (1) to (4), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1a.

상기 화학식 1a에서, [Chemical formula 1a]

In the above chemical formula 1a,

A is a heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and ,

R ₃ and R ₄ appear independently, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(8) In the above (1) or (2), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1b.

상기 화학식 1b에서, [Chemical formula 1b]

In the above chemical formula 1b,

A is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of A may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or aryl, and R ₁ and R ₄ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl), C1-

C5 haloalkyl or CN, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. (9) In one of the above (1) to (3), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1b.

상기 화학식 1b에서, [Chemical formula 1b]

In the above chemical formula 1b,

A is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of A may be independently substituted with halogen, C1-C5 haloalkyl or 0-CC1-C5 alkyl, R ₁ and R ₄ are each independently H, halogen or C1-C5 alkyl, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above formula 1.

(10) In one of the above (1) to (4), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1b.

[Chemical formula 1b]

상기 화학식 1b에서,

In the above chemical formula 1b,

A is heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and , R ₁ and R ₄ each appear independently, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above formula 1.

상기 화학식 1C에서, (11) In the above (1) or (2), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1c. [Chemical formula 1c]

In the above chemical formula 1C,

A is cycloalkyl, heterocycloalkyl or heteroaryl, and one of A Each of the above can be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or OH, and R ₁ and R ₂ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl), C1- C5 haloalkyl or CN, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(12) In any one of the above (1) to (3), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1c.

상기 화학식 1c에서, [Chemical formula 1c]

In the above chemical formula 1c,

A is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of A may be independently substituted with halogen, C1-C5 haloalkyl or 0-CC1-C5 alkyl, R ₁ and R ₂ are each independently H, halogen or C1-C5 alkyl, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above formula 1. (13) In any one of the above (1), (2), and (5), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1a-1.

상기 화학식 1a- 1에서, [Chemical formula 1a-1]

In the above chemical formula 1a-1,

Wi and W2 are each independently CH, CH ₂ , N, NH or S,

R _x is H, halogen, C1-C5 alkyl, C1-C5 haloalkyl, 0H, 0- (Cl- C5 alkyl) or CN,

R ₃ and R ₄ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl), C1- C5 haloalkyl or CN,

= is each independently a single bond or a double bond, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(14) In any one of the above (1) to (3), (5) and (6), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1a-1.

[Chemical formula 1a-1]

상기 화학식 1a- 1에서,

In the above chemical formula 1a-1,

Wi and W2 are each independently CH, CH ₂ , N, NH or S,

R _x is H, halogen, C1-C5 haloalkyl or 0-CC1-C5 alkyl), R ₃ and R ₄ are each independently H, halogen or C1-C5 alkyl,

= is each independently a single bond or a double bond, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(15) In any one of the above (1) to (7), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1a-1.

상기 화학식 1a- 1에서, Wi 및 W2는 각각독립적으로 CH, CH₂, N, NH또는 S이고,[Chemical formula 1a-1]

In the above chemical formula 1a-1, Wi and W2 are each independently CH, CH ₂ , N, NH or S,

R _x is visible,

Rs and R ₄ are reported independently,

= is each independently a single bond or a double bond, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(16) In any one of the above (1), (2), (5), and (13), the compound represented by the chemical formula can be represented by the following chemical formula 1a-2 or chemical formula 1a-3.

[Chemical formula 1a-2]

상기 화학식 1a-2또는 화학식 1a-3 각각에서 , R₃ 및 R₄는 각각독립적으로 H, 할로겐, C1-C5 알킬, C1-C5 할로알킬, 0-[Chemical formula 1a-3]

In each of the above chemical formula 1a-2 or chemical formula 1a-3, R ₃ and R ₄ are each independently H, halogen, C1-C5 alkyl, C1-C5 haloalkyl, 0-

(C1-C5 alkyl) or CN, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. (17) In any one of (1) to (3), (5), (6), (13) and (14), the compound represented by the above chemical formula 1 can be represented by the following chemical formula 1a-2 or chemical formula 1a-3.

[화학식 1a- 3]

상기 화학식 1a-2또는 화학식 1a-3 각각에서 , [Chemical formula 1a-2]

[Chemical formula 1a-3]

In each of the above chemical formula 1a-2 or chemical formula 1a-3,

Rs and R ₄ are each independently H, halogen or C1-C5 alkyl, R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1.

(18) In any one of the above (1) to (7) and (13) to (15), the compound represented by the chemical formula 1 can be represented by the following chemical formula 1a-2 or chemical formula 1a-3.

상기 화학식 1a-2 또는 화학식 1a-3 각각에서 , [Chemical formula 1a-2]

In each of the above chemical formula 1a-2 or chemical formula 1a-3,

Rs and R ₄ appear independently, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. In the present invention, “Cm-Cn” (wherein m and n are each independently an integer of 1 or more) means the number of carbons, and for example, “C1-C5 alkyl” represents alkyl having 1 to 5 carbon atoms. In the present invention, “alkyl” means a straight-chain or branched-chain saturated hydrocarbon group. In the present invention, alkyl may have 1 to 5 carbon atoms. In one embodiment, alkyl may have 1 to 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neo-pentyl, and the like. In the present invention, “alkenyl” means a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds. In the present invention, the alkenyl may have 2 to 5 carbon atoms. In one embodiment, the alkenyl may have 2 to 4 carbon atoms. Examples of the alkenyl include, but are not limited to, ethenyl, allyl, and propenyl. In the present invention, “alkynyl” means a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds. In the present invention, the alkynyl may have 2 to 5 carbon atoms. In one embodiment, the alkynyl may have 2 to 4 carbon atoms. Examples of the alkynyl include, but are not limited to, ethynyl, propynyl, and butynyl. In the present invention, “haloalkyl” means alkyl substituted with a halogen such as F, Cl, Br, or I of a hydrogen atom or higher. The meaning of alkyl is as defined above. In the present invention, “cycloalkyl” means a saturated or A partially unsaturated hydrocarbon ring, which includes both monocyclic and polycyclic ring structures. For example, in the present invention, the cycloalkyl may be a saturated hydrocarbon ring, or a partially unsaturated hydrocarbon ring fused to an aromatic ring (e.g., aryl or heteroaryl). For example, in the present invention, the cycloalkyl may be a ring having 3 to 12, 3 to 10, or 3 to 8 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl, spiropentyl, spiroheptyl, spiroononyl, cyclobutyl fused to phenyl, cyclopentyl fused to phenyl, cyclohexyl fused to phenyl, cycloheptyl fused to phenyl, and cycloheptyl fused to phenyl. In the present invention, “cycloalkenyl” means an unsaturated hydrocarbon ring having 3 or more carbon atoms including at least one double bond, and this includes both monocyclic and polycyclic ring structures. That is, in the present invention, cycloalkenyl can mean a ring structure including at least one carbon-carbon double bond in the cycloalkyl ring defined above. In the present invention, cycloalkenyl may be a ring having 3 to 12, 3 to 10, or 3 to 8 carbon atoms. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. In the present invention, "cycloalkynyl" means an unsaturated hydrocarbon ring containing one or more triple bonds, which may have both monocyclic and polycyclic ring structures. Included. That is, in the present invention, cycloalkynyl may mean a ring structure including one or more triple bonds in the cycloalkyl ring defined above. Examples of cycloalkynyl include, but are not limited to, cyclooctynyl. In the present invention, “heterocycloalkyl” means a cyclic functional group in which at least one carbon atom forming the cycloalkyl ring defined above is substituted with a heteroatom. Examples of the heteroatom may be nitrogen (N), oxygen (0), or sulfur (S). At this time, the heteroatom included in the ring of the heterocycloalkyl may be 1 type or 2 or more types, 1 type of heteroatom may be included 1 or 1 or more, and 2 or more types of heteroatoms may each be included at least 1 or more. For example, the heterocycloalkyl in the present invention may be a 3-membered to 12-membered ring. For example, the heterocycloalkyl in the present invention may be a 3- to 8-membered ring having 1 to 3 heteroatoms. For example, the heterocycloalkyl in the present invention may be a 4- to 6-membered ring having 1 or 2 heteroatoms. Examples of heterocycloalkyl include, but are not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. “Heterocycloalkenyl” in the present invention means a cyclic functional group in which at least one carbon atom forming the cycloalkenyl ring as defined above is substituted with a heteroatom. Examples of the above heteroatoms include nitrogen (N), oxygen (0), or sulfur (S). In this case, the heteroatoms included in the ring of heterocycloalkenyl may be one or two or more. and may contain one or more of one type of heteroatom, and may contain at least one of two or more types of heteroatoms each. In the present invention, “heterocycloalkynyl” means a cyclic functional group in which at least one carbon atom forming the cycloalkynyl ring defined above is substituted with a heteroatom. Examples of the heteroatom include nitrogen (N), oxygen (0), or sulfur (S). At this time, the heteroatom contained in the heterocycloalkynyl ring may be one or more than two types, and may contain one or more of one type of heteroatom, and may contain at least one of two or more types of heteroatoms each. In the present invention, “aryl” means a monocyclic or polycyclic aromatic hydrocarbon ring. For example, aryl in the present invention may have 6 to 20 carbon atoms. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthalenyl, etc. In the present invention, “heteroaryl” means a monocyclic or polycyclic aromatic hydrocarbon ring containing at least one heteroatom such as nitrogen (N), oxygen (0), or sulfur (S). For example, the heteroaryl in the present invention may be 5- to 12-membered. For example, the heteroaryl in the present invention may be a 5- to 8-membered ring having 1 to 3 heteroatoms. For example, the heteroaryl in the present invention may be a 5- or 6-membered ring having 1 or 2 heteroatoms. When the heteroaryl contains two or more heteroatoms, the types of the heteroatoms may be the same or different. For example, when heteroaryl contains two or more heteroatoms selected from nitrogen, oxygen and sulfur, it means various combinations such as containing two nitrogens, containing one nitrogen and one oxygen, containing two oxygens and one nitrogen, etc. Examples of heteroaryl include pyridinyl, thiophenyl, triazolyl, tetrazolyl, Benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrole, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridazinyl, indazolyl, Examples thereof include, but are not limited to, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazole, and isomers thereof. In the present invention, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl all mean a monovalent substituent or a polyvalent substituent of two or more valences of the chemical structure according to their respective definitions. For example, “alkyl” can include a monovalent alkyl or a divalent alkyl (alkylene), and “aryl” can include a monovalent aryl or a divalent aryl (arylene). In the present invention, “halogen” may be F, Cl, Br or I.

(19) The compound according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be a compound described in Table 1 below.

본 발명에서 “약학적으로 허용 가능한 염” 은 의약업계에서 통상적으로 사용되는 염을 의미하며 , 당업계 통상의 기술자에게 공지된 통상적인 방법에 의해 제조될 수 있다. 본 발명에서 약학적으로허용 가능한염은, 예를들어 칼슘, 칼륨, 나트륨 또는 마그네슘 등으로 제조된 무기이온염 ; 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 또는 황산 등으로 제조된 무기산염 ; 아세트산, 트라이플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산 , 아스파르트산 , 아스코르브산 , 카본산 , 바닐릭산 , 하이드로 아이오딕산 등으로 제조된 유기산염 ; 메탄설폰산, 에탄설폰산, 벤젠설폰산, P- 톨루엔설폰산 또는 나프탈렌설폰산 등으로 제조된 설폰산염 , 글리신 , 아르기닌 , 라이신 등으로 제조된 아미노산염 ; 또는 트리메틸아민 , 트리에틸아민 , 암모니아, 피리딘 , 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 제한되는 것은 아니다. 본 발명에서 “입체 이성질체 (stereoisomer)” 는 부분 입체 이성질체 (diastereomer) 및 광학 이성질체 (enant iomer)를 포함하는 것으로, 광학 이성질체는 거울상 이성질체뿐만 아니라 거울상 이성질체의 혼합물 및 라세미체까지 모두 포함한다. 이러한 이성질체는 종래기술 , 예를 들어 관 크로마토그래피 또는 HPLC 등의 분할에 의해 분리가 가능하다. 또는 , 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물 각각의 입체 이성질체는 공지된 배열의 광학적으로 순수한 출발 물질 및/또는 시약을 사용하여 입체 특이적으로 합성할 수 있다. 본 발명에서 “예방” 은 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물 , 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 투여에 의해 질환의 발병을 억제시키거나 지연시키는 모든 행위를 의미한다. 본 발명에서 “치료” 는 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물 , 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 투여에 의해 질환의 의심 및 발병 개체의 증상이 호전되거나이롭게 변경되는모든행위를 의미한다. 본 발명에서 “NLRP3” 는 핵산, 폴리뉴클레오티드, 올리고뉴클레오티드, 센스 및 안티센스 폴리뉴클레오티드 가닥, 상보성 서열, 펩티드, 폴리펩티드, 단백질, 상동성 및/또는 이종상동성 NLRP3 분자, 이소형, 전구체, 돌연변이체, 변이체, 유도체, 스플라이스 변이체, 대립형질, 다른 종 및 이들의 활성 단편을 포함함을 의미한다. 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염은 NLRP3 활성 관련 질환의 예방 또는 치료에 유용하게 사용될 수 있다. 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염은 NLRP3의 억제 또는 NLRP3 인플라마좀 경로를 억제할수 있으며 , 이는 IL- 1P의 생성을유도하는 NLRP3 또는 NLRP3 인플라마좀 경로의 능력 감소를 포함할수 있다. 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물, 이의 입체 이성질체 또는 이의 약학적으로허용가능한 염은종래에 알려져 있는 NLRP3활성 관련 질환의 예방 또는 치료를 위한 약물과 유사하거나 실질적으로 동일한 수준 또는 보다 우수한수준으로 NLRP3활성 관련 질환의 예방또는치료효과를 나타낼 수 있다. 조성물, 방법 및 용도 본 발명은 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물을 제공한다. 또한 본 발명은, 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물, 이의 입체 이성질체 또는이의 약학적으로허용가능한염을 유효성분으로 포함하는, NLRP3 활성 관련 질환의 예방 또는 치료를 위한 약학적 조성물을 제공한다. 즉, 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물은 NLRP3 활성 관련 질환의 예방 또는 치료에 유용하게 사용될 수 있다. 상기 NLRP3 활성 관련 질환은, 염증, 자가면역 질환, 암, 감염, 중추신경계 질환, 대사 질환, 심혈관 질환, 호흡기 질환, 간 질환, 신장 질환, 안구 질환, 피부 질환, 림프 병태, 심리 장애, 이식편대숙주 질환, 이질통, 창상, 반흔 등을 포함할수 있다. 염증은, 염증성 장애의 결과로서 일어나는 염증, 예컨대, 자가염증성 질환, 비-염증성 장애의 증상으로서 일어나는 염증, 감염의 결과로서 일어나는 염증 또는 손상 또는 자가면역에 부차적인 감염 또는 염증의 결과로서 일어나는 염증 등을 포함할수 있다. 자가면역 질환은, 급성 파종성 뇌염, 애디슨병, 강직성 척추염, 항인지질항체 증후군 (ant iphospho lipid antibody syndrome： APS) , 항합성효소항체 증후군, 재생불량성 빈혈, 자가면역 부신염, 자가면역 감염, 자가면역 난소염, 자가면역 뭇샘성 기능상실 , 자가면역 갑상선염 , 셀리악병 , 크론병 , 제 1형 당뇨병 (type 1 diabetes： T1D) , 굿파스처 증후군, 그레이브병 , 갈랑바레 중후군 (GBS), 하시모토병, 특발성 혈소판, 감소성 자색반증, 가와사키병, 전신 홍반 루푸스 (SLE)를 포함하는 홍반성 낭창, 1차 진행성 다발성 경화증 (primary progressive multiple sclerosis： PPMS) , 2차 진행성 다발성 경화증 (secondary progressive multiple sclerosis： SPMS) 및 재발완화형 다발성 경화증 (relapsing remitting multiple sclerosis： RRMS)을 포함하는 다발성 경화증 (MS), 중증 근무력증, 안구간대경련근간대경련증후군 (opsoclonus myoclonus syndrome： OMS) , 시신경염, 오드 갑상선염, 천포창, 악성 빈혈, 다발성 관절염, 원발성 담즙성 경변증, 류마티스관절염 (rheumatoid arthritis： R_A) , 건선성 관절염, 소아특발성 관절염 또는 스틸병, 난치성 통풍성 관절염, 라이터 증후군, 쇼그렌 증후군, 다발성 경화증전신 결합조직 장애 , 타카야수동맥염 , 측두동맥염 , 온난자가면역 용혈성 빈혈, 베게너 육아종증, 전신성 탈모증, 베체트병, 샤가스병, 자율신경실조증, 자궁내막증, 화농성 한선염 (hidradenitis suppur at iva： HS) , 간질성 방광염, 신경근육긴장증, 건선, 사르코이드증, 피부경화증, 울혈성 결장염, 슈니츨러 증후군, 대식세포활성화증후군, 블라우증후군 (Blau syndrome) , 백반증 또는 외음부 통증 등을 포함할수 있다. 암은, 폐암, 췌장암, 위암, 골수이형성 증후군, 급성 림프구성 백혈병 (acute lymphocytic leukaemia： ALL) 및 급성 골수성 백혈병 (acute myeloid leukaemia： AML)을 포함하는 백혈병, 부신암, 항문암, 기저 편평세포 피부암, 담관암, 방광암, 골암, 뇌척수종양, 유방암, 자궁경부암, 만성 림프구성 백혈병 (CLL), 만성 골수성 백혈병 (CML), 만성 골수단핵구 백혈병 (CMML), 결장직장암, 자궁내막암, 식도암, 유잉 계열 종양, 눈암, 담낭암, 위장 유암종, 위장관 기질 종양 (gastrointestinal stromal tumour : GIST) , 임신융모질환, 신경교종, 호지킨 림프종, 카포시 육종, 신장암, 하인두암, 간암, 폐유암종, 피부 T 세포 림프종을 포함하는 림프종, 악성 중피종, 흑색종 피부암, 머켈 세포 피부 암, 다발성 골수종, 비강및 부비강암, 비인두암, 신경모세포종, 비호지킨림프종, 비소세포 폐암, 구강 및 구인두암, 골육종, 난소암, 음경암, 뇌하수체 종양, 전립선암, 망막모세포종, 횡문근육종, 침샘암, 피부암, 소세포 폐암, 소장암, 연조직 육종, 위암, 고환암, 흉선암, 미분화 갑상선암을 포함하는 갑상선암, 자궁육종, 질암, 외음부암, 발텐스트롬 마크로글로불린혈증, 윌름스 종양 등을 포함할 수 있다. 감염은, 바이러스 감염 (예컨대 , 인플루엔자 바이러스, 인간 면역결핍 바이러스 (HIV), 알파바이러스 (예컨대, 치쿤구니야 및 로스 리버 바이러스 (Chikungunya and Ross River virus)) , 플라비바이러스 (예컨대 , 댕기 바이러스 및 지카바이러스), 헤르페스 바이러스 (예컨대, 엡스타인 바 바이러스, 거대세포바이러스, 수두-대상포진 바이러스 및 KSHV) , 폭스바이러스 (예컨대 , 백시니아 바이러스 (변형된 백시니아 바이러스 안카라 (Ankara)) 및 점액종 바이러스) , 아데노바이러스 (예컨대 , 아데노바이러스 5 또는 유두종바이러스) , 박테리아 감염 (예컨대 , 스타필로코커스 아우레우스 aureus) , 헬리코박터 파알로리 (、Hel icobacter pylori') , 바실러스 안트라시스 (Bacillus anthracis) , 보르다텔라 파트八스 {Bordatel la pertussis) , 부르코홀데리아 슈도말레이 (Burkholderia pseudomallei} , 코리네박테륨 디프테리아 (Corynebacterium aiptheriae) , 클로스트리듐 테타니 (Clostridium tetani) , 클로스트리듐 보툴군눔 (Clostridium botulinum), 스트렙토코커스 뉴모니애 (Streptococus pneumoniae) , 스트렙토코커스 피오게네스 (Streptococus pyogenes) , 리스테리아 모노사이토게네스 (Listeria monocytogenes) , 헤모필루스 인플루엔자 (Hemophilus influenzae) , 파스퇴렐라 멀티시다(Pasteurella multi ci da) , 시겔라 디센테리애 (Shigel1a dysenteriae) , 마이코박테륨 투베르쿨로시스 ( Mycobacterium tuberculosis) , 마이코박테륨 레프래 ( my co bacterium leprae) , 마이코플라즈마뉴모니애 (Mycoplasma pneumoniae) , 마이코플라즈마 호미니스 (Mycoplasma hominis) , 네이세리아 메닌기티디스 (Neisseria meningitidis) , 네이세리아 고노르호애 (Neisseria gonorrhoeae) , 리케트시아 리케트시이 (Rickettsia rickettsii ) , 레지오네라 뉴모필라 (Legionella pneumophila) , 클레브시엘라 뉴모니애 (Klebsiella pneumoniae) , 슈도모나스 아에루기노사(Pseudomonas aeruginosa) , 프로피오니박테륨 아크네스 (Propionibacteriiim acnes) , 트레포네마 팔리둠 ( Treponema pallidum), 클라미디아 트라코마티스 (Chlamydi a trachomatis), 비브리오 콜레라 cholerae) , 살모넬라티피무륨 (Salmonel1a typhimurium) , 살모넬라 티피 (Sahnonella typhf) , 보렐리아 부르그도르페리(Borrelia burgdorferi} 또는 에르시니아 페스티스 ( Yersinia pestis) , 진균 감염 (예컨디］, 캔디다 (Candida)종 또는 아스퍼질러스 (Aspergillus)종 유래 ) , 원생동물감염 (예컨대, 말라리아원충, 바베시아 (Babesia), 기아르디아 (Giardia) , 엔타모에바 (Entamoeba) , 리슈마니아 (Leishmania) 또는 트리파노소마 (Trypanosome) 유래), 연충 감염 (예컨대, 주혈흡충, 회충, 촌충 또는 흡충류 유래), 프리온 감염 등을 포함할 수 있다. 중추신경계 질환은, 파킨슨병, 알츠하이머병, 치매, 운동 뉴런 질환, 헌팅턴병, 뇌 말라리아, 폐렴 구균성 수막염으로부터의 뇌 손상, 뇌동맥류, 외상성 뇌손상 및 근위축성 축삭 경화증 등을 포함할수 있다. 대사 질환은, 제 2형 당뇨병 (type 2 diabetes： T2D) , 죽상경화증, 비만, 통풍, 가성 통풍 등을 포함할수 있다. 심혈관 질환은고혈압, 허혈, MI후허혈성 재관류손상을포함하는재관류 손상, 허혈성 뇌졸중을 포함하는 뇌졸중, 일과성 허혈성 발작, 재발성 심근경색증을 포함하는 심근경색증, 울혈성 심부전 및 심박출계수보존 심부전을 포함하는 신부전, 색전증, 복부 대동맥류를 포함하는 동맥류 또는 드레슬러 증후군을 포함하는 심낭염 등을 포함할수 있다. 호흡기 질환은, 만성 폐쇄성 폐 장애 (COPD), 천식 (예컨대 , 알러지 천식 및 스테로이드-내성 천식), 석면증, 규폐증, 나노입자 유도염증, 낭성 섬유증, 특발성 폐 섬유증 등을 포함할수 있다. 간 질환은, 진행성 섬유증 제 F3기 및 제 F4기를 포함하는 비알코올성 지방간 질환 (non- alcohol ic fatty 1 iver disease： NAFLD) 및 비알코올성 지방간염 (non- alcohol ic steatohepatitis： NASH) , 알코올성 지방간 질환 (alcoholic fatty 1 iver disease： AFLD) , 알코올성 지방간염 (alcohol ic steatohepatitis： ASH)을 포함할수 있다. 신장 질환은, 만성 신장 질환, 옥살레이트 신장병증, 신장석회증, 사구체신염 , 당뇨성 신장병증 등을 포함할수 있다. 안구 질환은, 안구 상피 , 연령-관련 황반 변성 (age- related macular degeneration： AMD) (건성 및 습성), 포도막염, 각막 감염, 당뇨성 망막병증, 시신경 손상, 안구 건조증, 녹내장등을 포함할수 있다. 피부 질환은, 피부염 (예컨대, 접촉성 피부염 및 아토피 피부염), 접촉 과민증, 일광화상, 피부 병변, 화농성 한선염 (HS), 기타 낭종-초래 피부 질환, 집족성 여드름 등을 포함할수 있다. 림프 병태는, 림프관염 , 캐슬만병 등을 포함할수 있다. 심리 장애는, 우울증, 심리적 스트레스 등을 포함할수 있다. 본 발명의 약학적 조성물은본발명의 상기 (1) 내지 (19)중어느하나에 따른 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염 외에 추가로 약학적으로 허용 가능한 담체를 1종 이상 포함할 수 있다. 약학적으로 허용 가능한 담체는당업계에서 통상적으로이용되는 것으로, 구체적으로락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알지네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로오스, 폴리비닐피롤리딘, 셀룰로오스, 물, 시럽, 메틸 셀룰로오스, 메틸 히드록시벤조네이트, 프로필 히드록시벤조네이트, 활석 , 스테아르산 마그네슘 또는 미네랄오일일 수 있으나, 이에 제한되는것은아니다. 본발명의 약학적 조성물은상기 성분들외에 윤활제, 습윤제 , 감미제 , 향미제 , 유화제 , 현탁제 , 보존제 , 분산제 , 안정화제 등을추가로 포함할 수 있다. 또한, 본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체 및 부형제를 이용하여 정제, 산제, 과립제, 환제, 캡슐제, 현탁액, 에멀젼, 내용액제, 유제, 시럽 등의 경구용 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제제화하여 단위 용량형태로제조되거나 또는 다용량용기 내에 내입시켜 제조될 수 있다. 제제는 당업계에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(19th ed. , 1995)에 개시되어 있는 방법으로 제조될 수 있으며 , 각 질환또는 성분에 따라다양한제제로제제화될 수 있다. 본 발명의 약학적 조성물을이용한경구 투여용 제제의 비제한적인 예로는, 정제, 트로키제 (troches), 로젠지 (lozenge), 수용성 현탁액, 유성 현탁액, 조제 분말, 과립, 에멀젼, 하드 캡슐, 소프트 캡슐, 시럽 또는 엘릭시르제 등을 들수 있다. 본발명의 약학적 조성물을경구 투여용으로제제화하기 위하여 , 락토오스, 사카로오스, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스 또는 젤라틴 등과 같은 결합제; 디칼슘 포스페이트 등과 같은 부형제; 옥수수 전분 또는 고구마 전분 등과 같은 붕해제; 스테아르산 마그네슘, 스테아르산 칼슘, 스테아릴 푸마르산 나트륨 또는 폴리에틸렌 글리콜 왁스 등과 같은 윤활유 등을사용할 수 있으며 , 감미제 , 방향제 , 시럽제 등도사용할수 있다. 나아가캡슐제의 경우에는 상기 언급한물질 외에도지방유와 같은 액체 담체 등을추가로사용할 수 있다. 본 발명의 약학적 조성물을 이용한 비경구용 제제의 비제한적인 예로는, 주사액 , 좌제 , 호흡기 흡입용분말, 스프레이용에어로졸제 , 연고, 도포용파우더 , 오일, 크림 등을 들 수 있다. 본 발명의 약학적 조성물을 비경구 투여용으로 제제화하기 위하여, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결 건조 제제, 외용제 등을 사용할 수 있으며, 상기 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있으나, 이에 제한되지 않는다. 본 발명은 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 개체에 투여하는 단계를 포함하는 NLRP3 활성 관련 질환의 예방또는 치료 방법을 제공한다. 본 발명에서 “투여” 는 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미한다. 본 발명에서 “개체” 는 NLRP3활성 관련 질환이 발병하였거나발병할수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미하며, 구체적으로 인간을 포함하는 포유동물일 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 NLRP3 활성 관련 질환의 예방 또는 치료 방법은 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염을 치료학적으로유효한 양으로 투여하는 것일수 있다. 본 발명에서 “치료학적으로유효한 양” 이란의학적 치료에 적용가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 이는 환자의 성별, 연령, 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 결정될 수 있다. 특정 환자에 대한 구체적인 치료학적으로 유효한 양은 달성하고자 하는 반응의 종류와 정도, 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 조성물, 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 구체적 조성물과함께사용되거나동시 사용되는약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다. 본 발명은 NLRP3 활성 관련 질환의 예방 또는 치료를 위한 본 발명의 상기 (1) 내지 (19) 중 어느 하나에 따른화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염 또는 이를 포함하는 조성물의 용도를 제공한다. 본 발명은 NLRP3 활성 관련 질환의 예방 또는 치료용 약제의 제조를 위한, 본 발명의 상기 ( 1) 내지 ( 19) 중 어느 하나에 따른 화합물 , 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염 또는 이를 포함하는 조성물의 용도를 제공한다. 약제의 제조를 위하여 본 발명의 상기 ( 1) 내지 ( 19) 중 어느 하나에 따른 화합물 , 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염에 약학적으로 허용 가능한 보조제 , 희석제 , 담체 등을 혼합할 수 있으며 , 기타 활성제제와 함께 복합 제제로 제조되어 상승 작용을 가질 수도 있다. 본 발명의 화합물 , 약학적 조성물 , 치료 방법 및 용도에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다. [Table 1]

In the present invention, “pharmaceutically acceptable salt” means a salt commonly used in the pharmaceutical industry, and can be prepared by a conventional method known to those skilled in the art. In the present invention, the pharmaceutically acceptable salt includes, for example, an inorganic ion salt prepared with calcium, potassium, sodium or magnesium; hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, Inorganic acid salts manufactured with perchloric acid or sulfuric acid, etc.; Organic acid salts manufactured with 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, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; Sulfonate salts manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; Amino acid salts manufactured with glycine, arginine, lysine, etc. Or there are amine salts manufactured with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are not limited by these listed salts. In the present invention, “stereoisomer” includes diastereomers and enantiomeric isomers, and enantiomeric isomers include not only enantiomeric isomers but also mixtures of enantiomeric isomers and racemates. Such isomers can be separated by resolution using conventional techniques, for example, column chromatography or HPLC. Alternatively, each stereoisomer of the compound according to any one of (1) to (19) of the present invention can be stereospecifically synthesized using an optically pure starting material and/or reagent of a known arrangement. In the present invention, “prevention” means any act of inhibiting or delaying the onset of a disease by administering a compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In the present invention, “treatment” means any act of inhibiting or delaying the onset of a disease by administering a compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. It means any act by which the symptoms of a diseased individual are improved or beneficially changed. In the present invention, “NLRP3” means nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, other species and active fragments thereof. The compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof can be usefully used for the prevention or treatment of a disease associated with NLRP3 activity. The compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can inhibit NLRP3 or the NLRP3 inflammasome pathway, which may include a decrease in the ability of NLRP3 or the NLRP3 inflammasome pathway to induce the production of IL-1P. The compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can exhibit a preventive or therapeutic effect on NLRP3 activity-related diseases at a level similar to or substantially the same as or better than a drug for preventing or treating NLRP3 activity-related diseases known in the art. Compositions, methods, and uses The present invention relates to a compound according to any one of (1) to (19) of the present invention, A pharmaceutical composition comprising a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient is provided. In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of a disease associated with NLRP3 activity, comprising a compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. That is, a pharmaceutical composition comprising a compound according to any one of (1) to (19) 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 a disease associated with NLRP3 activity. The NLRP3 activity-related disease may include inflammation, autoimmune disease, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, ocular disease, skin disease, lymphatic pathology, psychological disorder, graft-versus-host disease, allodynia, wound, scar, etc. Inflammation may include inflammation that occurs as a result of an inflammatory disorder, such as an autoinflammatory disorder, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection, or inflammation that occurs as a result of injury or infection or inflammation secondary to autoimmunity. Autoimmune diseases include acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase antibody syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune infection, autoimmune oophoritis, autoimmune polyglandular insufficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 Diabetes mellitus (type 1 diabetes: T1D), Goodpasture syndrome, Graves' disease, Galin-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenia, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis ( _RA ), This may include psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, multiple sclerosis, systemic connective tissue disorders, 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, neuromyotonia, psoriasis, sarcoidosis, scleroderma, congestive colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo, or vulvar pain. Cancer, including lung cancer, pancreatic cancer, stomach cancer, myelodysplastic syndrome, leukemia including acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML), adrenal cancer, anal cancer, basal squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing's series tumor, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, This may include gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, renal cancer, hypopharyngeal cancer, liver cancer, pulmonary carcinoid tumor, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestinal cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, etc. Infections include viral infections (e.g., influenza virus, human immunodeficiency virus (HIV), alphaviruses (e.g., Chikungunya and Ross River virus), flaviviruses (e.g., Dengue virus and Zika virus), 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), adenoviruses (e.g., adenovirus 5 or papillomavirus), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori', Bacillus anthracis, and Bordatella parthenosi). {Bordatel la pertussis), Burkholderia pseudomallei, Corynebacterium aiptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus Streptococus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, 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), protozoan infections (e.g., from malaria parasites, Babesia, Giardia, Entamoeba, Leishmania or Trypanosome), helminth infections (e.g., from schistosomiasis, roundworms, tapeworms or trematodes), prion infections, 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 lateral sclerosis, etc. Metabolic diseases may include type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudogout, etc. Cardiovascular diseases may include hypertension, ischemia, reperfusion injury including ischemic reperfusion injury after MI, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, renal failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysm including abdominal aortic aneurysm, or pericarditis including Dressler syndrome, etc. Respiratory diseases may include chronic obstructive pulmonary disease (COPD), asthma (e.g., allergic asthma and steroid-resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, idiopathic pulmonary fibrosis, and the like. Liver diseases may include non-alcoholic fatty liver disease (NAFLD) including progressive fibrosis stages F3 and F4 and non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH). Kidney diseases may include chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, diabetic nephropathy, and the like. Eye diseases may include ocular epithelial diseases, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma. Skin diseases may include dermatitis (e.g., contact dermatitis and atopic dermatitis), contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-induced skin diseases, acne clusters, etc. 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 according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable carriers are those commonly used in the art, and specifically, may be lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzonate, propyl hydroxybenzonate, talc, magnesium stearate or mineral oil, but are not limited thereto. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, a dispersing agent, a stabilizer, etc. In addition, the pharmaceutical composition of the present invention may be formulated in the form of oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, liquid solutions, emulsions, syrups, etc., external preparations, suppositories, or sterile injection solutions using pharmaceutically acceptable carriers and excipients, and may be manufactured in unit dosage forms or may be manufactured by placing the composition in a multi-dose container. The formulation may be manufactured by a conventional method used in formulation in the art or by a method disclosed in Remington's Pharmaceutical Science (19th ed., 1995). The pharmaceutical composition of the present invention can be manufactured and formulated into various preparations depending on the disease or component. Non-limiting examples of preparations for oral administration using the pharmaceutical composition of the present invention include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs. In order to formulate the pharmaceutical composition of the present invention for oral administration, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; an excipient such as dicalcium phosphate; a disintegrant 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, liquid carriers such as fatty oils 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. In order to formulate the pharmaceutical composition of the present invention for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. can be used, and the non-aqueous solvents and suspending agents can include, but are not limited to, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable esters such as ethyl oleate. The present invention provides a method for preventing or treating a disease associated with NLRP3 activity, comprising administering to a subject a compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In the present invention, “administration” means administering to a subject a predetermined substance by an appropriate method. In the present invention, “subject” means all animals, such as rats, mice, and livestock, including humans, that have developed or can develop a disease related to NLRP3 activity, and specifically, may be mammals including humans, but is not limited thereto. The method for preventing or treating a disease related to NLRP3 activity of the present invention may be to administer a therapeutically effective amount of a compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The “therapeutically effective amount” in the present invention means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing side effects, which may be determined by a person skilled in the art based on factors including the patient’s sex, age, weight, health condition, type of disease, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route, excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field. It is preferable that a specific therapeutically effective amount for a specific patient be applied differently depending on various factors including the type and degree of the response to be achieved, the specific composition including whether other agents are used in some cases, the patient's age, weight, general health, sex and diet, the time of administration, the route of administration and the secretion rate of the composition, the treatment period, drugs used together or simultaneously with the specific composition, and similar factors well known in the medical field. The present invention relates to a compound according to any one of the above (1) to (19) of the present invention, a stereoisomer thereof or a compound thereof for the prevention or treatment of a disease associated with NLRP3 activity. The present invention provides a use of a pharmaceutically acceptable salt or a composition comprising it. The present invention provides a use of a compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a composition comprising it, for the manufacture of a medicament for the prevention or treatment of a disease associated with NLRP3 activity. For the manufacture of the medicament, a pharmaceutically acceptable excipient, diluent, carrier, etc. can be mixed with the compound according to any one of (1) to (19) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and may be manufactured into a complex preparation together with other active agents to have a synergistic effect. The matters mentioned in the compound, pharmaceutical composition, treatment method, and use of the present invention are equally applicable unless they are contradictory.

【Effect of the invention】 The compound as an NLRP3 inhibitor of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same as an active ingredient can be usefully used for the prevention or treatment of diseases related to NLRP3 activity.

【Form for implementing the invention】 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 obvious to those skilled in the art that the scope of the present invention is not construed as being limited by these examples. PREPARATION OF THE COMPOUNDS The compounds of the present invention can be prepared by the methods described below. Unless otherwise stated, the starting materials are commercially available or can be prepared by known methods. The use of any examples or exemplary language provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the claimed invention.

＜Intermediate synthesis＞

[Step 1] Synthesis of Inter-A1 Under a nitrogen atmosphere, (R)-tert-butyl piperidin-3-ylcarbamate (600 mg, 3 mmol) and potassium carbonate (622 mg, 4.5 mmol) were dissolved in acetonitrile (ACN, 6.6 ml), and iodoethane (0.27 ml, 3.3 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium 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 concentrated reaction mixture was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter-A1 (567 mg, 83%) as a yellow oil. ^1H NMR (400MHz, DMSO—d6) 5 6.65 (d, J = 7.8Hz, 1H) , 3.32 (s, 1H) , 2.70 (dd, J = 41.0, 9.7Hz, 2H) , 2.29 (q, J = 7.1Hz, 2H) , 1.83-1.53 (m, 4H), 1.48-1.40 (m, IH), 1.37 (s, 9H), 1.11 (qd, J = 11.8, 3.7Hz, IH), 0.96 (t, J = 7.2Hz, 3H); LC/MS: m/z 229.2 (M+H)+(ES). [Step 2] Synthesis of Inter-A2 Under a nitrogen atmosphere, Inter-A1 (567 mg, 2.34 mmol) was added to a 4N hydrochloric acid solution (4N HCI in 1,4-di oxane, 9.6 ml). The reaction was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A2 (420.78 mg, 89.4%) as a yellow solid.

^1H NMR (400MHz, DMS0-d ₆ ) 5 3.59-3.57 (m, 2H) , 3.43 (br, IH) , 3.17-

3.14 (m, 2H), 2.85-2.78 (m, 2H), 2.10-2.08 (m, IH), 1.91-1.90 (m, 2H), 1.55

(br, IH), 1.26 (t, J = 7.2, 3H); LC/MS: m/z 129.1 (M+H)+(ES). Intermediate Inter—A4

[Step 1] Synthesis of Inter-A3 Under nitrogen atmosphere, (R)-tert-butyl piperidin-3-ylcarbamate (600 mg,

3 mmol) was dissolved in methanol (MeOH, 6 ml), and then potassium carbonate (1.66 g, 12 mmol) and 2-bromoethane-1-ol (0.42 ml, 6 mmol) were added. After that, the reaction was stirred at room temperature. The mixture was stirred for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter-A3 (663 mg, 91%) as a yellow oil.

^1H NMR (400MHz, DMS0-d ₆ ) 5 2.73-2.71 (m, 1H) , 2.62-2.59 (m, 1H) , 1.99-1.91 (m, IH), 1.84-1.79 (m, IH) , 1.64-1.56 (m, 2H) , 1.22-1.10 (m, IH); LC/MS: m/z 245.2 (M+H)+(ES).

[Step 2] Synthesis of Inter-A4 Under nitrogen atmosphere, Inter-A3 (663 mg, 2.71 mmol)> 4N hydrochloric acid solution (4N

HC1 in 1,4-di oxane, 11.1 ml) was added. The reaction was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A4 (467 mg, 79%) as a white solid.

^1H NMR (400MHz, DMS0-d ₆ ) 5 3.80-3.78 (m, 2H) , 3.72-3.68 (m, IH) , 3.57 (s, 2H), 3.52-3.48 (m, IH) , 3.02-2.90 (m, 2H) , 2.09-2.07 (m, IH), 1.91

-1.87 (m, 2H), 1.60-1.49 (m, IH)； LC/MS： m/z 145.1 (M+H)+(ES). Intermediate Inter— A6

[Step 1] Synthesis of Inter-A5 Under a nitrogen atmosphere, (R)-tert-butyl piperidin-3-ylcarbamate (600 mg, 3 mmol) was dissolved in dichloromethane (DCM, 15 ml), and then sodium triacetoxyborohydride (954 mg, 4.5 mmol) and acetone (0.24 ml, 3.3 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium carbonate solution, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter-A5 (461 mg, 63%) as a yellow solid.

^1H NMR (400MHz, CDCI3) 8 5.10 (s, IH) , 3.73 (s, IH) , 2.76-2.68 (m, IH), 2.59-2.57 (m, IH) , 2.49-2.37 (m, 2H) , 1.69-1.67 (m, IH) , 1.55-1.50 (m, 3H), 1.45 (s, 9H), 0.99 (d, J = 6.8 Hz, 6H); LC/MS: m/z 243.2 (M+H)+(ES).

[Step 2] Synthesis of Inter-A6 Under nitrogen atmosphere, Inter-A5 (461 mg, 2.71 mmol) > 4N hydrochloric acid solution (4N

HCI in 1,4-di oxane, 11.1 ml) was added. The reaction was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A6 (395 mg, 68%) as a brown solid.

^1H NMR (400MHz, CDC1 ₃ ) 8 12.04 (s, 1H) , 9.32 (s, 3H) , 4.54-4.50 (m, 2H) , 4.33-4.30 (m, 3H) , 3.72-3.63 (m, 2H) , 2.90-2.87 (m, 1H) , 2.80-2.71 (m, 2H) , 2.43-2.35 (m, 1H) , 2.04 (d, J = 5.2 Hz , 6H)； LC/MS： m/z 143.1 (M+H)+(ES) . Intermediates Inter— A7 to Inter— A12 Inter-A7 to Inter- A12 in Table 2 below were synthesized by substantially the same synthetic method as that of Inter- A6, except that the carbonyl in Table 2 below was used instead of propan-2-one in the synthetic scheme of Inter-A6.

중간체 Inter— A14

[Table 2]

Intermediate Inter— A14

[Step 1] Synthesis of Inter-A13 (R)-tert-butyl piperidin-3-ylcarbamate (400 mg, 2 mmol) was dissolved in acetonitrile (ACN, 4 ml), and then sodium carbonate (417 mg, 3 mmol) and bromomethylcyclobutane (0.29 ml, 2.6 mmol) were added. The reaction mixture was stirred at reflux temperature for 16 hours. After completion of the reaction, the reaction mixture was After washing with a sodium carbonate aqueous solution, the organic layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure to obtain the target compound Inter-A13 (477 mg, 97%) as a white solid.

^1H NMR (400MHz, CDCls) 8 5.00 (s, 1H) , 3.70 (s, 1H) , 2.54-2.38 (m, 3H), 2.34-2.33 (m, 2H) , 2.94-2.21 (m, 2H) , 2.08-2.00 (m, 2H) , 1.92-1.76 (m,

2H), 1.70-1.60 (m, 3H), 1.53-1.48 (m, 2H), 1.44 (s, 9H); LC/MS: m/z 269.2

(M+H)+(ES).

[Step 2] Synthesis of Inter-A14

Inter-A13 (477 mg, 1.97 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 8 ml). The reaction was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A14 (437 mg, 92%) as a white solid.

메틸 3-((터트-부톡시카르보닐)아미노)바이사이클로 [1.1.1]펜탄- 1- 카복실레이트 (200 mg, 0.829 mmol)을 4N염산용액 (4N HC1 in 1,4-di oxane, 5.0 ml)에 첨가하였다. 이후, 반응물을 상온에서 2시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 감압 농축하여 , 흰색 고체의 목적 화합물 Inter-A15 (171 mg, 96.6%)를수득하였다. ^1H NMR (400MHz, DMS0-d ₆ ) 5 10.85 (s, IH) , 8.34 (s, 3H) , 3.54-3.46 (m, 2H), 3.18-3.16 (m, 2H) , 2.83-2.75 (m, 3H) , 2.11-2.03 (m, 3H), 1.94-1.78 (m, 7H), 1.51-1.42 (m, IH); LC/MS: m/z 169.1 (M+H)+(ES). Intermediate Inter—A15

Methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane- 1-carboxylate (200 mg, 0.829 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 5.0 ml). The reaction was then stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A15 (171 mg, 96.6%) as a white solid.

¹ H NMR (400MHz, DMS0-d ₆ ) 5 8.91 (s, 2H), 3.63 (s, 3H), 2.24 (s, 6H)；

LC/MS: m/z 142.1 (M+H)+(ES).

[Step 1] Synthesis of Inter-A16

(R)-tert-butyl azepane-3-ylcarbamate (600 mg, 2.8 mmol), potassium carbonate

(774 mg, 5.6 mmol) was dissolved in acetonitrile (ACN, 11 ml), and iodomethane (0.2 ml, 3.4 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/MC=1/20) to obtain the target compound Inter- A16 (257 mg, 40%) as a yellow liquid.

¹ H NMR (400MHz, Methanol -d4) 5 3.85-3.81 (m, IH), 3.39-3.28 (m, 4H), 2.92 (s, 3H), 2.04-1.83 (m, 4H), 1.77-1.66 (m, 2H), 1.47 (s, 9H); LC/MS: m/z 229.2 (M+H)+(ES).

[Step 2] Synthesis of Inter-A17 Under a nitrogen atmosphere, Inter-A16 (257 mg, 1.13 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 2.8 ml). The reaction was then stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A17 (182 mg, 80.4%) as an orange solid.

¹ H NMR (400MHz, Methanol -d4) 5 3.87-3.84 (m, 1H), 3.58-3.56 (m, 2H), 3.39-3.34 (m, IH), 2.24-2.19 (m, IH), 2.02-1.87 (m, 6H)； LC/MS：m/z 129.1 (M+H)+(ES). Intermediates Inter— A18 to Inter— A20 and Inter— A30 to Inter— A33 were synthesized by substantially the same synthetic method as that of Inter- A4 and Inter- A18 to Inter- A20 and Inter- A30 to Inter- A33 in Table 3 below, respectively, except that the halides in Table 3 below were used instead of 2-bromoethane-1-ol in the synthetic scheme of Inter- A4.

중간체 Inter— A22

[Table 3]

Intermediate Inter— A22

[Step 1] Synthesis of Inter- A21 (R)-tert-butyl piperidin-3-ylcarbamate (600 mg, 3 mmol) was dissolved in acetonitrile (ACN, 6 ml), and potassium carbonate (553 mg, 4 mmol) and methyl chloroacetate (0.53 ml, 6 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM=l:9) to obtain the target compound Inter- A21 (810 mg, 99.1%) as a white solid.

^1H NMR (400MHz, CDCls) 8 5.06 (s, 1H) , 3.76 (m, 1H) , 3.71 (s, 3H) , 3.22 (s, 2H), 2.68-2.59 (m, 2H) , 2.47-2.45 (m, 2H) , 1.77-1.68 (m, IH), 1.59-1.54 (m, 3H), 1.44 (s, 9H); LC/MS: m/z 273.1 (M+H)+(ES). [Step 2] Synthesis of Inter-A22 Under a nitrogen atmosphere, Inter-A21 (810 mg, 2.97 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 12 ml). The reaction was then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A22 (441 mg, 86.1%) as a white solid.

^1H NMR (400MHz, DMS0-d ₆ ) 5 8.44 (s, 2H) , 4.13-4.12 (m, 2H) , 3.74 (s, 3H), 3.60-3.39 (m, 3H) , 2.94-2.68 (m, 2H) , 1.99-1.80 (m, 3H), 1.50 (m, IH); LC/MS: m/z 173.1 (M+H)+(ES).

[Step 1] Synthesis of Inter-A23

(R)-tert-butyl piperidin-3-ylcarbamate (1.2 g, 6 mmol) was dissolved in acetic acid (AcOH, 3.42 ml) and methanol (48 ml), and then sodium cyanoborohydride (1.51 g, 24 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (1.81 ml, 9 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM=l:9). The product was purified to obtain the target compound Inter-A23 (860 mg, 62%) as a white solid.

¹ H NMR (400MHz, CDCls) 8 5.23-4.75 (m, 1H) , 3.80-3.60 (m, 1H) , 2.80- 2.10 (m, 4H), 1.75-1.25 (m, 13H) , 0.75-0.25 (m, 4H)； LC/MS: m/z 241.1 (M+H)+(ES).

[Step 2] Synthesis of Inter-A24 Under a nitrogen atmosphere, Inter-A23 (860.4 mg, 3.58 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 14.7 ml). The reaction was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A24 (787 mg, 75%) as a white solid.

¹ H NMR (400MHz, Methanol -d4) 5 3.69-3.62 (m, 3H) , 3.21-3.18 (m, 2H), 2.86 (s, IH), 2.15-1.92 (m, 3H) , 1.66 (s, IH) , 1.14-1.11 (m, 2H) , 0.97-0.91 (m, 2H); LC/MS: m/z 141.1 (M+H)+(ES). Intermediate Sieve Inter—A26

[Step 1] Synthesis of Inter-A25 Under a nitrogen atmosphere, 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (1.68 g, 7.2 mmol) was added to ethyl acetate (6 ml) and water. (6 ml) was added and dissolved, and then sodium bicarbonate (3.8 g, 30 mmol) was added. Thereafter, (R)-tert-butyl piperidin-3-ylcarbamate (1.2 g, 6 mmol) dissolved in ethyl acetate (4 ml) was slowly added, and the mixture was stirred at 50°C for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted using ethyl acetate. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter- A25 (1.36 g, 81%) as a white solid.

^1H NMR (400 MHz, CDCI ₃ ) 8 4.97 (s, 1H) , 3.75 (s, 1H) , 2.98 (q, J = 9.4 Hz, 2H), 2.82 (d, J = 11.7 Hz, IH) , 2.64-2.76 (m, IH) , 2.46-2.64 (m, 2H), 1.66-1.81 (m, IH), 1.60 (m„ 3H), 1.45 (s, 9H); LC/MS: m/z 283.1 (M+H)+(ES).

[Step 2] Synthesis of Inter-A26 Under a nitrogen atmosphere, Inter-A25 (1.36 g, 4.82 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 19.8 ml). The reaction was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A26 (1.1 g, 86%) as a white solid.

¹ H NMR (400MHz, DMS0-d ₆ ) 5 8.27 (s. , 3H) , 3.39 (q, J= 10.2 Hz, 2H) , 3.15-3.27 (m, IH) , 3.10 (dd, J= 11.3, 3.0 Hz, IH) , 2.83 (d,J= 11.7 Hz, IH) , 2.56 (d, J= 10.2 Hz, IH) , 2.45 (d, J= 9.8 Hz, IH) , 1.83-2.04 (m, IH) , 1.62- 1.83 (m, IH), 1.45-1.62 (m, IH) , 1.25-1.45 (m, IH); LC/MS: m/z 183.1 (M+H)+(ES).

[Step 1] Synthesis of Inter-A27 Under a nitrogen atmosphere, ethyl (S)-(-)-2-(tert-butyldimethylsilyloxy) propionate (330 |iL, 1 mmol) was dissolved in dichloromethane (5 ml), and diisobutylaluminum hydride (1.2 ml, 1.2 mmol) was slowly added at -78°C. The reaction mixture was stirred at -78°C for 2 hours, and then methanol and an aqueous solution of potassium sodium tartrate were added to terminate the reaction. The reaction mixture was then extracted with hexane, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound Inter-A27 (188 mg, 92%) as a transparent liquid.

¹ H NMR (400MHz, DMS0-d ₆ ) 5 9.54 (d, J= 0.7 Hz, 1H) , 4.25 (qd, J= 6.9, 0.7 Hz, IH), 1.21 (d, J= 3.0 Hz, 3H) , 0.89 (s, 9H) , 0.08 (d, J = 4.6 Hz, 6H).

[Step 2] Synthesis of Inter-A28 Under a nitrogen atmosphere, Inter- A27 (47 mg, crude) was dissolved in dichloromethane (1 ml), and then sodium triacetoxyborohydride (85 mg, 0.4 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (46 mg, 0.23 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted with water and dichloromethane, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter- A28 (65 mg, 76%) as a white solid.

^1H NMR (400MHz, CDC1 ₃ ) 8 5.02 (br, 1H) , 3.92-3.84 (m, 1H) , 3.72 (br, 1H), 2.50 (br, 2H) , 2.33-2.26 (m, 3H) , 2.18-2.14 (m, IH) , 1.67 (br, IH), 1.56 (s, 3H), 1.45 (s, 9H), 1.13 (d, J = 6.0Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); LC/MS: m/z 273.3 (M+H)+(ES).

lnter-A35 [Step 3] Synthesis of Inter-A29 Under a nitrogen atmosphere, Inter-A28 (70 mg, 0.19 mmol) was dissolved in tetrahydrofuran (1.2 ml), and then tetrabutyl ammonium fluoride (282 山, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted using water and dichloromethane, and the organic layer was dried using sodium sulfate and concentrated under reduced pressure. Thereafter, a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 1.5 ml) was added to the reaction concentrate, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A29 (44 mg, 99.1%) as a white solid. HN NMR (400MHz, CDCls) 6 8.42 (s, 3H) , 5.49 (br, 1H) , 4.15 (br, 1H) , 3.22-2.85 (m, 4H) , 2.07-1.75 (m, 1H) , 1.53-1.48 (m, 3H) , 1.11 (s, 3H); LC/MS: m/z 159.1 (M+H)+(ES). Intermediate Inter—A35

lnter-A35

[Step 1] Synthesis of Inter-A34

1,1-Dimethylethyl N- [(1R)- 4 -hydroxy- 1-

(Hydroxymethyl)butyl]carbamate (836 mg, 3.81 mmol) was dissolved in dichloromethane (DCM, 13.1 mL), and triethylamine (TEA, 2.7 ml, 19.1 mmol) and methanesulfonyl chloride (0.71 ml, 9.2 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with an aqueous sodium bicarbonate solution, and the organic layer was extracted with dichloromethane. The organic layer was dried with sodium sulfate and then concentrated under reduced pressure. was concentrated. Tert-butyl amine (6 ml, 57.2 mmol) was added to the reaction concentrate. The reaction mixture was then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with an aqueous sodium carbonate solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM=lO:l) to obtain the target compound Inter-A34 (500 mg, 51%) as a brown liquid.

¹ H NMR (400MHz, Methanol -d4) 5 3.57-3.54 (m, 1H) , 3.06-3.04 (m, 1H), 2.90-2.87 (m, IH) , 2.22-2.17 (m, IH) , 2.05-2.02 (m, IH) , 1.85-1.81 (m, IH), 1.77-1.71 (m, IH), 1.63-1.54 (m, IH), 1.45 (s, 9H), 1.271.15 (m, IH), 1.12 (s, 9H); LC/MS: m/z 257.1 (M+H)+(ES).

[Step 2] Synthesis of Inter-A35

Inter-A34 (500 mg, 1.95 mmol) was dissolved in methanol (MeOH, 7.8 mL), and hydrochloric acid (HC1, 0.78 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A35 (376 mg, 98%) as a white solid.

[단계 1] Inter- A36의 합성 질소 분위기 하에, 터트-부틸 (3R,5R)- 5 -플루오로피페리딘- 3- 일카르바메이트 (400 mg, 1.83 mmol), 탄산 칼륨 (380 mg, 2.75 mmol)을 아세토나이트릴 (ACN, 4 ml)에 첨가하여 녹인 후, 아이오도에테인 (0.16 ml, 2.02 mmol)을 0°C에서 천천히 첨가하였다. 이후, 반응물을 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 감압 농축한 후, 반응 농축물을 실리카겔 컬럼 크로마토그래피 (Me0H/DCM=1/10)로 정제하여 노란색 고체의 목적 화합물 Inter-A36 (422 mg, 94%)을수득하였다. LC/MS: m/z 157.1 (M+H)+(ES). Intermediate Inter—A37

[Step 1] Synthesis of Inter-A36 Under a nitrogen atmosphere, tert-Butyl (3R,5R)-5-fluoropiperidin-3-ylcarbamate (400 mg, 1.83 mmol) and potassium carbonate (380 mg, 2.75 mmol) were dissolved in acetonitrile (ACN, 4 ml), and iodoethane (0.16 ml, 2.02 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter-A36 (422 mg, 94%) as a yellow solid.

^1H NMR (400MHz, CDCls) 8 4.89-4.69 (m, 2H) , 3.99 (bs, 1H) , 2.86 (m, 1H), 2.54-2.44 (m, 4H) , 2.33-2.30 (m, IH) , 2.05 (m, IH) , 1.74-1.82 (m, IH), 1.45 (s, 9H), 1.06 (t, J= 7.2 Hz, 3H); LC/MS: m/z 247.1 (M+H)+(ES).

[Step 2] Synthesis of Inter-A37 Under a nitrogen atmosphere, Inter-A36 (422 mg, 1.71 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 5 ml). The reaction was then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A37 (486 mg, 100%) as a beige solid.

LC/MS：m/z 147.1 (M+H)+(ES). Intermediate Inter— A38 to Inter— A40 were synthesized using the synthetic scheme of Inter- A37 in place of ethyl iodide, as shown in Table 4 below. Inter-A38 to Inter-A40 in Table 4 below were each synthesized using a synthetic method substantially identical to that of Inter-A37, except that a halide was used.

중간체 Inter- A42

lnter-A41 lnter-A42[Table 4]

Intermediate Inter- A42

lnter-A41 lnter-A42

[Step 1] Synthesis of Inter-A41 Under a nitrogen atmosphere, tert-butyl (3R, 5R)-5-fluoropiperidin-3-ylcarbamate (400 mg, 1.83 mmol) was dissolved in dichloromethane (DCM, 6 ml), and then sodium triacetoxyborohydride (437 mg, 2.06 mmol), Cyclobutanone (0.11 ml, 1.51 mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium carbonate solution, and the organic layer was extracted using dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter-A41 (266 mg, 71%) as a yellow solid.

^1H NMR (400MHz, CDCls) 8 4.88-4.66 (m, 2H) , 3.97 (bs, 1H) , 2.80-2.74 (m, 2H), 2.32-2.27 (m, 2H) , 2.11-1.97 (m, 4H) , 1.91-1.60 (m, 8H), 1.74-1.82 (m, IH), 1.45 (s, 9H); LC/MS: m/z 273.1 (M+H)+(ES).

[Step 2] Synthesis of Inter-A42 Under a nitrogen atmosphere, Inter-A41 (266 mg, 0.977 mmol) was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 7 ml). The reaction was then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A42 (239 mg, 100%) as a white solid.

중간체 Inter— A47

LC/MS：m/z 173.1 (M+H)+(ES). Intermediate Inter— A43 Inter-A43 in Table 5 below was synthesized through a synthetic method substantially identical to that of Inter-A42, except that the carbonyls in Table 5 below were used instead of cyclobutanone in the synthetic scheme of Inter-A42 above. [Table 5]

Intermediate Inter— A47

[Step 1] Synthesis of Inter- A44 Under a nitrogen atmosphere, diisobutyl aluminum hydride solution (1 M DIBAL in toluene, 24 ml) was dissolved in toluene (10 ml), and 1-(tert-butyl-dimethyl-silanyloxy)-cyclopropanecarboxylic acid methyl ester (1 g, 4.34 mmol) was added at -78°C. The mixture was stirred for 3 hours at -78°C. The reaction was terminated using methanol and sodium potassium tartrate solution, and the reaction mass was stirred at room temperature for 10 minutes. The reaction mixture was washed with sodium bicarbonate aqueous solution, and the organic layer was extracted using diethyl ether. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the target compound Inter- was obtained as a transparent liquid. A44 (512 mg, 58.3%) was obtained.

^1H NMR (400MHz, CDCls) 8 3.43-2.42 (m, 2H) , 2.23 (s, 4H) , 1.68 (t, J = 6.0 Hz, IH), 1.48 (s, 2H), 0.75 (s, 9H) , 0.67-0.64 (m, 2H) , 0.48-0.45 (m, 2H); LC/MS: m/z 203.1 (M+H)+(ES).

[Step 2] Synthesis of Inter-A45 Under nitrogen atmosphere, dimethyl sulfoxide (DMS0, 0.4 ml) was added to dichloromethane (DCM, 8.6 ml) at -78°C, then oxalyl chloride (0.2 ml, 2.8 mmol) and Inter-A44 (512 mg, 2.53 mmol) were slowly added. The mixture was stirred at -78°C for 1 hour, and triethylamine (TEA, 1.76 ml) was added. After completion of the reaction, the reaction mixture was warmed to 0°C, washed with 1 N hydrochloric acid solution (IN HC1), and the organic layer was extracted with dichloromethane to obtain the target compound Inter-A45 (849.5 mg) as a transparent liquid.

¹ H NMR (400MHz, CDCI3) 8 8.92 (s, IH), 1.29-1.08 (m, 4H), 0.77 (s, 9H), 0.59 (s, 6H); LC/MS: m/z 201.1 (M+H)+(ES).

[Step 3] Synthesis of Inter-A46 Under a nitrogen atmosphere, Inter-A45 (849.5 mg, 4.2 mmol) was dissolved in dichloromethane (DCM, 19 ml), and then sodium triacetoxyborohydride (1.06 g, 5 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (771 mg, 3.85 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium carbonate solution, and the organic layer was extracted with dichloromethane. The organic layer was dried with sodium sulfate and then stirred at reduced pressure. Concentration gave the target compound Inter-A46 (667 mg, 85%) as a white solid.

^1H NMR (400MHz, CDCls) 8 5.16 (br, 1H) , 3.74 (br, 1H) , 2.66-2.61 (br, 2H), 2.46-2.40 (m, IH) , 2.33-2.29 (m, IH) , 2.20 (br, IH) , 1.86 (br, IH) , 1.74-1.65 (m, IH), 1.59-1.48 (m, 3H) , 1.44 (s, 9H) , 0.86 (s, 9H) , 0.71-0.68 (m, 2H), 0.46-0.44 (m, 2H) , 0.11-0.10 (m, 6H)； LC/MS: m/z 385.3 (M+H)+(ES).

[Step 4] Synthesis of Inter-A47 Under a nitrogen atmosphere, Inter-A46 (667 mg, 1.73 mmol) was added to tetrahydrofuran (THF, 7.3 ml), and then tetrabutylammonium fluoride solution (TBAF in THF, 3.4 ml) was added. The reaction mass was then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted using dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Thereafter, under a nitrogen atmosphere, the reaction mixture was added to a 4N hydrochloric acid solution (4N HC1 in 1,4-di oxane, 13.6 ml). The reaction mass was then stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A47 (387 mg, 92%) as a white solid.

LC/MS: m/z 171.1 (M+H)+(ES). Intermediate Inter—A49

[Step 1] Synthesis of compound Inter- A48 Under a nitrogen atmosphere, tert-butyl (3R, 5R)-5-fluoropiperidin-3-ylcarbamate (400 mg, 1.83 mmol) and diisopropylethylamine (DIPEA, 0.958 mL, 5.50 mmol) were dissolved in acetonitrile (ACN, 4 ml), and ethyl chloroformate (0.21 ml, 2.75 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter-A48 (523 mg, 99%) as a yellow solid.

¹ H NMR (400MHz, Methanol -d ₄ ) 5 4.91-4.79 (m, 1H) , 4.18-4.13 (m, 4H) , 3.76 (bs, IH), 3.07 (dd, J= 21.6 Hz, 14.4 Hz, IH) , 2.75-2.65 (m, IH) , 1.72- 1.46 (m, 10H), 1.28 (t, J= 6.8 Hz, 7.2H); LC/MS: m/z 291.1 (M+H)+(ES).

[Step 2] Synthesis of compound Inter-A49 Under a nitrogen atmosphere, compound Inter-A48 (523 mg, 1.80 mmol) was added to a 4N hydrochloric acid solution (4N HCI in 1,4-dioxane, 10 ml). The reaction was then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-A49 (423 mg, 89.4%) as a light-colored solid.

LC/MS: m/z 191.1 (M+H)+(ES). Intermediate Inter— B5

[Step 1] Synthesis of Inter-Bl CuBr ₂ (73.3 g, 328 mmol)> Added to ethyl acetate (EA, 100 ml),

The mixture was stirred at 80°C for 30 minutes. Then, 4, 5, 6, 7-tetrahydrobenzothiophen- 4 -one (10 g, 65.6 mmol) was added and dissolved in chloroform (CHCh, 100 ml), and then slowly added at 80°C. Then, the reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter-Bl (18.1 g, 89%) as a brown solid.

^1H NMR (400MHz, CDCls) 8 7.07 (d, J = 3.6Hz, 1H) , 6.75 (s, 1H) , 6.30

(d, J = 3.6Hz, IH), 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 Inter-B2 Compound Inter-Bl (18.1 g, 58.4 mmol) was dissolved in dimethylformamide (DMF, 180 ml), and lithium carbonate (25.9 g, 350 mmol) was added. The reaction mixture was stirred at 100°C for 6 hours. After completion of the reaction, the reaction mixture was washed with water and an ammonium chloride aqueous solution, and the organic layer was extracted using ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound Inter-B2 (13 g, 97%) as a purple solid.

^1H NMR (400MHz, CDCls) 8 8.67 (br, 1H) , 6.75 (s, 1H) , 6.32 (s, 1H) , 4.34 (q, J = 7.2Hz, 2H) , 1.37 (t, J = 7.2Hz, 3H)； LC/MS： m/z 214.0 (M+H)+(ES).

[Step 3] Synthesis of Inter-B3 Compound Inter-B2 (13.0 g, 56.7 mmol) was dissolved in acetone (130 ml), and potassium carbonate (15.7 g, 113 mmol) and iodomethane (7.07 ml, 113 mmol) were added. The reaction mixture was stirred at 40°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 (EA/Hexane=1/10) to obtain the target compound Inter-B3 (9.41 g, 68%) as a white solid.

¹ H NMR (400MHz, DMS0-d ₆ ) 5 11.47 (br, IH) , 9.36 (s, IH) , 6.77 (s, IH), 6.65 (s, IH), 4.35 (br, 2H); LC/MS: m/z 200.0 (M+H)+(ES).

[Step 4] Synthesis of Inter-B4 Compound Inter-B3 (500 mg, 2.06 mmol) was dissolved in 1,4-dioxane (15 ml), and Pd(PPh3)4 (713 mg, 0.617 mmol), bis(pinacolato)diboron (2.09 g, 8.23 mmol), and potassium acetate (808 mg, 8.23 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/4) to obtain the target compound Inter-B4 (358 mg, 60%) as a white solid.

^1H NMR (400MHz, CDC1 ₃ ) 8 9.05 (br, 1H) , 7.15 (s, 1H) , 6.59 (s, 1H) , 3.21 (sixt, J = 6.8, 13.6 Hz, IH) , 1.40 (d, J = 6.8Hz, 6H)； LC/MS: m/z 251.9 (M+H)+(ES).

[Step 5] Synthesis of Inter-B5 Compound Inter-B4 (350 mg, 1.21 mmol) was dissolved in dichloromethane (DCM, 20 ml), and 1 M boron tribromide (1 M BBrs in DCM, 2.41 ml, 2.41 mmol) was added at 0°C. The reaction was stirred at 0°C for 1 hour. - The reaction was stopped by slowly adding ice water at -15°C, and the organic layer was extracted using ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM=l:9) to obtain the target compound Inter-B5 (125 mg, 53%) as a white solid.

^1H NMR (400MHz, CDCI3) 8 7.13 (s, IH) , 6.58 (s, IH) , 6.42 (d, J = 6.8 Hz, IH), 4.68 (s, 2H) , 4.00 (sixt, J = 8 Hz, IH) , 3.20 (sept, J = 6.8 Hz, IH), 2.53-2.48 (m, 2H), 2.04-1.98 (m, 2H), 1.40 (d, J = 6.4 Hz, 6H), 1.36 (s, 3H); LC/MS: m/z 393.0 (M+H)+(ES). Intermediate Inter- B7

[Step 1] Synthesis of Inter-B6 Compound Inter-B2 (466 mg, 2.03 mmol) was dissolved in dichloromethane (DCM, 1.65 ml), and N,N-diisopropylethylamine (DIPEA, 0.57 ml, 3.25 mmol) and chloromethyl methyl ether (0.23 g, 3.05 mmol) were slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter-B6 (412 mg, 74%) as a clear liquid.

^1H NMR (400MHz, CDCls) 8 7.51-7.47 (m, 3H) , 7.43-7.42 (m, 1H) , 5.27

(s, 2H), 3.70 (s, 3H). [Step 2] Synthesis of Inter-B7 Under a nitrogen atmosphere, Inter-B6 (412 mg, 1.51 mmol), Pd(dppf)C12 (55 mg, 0.08 mmol), bis(pinacolato)diboron (766 mg, 3.02 mmol), potassium acetate (444 mg, 4.52 mmol) were added to 1,4-dioxane (1,4-dioxane, 4.9 ml). The reaction mixture was then stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter-B7 (340 mg, 70%) as a white solid.

^1H NMR (400 MHz, CDCls) 8 7.71 (d, J = 8.0 Hz, 1H) , 7.63 (dd, J = 8.2, 0.6 Hz, IH), 7.55 (dd, J = 5.6, 0.8 Hz, IH) , 7.35 (d, 5.6 Hz, IH) , 5.25

(s, 2H), 3.62 (s, 3H), 1.37 (s, 12H). Intermediate Inter- B13

[Step 1] Synthesis of Inter-B8

6, 7 -dehydro-4-benzo［b］thiophene (6 g, 39.42 mmol), potassium hydroxide (8 g,

141.91 mmol) was dissolved in ethylene glycol (62 ml), and then hydrazine monohydrate (NH ₂ NH ₂ -H ₂ 0, 6.35 ml, 130.08 mmol) was added. The reaction was then stirred at 190°C.

The mixture was stirred for 4 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. 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=1/30) to obtain the target compound Inter-B8 (1.96 g, 36%) as a transparent liquid.

^1H NMR (400MHz, CDCls) 8 7.03 (d, J = 5.2 Hz, 1H) , 6.74 (d, J = 5.2 Hz, IH), 2.77 (t, J = 5.8 Hz, 2H), 2.62 (t, J = 6.0 Hz, 2H) , 1.86-1.78 (m, 4H).

[Step 2] Synthesis of Inter-B9

Inter- B8 (1.96 g, 14.18 mmol) was dissolved in acetic acid (AcOH, 58 ml), and then ammonium cerium (IV) nitrate (31.09 g, 56.72 mmol) dissolved in water OW, 19 ml) was added. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/20) to obtain the target compound Inter-B9 (1.10 g, 51%) as a red liquid.

¹ H NMR (400 MHz, CDCls) 8 7.61 (d, J = 4.8 Hz, 1H) , 6.97 (d, J = 4.8 Hz, IH), 2.77 (t, J = 5.8 Hz, 2H) , 2.62 (t, J = 6.0 Hz, 2H) , (quin, J = 12.3, 6.3 Hz, 2H).

[Step 3] Inter-BIO Synthesis

CuBr ₂ (9.68 g, 43.361 mmol) was added and dissolved in ethyl acetate (EA, 24 ml), and Inter-B9 (1.10 g, 7.23 mmol) dissolved in chloroform (CHCh, 24 ml) was added. The reaction mixture was then stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate 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 reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter-B10 (1.61 g, 72%) as a pink solid. ¹ H NMR (400 MHz, CDCls) 8 7.74 (d, J = 4.8 Hz, 1H) , 6.99 (d, J = 4.8 Hz, IH), 3.12 (t, J = 5.8 Hz, 2H) , 3.00 (t, J = 6.0 Hz, 2H) .

[Step 4] Synthesis of Inter-Bll

Inter-B10 (1.61 g, 5.35 mmol) and lithium carbonate (2.37 g, 32.09 mmol) were added to dimethylformamide (DMF, 19 ml). The reaction mass was then stirred at 100°C for 6 hours. After completion of the reaction, the reaction mixture was washed with water, aqueous ammonium chloride solution, and aqueous sodium 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 reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/20) to obtain the target compound Inter- B11 (863 mg, 70%) as a pink solid. P NMR (400 MHz, CDCI3) 8 7.45-7.42 (m, 2H), 7.32-7.29 (m, 2H), 5.93 (s, IH).

[Step 5] Synthesis of Inter-B12

Inter-Bll (353 mg, 1.54 mmol) and potassium carbonate (426 mg, 3.08 mmol) were dissolved in acetone (4 ml), and iodomethane (0.19 ml, 3.08 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/30) to obtain the target compound Inter-B12 (289 mg, 77%) as an orange liquid. Ni NMR (400 MHz, CDCI3) 8 7.50 (d, J = 8.4 Hz, IH) , 7.45-7.42 (m, 2H), 7.31 (d, J = 5.6 Hz, IH) , 4.05 (s, 3H) . [Step 6] Synthesis of Inter-B13 Under a nitrogen atmosphere, 1,4-dioxane (2.4 ml) was added to Inter-B12 (100 mg, 0.41 mmol), bis(pinacolato)diboron (157 mg, 0.62 mmol), Pd(PPhs)2C12 (58 mg, 0.08 mmol), and potassium acetate (121 mg, 1.23 mmol). The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/30) to obtain the target compound Inter-B13 (18 mg, 15%) as a white solid.

[단계 1] Inter- B14의 합성 화합물 6 -브로모벤조 [b]티오펜- 7 -올 (1.93 g, 8.43 mmol)를 다이클로로메탄 (DCM, 7 ml)에 첨가하여 녹인 후, N,N-디이소프로필에틸아민 (DIPEA, 2.35 ml, 13.48 mmol), 클로로메틸 메틸 에터 (1.02 g, 12.64 mmol)> 0°C에서 천천히 첨가하였다. 이후, 반응물을 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 물과 염화나트륨 수용액을 이용하여 세척하고, 다이클로로메탄을 이용하여 유기층을 추출하였다. 유기층을 황산 마그네슘을 이용하여 건조한 후, 감압 농축하였다. 반응 농축물을 실리카겔 컬럼 크로마토그래피 (EA/Hexane=1/10)로 정제하여 투명한 액체의 목적 화합물 Inter- B14 (2.06 g, 90%)을수득하였다. ^1H NMR (400MHz, CDCI3) 8 7.70 (d, J = 8.0 Hz, 1H) , 7.55 (d, J = 8.0 Hz, IH), 7.49 (d, J = 5.2 Hz, IH) , 7.34 (d, J = 5.2 Hz, IH) , 4.05 (s, 3H), 1.39 (s, 12H); LC/MS: m/z 291.1 (M+H)+(ES).

[Step 1] Synthesis of Inter- B14 Compound 6-bromobenzo[b]thiophene- 7-ol (1.93 g, 8.43 mmol) was dissolved in dichloromethane (DCM, 7 ml), and N,N-diisopropylethylamine (DIPEA, 2.35 ml, 13.48 mmol) and chloromethyl methyl ether (1.02 g, 12.64 mmol) were slowly added at > 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter- B14 (2.06 g, 90%) as a clear liquid.

¹ H NMR (400 MHz, CDCls) 8 7.52 (d, J = 8.4 Hz, 1H) , 7.45 (d, J = 8.4 Hz, IH), 7.42 (d, J = 5.6 Hz, IH) , 7.30 (d, J = 5.2 Hz, IH) , 5.34 (s, 2H), 3.73 (s, 3H).

[Step 2] Synthesis of Inter-B15 Under a nitrogen atmosphere, Inter-B14 (500 mg, 1.83 mmol), Pd(dppf hCl/DCM (75 mg, 0.09 mmol), bis(pinacolato)diboron (930 mg, 3.66 mmol), potassium acetate (538 mg, 5.50 mmol) were added to 1,4-dioxer]in (1,4-di oxane, 6 ml). Then, the reaction mixture was stirred at 100 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter-B15 as a white solid.

(373 mg, 64%) was obtained. ^1H NMR (400MHz, CDCls) 8 7.73 (d, J = 8.0 Hz, 1H) , 7.58 (d, J = 8.0

Hz, 1H), 7.50 (d, J = 5.6 Hz, IH), 7.33 (d, J = 5.2 Hz, IH), 5.30 (s, 2H), 3.68 (s, 3H), 1.37 (s, 12H); LC/MS: m/z 321.1 (M+H)+(ES). Intermediate Inter—B19

[Step 1] Synthesis of Inter-B16

5-Bromo-2-fluoro-4-methoxybenzaldehyde (300 mg, 1.29 mmol), methyl thioglycolate (0.12 ml, 1.35 mmol), and potassium carbonate (267 mg, 1.93 mmol) were added to dimethylformamide (DMF, 3 ml). The reaction was then stirred at 60°C for 1 hour. After completion of the reaction, the reaction mixture was washed with water, aqueous ammonium chloride solution, and aqueous sodium 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 reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/20) to obtain the target compound Inter-B16 (122 mg, 32%) as a white solid. ¹ H NMR (400MHz, CDCls) 8 8.04 (s, 1H) , 7.91 (s, 1H) , 7.30 (s, 1H) , 3.99 (s, 3H), 3.93 (s, 3H)； LC/MS： m/z 301.0, 303.0 (M+H)+(ES).

[Step 2] Synthesis of Inter-B17 Under a nitrogen atmosphere, Inter-B16 (39 mg, 0.13 mmol), lithium hydroxide monohydrate (Li0H-H ₂ 0 , 54 mg, 1.30 mmol) were added to tetrahydrofuran (THF, 0.5 ml) and water (C0, 0.2 ml). The reaction mixture was then stirred at 60°C for 3 hours. After completion of the reaction, acetic acid and water were added to the reaction mixture, and the produced solid was filtered. After drying in vacuo, the target compound Inter-B17 (23 mg, 62.1%) as a white solid was obtained.

^1H NMR (400MHz, CDCI3) 8 8.26 (s, IH) , 7.98 (s, IH) , 7.80 (s, IH) , 3.94 (s, 3H).

[Step 3] Synthesis of Inter-B18 Under a nitrogen atmosphere, Inter-B17 (28 mg, 0.10 mmol) o} Cu (11 mg, 0.17 mmol) was added to quinoline (0.3 ml). The reaction mixture was then stirred at 190°C for 3 hours. After completion of the reaction, the reaction mixture was washed with a 4N hydrochloric acid aqueous solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/20) to obtain the target compound Inter-B18 (10 mg, 42%) as a white solid.

¹ H NMR (400 MHz, CDCI3) 8 8.12 (s, IH) , 7.77 (s, IH) , 7.62 (d, J = 5.2 Hz, IH), 7.34 (d, J = 5.6 Hz, IH) , 3.91 (s, 3H) . [Step 4] Synthesis of Inter-B19 Under a nitrogen atmosphere, 1,4-dioxane (0.9 ml) was added to Inter-B18 (66 mg, 0.27 mmol), bis(pinacolato)diboron (138 mg, 0.54 mmol), Pd(dppf)2C12 (10 mg, 0.01 mmol) and potassium acetate (80 mg, 0.81 mmol). The reaction mixture was then stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/9) to obtain the target compound Inter-B19 (58 mg, 74%) as a white solid. I NMR (400MHz, _CDC13 ) 6 8.13 (s, 1H), 7.31 (s, 1H), 7.24-7.20 (m,

2H), 3.90 (s, 3H), 1.39 (s, 12H); LC/MS: m/z 291.1 (M+H)+(ES). Intermediate Inter- B23

[Step 1] Synthesis of Inter-B20

5,6-Dihydrobenzo[(1]thiazol-7(sa-1)-one (300 mg, 1.96 mmol) was dissolved in acetic acid (AcOH, 2.6 ml) was added and dissolved, and a 48% aqueous bromic acid solution (0.17 ml, 0.98 mmol) was slowly added. Thereafter, bromine (0.2 ml, 3.92 mmol) was slowly added, and the reaction mixture was stirred at 45°C for 16 hours. After completion of the reaction, the reaction mixture was basified using an aqueous sodium bicarbonate solution, and the organic layer was extracted using ethyl acetate. The organic layer was dried using magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/2) to obtain the target compound Inter-B20 (450 mg, 73%) as a yellow solid.

^1H NMR (400MHz, CDC1 ₃ ) 8 9.08 (s, 1H) , 3.24 (t, J = 6.0 Hz, 2H) , 3.17 (t, J = 5.4 Hz, 2H).

[Step 2] Synthesis of Inter-B21

Inter-B20 (100 mg, 0.32 mmol) was dissolved in tetrahydrofuran (THF, 1.6 ml), and then DBU (0.14 ml, 0.96 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with 1 N aqueous hydrochloric acid, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/1) to obtain the target compound Inter- 621 (58 mg, 79%) as a white solid. NI NMR (400 MHz, CDCI3) 8 8.98 (s, IH), 7.62 (q, J = 9.6 Hz, 2H), 6.09 (s, IH).

[Step 3] Synthesis of Inter-B22

Inter-B21 (58 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.50 mmol) were dissolved in acetone (Acetone, 0.6 ml) was added to dissolve the product, and iodomethane (0.03 ml, 0.50 mmol) was added. The reaction was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/1) to obtain the target compound Inter-B22 (47 mg, 77%) as a white solid.

^1H NMR (400MHz, CDCls) 8 8.96 (s, 1H) , 7.77 (d, J = 8.8 Hz, 1H) , 7.67 (d, J = 8.8 Hz, 1H) , 4.05 (s, 3H) .

[Step 4] Synthesis of Inter-B23 Under a nitrogen atmosphere, Inter-B22 (75 mg, 0.31 mmol), bis(pinacolato)diboron (156 mg, 0.61 mmol), Pd(dppf)2612 (11 mg, 0.02 mmol), and potassium acetate (90 mg, 0.92 mmol) were dissolved in 1,4-dioxane (1.0 ml). The reaction mixture was then stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/5) to obtain the target compound Inter-B23 (60 mg, 66%) as a white solid.

^1H NMR (400MHz, CDCI3) 8 9.02 (s, 1H) , 7.86 (d, J = 2.4 Hz, 2H),

lnter-B27 lnter-B284.04 (s, 3H), 1.39 (s, 12H)； LC/MS： m/z 292.1 (M+H)+(ES). Intermediate Inter— B28

lnter-B27 lnter-B28

[Step 1] Synthesis of Inter-B24 Sodium hydroxide (4.5 g, 120 mmol) was dissolved in water (OW, 40 ml), and bromine (1.4 ml, 27.3 mmol) was added. The reaction mixture was stirred at 50°C for 3 hours, and 2,4-dinitroaniline (1 g, 5.46 mmol) and potassium hydroxide (460 mg, 8.20 mmol) were dissolved in methanol (MeOH, 20 ml), and then added slowly. The reaction mixture was stirred at 50°C for 30 minutes. After completion of the reaction, the reaction mixture was lowered to room temperature, and the generated solid was filtered to obtain the target compound Inter-B24 (301 mg, 27.3 mmol) as a yellow solid.

19%) was obtained. 1H NMR (400MHz, DMS0-d ₆ ) 5 7.46 (d, J = 9.2Hz, 1H) , 7.19 (d, J =

9.2 Hz, 1H), 4.32 (s, 3H).

[Step 2] Synthesis of Inter-B25 Under a hydrogen atmosphere, compound Inter-B24 (224 mg, 0.91 mmol) was dissolved in ethyl acetate (EA, 10 ml), and Pd/C (33 mg, 10 wt%) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure to obtain Inter-B25 (127 mg, 65%) was obtained.

¹ H NMR (400MHz, CDCls) 8 7.80 (d, J = 8.4Hz, 1H), 6.36 (d, J = 8.4Hz, 1H), 3.80-3.77 (m, 5H), 3.65-3.62 (m, 2H)； LC/MS： m/z 217.0 (M+H)+(ES).

[Step 3] Synthesis of Inter-B26 Compound Inter-B25 (50 mg, 0.230 mmol) was added to formic acid (2 ml). The reaction mixture was then stirred at 100°C for 16 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 8 using 2 M sodium hydroxide aqueous solution. The mixture was washed with water, and the organic layer was extracted using ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM=l:9) to obtain the target compound Inter-B26 (32 mg, 61.5%)* as a brown solid.

¹ H NMR (400MHz, DMS0-d ₆ ) 5 12.72 (bs, IH) , 8.21 (s, IH) , 7.33 (d, J = 8.4 Hz, IH), 7.17 (d, J = 8.4 Hz, IH) , 4.26 (s, 3H)； LC/MS： m/z 226.9, 228.9 (M+H)+(ES).

[Step 4] Synthesis of Inter-B27 Compound Inter-B26 (100 mg, 0.44 mmol) was dissolved in tetrahydrofuran (THF, 2 ml), and then di-tertbutyl dicarbonate (116 mg, 0.53 mmol), triethylamine (TEA, 0.09 ml, 0.66 mmol), and 4-dimethylaminopyridine (5.4 mg, 0.04 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic phase was extracted using ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and a yellow solid was obtained. The target compound Inter-B27 (120 mg, 83%) was obtained.

¹ H NMR (400MHz, DMS0-d ₆ ) 5 8.64 (s, 1H) , 7.57 (q, J = 8.0 Hz, 8.8 Hz, 2H), 4.31 (s, 3H), 1.65 (s, 9H)； LC/MS： m/z 226.9, 228.9, 270.9, 272.9 (M+H)+(ES). [Step 5] Synthesis of Inter- B28 Compound Inter-B27 (50 mg, 0.15 mmol) was dissolved in 1,4-dioxane,

1 ml) was added to dissolve the resulting solution, and Pd(dppf)2C12 (12 mg, 0.0153 mmol), bis(pinacolato)diboron (78 mg, 0.306 mmol), and potassium acetate (45 mg, 0.458 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/4) to obtain the target compound Inter-B28 (57 mg, 32%) as a clear liquid.

¹ H NMR (400MHz, CDC1 ₃ ) 8 8.32 (s, IH), 7.66 (q, J = 7.2 Hz, 8.0 Hz, 2H), 4.30 (s, 3H), 1.69 (s, 9H), 1.38 (s, 12H)； LC/MS： m/z 319.1 (M+H)+(ES). Intermediate Inter- B31

[Step 1] Synthesis of Inter-B29

1-Benzothiophen-5-ol (61 mg, 0.41 mmol) was dissolved in acetic acid (1.4 ml), and then a solution of bromine (17 pl, 0.41 mmol) in acetic acid (0.7 ml) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated sodium thiosulfate solution was added to form a solid, which was filtered to obtain the solid. The filtrate was washed with water and dried under vacuum to obtain the target compound Inter-B29 (55 mg, 59%) as a white solid.

^1H NMR (400MHz, CDC1 ₃ ) 8 7.68 (d, J = 8.8 Hz, 1H) , 7.53 (d, J = 5.6 Hz, IH), 7.35 (d, J = 5.2 Hz, IH) , 7.09 (d, J = 8.4 Hz, IH) , 5.54 (s, IH) .

[Step 2] Synthesis of Inter-B30 Compound Inter-B29 (1.42 g, 6.18 mmol) was dissolved in dichloromethane (DCM, 5 ml), and chloromethyl methyl ether (0.70 ml, 9.27 mmol) and diisopropylethylamine (DIPEA, 1.72 ml, 9.89 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered through Celite. The residue was filtered using ethanol and concentrated under reduced pressure. The concentrate was extracted with water and dichloromethane to form an organic layer. The organic layer was dried using magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/20) to obtain the target compound Inter-B30 (750 mg, 44%) as a yellow liquid.

^1H NMR (400MHz, CDCls) 8 7.73 (d, J = 8.8 Hz, 1H) , 7.52 (d, J = 5.2 Hz, IH), 7.46 (d, J = 5.6 Hz, IH) , 7.24 (d, J = 8.8 Hz, IH) , 5.29 (s, 2H), 3.55 (s, 3H).

[Step 3] Synthesis of Inter-B31 Compound Inter-B30 (750 mg, 2.75 mmol) was dissolved in 1,4-dioxane (1,4-dioxane, 9 ml), and Pd(dppf )2C12'DCM (112 mg, 0.14 mmol), bis(pinacolato)diboron (1.39 g, 5.49 mmol), and potassium acetate (808 mg, 8.24 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/20) to obtain the target compound Inter-B31 (715 mg, 81%) as a transparent solid.

^1H NMR (400 MHz, CDCI3) 8 7.83 (d, J = 8.8 Hz, IH) , 7.71 (d, J = 5.6 Hz, IH), 7.46 (d, J = 5.2 Hz, IH) , 7.12 (d, J = 8.8 Hz, IH) , 5.20 (s, 2H), 3.55 (s, 3H), 1.42 (s, 12H) . Intermediate Inter- B36

[Step 1] Synthesis of Inter-B32

2-Bromo-6-methoxyaniline (5 g, 24.7 mmol) was added to acetone (80 mL), and benzoyl isothiocyanate (4.01 mL, 29.7 mmol) was added dropwise. Acetone (40 mL) was further added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and then the mixture was filtered under reduced pressure to obtain the target compound Inter-B32 (8.55 g, 94.6%) as a light-colored solid.

^1H NMR (400MHz, CDCls) 8 13.12 (s, 1H) , 9.09 (s, 1H) , 8.82 (dd, J = 8 Hz, 7.2 Hz, IH), 7.94-7.91 (m, 2H) , 7.68-7.64 (m, IH) , 7.68-7.54 (m, 2H) , 7.44 (dd, J = 1.2 Hz, 6.4 Hz, IH) , 7.07 (t, J = 8Hz, IH) , 3.97 (s, 3H)； LC/MS: m/z 365.0, 367.0 (M+H)+(ES).

[Step 2] Synthesis of Inter-B33

Inter-B32 (8.55 g, 23.4 mmol) was dissolved in methanol (MeOH, 100 mL), and 2 M sodium hydroxide aqueous solution (36 mL, 70.2 mmol) was added. The reaction mixture was stirred at 65°C for 2 hours. After completion of the reaction, 2 M hydrochloric acid aqueous solution and water were added to the reaction mixture, and the organic layer was extracted using ethyl acetate. The residue was concentrated under reduced pressure to obtain the target compound Inter-B33 (1.58 g, 25.9%) as a light brown solid.

^1H NMR (400MHz, DMS0-d ₆ ) 5 9.30 (s, 1H) , 7.85 (dd, J = 1.6 Hz, 7.2 Hz, IH), 7.94-7.91 (m, 2H) , 7.42 (dd, J = 1.6 Hz, 6.4 Hz, IH) , 7.05 (t, J = 8Hz, IH), 3.74 (s, 3H); LC/MS: m/z 260.9 262.9 (M+H)+(ES).

[Step 3] Synthesis of Inter-B34

Inter-B33 (1.44 g, 5.51 mmol) was dissolved in chloroform (CHCh, 20 mL), and bromine (0.213 mL, 11.0 mmol) was added dropwise at 0°C. The reaction mixture was then stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM=1/3O) to obtain the target compound Inter-B34 (1.10 g, 76.9%) as a pale yellow solid.

¹ H NMR (400MHz, CDCls) 8 7.29 (d, J = 8.4 Hz, IH) , 7.19 (d, J = 8.4 Hz, IH), 5.43 (bs, 2H) , 4.07 (s, 3H)； LC/MS： m/z 258.9, 260.9 (M+H)+(ES).

[Step 4] Synthesis of Inter-B35

Inter-B34 (1.10 g, 4.25 mmol) was dissolved in DMF (7 mL), tert-butyl Nitrite (1.8 mL, 15.3 mmol) was added. The reaction mass was then stirred at 60°C for 6 hours. After completion of the reaction, the reaction mixture was washed with an aqueous ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter-B35 (610 mg, 58.7%) as a yellow liquid. Ni NMR (400MHz, CDCls) 8 8.94 (s, 1H) , 7.60 (d, J = 8.4 Hz, 1H) , 7.53 (d, J = 8.4 Hz, 1H) , 4.30 (s, 3H)； LC/MS： m/z 243.9, 245.9 (M+H)+(ES).

[Step 5] Synthesis of Inter-B36 Under a nitrogen atmosphere, Inter-B35 (610 mg, 2.54 mmol), bis(pinacolato)diboron (1.29 g, 5.08 mmol), Pd(dppf hCl/DCM (104 mg, 0.127 mmol), potassium acetate (748 mg, 7.62 mmol) was added 1,4-dioxane (1,4-dioxane, 6 ml). Then, the reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/10) to obtain the target compound Inter-B36 (553 mg, 74.7%) as a yellow solid. P NMR (400 MHz, CDCI3) 8 8.91 (s, 1H) , 7.73 (d, J = 8.0 Hz, 1H) , 7.65 (d, J = 8.4 Hz, 1H) , 4.23 (s, 3H) , 1.39 (s, 12H)； LC/MS： m/z 292.3 (M+H)+(ES). Intermediate Inter—C2

[Step 1] Synthesis of Inter-Cl Under a nitrogen atmosphere, 3, 5, 6-trichloro 1,2, 4-triazine (3 g, 16.27 mmol) was dissolved in tetrahydrofuran (THF, 160 ml), and cooled to -78°C. Then, 3M methylmagnesium bromide solution (3M MeMgBr in THF, 8.1 ml, 24.40 mmol) was slowly added. Then, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was terminated by adding aqueous ammonium chloride solution at 0°C, ethyl acetate was extracted using the organic layer. The organic layer was dried using magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/20) to obtain the target compound Inter-Cl (1.51 g, 57%) as a yellow solid.

¹ H NMR (400MHz, CDCls) 8 2.70 (s, 3H); LC/MS: m/z 164.0, 166.0 (M+H)+(ES).

[Step 2] Synthesis of Inter-C2

Inter-Cl (90 mg, 0.55 mmol) was dissolved in dimethyl sulfoxide (DMSO, 1.1 ml), and (R)-1-methylpiperidin-3-amine (366 uL, 2.92 mmol) and N,N-diisopropylethylamine (DIPEA, 0.93 ml, 5.37 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography. The target compound Inter- C2 (68 mg, 51%) was obtained as a blackish brown solid by purification by chromatography (MeOH/DCM=l:2).

^1H NMR (400MHz, Methanol -d ₄ ) 5 4.10-4.05 (m, 1H) , 3.01 (d, J = 9.2 Hz, IH), 2.73 (d, J = 10.0 Hz, IH) , 2.47 (s, 3H) , 2.31 (s, 3H) , 2.17-1.96 (m, 3H), 1.86-1.78 (m, IH), 1.74-1.63 (m, IH), 1.46-1.38 (m, IH); LC/MS: m/z

242.1, 244.1 (M+H)+(ES). Intermediates Inter-C3 to Inter-C48 and Inter-C53 to Inter-C63 Except that the amine or the hydrochloride of the amine of Table 6 below was used instead of (R)-1-methylpiperidin-3-amine in the synthetic scheme of Inter-C2, respectively, Inter-C3 to Inter-C48 and Inter-C53 to Inter-C63 of Table 6 below were synthesized through substantially the same synthetic method as the synthetic method of Inter-C2.

중간체 Inter— C50

[Table 6]

Intermediate Inter— C50

[Step 1] Synthesis of tert-butyl (S)-2-( ((6-chloro-5-methyl-1,2,4-triazine-3- from Inter-C49 (705 mg, 2.15 mmol) was dissolved in dichloromethane (DCM, 43 ml), and trifluoroacetic acid (1.7 ml, 21.5 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter-049 (730 mg, 98%) as an orange solid.

LC/MS: m/z 228.1, 230.1 (M+H)+(ES).

[Step 2] Synthesis of Inter-C50

Inter-C49 (300 mg, 0.88 mmol) was dissolved in methanol (MeOH, 1.0 ml), and formaldehyde (37% in H2O, 0.52 ml) and sodium cyanoborohydride (155 mg, 2.47 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the pH was adjusted to 9 by adding aqueous potassium hydroxide solution to the reaction mixture, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound Inter-C50 (71 mg, 33%) as a yellow-brown solid.

^1H NMR (400MHz, CDCI3) 8 6.06 (br, 1H) , 3.72 (m, 1H) , 3.48-3.43 (m, 1H), 3.19-3.16 (m, IH) , 2.64-2.62 (m, IH) , 2.46 (s, 3H) , 2.40 (s, 3H), 2.37-2.30 (m, IH), 2.04-1.93 (m, IH), 1.86-1.65 (m, 3H); LC/MS: m/z 242.1, 244.1 (M+H)+(ES). Intermediate Inter- C52

[Step 1] Synthesis of Inter- C51 Tert-Butyl (3S, 4S)-3-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)-4-hydroxypiperidine- 1-carboxylate (593 mg, 1.73 mmol) was dissolved in dichloromethane (DCM, 8.6 ml), and 4 N hydrochloric acid solution (4 N HCI in 1,4-dioxane, 2.2 ml) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Inter- C51 (546 mg, 98%) as a reddish brown solid.

[Step 2] Synthesis of Inter-C52 Inter-C51 (496 mg, 1.77 mmol) was dissolved in acetonitrile (ACN, 3.9 ml), and potassium carbonate (734 mg, 5.31 mmol) and iodoethane (0.16 ml, 1.95 mmol) were slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to give the target compound Inter-C52 as an ivory solid.

(130 mg, 27%) was obtained. ¹ H NMR (400MHz, Methanol -d ₄ ) 5 3.97-3.92 (m, IH) , 3.52-3.46 (m, IH) , 3.09-3.06 (m, IH) , 2.88-2.84 (m, IH) , 2.42 (q, J = 7.2 Hz, 2H) , 2.36 (s, 3H) , 2.13-2.08 (m, IH) , 1.99-1.90 (m, 2H) , 1.64-1.56 (m, IH) , 1.02 (t J = 7.2 Hz, 3H) : NH peak and 0-H peak are not observed. LC/MS: m/z 272.0, 274.1 (M+H)+(ES). Intermediate Inter—C64

3, 6-Dichloro- 5 -methyl- 1,2, 4-triazine (264 mg, 1.61 mmol) was dissolved in acetonitrile (ACN, 7 ml), and methyl (3R, 5R)- 3 -amino- 5-fluoropiperidine- 1-carboxylate dihydrochloride (423 mg, 1.61 mmol) and potassium carbonate (890 mg, 6.43 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=10/l) to obtain the target compound Inter-C64 (82 mg, 16%) as a brown oil.

¹ H NMR (400MHz, Methanol -d ₄ ) 5 4.28-4.13 (m, 5H) , 3.18 (dd, J= 20.4 Hz, 12.0 Hz, IH), 2.92-2.83 (m, IH) , 2.50 (s, 3H) , 2.37-2.34 (m, IH) , 1.90- 1.80 (m, IH), 1.27 (t. J=7.2 z, 3H); LC/MS: m/z 304.0, 306.0 (M+H)+(ES).

질소 분위기 하에, (3R,4S)- 4- ((6 -클로로- 5 -메틸- 1,2, 4 -트리아진 -3- 일)아미노)테트라하이드로퓨란- 3 -올 (24 mg, 0.10 mmol), (4 - 하이드록시벤조 [b]티오펜- 5 -일)보로닉 에시드 (34 mg, 0.18 mmol), Pd(dppf)2C12'DCM (17 mg, 0.02 mmol), 탄산 칼륨 (69 mg, 0.50 mmol)을 1.4 - 다이옥세인 (1,4- dioxane, 0.6 ml)과 물 (EbO, 0.3 ml)에 첨가하였다. 이후, 반응물을 90°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 셀라이트와 황산 마그네슘을 이용하여 여과하고, 감압농축하였다. 반응농축물을 실리카겔 컬럼 크로마토그래피 (Me0H/DCM=1/10)로 정제하여 노란색 고체의 목적 화합물 1 (11 mg, 29%)을수득하였다. ＜Example＞ Example 1: (3R,4S)-4-((6-(4-hydroxybenzo[b]thiophene-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)tetrahydrofuran-3-ol

Under a nitrogen atmosphere, (3R,4S)-4-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)tetrahydrofuran-3-ol (24 mg, 0.10 mmol), (4-hydroxybenzo[b]thiophene-5-yl)boronic acid (34 mg, 0.18 mmol), Pd(dppf)2C12'DCM (17 mg, 0.02 mmol), potassium carbonate (69 mg, 0.50 mmol) were added to 1,4-dioxane (1,4-dioxane, 0.6 ml) and water (EbO, 0.3 ml). The reaction mass was then stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was filtered using celite and magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound 1 (11 mg, 29%) as a yellow solid.

^1H NMR (400MHz, Methanol -d ₄ ) 5 7.62 (dd, J = 5.6, 0.8 Hz, 1H) , 7.57-

7.54 (m, 2H), 7.28 (d, J = 8.4 Hz, IH), 4.41-4.38 (m, 2H), 4.25 (dd, J = 9.4, 5.0 Hz, 1H), 4.10 (dd, J = 9.8, 4.2 Hz, 1H), 3.87 (dd, J = 9.4, 2.6 Hz, 1H),

3.77 (dd, J = 9.6, 2.0 Hz, 1H) , 2.38 (s, 3H)； LC/MS： m/z 345.1 (M+H)+(ES). Synthesis of Examples 2 to 4 Except that Inter-C4 to Inter-C6 of Table 6 were used instead of (3R,4S)-4-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)tetrahydrofuran-3-ol of Example 1, respectively, the compounds of Examples 2 to 4 of Table 7 below were synthesized through substantially the same synthetic method as the synthetic method of Example 1.

실시예 5 및 6： （R）- 6-（4 -메톡시벤조 [b]티오펜- 5 -일）- 5 -메틸- N-（l- 메틸피페리딘 — 3 —일）~! , 2 , 4 —트리아진 — 3 —아민 및 （R）~5~（5 "메틸 — 3~（（ 1~ 메틸피페리딘- 3 -일）아미노）- 1,2, 4 -트리아진 -6 -일）벤조 [b]티오펜- 4 -올 [Table 7]

Examples 5 and 6: (R)-6-(4-methoxybenzo[b]thiophene-5-yl)-5-methyl-N-(l-methylpiperidine-3-yl)~!, 2,4-triazine-3-amine and (R)~5~(5"methyl-3~((1-methylpiperidine-3-yl)amino)-1,2,4-triazin-6-yl)benzo[b]thiophene-4-ol

6

［Step 1］ Synthesis of compound 5 Under a nitrogen atmosphere, (R)-6-chloro-5-methyl-N-(l-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (30 mg, 0.12 mmol), 2-(4-methoxybenzo［b］thiophene-5-yl)- 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (61 mg, 0.21 mmol), Pd(dppf hCl/DCM

(20 mg, 0.03 mmol), potassium carbonate (20 mg, 0.60 mmol) were added to 1,4-dioxa]in (1,4-dioxane, 0.72 ml) and water (H ₂ 0, 0.36 ml). The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM=1/5) to obtain the target compound 5 (33 mg,

70%) was obtained.

^1H NMR (400MHz, CDCls) 8 7.72 (d, J = 8.4 Hz, 1H) , 7.51 (d, J = 5.6 Hz, IH), 7.47 (d, J = 5.6 Hz, IH) , 7.36 (d, J = 8.4 Hz, IH) , 5.83 (br, IH) , 4.32 (br, 1H), 3.72 (s, 3H), 2.69 (m, 1H), 2.46-2.34 (m, 3H), 2.96 (s, 3H), 2.29 (s, 3H), 1.86-1.67 (m, 4H); LC/MS: m/z 370.2 (M+H)+(ES).

［Step 2］ Synthesis of compound 6 Compound 5 (32 mg, 0.09 mmol) was dissolved in dichloromethane (DCM, 2.0 ml), and 1 M boron tribromide (IM BBr ₃ in DCM, 0.08 ml, 0.90 mmol) was added at -78°C. The reaction was then stirred at room temperature for 16 hours. The reaction was quenched using methanol, and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography (MeOH/DCM=1/5) to obtain the target compound 6 (7.8 mg, 25%) as a pale yellow solid.

^1H NMR (400 MHz, CDCls) 8 11.5 (br, 1H) , 7.66 (dd, J = 5.4, 0.6 Hz, 1H), 7.44 (dd, J = 8.4, 0.8 Hz, IH) , 7.37-7.34 (m, 2H) , 5.91 (br, IH) , 4.29 (br, IH), 2.61 (s, 3H), 2.57-2.45 (m, 3H), 2.30 (m, 4H), 1.86-1.63 (m, 4H); LC/MS: m/z 356.2 (M+H)+(ES). Synthesis of Examples 7 to 13, 73 and 74 Except that Inter-B4, Inter-B13, Inter-B19, Inter-B23, Inter-B28 and Inter-B36 were used instead of 2-(4-methoxybenzo［b］thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Example 6 and Inter-C2, Inter-C5, Inter-C7 to Inter-C9 and Inter-C17 were used instead of (R)-6-chloro-5-methyl-N-(l-methylpiperidin-3-yl)-1,2,4-triazin-3-amine, Compounds of Examples 7 to 13, 73 and 74 in Table 8 below were prepared through substantially the same synthetic method as that of Example 6. Each was synthesized.

실시예 14： 5- (3- (((IS, 2S)- 2 -하이드록시사이클로헥실)아미노) -5 -메틸- ,2, 4 -트리아진- 6 -일 )벤조 [b]티오펜- 4 -올 [Table 8]

Example 14: 5-(3-(((IS, 2S)-2-hydroxycyclohexyl)amino)-5-methyl-,2,4-triazin-6-yl)benzo[b]thiophene-4-ol

[Step 1] Synthesis of compound A1 Under a nitrogen atmosphere, (1S,2S)-2-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)cyclohexan-1-ol (30.0 mg, 0.12 mmol), 2-(4-(methoxymethoxy)benzo[b]thiophene-5-yl)- 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane

(59 mg, 0.19 mmol), Pd(dppf hCl/DCM (20 mg, 0.03 mmol), potassium carbonate (82 mg, 0.6 mmol) were added 1,4-dioxane (1,4-di oxane, 0.72 ml) and water (H2O, 0.04 ml). The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=1/1) to obtain the target compound A1 (26 mg, 52%) as a sticky transparent liquid. Ni NMR (400 MHz, CDCls) 8 7.75 (d, J = 8.4 Hz, 1H), 7.54 (dd, J =

0.6, 5.6 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 5.84 (br, 1H), 4.95 (s, 2H), 3.88 (m, 1H), 3.54 (dt, J = 4.4, 10.0 Hz, 1H), 3.26 (s, 3H), 2.32 (s, 3H), 2.21-2.18 (m, 1H), 2.13-2.10 (m, 1H) , 1.79-1.75 (m, 2H), 1.49-1.35 (m, 4H) .

[Step 2] Synthesis of compound 14 Compound A1 (26 mg, 0.07 mmol) was dissolved in dichloromethane (DCM, 1.3 ml), and trifluoroacetic acid (0.05 ml, 0.65 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was washed with an aqueous sodium bicarbonate solution, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=5/1) to obtain the target compound 14 (7 mg, 30%) as a yellow solid.

^1H NMR (400 MHz, Methanol -d ₄ ) 5 7.61 (d, J = 5.2 Hz, 1H) , 7.54 (dd, J = 8.2, 0.6 Hz, IH), 7.53 (d, J = 5.6, Hz, IH) , 7.27 (d, J = 8.4 Hz, IH), 3.94-3.88 (m, IH), 3.58-3.52 (m, IH), 2.36 (s, 3H), 2.19-2.07 (m, 2H), 1.82-1.76 (m, 2H), 1.50-1.28 (m, 4H); LC/MS: m/z 357.1 (M+H)+(ES). Synthesis of Examples 15 to 35, 37 to 49, 68 to 72, 75, 92, 93 and 100 to 106 In place of the (1S,2S)-2-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)cyclohexan-1-ol of Example 14, Inter-C10 to Inter-C16, Inter-C19 to Inter-C30, Inter-C32 to Inter-C48, Inter-C50 and Inter-C52 to Inter- Except for using C62, Examples 15 to 35, 37 to 49, 68 to 70 of Table 9 were prepared by a synthetic method substantially identical to that of Example 14.

Compounds 72, 75, 92, 93, and 100 to 106 were synthesized respectively.

[Table 9]

실시예 36： 5-（3-（（3-（하이드록시메틸）바이사이클로 [1.1.1]펜탄- 1- 일）아미노） -5 -메틸- 1,2, 4 -트리아진 -6 -일）벤조 [b]티오펜- 4 -올

메틸 3- ((6- (4 -하이드록시벤조［b］티오펜- 5 -일)- 5 -메틸- 1,2, 4 -트리아진- 3 -일)아미노)바이사이클로［1.1.1］펜탄- 1-카복실레이트 (10 mg, 0.0261 mmol)을 테트라하이드로퓨란 (THF, 1 ml)에 첨가하였다. 수소화 알루미늄 리튬 (LAH, 2.2 mg, 0.0575 mmol)을 0°C에서 넣고상온에서 2시간동안교반하였다. 반응혼합물을 0°C에서 얼음물을 천천히 첨가하여 반응을 종결하고, 염화암모늄 수용액과 타르타르산나트륨칼륨 수용액을 넣어준 뒤 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을황산나트륨을 이용하여 건조한후, 감압농축하였다. 반응 농축물을 실리카겔 컬럼 크로마토그래피 (EA/Hexane=5/1)로 정제하여 노란색 고체의 목적 화합물 36 (2.77 mg, 29.9%)를수득하였다.

Example 36: 5-(3-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzo[b]thiophene-4-ol

Methyl 3-((6-(4-hydroxybenzo［b］thiophene-5 -yl)-5 -methyl- 1,2, 4-triazin- 3 -yl)amino)bicyclo［1.1.1]pentane- 1-carboxylate (10 mg, 0.0261 mmol) was added to tetrahydrofuran (THF, 1 ml). Lithium aluminum hydride (LAH, 2.2 mg, 0.0575 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. Ice water was slowly added to the reaction mixture at 0°C to quench the reaction, and an aqueous ammonium chloride solution and an aqueous sodium potassium tartrate solution were added. The organic layer was extracted using ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EA/Hexane=5/1) to obtain the target compound 36 (2.77 mg, 29.9%) as a yellow solid.

^1H NMR (400 MHz, CDCls) 8 11.54 (s, 1H) , 7.66 (dd, J = 5.6 Hz, 4 Hz, 1H), 7.44 (dd, J = 8.0 Hz, 0.4 Hz, IH) , 7.38 (d, J = 5.6 Hz, IH) , 7.36 (d, J = 8.4 Hz, IH), 5.84 (s, IH), 3.80- (s, IH), 2.66 (s, H), 2.18 (s, 6H); LC/MS: m/z 355.1 (M+H)+(ES). Example 50: (R)-2-(3-((6-(4-hydroxybenzo［b］thiophene-5-yl)-5-methyl-

메틸 (R)- 2- (3- ((6- (4 -하이드록시벤조 [b]티오펜- 5 -일)- 5 -메틸- 1,2,4- 트리아진 -3 -일)아미노)피페리딘- 1-일)아세테이트 (50 mg, 0.12 mmol)을 메탄올 (MeOH, 3 ml)에 첨가하여 녹인 후, 2 M 수산화나트륨 수용액 (0.18 mL, 0.363 mmol)을 첨가하였다. 이후반응물을상온에서 16시간동안교반하였다. 반응종료 후, 에틸 아세테이트로물층을씻어준 뒤 , 1 M염산수용액을이용하여 pH를 3으로 맞추었다. 물층을 감압 농축한 뒤, 테트라하이드로퓨란 (THF)을 첨가하고, 황산 나트륨을 이용하여 건조한후, 감압농축하여 노란색 고체의 화합물 50 (21.1 mg, 41.7%)를수득하였다. 1,2,4-triazine-3-yl)amino)piperidine-1-yl)acetic acid

Methyl (R)-2-(3-((6-(4-hydroxybenzo[b]thiophene-5-yl)-5-methyl- 1,2,4-triazin-3-yl)amino)piperidin- 1-yl)acetate (50 mg, 0.12 mmol) was dissolved in methanol (MeOH, 3 mL), and 2 M sodium hydroxide aqueous solution (0.18 mL, 0.363 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the aqueous layer was washed with ethyl acetate, and the pH was adjusted to 3 with 1 M hydrochloric acid aqueous solution. After concentrating the aqueous layer under reduced pressure, tetrahydrofuran (THF) was added, dried using sodium sulfate, and concentrated under reduced pressure to obtain compound 50 (21.1 mg, 41.7%) as a yellow solid.

¹ H NMR (400MHz, Methanol -d ₄ ) 5 1H NMR (400 MHz, CDC13) 5 7.65 (dd,

J = 5.6 Hz, 8Hz, 1H), 7.60-7.58 (m, 2H) , 7.29 (d, J = 8.4 Hz, 1H) , 4.52-4.50 (m, 2H), 4.50-3.38 (m, 1H) , 3.18 (s, 2H) , 3.95-3.85 (m, 2H) , 3.71- 3(m, 1H) , 3.19 (m, 1H), 2.54-2.31 (m, 4H) , (2.27-2.18 (m, 4H) , 2.55-2.07 (m, 3H) , 2.03- 1.79 (m, 5H); LC/MS: m/z 400.1 (M+H)+(ES). Synthesis of Examples 51 to 66 In the above Example 14, 2-(4-(methoxymethoxy)benzo[b]thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(7-(methoxymethoxy)benzo[b]thiophene-6- Except that Inter-C5 to Inter-Cll, Inter-C19, Inter-C24 to Inter-C26, Inter-C28, Inter-C33, Inter-35, Inter-C40 and Inter-C41 were used instead of (1S,2S)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and (1S,2S)-2-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)cyclohexan-1-ol, respectively, compounds of Examples 51 to 66 in Table 10 below were synthesized through substantially the same synthetic method as that of Example 14.

실시예 67： (R)- 2- (3- ((6- (4 -하이드록시벤조［b］티오펜- 5 -일)- 5 -메틸-[Table 1

Example 67: (R)-2-(3-((6-(4-hydroxybenzo［b］thiophene-5-yl)-5-methyl-

메틸 (R)- 2- (3- ((6- (4 -하이드록시벤조［b］티오펜- 5 -일)- 5 -메틸- 1,2,4- 트리아진 - 3 -일)아미노)피페리딘— 1—일)아세테이트 (50 mg, 0.12 mmol)을 33% 메틸아민용액 (33%MeNH2 in ethanol, 5 ml)에 첨가하여 녹인후, 상온에서 16시간 동안교반하였다. 반응 종료후, 반응 혼합물을 감압 농축하였다. 반응 농축물을 실리카겔 컬럼 크로마토그래피 (Me0H/DCM=1/10)로 정제하여 노란색 고체의 화합물1,2,4-triazine-3-yl)amino)piperidine-1-yl)-N-methylacetamide

Methyl (R)-2-(3-((6-(4-hydroxybenzo［b］thiophene-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine— 1—yl)acetate (50 mg, 0.12 mmol) 33% After adding to methylamine solution (33% MeNH2 in ethanol, 5 ml) and dissolving, it was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain a yellow solid compound.

67 (39 mg, 79.7%) was obtained.

¹ H NMR (400MHz, CDCls) 8 11.42 (br, 1H) , 7.51 (dd, J = 5,2 Hz, 0.4

Hz, IH), 7.45 (dd, J = 8.4 Hz, 0.8 Hz, IH), 7.39-7.34 (m, 2H), 7.06 (br, IH),

4.29 (br, IH), 3.04 (s, 2H), 2.97-2.90 (m, IH), 2.86 (d, J = 4.8 Hz, 2H),

2.64 (s, 3H), 2.54-2.44 (m. 2H) , 1.92-1.83 (m, 2H) , 1.75-1.65 (m, 6H)； LC/MS：m/z 413.1 (M+H)+(ES). Example 76：(R)-5-(3-((1-((1-hydroxycyclopropyl)methyl)piperidine ~

3 -yl)amino)-5 -methyl-1 , 2 , 4 -triazine-6 -yl)benzo [b]thiophene-4 -ol

[Step 1] Synthesis of compound Bl Under nitrogen atmosphere, (R)-1-((3-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)methyl)cyclopropan-1-ol (133 mg, 0.45 mmol), 2-(4-(methoxymethoxy)benzo[b]thiophen-5-yl)- 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (218 mg, 0.68 mmol), Pd(dppf hCl/DCM (66 mg, 0.09 mmol), potassium carbonate (193 mg, 1.4 mmol) was added to 1,4-dioxane (1,4-di oxane, 0.53 ml) and water (H2O, 0.27 ml) was added. Thereafter, the reaction was stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and magnesium sulfate, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (MeOH/DCM=1/5) to obtain the target compound B1 (127 mg, 62%) as a yellow solid.

^1H NMR (400MHz, Methanol -d ₄ ) 5 7.86 (dd, J = 8.2 Hz, 0.64 Hz, 1H) , 7.69 (d, J = 5.5 Hz, IH) , 7.57 (dd, J = 5.6 Hz, 0.6 Hz, IH) , 7.37 (d, J = 8.2 Hz, IH), 5.52 (s, IH) , 5.01 (s, 2H) , 4.22 (br, IH) , 3.60-3.57 (m, 2H), 3.37 (s, 3H), 3.13 (s, 3H) , 3.10 (br, IH) , 2.77 (br, IH) , 2.71-2.61 (m, 2H) , 2.31 (s, 3H), 1.99-1.96 (m, IH) , 1.92-1.80 (m, IH) , 1.76-1.70 (m, IH) , 1.53- 1.51 (m, IH)； LC/MS： m/z 456.2 (M+H)+(ES).

[Step 2] Synthesis of compound 76

(R)- 1-((3- ((6- (4-(methoxymethoxy)benzo [b] thiophen- 5 -yl)- 5 -methyl- 1,2,4- triazin-3 -yl) amino) piperidin- 1-yl) methyl) cyclopropan-1-ol (127 mg, 0.75 mmol) was dissolved in dichloromethane (DCM, 1.6 ml) and methanol (MeOH, 0.8 ml), and 4 N hydrochloric acid solution (4 N HC1 in 1,4-di oxane, 1.9 ml) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound 76 (52 mg, 47%) as a yellow solid. ^1H NMR (400MHz, Methanol -d ₄ ) 5 7.62 (dd, J = 5.6 Hz, 1H) , 7.56-7.54 (m, 2H), 7.28 (d, J = 8.4 Hz, IH) , 4.39-4.28 (m, IH) , 4.03-3.99 (m, IH) , 3.54-3.48 (m, IH) , 2.89-2.83 (m, IH) , 2.52-2.51 (m, 3H) , 2.36 (s, 3H) , 1.99- 1.91 (m, 2H), 1.79-1.73 (m, IH) , 1.67-1.63 (m, IH), 1.20-1.17 (m, 3H)； LC/MS： m/z 412.1 (M+H)+(ES). Example 107： 5-(3-(((3R,5R)- 5 -fluoropiperidin- 3 -yl)amino) -5 -methyl-

1,2,4-triazine-6-yl)benzo[b]thiophene-4-ol

[Step 1] Synthesis of compound Cl Methyl (3R, 5R)-3-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)-5-fluoropiperidine-1-carboxylate (82 mg, 0.26 mmol), 2-(4-methoxymethoxy)benzo[b]thiophene-5-yl)- 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (124 mg, 0.39 mmol), Pd(dppf)Cl ₂ (38 mg, 0.05 mmol), potassium carbonate (107 mg, 0.77 mmol) was added to 1.4 -dioxer] (1,4-di oxane, 2 ml) and ethanol (EtOH, 1 ml). The reaction was then stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound C1 (73 mg, 60%) as a brown solid.

^1H NMR (400MHz, Methanol -d ₄ ) 5 7.71 (d, J = 8.0 Hz, 1H) , 7.54 (d, J = 7.2 Hz, IH), 7.43 (d 7 = 7.2 Hz, IH) , 7.24 (d 7 = 8.4 Hz, IH) , 4.87 (s, 2H), 4.14-4.05 (m, 3H) , 3.01 (s, 3H) , 2.76-2.74 (m, IH) , 2.31-2.28 (m, IH) , 2.19 (s, 2H), 1.84-1.67 (m, IH) , 1.13 (t 7 = 7.2 Hz 3H)； LC/MS: m/z 476.1 (M+H)+(ES).

［Step 2］ Synthesis of Compound C2 Compound Cl (73 mg, 0.15 mmol) was dissolved in dichloromethane (DCM, 2 mL) and methanol (MeOH, 1 mL), and then hydrochloric acid solution (4N HC1 in 1,4-di oxane, 0.39 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound C2 (58 mg, 89%) as a light-colored solid.

^1H NMR (400MHz, Methanol- _{d 4} ) 5 7.62 (d, J = 5.6 Hz, IH) , 7.56-7.54 (m, 2H), 7.28 (d, J = 8.0 Hz, IH) , 4.44-4.38 (m, 2H) , 4.30-4.17 (m, 2H) , 3.73 (s, 2H), 2.97-2.88 (m, IH) , 2.45-2.36 (m, 4H) , 2.00-1.81 (m, IH) , 1.84- 1.67 (m, IH), 1.31-1.22 (m, 3H)； LC/MS: m/z 432.1 (M+H)+(ES).

[Step 3] Synthesis of compound 107 Compound C2 (58 mg, 0.13 mmol) was dissolved in ethanol (EtOH, 3 mL), and 2 M sodium hydroxide aqueous solution (0.1 mL, 6.5 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and magnesium sulfate, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound 107 (36 mg, 74%) as a yellow solid.

108 (R)- 6 -클로로- 5 -메틸- N- (1-프로필피페리딘- 3 -일)- 1 , 2 , 4 -트리아진- 3 -아민 ^1H NMR (400MHz, Methanol -d ₄ ) 5 7.62 (d, J = 0.8 Hz, 1H) , 7.61-7.53 (m, 2H), 7.28 (d, J = 8.0 H, IH) , 4.44-4.36 (m, IH) , 3.15 (t, J = 13.2 Hz, IH), 2.88-2.75 (m, IH), 2.57 (t, J = 10.8 Hz, IH), 2.50-2.34 m, 4H), 1.97- 1.80 (m, IH); LC/MS: m/z 360.0 (M+H)+(ES). Example 108: (R)-6-(Benzo[b]thiophene-5-yl)-5-methyl-N-(l-propylpiperidine-3-y1)-1,2,4-triazin-3-amine

108 (R)- 6 -Chloro- 5 -methyl- N - (1-propylpiperidin- 3 -yl)- 1 , 2 , 4 -triazin- 3 -amine

(51 mg, 0.19 mmol), benzo［b］thiophene-5-ylboronic acid (52 mg, 0.29 mmol), Pd(dppf)C12 (29 mg, 0.04 mmol), potassium carbonate (79 mg, 0.57 mmol) were added to 1,4-dioxane (1,4-di oxane, 0.3 ml) and water (EbO, 0.1 ml). The reaction mixture was then The mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and magnesium sulfate, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Me0H/DCM=1/10) to obtain the target compound 108 (39 mg, 56%) as a brown solid.

¹ H NMR (400MHz, Methanol -d ₄ ) 5 7.73 (m, 2H) , 7.65 (s, 1H) , 6.99 (t,

J = 72.8 Hz, IH), 4.20 (m, IH), 3.09 (m, IH), 2.77 (m, IH), 2.35 (s, 3H),

2.26 (s, 3H), 2.18-2.14 (m, 2H), 2.05-2.03 (m, IH), 1.89-1.83 (m, IH), 1.78-

1.67 (m, IH), 1.50-1.41 (m, IH); LC/MS: m/z 368.2 (M+H)+(ES).

<Experimental Example> Experimental Example 1: ELISA for interleukin- lg (IL- 1(3) Mouse cell line J774A.1 (ATCC) was cultured in DMEM medium [DMEM (Hyclone) + 10% fetal bovine serum (Hyclone) + 1% penicillin-streptomycin (Hyclone)]. Human cell line THP-1 (ATCC) was cultured in RPMI medium [RPMI (Hyclone) + 10% fetal bovine serum (Hyclone) + 1% penicillin-streptomycin (Hyclone) + 0.05 mM 2-mecaptoethanol].

J774A.1 cells were seeded at a density of 100,000 cells/well in a 96-well plate (tissue culture plate, 96 well, Falcon), treated with LPS (Sigma) (2 ug/ml) for 4 hours, and then treated with each of the compounds of the present invention (0.001 to 10,000 nM) for 30 minutes. Afterwards, inflammasome was induced by treating with ATP (Sigma) (5 mM) for 1 hour.

THP-1 cells were seeded at a density of 50,000 cells/well in a 96-well plate (tissue culture plate, 96 well, Falcon), treated with LPS (sigma) (2 ug/ml) for 4 hours, and then treated with each of the compounds of the present invention (0.001 to 10,000 nM) for 30 minutes. Thereafter, inflammasomes were induced by treatment with nigericin (sigma) (5 uM).

IL-ip was measured using an ELISA kit (Invitrogen) according to the manufacturer's instructions, and absorbance was measured at 450 nm using a spectrophotometric microplate reader (BioTek, Synergy H4). IC50 values were calculated based on inflammasome-induced and non-induced samples. The results are shown in Table 11 below.

상기 표 11에서 확인할 수 있듯이, 본 발명의 화합물은 인플라마좀 억제 활성을 나타낸다. 실험예 2： CYP(Cytrochrome P450)의 활성 저해 능력 평 7} 본 발명의 화합물의 CYP( Cytochrome P450)에 대한 활성 저해 능력을 평가하기 위하여, 사람에서 약물대사에 중요하게 관여하는 것으로 알려진, CYP3A4 및 CYP2C9를 대상으로 본 발명의 화합물의 약물대사 효소에 대한 억제활성을 평가하였다. 구체적으로, CYP3A4 및 CYP2C9의 억제 활성 분석은 Invitrogen (P2861, P2858) kit를 사용하였다. 상기 Invitrogen kit의 경우, 본 발명의 화합물은 최종실험농도의 2.5X가되도록 Vivid CYP450 반응 버퍼 (reaction buffer)(lx)에 희석하여 준비하고, P450 BACULOSOMES 시료와 재생 시스템 (Regenerat ion system)(100x)을 Vivid CYP450 반응 버퍼 (lx)에 CYP450 종류에 맞는 농도로 희석하여 준비하였다. U-bottom 96 -웰 플레이트에, 최종실험농도의 2.5X로 준비된 본 발명의 화합물 40 M와 희석한 P450 BACULOSOMES 시료 혼합물 50 씨를 섞어준 후, 20분〜 30분간 전반응 (pre- incubation) 하였다. Vivid CYP450 Substrate와 NADP+(100＞〈 )를 CYP450과 Substrate종류에 맞는농도로 Vivid CYP450 반응 버퍼 (IX)에 희석하여 준비한 후, 전반응이 끝난 플레이트에 Substrate- NADP+ mix 10 M를 넣어주고 30분〜 1시간 동안 반응시켰다. 반응이 끝난 후, 반응물을 흰색 플레이트 (white plate)에 옮겨 마이크로플레이트 리더 (microplate reader)에서 형광 파장을 읽었다 (1A2, 2B6, 2C9, 2C19, 2D6, 3A4 excitation 409 nm, emission 460 nm, 2C8 excitation 485 nm, emission 535 nm) . 실험결과는 (1-(시험물질 형광 값/ Vehicle 형광 값)) X 100%로 계산하여 하기 표 12에 나타내었다. [Table 11]

As can be confirmed in the above Table 11, the compound of the present invention exhibits inflammasome inhibitory activity. Experimental Example 2: Evaluation of CYP (Cytrochrome P450) activity inhibition ability 7} In order to evaluate the activity inhibition ability of the compound of the present invention against CYP (Cytochrome P450), the inhibitory activity of the compound of the present invention against drug metabolizing enzymes, CYP3A4 and CYP2C9, which are known to be importantly involved in drug metabolism in humans, was evaluated. Specifically, the inhibitory activity analysis of CYP3A4 and CYP2C9 was performed using the Invitrogen (P2861, P2858) kit. For the Invitrogen kit above, the compound of the present invention was prepared by diluting it in Vivid CYP450 reaction buffer (lx) to 2.5X the final experimental concentration, and the P450 BACULOSOMES sample and the Regenerat ion system (100x) were prepared by diluting it in Vivid CYP450 reaction buffer (lx) to a concentration appropriate for the CYP450 type. In a U-bottom 96-well plate, 40 M of the compound of the present invention prepared at 2.5X the final experimental concentration and 50 seeds of the diluted P450 BACULOSOMES sample mixture were mixed, and then pre-incubated for 20 to 30 minutes. Vivid CYP450 Substrate and NADP+ (100＞〈 ) were diluted in Vivid CYP450 reaction buffer (IX) at a concentration appropriate for the CYP450 and substrate types, and then Substrate-NADP+ mix 10 M was added to the plate where the pre-reaction was completed and reacted for 30 minutes to 1 hour. After the reaction was completed, the reactants were transferred to a white plate and the fluorescence wavelength was read using a microplate reader (1A2, 2B6, 2C9, 2C19, 2D6, 3A4 excitation 409 nm, emission 460 nm, 2C8 excitation 485 nm, emission 535 nm). The experimental results were calculated as (1-(test substance fluorescence value/vehicle fluorescence value)) X 100% and are shown in Table 12 below.

일반적으로 10 iiM농도의 화합물이 CYP효소의 활성을 50%이상저해하는 경우 해당 CYP효소의 활성에 주의를요하는 물질로 예측한다. 상기 표 12 에서 확인할 수 있듯이, 본 발명의 화합물은 CYP3A4 및 CYP2C9에 대한 저해능이 50%미만인 물질로 확인된다. 실험예 3： In vivo 인터루킨- 13 (IL- 13) 저해 능력 평가 본 발명의 화합물의 인플라마좀활성 저해능력을 평가하기 위하여 다음과 같이 실시하였다. 6- 8주령 C57BL/6J 수컷 마우스에 본 발명의 화합물을 경구 투여한 후 한 시간뒤 saline에 용해한 LPS (Lipopoly saccharide, Invivogen)를 마우스당 50 뚜씩 복강 주사하였다. LPS 주사 두 시간 뒤 saline에 용해한 ATP (Adenosine triphosphate, Sigma)를 마우스당 12.5 mg 씩 복강 주사하여 인플라마좀을 유도하였다. ATP주사 30분후마우스 안와정맥에서 모세관을통하여 채혈한 혈액을 1.7 ml 튜브에 담아 6000g, 4 °C, 5 분 원심분리하여 혈장을 분리하였다. 혈장 내 IL- 1P를 측정하기 위하여 제조사의 지시에 따라 ELISA 키트 (Invitrogen)와 분광 광도계 마이크로 플레이트 판독기를 사용하여 450 nm에서 흡광도를측정하였다. 흡광도로혈장 내 IL- 1P의 농도를산출하여 비히클 (0.5% 메틸셀룰로오스) 대비 IL- 1P가 감소하는 비율로 인플라마좀 저해 효능을 나타내었다. 그 결과를 하기 표 13에 나타내었다. [Table 12]

In general, if a compound at a concentration of 10 iiM inhibits the activity of a CYP enzyme by more than 50%, it is predicted to be a substance requiring attention regarding the activity of the CYP enzyme. As can be confirmed in Table 12 above, the compound of the present invention is confirmed to be a substance with an inhibitory ability of less than 50% for CYP3A4 and CYP2C9. Experimental Example 3: Evaluation of In vivo Interleukin-13 (IL-13) Inhibitory Ability In order to evaluate the inflammasome activity inhibition ability of the compound of the present invention, the following was performed. The compound of the present invention was orally administered to 6-8 week old C57BL/6J male mice, and one hour later, 50 g of LPS (Lipopoly saccharide, Invivogen) dissolved in saline was intraperitoneally injected per mouse. Two hours after the LPS injection, 12.5 mg of ATP (Adenosine triphosphate, Sigma) dissolved in saline was intraperitoneally injected per mouse to induce inflammasome. 30 minutes after the ATP injection, blood was collected through a capillary tube from the orbital vein of the mouse, placed in a 1.7 ml tube, and centrifuged at 6000 g, 4 °C, and 5 minutes to separate plasma. In order to measure IL-1P in plasma, the absorbance was measured at 450 nm using an ELISA kit (Invitrogen) and a spectrophotometer microplate reader according to the manufacturer's instructions. The concentration of IL-1P in plasma was calculated by absorbance, and the inflammasome inhibition efficacy was indicated by the ratio of IL-1P decrease compared to the vehicle (0.5% methylcellulose). The results are shown in Table 13 below.

상기 표 13에서 확인할수있듯이 , 본발명의 화합물은인플라마좀에 의해 유도된 IL- 1P의 방출을 억제할 수 있다. 즉, 본 발명의 화합물은 인플라마좀 억제 활성을 나타낸다. 실험예 4： hERG channel 결합저해능 평가 본 발명의 화합물의 hERG channel에 대한 결합저해 능력을 평가하기 위하 여 Predictor hERG f luorescence polarization assay kit(Invitrogen)을 활용하 여 결합 저해능을 평가하였다. 상기 Invitrogen kit의 경우, hERG tracer 및 membrane fraction은 사용 전 실온에서 녹여 준비하였다. Tracer와 hERG assay buffer를 1：62.5로 희석하였 다. 음성대조군은 hERG assay buffer를 이용하였다. 양성대조군 E- 4031은 hERG assay buffer와 1：25로 희석하여 준비하였다. 본 발명의 화합물은 최종실험농도 의 4x가되도록 hERG assay buffer(lx)에 희석하여 준비하였다. 각각의 희석된실 시예 화합물 용액을 384 -웰 low volume flat bottom microplates에 10 p.1씩 분주 하였다. 각 웰에 membrane fraction을 각각 20 山씩 분주하였다. hERG tracer를 각각 10 山씩 분주하였다. 빛을 차단하고 25°C에서 2시간동안 배양하였다. 마이 크로플레이트 리더 (microplate reader-Bioteck Synergy H4)에서 Excitaion 530nm , Emission 590nm를 이용해 Measure f luorescence polarization (MP)을즉정하였다. 실험 결과는 (화합물 MP -음성대조군 MP)/ (양성대조군 MP -음성대조군 MP) X 100%로 계산하여 하기 표 14에 나타내었다. [Table 13]

As can be confirmed in the above Table 13, the compound of the present invention can inhibit the release of IL-1P induced by inflammasome. That is, the compound of the present invention exhibits inflammasome inhibition activity. Experimental Example 4: Evaluation of hERG channel binding inhibition ability In order to evaluate the binding inhibition ability of the compound of the present invention to the hERG channel, the binding inhibition ability was evaluated using the Predictor hERG fluorescence polarization assay kit (Invitrogen). In the case of the Invitrogen kit, the hERG tracer and membrane fraction were prepared by melting at room temperature before use. The tracer and hERG assay buffer were diluted 1:62.5. The negative control group used hERG assay buffer. The positive control group E-4031 was prepared by diluting 1:25 with hERG assay buffer. The compound of the present invention was prepared by diluting it in hERG assay buffer (lx) to 4x the final experimental concentration. Each diluted chamber The compound solution was dispensed into 384-well low volume flat bottom microplates, 10 μl each. The membrane fraction was dispensed into each well, 20 μl each. The hERG tracer was dispensed into each well, 10 μl each. The plates were blocked from light and incubated at 25°C for 2 hours. The fluorescence polarization (MP) was measured using Excitation 530 nm and Emission 590 nm in a microplate reader (microplate reader-Bioteck Synergy H4). The experimental results are shown in Table 14 below, calculated as (compound MP - negative control MP) / (positive control MP - negative control MP) X 100%.

일반적으로 10 11M농도의 화합물이 hERG inhibition 50% 이상 저해하는 경우, hERG K⁺ CHANNEL저해에 의한심장독성 유발물질로판단한다. 상기 표 14에서 확인할 수 있듯이 , 10 iiM농도의 본 발명의 화합물에서 저해율이 50%미만으로나타나 hERG K⁺ CHANNEL결합에 의한심장독성 유발에 대해 안전한 것으로판단된다. 실험예 5： NASH효능평가 화합물의 NASH저해 효능을알아보기 위하여 다음과같이 실시한다. 5주령 수컷 C57BL/6J 마우스는 표준 조건 (24 °C, 50 %습도, 12： 12 명암사이클) 하에서 수용되었으며 정상사료와음수로 일주일의 순화기간을가진다. 마우스에 NASH를 유발하기 위하여 마우스에 MCD (Methionine-Chol ine Deficient) 식이를 4주 동안 급여하였으며 이후 MCD식이 급여와동시에 비히클, 양성 대조군약물과본발명의 화합물을 4주동안경구 투여한다. 연구마지막날 아이소프렌 용액으로마우스를 마취시킨 뒤 복대정맥을 통해 혈액을 수집하고 C0₂ 질식으로 마우스를 희생시켜 간을 수집한다. 채혈한혈액은 1.7 ml 튜브에 담아 6000g, 4 °C , 5분 원심분리하여 혈장을 분리하였으며 혈장과 혈액생화학분석기를 이용하여 ALT, AST등 간수치와 혈액 내 중성지방 농도를 검사한다. 간은 포르말린 용액에 즉시 처리하여 추후 염색을 진행한 뒤 섬유화 정도를 판단한다. 이상, 본 발명을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한구체적 기술은 단지 바람직한실시예일뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. [Table 14]

In general, if a compound at a concentration of 10 11 M inhibits hERG inhibition by more than 50%, it is determined to be a substance that causes cardiotoxicity due to hERG K ⁺ CHANNEL inhibition. As can be confirmed in Table 14 above, the inhibition rate of the compound of the present invention at a concentration of 10 ii M is less than 50%, so it is determined to be safe with respect to inducing cardiotoxicity due to hERG K ⁺ CHANNEL binding. Experimental Example 5: To determine the NASH inhibitory efficacy of a compound for evaluating NASH efficacy, the following procedure was conducted. Five-week-old male C57BL/6J mice were housed under standard conditions (24 °C, 50% humidity, 12:12 light/dark cycle) and given a one-week acclimation period with normal feed and water. In order to induce NASH in the mice, the mice were fed an MCD (Methionine-Chol ine Deficient) diet for 4 weeks, and thereafter, the vehicle, positive control drug, and the compound of the present invention were orally administered for 4 weeks simultaneously with the MCD diet. On the last day of the study, the mice were anesthetized with an isoprene solution, and blood was collected through the abdominal vena cava, and the mice were sacrificed by C0 ₂ asphyxiation to collect the liver. The collected blood was placed in a 1.7 ml tube and centrifuged at 6000 g, 4 °C, for 5 minutes to separate the plasma. ALT, AST, and other liver function tests and the concentration of neutral fat in the blood were performed using a plasma and blood biochemistry analyzer. The liver was immediately treated with a formalin solution and stained later to determine the degree of fibrosis. While the present invention has been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereby. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims

【Scope of Claim】 【Claim 1】 A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1]

In the above chemical formula 1, two of R ₁ to R ₄ , which are adjacent to each other, form a ring together with the atoms to which they are attached, and the remaining two are each independently H, halogen, C1-C5 alkyl, 0-（Cl-C5 alkyl）, C1-C5 haloalkyl or CN, wherein the ring is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of the groups of cycloalkyl, heterocycloalkyl or heteroaryl may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl） or CN, and wherein, when R ₁ and R ₂ form a ring, the ring is heterocycloalkyl or heteroaryl including one or more heteroatoms independently selected from the group consisting of N and S, R ₅ is H, C1-C5 alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, Heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)-cycloalkenyl, (C1-C5 alkyl)-cycloalkynyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkenyl, (C1-C5 alkyl)-heterocycloalkynyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)-N（R _x ）（R _y ）, (C1-C5 alkyl)-CN or (C1-C5 alkyl)-O（R _Z ）, and One or more hydrogens of R ₅ may be independently substituted with R _A , and R _A is selected from the group consisting of halogen, OH, CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)-cycloalkenyl, (C1-C5 alkyl)-cycloalkynyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkenyl, (C1-C5 alkyl)-heterocycloalkynyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)-N(R _x )(R _y ), (C1-C5 alkyl)-CN, (C1-C5 alkyl)-O(R _Z ), C(=O)R ₁ or (C1-C5 alkyl)-C(=O)R _m , One or more hydrogens of R _A can be independently substituted with R _B , wherein R _B is halogen, CN, C1-C5 alkyl, C1-C5 haloalkyl, N（R _x ）（R _y ）, O（R _Z ）, C（=O）R ₁ or S（=0） ₂ R _n , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, and R ₁ , R m and R _n are each independently H, OH, C1-C5 alkyl, 0-（Cl- C5 alkyl）, N（R _a ）（R _b ） or (C1-C5 alkyl） - N（R _c ）（R _d ）, wherein R _a , R _b , R _c and R _d are each Independently H, C1-C5 alkyl or C1-C5 haloalkyl, R ₆ is H, OH, 0-CC1-C5 alkyl) or C1-C5 haloalkyl, R ₇ is H, C1-C5 alkyl or C1-C5 haloalkyl, and halogen is F, Cl, Br or I. 【Claim 2】 In claim 1, the compound represented by the chemical formula 1 is a compound represented by the following chemical formula 1a, a compound represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1a]

In the above chemical formula 1a, A is a heterocycloalkyl or heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and , and one or more groups of A are each independently halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or can be substituted with ash, R ₃ and R ₄ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl), C1- C5 haloalkyl or CN, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. 【Claim 3】 In claim 1, the compound represented by the chemical formula 1 is a compound represented by the following chemical formula 1b, a compound represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1b]

In the above chemical formula 1b, A is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more groups of A may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or oxy, and R ₁ and R ₄ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl), C1- C5 haloalkyl or CN, R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. 【Claim 4】 In claim 1, the compound represented by the chemical formula 1 is a compound represented by the following chemical formula 1c, a compound represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1c]

In the above chemical formula 1C, A is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of A may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl) or CN, and R ₁ and R ₂ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl) or C1- C5 haloalkyl or CN, R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. 【Claim 5】 In claim 1, the compound represented by the chemical formula 1 is a compound represented by the following chemical formula 1a-1, a compound represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1a-1]

In the above chemical formula 1a-1, W ₁ and W ₂ are each independently CH, CH ₂ , N, NH or S, R _x is H, halogen, C1-C5 alkyl, C1-C5 haloalkyl, 0H, O-（C1-C5 alkyl）, or CN, and R _y and R ₄ are each independently H, halogen, C1-C5 alkyl, 0-CC1-C5 alkyl）, C1- C5 haloalkyl or CN,

are each independently a single bond or a double bond, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. 【Claim 6】 In claim 1, the compound represented by the chemical formula 1 is a compound represented by the following chemical formula 1a-2 or chemical formula 1a-3, a compound represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1a-2]

[Chemical formula 1a-3]

In each of the above chemical formula 1a-2 or chemical formula 1a-3, R ₃ and R ₄ are each independently H, halogen, C1-C5 alkyl, C1-C5 haloalkyl, 0- (C1-C5 alkyl) or CN, and R ₅ , R ₆ , R ₇ and halogen are the same as defined in the above chemical formula 1. 【Claim 7】 In claim 1, R ₁ to R ₄ , two of which are adjacent to each other form a ring together with the atoms to which they are attached, and the remaining two are each independently H, halogen, C1-C5 alkyl, 0-（Cl-C5 alkyl）, C1-C5 haloalkyl or CN, wherein the ring is cycloalkyl, heterocycloalkyl or heteroaryl, and one or more of the groups of cycloalkyl, heterocycloalkyl or heteroaryl may be independently substituted with halogen, C1-C5 alkyl, C1-C5 haloalkyl, OH, 0-CC1-C5 alkyl） or CN, and wherein when R ₁ and R ₂ form a ring, the ring is heterocycloalkyl or heteroaryl including one or more heteroatoms independently selected from the group consisting of N and S, R ₅ is H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)-N (R _x ) (R _y ) or (C1-C5 alkyl)-0 (R _z ), One or more hydrogens of R ₅ may be independently substituted with R _A , and R _A is halogen, OH, CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, （C1-C5 alkyl）- Cycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl) - N(R _x )(R _y ), (C1-C5 alkyl)- O(R _Z ), C(=O)R ₁ or (C1-C5 alkyl) - C(=O)R _m , One or more hydrogens of R _A can be independently substituted with R _B , wherein R _B is halogen, CN, C1-C5 alkyl, C1-C5 haloalkyl, N(R _x )(R _y ), O(R _Z ), C(=O)R ₁ or S(=0) ₂ R _n , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, R ₁ , R m and R _n are each independently H, OH, C1-C5 alkyl, 0- (Cl- C5 alkyl), N(R _a )(R _b ) or (C1-C5 alkyl) - N(R _c )(R _d ), wherein R _a , R _b , R _c and R _d are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, R ₆ is H, OH or O-(C1-C5 alkyl), A compound represented by formula 1, wherein R ₇ is H, C1-C5 alkyl or C1-C5 haloalkyl, and halogen is F or Cl, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Claim 8】 In claim 1, R ₁ to R ₄ , two of which are adjacent to each other form a ring together with the atoms to which they are attached, and the remaining two are each independently H, halogen or C1-C5 alkyl, wherein the ring is cycloalkyl, heterocycloalkyl or heteroaryl, One or more of cycloalkyl, heterocycloalkyl or heteroaryl may be independently substituted with halogen, C1-C5 haloalkyl or 0-CC1-C5 alkyl, wherein when R ₁ and R ₂ form a ring, the ring is heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and S, R ₅ is C1-C5 alkyl, cycloalkyl, heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-heteroaryl, (C1-C5 alkyl)- N(R _x )(R _y ) or (C1-C5 alkyl)- O(R _Z ), One or more hydrogens of R ₅ may be independently substituted with R _A , wherein R _A is halogen, OH, C1-C5 alkyl, C2-C5 alkynyl, C1-C5 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)- O(R _Z ), C(=O)R ₁ or (C1-C5 alkyl) - C(=O)R _m , One or more hydrogens of R _A can be independently substituted with R _B , wherein R _B is halogen, CN, C1-C5 alkyl, O(R _Z ), C(=O)R ₁ or S(=O) ₂ R _n , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, and R ₁ , R _m and R _n are each independently OH, C1-C5 alkyl, 0-CC1-C5 alkyl) or N(R _a )(R _b ), wherein R _a and R _b are each independently H or C1-C5 alkyl, R ₆ is H, 0H or 0-CC1-C5 alkyl), A compound represented by the chemical formula 1, wherein R ₇ is C1-C5 alkyl or C1-C5 haloalkyl, and halogen is F or Cl, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Acceptable salt. 【In claim 1, R ₁ to RD are two of which are adjacent and form a ring together with the atoms to which they are attached, and the remaining one is shown, wherein the ring is heteroaryl containing one or more heteroatoms independently selected from the group consisting of N and S, R ₄ is visible, R ₅ is C1-C5 alkyl, cycloalkyl, heterocycloalkyl, (C1-C5 alkyl)-heterocycloalkyl, (C1-C5 alkyl)-aryl, (C1-C5 alkyl)-N(R _x )(R _y ) or (C1-C5 alkyl)- 0(R _z ), One or more hydrogens of R ₅ may be independently substituted with R _A , wherein R _A is halogen, OH, C1-C5 alkyl, C1-C5 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, (C1-C5 alkyl)-cycloalkyl, (C1-C5 alkyl)- 0(R _z ), C(=0)R ₁ or (C1-C5 alkyl) - C(=0)R _m , One or more hydrogens of R _A may be independently substituted with R _B , wherein R _B is halogen, C1-C5 alkyl, 0(R _z ) or C(=0)R ₁ , wherein R _x , R _y and R _z are each independently H, C1-C5 alkyl or C1-C5 haloalkyl, and R ₁ , R _m and R _n are each independently OH, C1-C5 alkyl, O-CC1-C5 alkyl) or N(R _a )( R _b ), wherein R _a and R _b are each independently C1-C5 alkyl, R ₆ is H, 0H or 0-（Cl- C5 alkyl）, A compound represented by chemical formula 1, wherein R ₇ is C1-C5 alkyl and halogen is F, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Claim 10】 A compound described in the table below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

【Claim 11】 A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Claim 12】 A pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is for the prevention or treatment of a disease associated with NLRP3 activity. 【Claim 13】 A pharmaceutical composition according to claim 12, wherein the NLRP3 activity-related disease comprises at least one disease selected from inflammation, autoimmune disease, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, ocular disease, skin disease, lymphatic pathology, psychological disorder, graft-versus-host disease, allodynia, wounds, and scars. 【Claim 14】 A method for preventing or treating a disease associated with NLRP3 activity, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Claim 15】 Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the prevention or treatment of a disease associated with NLRP3 activity. 【Claim 16】 Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a disease associated with NLRP3 activity.