Novel compound and uses thereof

Abstract

The present invention provides a novel compound and a pharmaceutical composition comprising same for preventing or treating diseases associated with a reduction in Sox9 expression. Accordingly, the diseases associated with a reduction in Sox9 expression can be effectively prevented or treated.

Description

Novel compounds and their uses

[0001] The present invention relates to a novel compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and its use for the prevention or treatment of diseases associated with decreased expression of SOX9.

[0002] Osteoarthritis (OA), also known as degenerative arthritis, is a disease that currently affects more than 7% of the global population (approximately 528 million people). Conventional treatments for OA primarily involve joint replacement surgery or pain relief with chondroprotectors like hyaluronic acid and anti-inflammatory drugs. However, the incidence of OA is increasing worldwide due to the aging population, necessitating the development of treatments that address more than simple pain relief. One of the contributing factors to the development of OA is the progressive loss of cartilage, resulting from the destruction of articular cartilage tissue caused by dysregulation of enzymes in the anabolic and catabolic pathways of articular cartilage proteins. Therefore, research is underway to develop disease-modifying OA drugs (DMOADs) that target these regulatory factors and thereby inhibit the progression of OA. The recently developed Lorecivivint (SM04690) is an example of an OA DMOAD.

[0003] SOX9 (SRY-Box Transcription Factor 9), a transcription factor that is one of the atypical proteins that plays a key role in regulating the expression of extracellular matrix genes in cartilage cells, is known to regulate the expression of cartilaginous extracellular matrix genes such as collagen required for bone joints. In particular, it was confirmed that the expression and transcriptional activity of SOX9 were reduced in a group of osteoarthritis patients, and it was observed that the expression levels of SOX9 and target proteins were significantly lowered depending on the severity of the patient. One of the mechanisms that regulates the activity of transcription factors is the aggregation of transcription factors. As aggregation is induced, transcription factor aggregates can regulate gene expression. That is, when the aggregation of SOX9 transcription factors is induced, the expression and transcriptional effect of SOX9 can be increased through the aggregates.

[0004] Therefore, research and development of DMOADs that can directly treat osteoarthritis by increasing SOX9 transcription efficiency by inducing aggregation of SOX9 transcription factors is required.

[0005] One object of the present invention is to provide a novel compound capable of inducing aggregation of SOX9 transcription factor, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0006] One object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease associated with reduced expression of SOX9 using a novel compound capable of inducing aggregation of the SOX9 transcription factor, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0007] Each description and embodiment disclosed in this specification may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this specification fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific descriptions described below.

[0008] One aspect of the present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0009] [Chemical Formula 1]

[0010]

[0011] In the above chemical formula 1, Y 1 and Y 2 One of them is N, and the other is S, O, or NR a1 am.

[0012] In the above chemical formula 1, X 1 and X 2 are each independently O, S or NR a2 am.

[0013] In the above chemical formula 1, U is NR n2 , a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms N, or these linked to each other.

[0014] In the above chemical formula 1, Z 1 Silver C 1-6 It is alkylene.

[0015] In the above chemical formula 1, Z 2 is a direct bond, C 1-6 alkylene, -NR n3 A 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms selected from CO- or N, O and S.

[0016] In the above chemical formula 1, R a1 and R a2 are each independently H or C 1-6 It's alkyl.

[0017] In the above chemical formula 1, R n1 , R n2 and R n3 are each independently H or C 1-6 It's alkyl.

[0018] In the above chemical formula 1, Z 2Go C 1-6 In the case of alkylene, any carbon of the alkylene can be halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, cyano, nitro, oxo or C 6-12 It is optionally substituted with aryl.

[0019] In the above chemical formula 1, Z 3 is a direct bond or -C(=O)-.

[0020] In the above chemical formula 1, ring A is a fused benzoheterocyclyl in which a benzene ring is fused to a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N or S, or a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N or S.

[0021] In the above chemical formula 1, ring A is 1 to 3 R A is arbitrarily replaced with .

[0022] R A is halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Selected from the group consisting of alkyl, cyano, nitro and oxo.

[0023] In the above chemical formula 1, ring E is a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- to 7-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl.

[0024] In the above chemical formula 1, ring E is 1 to 3 R E is arbitrarily replaced with .

[0025] R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; Carboxy; C 1-6 Alkoxycarbonyl; carbamoyl; C 1-6 Alkylcarbamoyl; di(C 1-6 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-6 Selected from the group consisting of alkyl.

[0026] In the above chemical formula 1, Y 1 and Y 2 One of them is N, and the other is S, O, or NR a1 It can be. For example, Y 1 is N, and Y 2 is S, O or NR a1 Either this or Y 2 is N, and Y 1 is S, O or NR a1may be. In some implementations, Y 1 and Y 2 One of them may be N and the other may be S or O. For example, the above Y 1 is N, and the above Y 2 is S or the above Y 1 is S or O, and the above Y 2 can be N.

[0027] In the above chemical formula 1, X 1 and X 2 are each independently O, S or NR a2 It could be. X 1 and X 2 may be identical or different. For example, X 1 and X 2 Each can be O.

[0028] In the above chemical formula 1, U is NR n2 , a 5-7 membered heterocyclyl containing 1 to 3 heteroatoms N, or these may be linked to each other. In some embodiments, U is NR n2 , a 5- or 6-membered heterocyclyl containing one or two heteroatoms N, or these may be linked to each other.

[0029] In some implementations, U is NR n2 ; piperidinediyl; piperazinediyl; or piperidinediyl or piperazinediyl to NR 2n These can be selected from the interconnected ones.

[0030] In some implementations, U is NR n2 And may be selected from the group consisting of the following structures. Among the following structures * 1 In chemical formula 1, -C(=X 2 ) is connected to the carbon atom of * 2 is Z 2 can be connected to.

[0031]

[0032] The above R a1 and R a2 are each independently H or C 1-6 may be alkyl. In some embodiments, R a1 and R a2 are each independently H or C 1-4 It can be alkyl. For example, R a1 and R a2 can each independently be H or methyl.

[0033] In the above chemical formula 1, R n1 , R n2 and R n3 are each independently H or C 1-6 may be alkyl. In some embodiments, R n1 , R n2 and R n3 are each independently H or C 1-4 It can be alkyl. For example, R n1 , R n2 and R n3 can each independently be H or methyl.

[0034] In the above chemical formula 1, Z 1 Silver C 1-6 may be alkylene. In some embodiments, Z 1 Silver C 1-4 may be alkylene. In some embodiments, Z 1 may be a straight-chain alkylene. In some embodiments, Z 1 may be methylene, ethylene, propylene, butylene, pentylene or hexylene.

[0035] In the above chemical formula 1, Z 2 is a direct bond, C 1-6 alkylene, -NR n3 CO- or 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S. The above -NR n3 CO- is * 3 -NRn3 CO-* 4 It can be, * 3 is connected to U in chemical formula 1, * 4 can be connected to ring E. In some implementations, Z 2 is a direct bond, C 1-4 alkylene, -NR n3 CO- or a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S. For example, Z 2 can be a direct bond, methylene, ethylene, propylene, butylene, -NHCO- or dithiazolediyl.

[0036] In the above chemical formula 1, Z 2 Go C 1-6 In the case of alkylene, any carbon of the alkylene can be halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, cyano, nitro, oxo or C 6-12 may be optionally substituted with aryl. In some embodiments, any carbon of the alkylene is carboxy, C 1-6 Alkoxycarbonyl or C 6-12 may be optionally substituted with aryl. For example, any carbon of alkylene may be replaced with methoxycarbonyl or phenyl. Z 2 The carbon atom adjacent to ring E in the alkylene may be substituted.

[0037] In some embodiments, U is a 5-7 membered heterocyclyl or NR containing 1 to 3 heteroatoms N. n2 When 5- to 7-membered heterocyclyls containing 1 to 3 heteroatoms N are linked to each other, Z 2is a direct bond or C 1-6 It may be alkylene.

[0038] In the above chemical formula 1, Z 3 can be a direct bond or -C(=O)-.

[0039] In some embodiments, the compound represented by the above formula 1 may be selected from a compound represented by the following formula 2 or formula 3.

[0040] [Chemical Formula 2]

[0041]

[0042] [Chemical Formula 3]

[0043]

[0044] In the above chemical formulas 2 and 3, Z 1 , Z 2 , X 1 , X 2 , U, R n1 , R n2 , ring A and ring E are as defined in the above chemical formula 1.

[0045] In some embodiments, Y of formula 2 1 and Y of chemical formula 3 2 can each independently be S or O.

[0046] In the above chemical formula 1, ring A may be a fused benzoheterocyclyl in which a benzene ring is fused to a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N or S, or a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N or S. In some embodiments, ring A can be a 6- to 12-membered aryl, a partially unsaturated 9- or 10-membered bicyclic carbocyclyl, a 6- to 10-membered heteroaryl comprising 1 or 2 heteroatoms selected from O, N or S, a 5- to 7-membered heterocyclyl comprising 1 or 2 heteroatoms selected from O, N or S, or a fused benzoheterocyclyl in which a benzene ring is fused to a 5- to 7-membered heterocyclyl comprising 1 or 2 heteroatoms selected from O, N or S.

[0047] In some embodiments, ring A can be phenyl, biphenylyl, tetrahydronaphthyl, pyranyl, pyranonyl(oxopyranyl), benzopyranyl, or benzopyronyl. The benzopyronyl can be coumarinyl.

[0048] In some implementations, ring A is , or and the above ring A comprises 1 to 3 R A can be arbitrarily replaced with .

[0049] In some implementations, Z 3 is a direct bond, and ring A is , or Either; or

[0050] Z 3 is -C(=O)-, and ring A is or It could be.

[0051] In the above chemical formula 1, ring A is 1 to 3 R A can be arbitrarily substituted with R A is halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 may be selected from the group consisting of alkyl, cyano, nitro and oxo. In some embodiments, R A is halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 It can be selected from the group consisting of alkyl and oxo.

[0052] In some implementations, R A is halo, hydroxy, C 1-4 Alkoxy, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 It can be selected from the group consisting of alkyl, cyano, nitro and oxo.

[0053] In some implementations, R A may be selected from the group consisting of F, Cl, Br, hydroxy, methoxy, dimethylamino, methyl or oxo.

[0054] In some embodiments, ring A may be selected from the following chemical structures:

[0055]

[0056]

[0057] .

[0058] In the above chemical formula 1, ring E may be a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- to 7-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl. In some embodiments, ring E can be a 6- to 12-membered aryl, a partially unsaturated 9- to 12-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 or 2 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl comprising 1 or 2 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- to 7-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from O, N or S is fused to phenyl. In some embodiments, ring E can be a 6- to 10-membered aryl, a partially unsaturated 9- or 10-membered bicyclic carbocyclyl, a 5- to 10-membered heteroaryl comprising 1 or 2 heteroatoms selected from O, N or S, a 5- to 7-membered heterocyclyl comprising 1 or 2 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from O, N or S is fused to phenyl.

[0059] In some embodiments, ring E can be phenyl, naphthalenyl(naphthyl), indanyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholinyl, thiomorpholinyl, piperidinyl, hexahydroxypyridazinyl, hexahydroxypyrimidinyl, piperazinyl, indolyl, indazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, or benzodioxolyl. For example, ring E can be phenyl, naphthalenyl(naphthyl), pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, thiophenyl, morpholinyl, thiomorpholinyl, piperazinyl, indolyl, quinolinyl, or benzodioxolyl.

[0060] In some embodiments, ring E is selected from the following chemical structures; ring E comprises 1 to 3 R E can be arbitrarily replaced with .

[0061]

[0062] .

[0063] In the above chemical formula 1, ring E is 1 to 3 R E can be arbitrarily substituted with R E If there are two or more, each R E may be identical or different.

[0064] R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; Carboxy; C 1-6 Alkoxycarbonyl; carbamoyl; C 1-6 Alkylcarbamoyl; di(C 1-6 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-6 Alkoxy, amino, C1-6 Alkylamino, di(C 1-6 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-6 may be selected from the group consisting of alkyl. In some embodiments, R E is halo; hydroxy; C 1-4 Alkoxy; Amino; C 1-4 Alkylamino; di(C 1-4 Alkyl)amino; Carboxy; C 1-4 Alkoxycarbonyl; carbamoyl; C 1-4 Alkylcarbamoyl; di(C 1-4 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-4 Alkoxy, amino, C 1-4 Alkylamino, di(C 1-4 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-4 It can be selected from the group consisting of alkyl.

[0065] In some implementations, R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 may be selected from the group consisting of hydroxyalkyl. In some embodiments, R E is halo; hydroxy; C 1-4 Alkoxy; Amino; C 1-4 Alkylamino; di(C 1-4 Alkyl)amino; halosulfonyl; sulfoxy; C 1-4 Alkylsulfonyl; cyano; nitro; oxo; C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4It can be selected from the group consisting of hydroxyalkyl.

[0066] In some implementations, R E may be selected from the group consisting of methoxy, hydroxy, amino, F, Cl, Br, trifluoromethyl, cyano, hydroxymethyl, methyl, fluorosulfonyl, nitro and oxo.

[0067] In some embodiments, ring E may be selected from the following chemical structures:

[0068]

[0069]

[0070]

[0071] .

[0072] In some embodiments, the compound represented by the above formula 1 may be represented by the following formulae I to III.

[0073] [Chemical Formula I]

[0074]

[0075] In the above chemical formula I, Y 1 is S, O or NR a1 and; R a1 is H or C 1-6 alkyl; R n1 and R n2 are each independently H or C 1-6 Alkyl; Z 4 is a direct bond or C 1-4 is alkylene; R 1 Silver H, Halo, Hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6Alkyl)carbamoyl, cyano, nitro, oxo or C 6-12 It could be Aryl.

[0076] In the above formula I, ring A is a fused benzoheterocyclyl in which a benzene ring is fused to a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 6- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a 5- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S; ring A is 1 to 3 R A is arbitrarily substituted with; R A is halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 It can be selected from the group consisting of alkyl, cyano, nitro and oxo.

[0077] In the above formula I, ring E is a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- to 7-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl; ring E is 1 to 3 R E is arbitrarily substituted with; R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; Carboxy; C 1-6Alkoxycarbonyl; carbamoyl; C 1-6 Alkylcarbamoyl; di(C 1-6 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-6 It can be selected from the group consisting of alkyl.

[0078] [Chemical Formula II]

[0079]

[0080] In the above chemical formula II, Y 2 is S, O or NR a1 and; R a1 is H or C 1-6 alkyl; R n1 and R n2 are each independently H or C 1-6 Alkyl; Z 4 is a direct bond or C 1-4 is alkylene; R 1 Silver H, Halo, Hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, cyano, nitro, oxo or C 6-12 It could be Aryl.

[0081] In the above chemical formula II, ring A 1 is a 6- to 14-membered aryl or a partially unsaturated 9- to 14-membered bicyclic carbocyclyl; Ring A 1 Silver 1 to 3 R A is arbitrarily substituted with; R A is halo, hydroxy, C1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 may be selected from the group consisting of alkyl, cyano, nitro and oxo. In some embodiments, ring A 1 It can be a 6 to 14-membered aryl.

[0082] In the above chemical formula II, ring E is a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N or S, a 5- to 12-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N or S is fused to phenyl; ring E is 1 to 3 R E is arbitrarily substituted with; R E is halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, halosulfonyl, sulfoxy, C 1-6 It can be selected from the group consisting of alkylsulfonyl, cyano, nitro and oxo.

[0083] In some embodiments, the compound represented by Formula 1 may be selected from a compound represented by Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, or Formula IIA.

[0084] [Chemical Formula III]

[0085]

[0086] In the above chemical formula III, U 1is a direct bond or NR n2 and Y 3 and Y 4 At least one of them is N, the rest are CH; Z 5 is a direct bond, C 1-6 alkylene, -NR n3 CO- or 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; R n1 , R n2 and R n3 are each independently H or C 1-6 is alkyl; s can be 0 or 1.

[0087] In the above formula III, ring A may be a fused benzoheterocyclyl in which a benzene ring is fused to a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a 5- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S.

[0088] In the above chemical formula III, ring A is 1 to 3 R A is arbitrarily substituted with; R A is halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 It can be selected from the group consisting of alkyl, cyano, nitro and oxo.

[0089] In the above formula III, ring E may be a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- to 7-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl.

[0090] In the above chemical formula III, ring E is 1 to 3 R E is arbitrarily substituted with; R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; Carboxy; C 1-6 Alkoxycarbonyl; carbamoyl; C 1-6 Alkylcarbamoyl; di(C 1-6 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-6 It can be selected from the group consisting of alkyl.

[0091] [Chemical Formula IA]

[0092]

[0093] [Chemical Formula IB]

[0094]

[0095] [Chemical Formula IC]

[0096]

[0097] [Chemical Formula ID]

[0098]

[0099] [chemical formula IE]

[0100]

[0101] [Chemical formula IIA]

[0102]

[0103] In the above chemical formulas IA, IB, IC, ID, IE and IIA, R A is halo, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 is selected from the group consisting of alkyl, cyano, nitro and oxo; n, m1, m2, o1, o2, p and q are each independently an integer from 0 to 3; the sum of m1 and m2 and o1 and o2 is each 3 or less; Y 1 , Y 2 , R n1 , R n2 , Z 4 , R 1 And ring E is as described in the above chemical formula I and the above chemical formula II.

[0104] In some embodiments, the compound represented by the above formula 1 may be selected from compounds represented by the following formulas:

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] .

[0116] In some embodiments, the compound represented by the above chemical formula 1 can be synthesized according to the following reaction scheme 1.

[0117] [Reaction Formula 1]

[0118]

[0119] In the above reaction formula 1, Y 1 , Y 2 , Z 3 , ring A, X 1 , X 2 , Z 1 , Z 2 , R 1n , U and ring E are as described in the above chemical formula 1.

[0120] Specifically, in step 1 of the above reaction scheme 1, ring A is optionally Z 3 Intermediate b can be synthesized by reacting intermediate a containing a 5-membered heteroarene ring substituted with amino with cyclic intermediate 1. The reaction of step 1 may be carried out under the condition of the presence of an appropriate organic solvent that dissolves intermediate a or intermediate i, or may be carried out in a molten state without using an organic solvent at a temperature higher than the melting point (120°C) of intermediate i. For example, the reaction of step 1 may be carried out at about 120°C to 180°C for 1 to 5 hours.

[0121] In step 2 of the above reaction scheme 1, a compound represented by chemical formula 1 can be prepared by reacting intermediate b with an amine intermediate c containing ring E. Step 2 can be performed under anhydrous conditions, and can be performed using an organic solvent such as dioxin at a temperature of about 80°C to 140°C for 5 to 24 hours.

[0122] The above intermediate a can be synthesized according to the following reaction scheme 2.

[0123] [Reaction Formula 2]

[0124]

[0125] In the above reaction scheme 2, rings A and Z 3 is as described in the above chemical formula 1.

[0126] Specifically, in step 1 of the above reaction scheme 2, a bromoacetyl compound can be synthesized by reacting an acetyl compound containing ring A with an excess of tetrabutylammonium tribromide (CAS: 38932-80-8) in an organic solvent. In the reaction, the organic solvent may be, but is not limited to, CH2Cl2, and the reaction temperature may be about 10°C to 50°C, for example, room temperature.

[0127] In step 2 of the above reaction scheme 2, the obtained product of step 1 and thiourea can be heated in ethanol to obtain intermediate a'. Intermediate a' can be provided as intermediate a of the above reaction scheme 1.

[0128]

[0129] As used herein, the term "halogen" or "halogen atom" refers to an atom belonging to Group 17 of the periodic table. Halogen atoms include F, Cl, Br, I, etc. The term "halo" refers to a halogen substituent.

[0130] The term "alkyl" refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon. The alkyl may be substituted or unsubstituted. The C 1-20 Alkyl is, for example, C 1-15 , C 1-10 , or C 1-6 It may be an alkyl group. The above C 1-6 Alkyl is C 1-5 , C 1-4 , C 1-3 , or C 1-2 It may be an alkyl. The alkyl may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, or n-hexyl.

[0131] The term "haloalkyl" refers to alkyl substituted with one or more halo or halogens, including dihaloalkyl, trihaloalkyl, and the like. "Haloalkyl" may include perhaloalkyl where all hydrogens of the alkyl are replaced with halogens.

[0132] The term "hydroxy" refers to the -OH functional group (hydroxyl group).

[0133] The term "hydroxyalkyl" refers to alkyl substituted with a hydroxy group.

[0134] The term "carbonyl" refers to -C(=O)-.

[0135] The term "alkoxy" refers to an alkyl group bonded to an oxygen atom. C 1-20 Alkoxy is, for example, C 1-15 , C 1-10 , or C 1-6 It may be an alkoxy. The above C 1-6 Alkoxy is C 1-5 , C 1-4 , C 1-3 , or C 1-2 It may be an alkoxy. The alkoxy may be methoxy, ethoxy, propoxy, butoxy, etc.

[0136] The term "alkoxyalkyl" refers to an alkoxy bonded to an alkyl. C 2-20 Alkoxyalkyl is, for example, C 2-15 , C 2-10 , or C 2-6 It may be an alkoxyalkyl. For example, C 2-20 Alkoxyalkyl is (C 1-10 Alkoxy)-(C 1-10 alkyl), (C 1-6 Alkoxy)-(C 1-6 alkyl), etc., and the number of carbon atoms in the alkoxy group and the alkyl group may be the same or different. The above alkoxy may be, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc.

[0137] The term "amino" refers to -NH2.

[0138] The term "amine group" refers to a substituent in which one, two or all three hydrogens of ammonia are replaced by an organic functional group, including primary amines, secondary amines and tertiary amines, and includes an amino group.

[0139] The term “alkylamine” refers to an amine in which one of the H groups of the amino (-NH2) is replaced by an alkyl group.

[0140] The term “di(alkyl)amine” refers to an amine in which both H groups of the amino group (-NH2) are replaced by alkyl groups. The two alkyl groups in a di(alkyl)amine may be the same or different.

[0141] The term "nitro" refers to -NO2.

[0142] The term "cyano", as in -CN, refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

[0143] The term "carboxy" refers to -COOH. A carboxy salt is the conjugate base of a carboxylic acid.

[0144] The term "alkoxycarbonyl" refers to a monovalent substituent in which the -OH of carboxy is replaced by an alkoxy group. For example, C 1-6 Alkoxycarbonyl is C 1-6 It refers to -C(=O)- substituted with alkyl.

[0145] The term "carbamoyl" refers to -CONH2.

[0146] The term “alkylcarbamoyl” refers to a substituent in which one hydrogen atom of -NH2 in carbamoyl is replaced by an alkyl.

[0147] The term "dialkylcarbamoyl" refers to a substituent in which the two hydrogen atoms of -NH2 in carbamoyl are each replaced by an alkyl group. The two alkyl groups in a dialkylcarbamoyl group may be the same or different.

[0148] The term “sulfonyl” or “sulfonyl” refers to the group -SO2-.

[0149] The term "halosulfonyl" refers to a monovalent substituent, sulfonyl, substituted with a halogen.

[0150] The term "carbocyclyl" refers to a monovalent non-aromatic hydrocarbon ring substituent. Carbocyclyl may be fully saturated or partially unsaturated, and may have a monocyclic structure or a bicyclic or tricyclic structure with a fused, bridged, or spiro structure. For example, a carbocyclyl may be a phenyl group having a saturated heterohexane ring fused thereto, such as tetrahydronaphthyl. A carbocyclyl may be a substituent having 9 to 14 carbon atoms in the ring.

[0151] The term “cycloalkyl” refers to a saturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon group. A cycloalkyl may contain from 3 to 20 carbon atoms, for example from 5 to 10, 3 to 8, or 3 to 6 carbon atoms. A monocyclic cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A bicyclic cycloalkyl may be, for example, bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl. A tricyclic cycloalkyl may be, for example, adamantyl.

[0152] The term “cycloalkane ring” refers to a saturated, non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring. The cycloalkane ring may be a complete (non-radical) functional group of the cycloalkyl. It may contain 3 to 20 carbon atoms, for example, 5 to 10, 3 to 8, or 3 to 6 carbon atoms. The monocyclic cycloalkane ring may be, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.

[0153] The term "aryl" refers to an aromatic hydrocarbon ring group. Aryl includes a hydrocarbon ring group having aromaticity by connecting multiple aryls. The above C 6-30 The aryl of is, for example, C 6-14 , C 6-12 or C 6-10 It can be aryl. The aryl can have a monocyclic structure, or a bicyclic or tricyclic structure with a fused, bridged or spiro structure. The aryl can be phenyl, naphthyl or biphenyl.

[0154] The term "arylalkyl" refers to an alkyl substituted with an aryl.

[0155] The term "aryloxy" refers to an aryl bonded to an oxygen atom.

[0156] The term "heteroaryl" or "heteroarene" refers to a monocyclic or bicyclic aromatic compound or substituent containing one or more heteroatoms and the remaining ring atoms being carbon. The heteroaryl may include a ring group having aromaticity as a whole by substituting oxo (=O), thioxo (=S), etc. on an unsaturated ring atom, even if the ring itself is partially unsaturated. The heteroaryl may contain, for example, 1 to 5, 1 to 3, 1 or 2 heteroatoms, and may contain 5 to 12 ring members. “Heteroaryl” can be, for example, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, oxopyranyl(pyranonyl), benzopyrronyl, coumarinyl, and the like.

[0157] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group containing at least one heteroatom. The heterocyclyl ring group can be a monocyclic ring group, a bicyclic ring group, or a tricyclic ring group. The bicyclic ring group can be a spiro-ring group, a bridged-ring group, or a fused-ring group. The heterocyclyl ring group can contain 3 to 20, 3 to 10, 3 to 8, 3 to 7, 5 to 7, 4 to 6, or 5 to 6 ring atoms. The heteroatoms can be one or more selected from the group consisting of N, O, and S, for example, 1, 2, or 3 heteroatoms. For example, the heterocyclyl may be pyranyl, aziridinyl, oxiranyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, or oxazolidinyl.

[0158] The term “fused benzoheterocyclyl” refers to a substituent in which a benzene ring is fused to a heterocyclyl. The fused benzoheterocyclyl may be a fused heterobicyclic ring group in which two adjacent carbon atoms in the ring of the heterocyclyl are shared with the benzene ring. The fused benzoheterocyclyl may be a 9- to 11-membered fused heterobicyclic ring group in which a benzene ring is fused to a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N, or S. For example, the fused benzoheterocyclyl may include benzopyranyl in which a benzene ring is fused to pyranyl.

[0159] The term "fused heterocycloaryl" refers to a substituent having a heterocyclic ring fused to an aryl. A fused heterocycloaryl may be a fused heterobicyclic ring group in which two adjacent carbon atoms of the heterocyclic ring are shared by the aryl. A fused heterocycloaryl may be a 9- to 7-membered fused heterobicyclic ring group in which a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N, or S is fused to an aryl. For example, a fused heterocycloaryl may include benzodioxolyl, in which a dioxolane ring is fused to phenyl.

[0160] The above heteroatom may be at least one selected from the group consisting of N, O, P, and S. The above heteroatom may be one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0161] The term "substitution" in "substituted or unsubstituted" refers to the introduction of a substituted hydrogen atom in the case where one or more hydrogen atoms in an organic compound are replaced with another atomic group to form a derivative, and "substituent" refers to the introduced atomic group. "Substitution" used herein without limitation of a substituent refers to, for example, a halogen atom, a C1-C substituted with a halogen atom. 20 Alkyl (e.g., CCF3, CHCF2, CH2F, CCl3, etc.), C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, hydroxyl group, -NH2, =NH, nitro, cyano, amidino, hydrazine, hydrazone, carboxyl group or its salt, sulfonyl, sulfamoyl, sulfonic acid group or its salt, phosphoric acid or its salt, C1-C 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, C6-C 20 Aryl, C6-C 20 Arylalkyl, C6-C 20 Heteroaryl, C7-C 20Heteroarylalkyl, C6-C 20 Heteroaryloxy, C6-C 20 Heteroaryloxyalkyl, or C6-C 20 It may mean that it is substituted with heteroarylalkyl, etc.

[0162] The term "isomer" in "stereoisomer" refers to compounds that have the same molecular formula but different ways of connecting or spatially arranging the constituent atoms within the molecule. Isomers include, for example, structural isomers and stereoisomers. The stereoisomers can be diastereomers or enantiomers. Enantiomers are isomers that are not superimposable with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are distinguished as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents are different at the chiral center carbon. Diastereomers are stereoisomers that are not mirror images, and are isomers that arise due to different spatial arrangements of atoms. The above diastereomers can be divided into cis-trans isomers and conformational isomers (or conformers).

[0163] The term "solvate" refers to a compound that is solvated in an organic or inorganic solvent. An example of a solvate is a hydrate.

[0164] The term "salt" refers to inorganic and organic acid addition salts of a compound. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The inorganic acid salt may be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfate. The organic acid salt may be a formate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a besylate, a camsylate, an edicyl salt, a trichloroacetic acid, a trifluoroacetate, a benzoate, a gluconate, a methanesulfonate, a glycolate, a succinate, a 4-toluenesulfonate, a galacturonate, an embronate, a glutamate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, or an aspartate. The above metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.

[0165]

[0166] The compound of the above formula 1 may be an agonist for SOX9 (SRY-Box Transcription Factor 9). SOX9, together with other members of the HMG-box family of DNA binding proteins, recognizes the CCTTGAG sequence and is known to be expressed by proliferation rather than hypertrophic chondrocytes, which are essential for differentiating precursor cells into chondrocytes. The compound of the above formula 1 may induce aggregation of the SOX9 transcription factor, thereby increasing the expression of SOX9. The compound of the above formula 1 may be an aggregation inducer of the SOX9 transcription factor, a SOX9 activator, or an activator.

[0167]

[0168] One aspect of the present invention provides a pharmaceutical composition comprising the compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0169] One aspect of the present invention provides a pharmaceutical composition for preventing or treating a disease associated with decreased expression of SOX9 (SRY-Box Transcription Factor 9), comprising the compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0170] The above compounds, stereoisomers, solvates, pharmaceutically acceptable salts, and SOX9 are as described above.

[0171] The diseases associated with the above-mentioned decrease in SOX9 expression may be due to the inhibition of SOX9.

[0172] In some embodiments, the disease associated with decreased expression of SOX9 may be osteoarthritis and osteoarthritis-related diseases.

[0173] In some embodiments, the osteoarthritis-associated condition may be chondropathia, osteonecrosis, or chronic pain.

[0174] The term "prevention" refers to any action that inhibits the occurrence or delays the onset of a disease associated with SOX9 by administering the pharmaceutical composition. The term "treatment" refers to any action that improves or beneficially changes the symptoms of a disease associated with SOX9 by administering the pharmaceutical composition.

[0175] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used to mean an excipient, diluent, or auxiliary. The carrier may be selected from the group consisting of, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, saline, a buffer such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anticoagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, or combinations thereof.

[0176] The pharmaceutical composition described above may be prepared in any dosage form according to conventional methods. For example, the composition may be formulated as an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule) or a parenteral dosage form (e.g., injection). Furthermore, the composition may be prepared as a systemic dosage form or a topical dosage form.

[0177] In the above pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid preparation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid preparation may further include a lubricant such as magnesium stearate or talc. In the above pharmaceutical composition, the liquid preparation for oral administration may be a suspension, an oral solution, an emulsion, or a syrup. The liquid preparation may include water or liquid paraffin. The liquid preparation may include an excipient such as a wetting agent, a sweetener, a flavoring agent, or a preservative. In the above pharmaceutical composition, the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solvent, suspension, emulsion, lyophilized product, or suppository. The non-aqueous solvent or suspension may contain a vegetable oil or ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, Tween 61, cocoa butter, laurin butter, or glycerogelatin.

[0178] The above pharmaceutical composition comprises a compound according to one aspect, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition. The term "active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (e.g., treatment of a disease associated with decreased expression of SOX9).

[0179] The pharmaceutical composition may comprise an effective amount of a compound according to one aspect, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The term "effective amount" refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need of prevention or treatment. The effective amount can be appropriately selected by a person skilled in the art depending on the cell or subject selected. The preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the subject, the degree of the disease, the drug form, the route and duration of administration, but can be appropriately selected by a person skilled in the art. The effective amount may be about 0.5 μg to about 2 g, about 1 μg to about 1 g, about 10 μg to about 500 mg, about 100 μg to about 100 mg, or about 1 mg to about 50 mg per pharmaceutical composition. However, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt may be administered in divided doses of, for example, about 0.0001 mg / kg to about 100 mg / kg, or about 0.001 mg / kg to about 100 mg / kg, once to 24 times a day, once to 7 times every 2 days to 1 week, or once to 24 times every 1 month to 12 months. In the pharmaceutical composition, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt may be included in an amount of about 0.0001 wt% to about 10 wt%, or about 0.001 wt% to about 1 wt%, based on the total weight of the entire composition.

[0180] Administration may be oral or parenteral. For example, the route of administration may be oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The composition may be administered systemically or locally, and may be administered alone or in combination with other pharmaceutically active compounds.

[0181]

[0182] One aspect of the present invention provides a method for preventing or treating a disease associated with reduced expression of SOX9, comprising administering to a subject the compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0183] The compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SOX9, diseases associated with decreased expression of SOX9, prevention, and treatment thereof are as described above.

[0184] The subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat. The subject may be suffering from, or likely to suffer from, symptoms associated with a disease associated with reduced expression of SOX9.

[0185] The method may further comprise a step of administering to the subject a known effective ingredient having an effect of preventing or treating a disease associated with SOX9. The known effective ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to one aspect, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0186] The route of administration may be oral or parenteral. For example, the route of administration may be oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The pharmaceutical composition may be administered systemically or locally, and may be administered alone or in combination with other pharmaceutically active compounds.

[0187] The preferred dosage of the pharmaceutical composition may vary depending on the patient's condition and weight, the extent of the disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art. The dosage may, for example, be in the range of about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg for adults. The administration may be administered once a day, twice to 24 times a day, once to twice every three days, once to six times a week, once to 10 times every two weeks, once to 15 times every three weeks, once to three times every four weeks, or once to 12 times a year.

[0188]

[0189] One aspect of the present invention provides a compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof for use in preventing or treating a disease associated with decreased expression of SOX9.

[0190] The compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SOX9, diseases associated with decreased expression of SOX9, prevention, and treatment thereof are as described above.

[0191]

[0192] One aspect of the present invention provides the use of a compound, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease associated with decreased expression of SOX9.

[0193] The compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SOX9, diseases associated with decreased expression of SOX9, prevention, and treatment thereof are as described above.

[0194]

[0195] One aspect of the present invention provides the use of a compound according to one aspect, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for preventing or treating a disease associated with decreased expression of SOX9.

[0196] The compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SOX9, diseases associated with decreased expression of SOX9, prevention, and treatment thereof are as described above.

[0197] According to the compound of the present invention and the pharmaceutical composition containing the compound for preventing or treating a disease associated with a decrease in the expression of SOX9, a disease associated with a decrease in the expression of SOX9 can be effectively prevented or treated.

[0198] Figure 1 shows data evaluating the SOX9 transcription effect of an example compound through a luciferase assay.

[0199] Figure 2a is a histogram showing the distribution of SOX9 transcriptional activation effects of the example compounds.

[0200] Figure 2b is a graph showing the transcriptional activation effect of SOX9 depending on the aggregation of the example compound as a box plot.

[0201] Figure 3a is a fluorescence image of SOX9 overexpressing cell lysates treated with compound B8 and compound C9 and measured.

[0202] Figure 3b is a graph measuring the transcriptional activation effect of SOX9 using the luciferase technique.

[0203] Figure 4a is a fluorescence image confirming the degree of SOX9 aggregate formation according to the structure of the drug.

[0204] Figure 4b is a graph measuring the change in the transcriptional activation effect of SOX9 according to the structure of the drug using the luciferase technique.

[0205] Figure 5a is a graph showing the degree of atypicality according to the structure and location of SOX9.

[0206] Figure 5b is a graph showing the degree of SOX9 aggregation induced by drugs according to the SOX9 deletion mutant.

[0207] Figure 5c is a graph showing the degree of drug-induced SOX9 aggregation according to a deletion variant for the atypical region of the C-terminus of SOX9.

[0208] Figure 6 is a graph showing the degree of drug-induced SOX9 aggregation according to substitution of aromatic amino acids at the C-terminus of SOX9.

[0209] Figure 7a is a schematic flowchart illustrating a method for identifying proteins in drug-induced aggregates using SOX9-turboID.

[0210] Figure 7b is a volcano plot showing proteins identified in large amounts according to drug treatment versus the solvent that dissolves the drug.

[0211] Figure 8a is a histogram showing the degree of amorphousness of frequently observed proteins depending on the solvent dissolving the drug and the drug treatment.

[0212] Figure 8b is a histogram showing the pattern similarity of aromatic amino acids at the C terminus of SOX9, a protein frequently observed in response to drug treatment and solvents dissolving the drug.

[0213] Figure 8c is a graph showing the relationship between the degree of pattern similarity between the aromatic amino acid at the C-terminus of SOX9 and the conditional probability of the protein frequently observed depending on the solvent dissolving the drug and the drug treatment.

[0214] Figure 9 is an image of SOX9 observed within the nucleus of a cell using a general fluorescence microscope and a super-resolution microscope (dSTORM).

[0215] Figure 10 shows the qPCR results measuring the mRNA levels of SOX9 target genes according to drug treatment.

[0216] Figure 11 is a fluorescence image of the mRNA of SOX9 target genes (Acan, Col9a1, Sox9) measured by FISH together with SOX9 protein.

[0217] Figure 12a is a histogram showing the size distribution of SOX9 aggregates near the mRNA of SOX9 target genes according to drug treatment.

[0218] Figure 12b is a graph showing changes in the size of SOX9 aggregates near the mRNA of SOX9 target genes according to drug treatment.

[0219] Figure 13 is a graph showing the degree to which SOX9 binds to the regulatory regions of genes in DNA depending on the solvent used to dissolve the drug and the drug treatment.

[0220] Figure 14 is a graph showing the extent to which SOX9 binds to individual gene regulatory regions of DNA depending on the solvent used to dissolve the drug and the drug treatment.

[0221] Figure 15a is a schematic flow chart for an experiment in which drugs are administered to osteoarthritis model mice.

[0222] Figure 15b is an image showing the extent to which cartilage tissue in the joint area of ​​an osteoarthritis model rat was restored according to drug treatment (red: cartilage, blue: bone).

[0223] Figure 15c is a graph showing the degree of tissue recovery evaluated using the OARSI grade according to drug treatment.

[0224] Figure 16 is a schematic flow chart and graph of the results of an experiment that compared the degree of weight-bearing on the leg of an osteoarthritis model rat treated with a drug compared to a leg that did not undergo surgery.

[0225] Figure 17 is a schematic flow chart and graph of the results of an experiment that quantitatively measured and evaluated the degree to which the sole of an osteoarthritis model rat could withstand a needle according to drug treatment.

[0226] The present invention will be described in more detail through the following examples. However, these examples are provided for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0227]

[0228] Manufacturing Example A1: Synthesis of 3-(2-aminothiazol-4-yl)-7-methoxycoumarin

[0229]

[0230] Step 1: 3-acetyl-7-methoxycoumarin

[0231] 2-Hydroxy-4-methoxybenzaldehyde (2 mmol, CAS: 673-22-3), ethyl acetoacetate (2.4 mmol), and piperidine (0.2 mmol) were added to ethanol (4 mL) and stirred. After the reaction was completed and the temperature of the reaction product was lowered using an ice-water bath, the precipitate was filtered to obtain 3-acetyl-7-methoxycoumarin in 88% yield.

[0232] 1 H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.7, 2.4 Hz, 1H), 3.90 (s, 3H), 2.56 (s, 3H).

[0233] Step 2: 3-Bromoacetyl-7-methoxycoumarin

[0234] The obtained product (1 mmol) from Step 1 above and tetrabutylammonium tribromide (TBATB, 2 mmol) were dissolved in CH2Cl2 (10 mL) and stirred at room temperature. After the reaction was completed, the resulting precipitate was separated by filtration, thereby obtaining 3-bromoacetyl-7-methoxycoumarin in a yield of 59%.

[0235] 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 8.7, 2.5 Hz, 1H), 4.87 (s, 2H), 3.92 (s, 3H).

[0236] Step 3: 3-(2-aminothiazol-4-yl)-7-methoxycoumarin

[0237] The obtained product (1 mmol) from step 2 above and thiourea (2 mmol) were added to ethanol (10 mL) and heated with stirring. After the reaction was completed, the resulting precipitate was filtered to obtain intermediate a-1 in 99% yield.

[0238] 1 H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 3.88 (s, 3H).

[0239] Manufacturing Examples A2 to A13

[0240] Intermediates a-2 to a-12 were obtained in the same manner as in Manufacturing Example A1, except that the hydroxybenzaldehyde compounds in Table 1 below were used instead of 2-hydroxy-4-methoxybenzaldehyde in Step 1 of Manufacturing Example A1.

[0241] [Table 1]

[0242]

[0243]

[0244] Manufacturing Example A13: Synthesis of 3-(2-aminooxazol-4-yl)-7-methoxycoumarin

[0245]

[0246] Intermediate a-13 (52%, 387 mg) was obtained in the same manner as in Manufacturing Example A1, except that urea (CAS: 57-13-6) was used instead of thiourea in step 3 of Manufacturing Example A1.

[0247] 1 H NMR (300 MHz, DMSO) δ 8.24 (s, 1H), 7.84 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 6.98 (dd, J = 8.7, 2.4 Hz, 1H), 6.83 (s, 2H), 3.87 (s, 3H).

[0248]

[0249] The compounds in the table below were used as intermediates a-14 to a-17.

[0250] [Table 2]

[0251]

[0252] Manufacturing Example A18: Synthesis of 4-(2-aminothiazol-4-yl)biphenyl

[0253]

[0254] Intermediate a-18 (94%, 476 mg) was obtained in the same manner as in step 3 of manufacturing example A1, except that 2-bromo-4'-phenylacetophenone (CAS: 135-73-9) was used instead of the obtained product of step 2 of manufacturing example A1.

[0255] 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 7.88 - 7.78 (m, 4H), 7.78 - 7.69 (m, 2H), 7.50 (dd, J = 8.5, 6.9 Hz, 2H), 7.44 - 7.36 (m, 1H), 7.32 (s, 1H).

[0256] Manufacturing Example A19: Synthesis of 3-(2-aminothiazol-4-yl)-6-methyl-2H-pyran-2,3(3H)-dione

[0257]

[0258] Step 1: 3-(2-bromoacetyl)-6-methyl-2H-pyran-2,4(3H)-dione

[0259] Dihydroacetic acid (5.0 mmol, CAS: 520-45-6) and p-TsOH (5.5 mmol, CAS: 6192-52-5) were stirred in acetonitrile (10 mL), and NBS (5.5 mmol, CAS: 128-08-5) was slowly added and heated. After 9 h, water was added to the reaction mixture, and the product was extracted with DCM and concentrated to obtain the product (see Synthetic Communications, 2012, 42(18), 2739-2747).

[0260] Step 2: 3-(2-Aminothiazol-4-yl)-6-methyl-2H-pyran-2,3(3H)-dione

[0261] Using the obtained product of step 1 above, intermediate a-19 (8%, 94 mg) was obtained in the same manner as step 3 of manufacturing example A1.

[0262] 1 H NMR (400 MHz, DMSO) δ 15.12 (s, 1H), 8.02 (s, 2H), 7.10 (s, 1H), 6.12 (d, J = 1.0 Hz, 1H), 2.20 (d, J = 0.9 Hz, 3H).

[0263] Manufacturing Example A20: Synthesis of (2-aminothiazol-5-yl)(phenyl)methanone

[0264]

[0265] Step 1: (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one

[0266] Acetophenone (2.0 mmol) and N,N-dimethylformamide dimethylacetal (4.0 mmol) were stirred and heated in toluene (2 mL) for 18 h, then the solvent was removed and (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (124 mg, 35%) was isolated through column chromatography (DCM / MeOH=5:1).

[0267] Step 2: (2-Aminothiazol-5-yl)(phenyl)methanone

[0268] The obtained product of Step 1 (0.4 mmol), S powder (1.7 mmol), cyanamide solution (1.7 mmol), and N-methylporpholine (NMM, 0.1 mmol) were stirred in N-methylpyrrolidone (NMP, 1 mL) and reacted at 100 °C for 16 h under an argon atmosphere. The reaction mixture was then cooled, diluted with EA, and extracted with water. The organic layer containing the product was removed with Na2SO4 to remove the remaining moisture, concentrated, and purified by column chromatography (Hex / EA = 1:1) to obtain intermediate a-20 (31%, 78 mg) (see J. Org. Chem. 2019, 84(18), 12237-12245).

[0269] 1 H NMR (600 MHz, CDCl3) δ 7.78 (dd, J = 8.3, 1.4 Hz, 2H), 7.62 (s, 1H), 7.60 - 7.56 (m, 1H), 7.53 - 7.46 (m, 2H), 6.22 (br s, 2H).

[0270] Manufacturing Example B1: Synthesis of 3-(2-succinimidylthiazol-4-yl)-7-methoxycoumarin

[0271]

[0272] Anhydrous succinic acid (10 mmol, 1.00 g) and intermediate a-1 (1 mmol) were placed in a mortar and mixed well, and then transferred to a reactor. The reaction mixture was stirred at 150 °C for 5 hours. After the reaction was completed, the obtained product was purified by silica gel chromatography (CH2Cl2: CH3C(O)CH3= 20:1) to obtain intermediate b-1 (yield: 84%, 300 mg).

[0273] 1 H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.39 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.7, 2.4 Hz, 1H), 3.88 (s, 3H), 2.87 (s, 4H).

[0274] Manufacturing examples B2 to B21

[0275] In Manufacturing Example B1, intermediate a-1 was changed to intermediates a-2 to a-20 to synthesize intermediates b-2 to b-20, respectively.

[0276] [Table 3]

[0277]

[0278]

[0279]

[0280] Example 1: N 1 -(3,4-dimethoxyphenethyl)-N 4 Synthesis of -(4-(7-methoxycoumarin-3-yl)thiazol-2-yl)succinamide

[0281]

[0282] Intermediate b-1 (0.20 mmol) was dissolved in anhydrous dioxane (2 mL) in a reactor equipped with a condenser under argon gas conditions, and 2-(3,4-dimethoxyphenyl)ethan-1-amine (0.22 mmol (CAS: 120-20-7, TCI / D0678)) was added. The reaction mixture was stirred at 110°C for 5 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum. Water (20 mL) was added to the obtained residue to precipitate the product. The precipitated product was separated by centrifugation or filtration and lyophilized to obtain the compound of Example 1 (Compound B8, yield: 89%, 96 mg).

[0283] 1 H NMR (400 MHz, DMSO) δ 12.30 (s, 1H), 8.54 (s, 1H), 7.99 (t, J = 5.6 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.6, 2.5 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.1, 2.0 Hz, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 3.23 (dt, J = 6.7, 6.7 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 2.44 (t, J = 7.0 Hz, 2H).

[0284] Examples 2 to 81

[0285] Compounds of Examples 2 to 81 were obtained in the same manner as in Example 1, except that intermediate b-1 and 2-(3,4-dimethoxyphenyl)ethan-1-amine of Example 1 were changed as follows.

[0286] Example No. Intermediate b Amine Compound Example 2 Intermediate b-13,4-dimethoxybenzylamine (CAS: 5763-61-1, Alfa Aesar / B25033) Example 3 Intermediate b-12-(2-aminoethyl)pyridine (CAS: 2706-56-1, TCI / A1999) Example 4 Intermediate b-12-(4-aminophenyl)ethylamine (CAS: 13472-00-9, Alfa Aesar / L15782) Example 5 Intermediate b-1L-phenylalanine methyl ester hydrochloride (CAS: 7524-50-7, TCI / P1278) Example 6 Intermediate b-14-(2-aminoethyl)morpholine (CAS: 2038-03-1, Sigma / A55004) Example 7 Intermediate b-12-phenylethylamine (CAS: 64-04-0, TCI / P0085) Example 8 Intermediate b-1 Dopamine hydrochloride (CAS: 62-31-7, Alfa / A11136) Example 9 Intermediate b-13-(2-aminoethyl)pyridine (CAS: 20173-24-4, Alfa / L16311) Example 10 Intermediate b-14-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 11 Intermediate b-1 Histamine (CAS: 51-45-6, Alfa / J61727) Example 12 Intermediate b-12-(4-nitrophenyl)ethylamine hydrochloride (CAS: 29968-78-3, Alfa / H64894) Example 13 Intermediate b-12-(2-aminoethyl)thiophene (CAS: 30433-91-1, TCI / A1637) Example 14 Intermediate b-12-(3-methoxyphenyl)ethylamine (CAS: 2039-67-0, TCI / M1891) Example 15 Intermediate b-12-(4-methoxyphenyl)ethylamine (CAS: 55-81-2, TCI / M0795) Example 16 Intermediate b-13-phenylpropylamine (CAS: 2038-57-5, TCI / P0664) Example 17 Intermediate b-1 Benzylamine (CAS: 100-46-9, TCI / B0406) Example 18 Intermediate b-1 2,2-diphenylethylamine (CAS: 3963-62-0, TCI / D2018) Example 19 Intermediate b-1 Tryptamine (CAS: 61-54-1,Alfa Aesar / A11116.09) Example 20 Intermediate b-12-(3,4-(methylenedioxy)phenyl)ethylamine hydrochloride (CAS: 1653-64-1, Alfa Aesar / H60208) Example 21 Intermediate b-12-naphthaleneethanamine (CAS: 2017-68-7, Sigma / 667167) Example 22 Intermediate b-12-(3,4-dichlorophenyl)ethylamine (CAS: 21581-45-3, TCI / D2927) Example 23 Intermediate b-12-(P-tolyl)ethylamine (CAS: 3261-62-9, Alfa Aesar / 15788) Example 24 Intermediate b-12-(2-fluorophenyl)ethylamine (CAS: 52721-69-4, TCI / F0933) Example 25 Intermediate b-12-(4-fluorophenyl)ethylamine (CAS: 1583-88-6, TCI / F0829) Example 26 Intermediate b-14-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (CAS: 30827-99-7, Alfa Aesar / H26473) Example 27 Intermediate b-1N-(2-aminoethyl)piperazine (CAS: 140-31-6, TCI / A0304) Example 28 Intermediate b-14-(2-aminoethyl)thiomorpholine 1,1-dioxide (CAS: 89937-52-0, TCI / A1803) Example 29 Intermediate b-14-picolylamine (CAS: 3731-53-1, TCI / P0779) Example 30 Intermediate b-13-(pyridin-4-yl)propan-1-amine (CAS: 30532-36-6, Ambeed / A139358) Example 31 Intermediate b-1 Pyrimidin-4-ylmethanamine dihydrochloride (CAS: 618446-08-5, Ambeed / A283503) Example 32 Intermediate b-1 Pyridazin-4-ylmethanamine dihydrochloride (CAS: 1028615-75-9, Ambeed / A524320) Example 33 Intermediate b-1(2-fluoropyridin-4-yl)methanamine dihydrochloride (CAS: 667906-60-7, Ambeed / A210034))Example 34 Intermediate b-1(2-chloropyridin-4-yl)methanamine hydrochloride (CAS: 916210-98-5,Ambeed / A166155))Example 35 Intermediate b-1 (2-bromopyridin-4-yl)methanamine (CAS: 858362-82-0, Ambeed / A150324)Example 36 Intermediate b-1 4-(aminomethyl)pyridin-2-amine (CAS: 199296-51-0, Ambeed / A548509)Example 37 Intermediate b-1 Pyridine-2,4-diamine (CAS: 461-88-1, Ambeed / A202971)Example 38 Intermediate b-1 3,4,5-trimethoxybenzylamine (CAS: 18638-99-8, TCI / T3087)Example 39 Intermediate b-18-aminoquinoline (CAS: 578-66-5, Alfa / C12371) Example 40 Intermediate b-14 2-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 41 Intermediate b-15 2-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 42 Intermediate b-16 2-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 43 Intermediate b-17 2-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 44 Intermediate b-42-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 45 Intermediate b-52-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 46 Intermediate b-32-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 47 Intermediate b-72-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 48 Intermediate b-82-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 49 Intermediate b-92-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 50 Intermediate b-62-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 51 Intermediate b-102-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7,TCI / D0678) Example 52 Intermediate b-2 2-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 53 Intermediate b-2 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 54 Intermediate b-2 2-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 55 Intermediate b-4 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 56 Intermediate b-5 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 57 Intermediate b-34-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 58 Intermediate b-74-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 59 Intermediate b-64-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 60 Intermediate b-104-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 61 Intermediate b-24-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 62 Intermediate b-9 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 63 Intermediate b-11 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 64 Intermediate b-12 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 65 Intermediate b-14 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 66 Intermediate b-15 4-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 67 Intermediate b-164-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 68 Intermediate b-174-(2-aminoethyl)pyridine (CAS: 13258-63-4,TCI / A1264) Example 69 Intermediate b-134-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 70 Intermediate b-132-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 71 Intermediate b-184-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 72 Intermediate b-204-(2-aminoethyl)pyridine (CAS: 13258-63-4, TCI / A1264) Example 73 Intermediate b-202-(3,4-dimethoxyphenyl)ethylamine (CAS: 120-20-7, TCI / D0678) Example 74 Intermediate b-15,6-dimethoxy-2-(4-piperidylmethyl)-1-indanone hydrochloride (CAS: 120013-39-0, TCI / D3997) Example 75 Intermediate b-14-(4-aminopiperidino)pyridine dihydrochloride (CAS: 1169396-92-2, Ambeed / A689438) Example 76 Intermediate b-11-(4-pyridyl)piperazine (CAS: 1008-91-9, TCI, P1863) Example 77 Intermediate b-14-(4-piperidyl)pyridine (CAS: 581-45-3, TCI / P2012) Example 78 Intermediate b-1 Trimetazidine dihydrochloride (CAS: 13171-25-0, TCI / T2726) Example 79 Intermediate b-1 Quinoline-4-carbohydrazide (CSA: 29620-62-0, Ambeed / A600347) Example 80 Intermediate b-1 1H-indole-6-carbohydrazide (CAS: 851211-74-0, Ambeed / A208763) Example 81 Intermediate b-1 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine (CAS: 2002-04-2, Ambeed / A857207)

[0287] [Table 5]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304] Experimental Example 1: Evaluation of SOX9 transcriptional effect activity

[0305] To determine whether the compound enhances SOX9 transcriptional activity, a luciferase assay capable of measuring SOX9 transcriptional activity was performed using the following experimental method.

[0306] Primary rat chondrocytes were extracted from rat cartilage. The extracted cells were stabilized in a low-oxygen (O23%, CO25%) incubator. The medium used was DMEM (Dulbecco's Modified Eagle Medium, LM001-05, Welgene) supplemented with 10% FBS (fetal bovine serum, Gibco).

[0307] Cells were stabilized and treated with hyaluronidase type IS (Sigma-Aldrich, Hase) for 4 hours for transfection of luciferase plasmid.

[0308] For transfection, cells were treated with the 4X48pCol2a1-Luicferase plasmid, whose expression is promoted by the transcriptional activity of SOX9, and the Renilla luciferase plasmid, which continuously expresses SOX9 as a control, for 6 h using Metafectene pro reagent (Biontex). The 4X48pCol2a1-Luicferase plasmid and the Renilla luciferase plasmid were used as described in Kim, S. et al. “Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation”. Nat Commun 10, 4898 (2019).

[0309] After 6 hours, the medium was replaced with a culture medium containing the compounds. At this time, each compound was dissolved in DMSO at a concentration of approximately 5 mM to 10 mM and used in the medium at a concentration of 7.5 mM.

[0310] After 48 hours, the cells were lysed using a Dual Luciferase Assay Kit (Promega) and reacted with a luciferase substrate. The luminescence (relative to DMSO) from luciferase was measured using a microplate reader, and the results are shown in Table 6 and the graph in Fig. 1 was obtained according to the following criteria.

[0311] ++++: 8 or more / +++: less than 8, 5 or more / ++: less than 5, 2 or more / +: less than 2, 1 or more

[0312] Example Compound No. SOX9 Activity Example Compound No. SOX9 Activity Example Compound No. SOX9 Active1B8++27C26+++53D14++2C1++++28C27+54D15++3C2++29C28++++55D16++4C3++30C29+++56D17++5C4++31C30++57D18++6C5+++32C31++58D19++7C6++++33 C32++59D20+++8C7++++34C33++60D21++9C8++++35C34++61D22++10C9++++36C35++62D23++11C10++37C36++63D24++12C11++38C37+++64D25++13C12++39C38 ++++65D26+14C13++40D1+68D29+++15C14++41D2+69D30+16C15++42D3+70D31 ++17C16++43D4++71D32+18C17++44D5++74C43++19C18++45D6++75C39+++20C1 9++46D7++76C40+++21C20++47D8++77C41++22C21++48D9++79C44++++23C22++49D10++80C45++++24C23+50D11++81C46++25C24++++51D12++26C25++52D13++

[0313] Referring to Table 6 and Figure 1, it was confirmed that the compound of the present invention has an excellent SOX9 transcriptional activation effect.

[0314] The compounds of the examples exhibited different effects in enhancing the degree of transcriptional activity (Fig. 2a), and when examining changes in the degree of transcriptional activity depending on the induction of aggregation, a statistically significant correlation was found between the aggregation phenomenon and the transcriptional activity effect (Fig. 2b). This suggests that the aggregation-inducing properties of the drugs at the SOX9 protein level influence and are related to their efficacy.

[0315] Experimental Example 2: Induction of SOX9 aggregation and evaluation of transcriptional activity

[0316] 9x10 cells to be transfected in a 100 mm dish5 The cells were grown in a cell incubator for two days. 7 ug of the overexpressible SOX9-eGFP plasmid was transfected into the grown cells using a transfection agent (Poly-jet). The cells were exposed to DMEM medium without FBS for 30 minutes, and after 30 minutes, the SOX9-eGFP plasmid and Polyjet were added to the DMEM, mixed together, and the medium was added after waiting for 10 minutes. After reacting in the incubator for 4 hours, DMEM medium containing FBS was added and kept in the incubator for two days. Afterwards, the cells were removed using a scraper, centrifuged, and only the cell pellet was frozen in liquid nitrogen and stored in a -80℃ freezer.

[0317] Cell lysis buffer containing TritonX100 0.2%, EDTA 1 mM, Hepes 50 mM, NaCl 150 mM, glycerol 10%, protease inhibitor cocktail 1%, phosphatase inhibitor cocktail (tyrosine, serine / threonine) 1%, and TCEP 2 mM was added to the cell pellet to lyse the pellet. The lysed cells were lysed using an ultrasonic homogenizer, and the lysate was centrifuged (15,000 g, 10 min) to obtain the supernatant. The total protein concentration of the obtained supernatant was measured using a DC (detergent-compatible) assay, and the SOX9-eGFP concentration was measured using a fluorometer. The cell lysates whose concentrations were measured were used immediately or frozen in liquid nitrogen and stored at -80℃.

[0318] SOX9, which is relatively difficult to purify from E. coli, was expressed and purified from HEK293T using the Halo-Tag purification method. Even when SOX9, not a soluble form, was used, the correlation between the induction of aggregation and the degree of transcriptional activity was repeated, confirming the validity of using a soluble form (Fig. 2b).

[0319] The compounds of the examples were diluted to 1 / 100 of the concentration to be reacted and transferred to tubes according to each reaction volume. The prepared cell lysates were added to the tubes containing compound B8 or compound C9 and reacted. The drug-reacted lysates were transferred to a 96-well plate with a cover glass surface and waited for 1 hour at room temperature until the reaction was complete. The 96-well plate with the completed reaction was transferred to a confocal fluorescence microscope for fluorescence imaging.

[0320] The captured fluorescence images were analyzed using a self-developed MATLAB code. K-means clustering was used to distinguish aggregates from non-aggregated ones, and the fluorescence intensity, area, shape, and number of aggregates were analyzed.

[0321] As a result, it was verified that compounds B8 and C9 induced SOX9 aggregation compared to DMSO (Fig. 3a). In addition, using a Luciferase plasmid that specifically reacts to the transcriptional activity of SOX9, it was confirmed that compounds B8 and C9, which induce aggregation, enhanced the activity of the SOX9 transcription factor (Fig. 3b). In particular, it was found that compound B8 increased the activity by about 2-fold, whereas compound C9 significantly increased the transcriptional activity by about 8-fold. At this time, the SOX9 aggregation disappeared due to a structural change in compound C9, such as a change in the position or substitution of a nitrogen atom, and it was confirmed that the presence or absence of such aggregation induction affected the regulation of transcriptional activity (Figs. 4a, 4b). This means that the induction of aggregation and the regulation of transcriptional activity occur based on the chemical structure of the compound.

[0322] Experimental Example 3: Evaluation of the degree of aggregation according to the site of SOX9 deletion.

[0323] We confirmed the mechanism by which compound C9 contributes to enhancing the effect of osteoarthritis.

[0324] Specifically, we explored the drug binding site based on compound C9, which was confirmed to have the best efficacy. SOX9 is divided into structured and unstructured regions, and in particular, the unstructured region, IDR, is large enough to account for approximately 80% of the protein (Fig. 5a). To investigate which region the aggregation-inducing phenomenon of compound C9 occurs through interaction with, SOX9 mutants with deletions in each region were constructed. As in the above experimental examples, cell lysates were prepared for SOX9 mutants, and it was confirmed that aggregation was absent when C9 was deleted in the IDR region corresponding to the C-terminus of the protein (Fig. 5b). Furthermore, in order to narrow down the binding site, we constructed cell lysates of mutants with 35 amino acid deletions from the front to the back of the C-terminus, and confirmed this. At this time, it was confirmed that the aggregation phenomenon was drastically reduced when the region corresponding to regions 8 and 9, where aromatic amino acids are clustered, was deleted (Fig. 5c).

[0325] Experimental Example 4: Changes in the degree of SOX9 aggregation according to mutations in aromatic amino acids at positions 8 and 9 of the C-terminus of SOX9.

[0326] The importance of aromatic amino acids was confirmed by producing cell lysates expressing mutants in which aromatic amino acids were substituted with alanine. Similar to mutants lacking regions 8 and 9, mutations in the aromatic amino acids corresponding to regions 8 and 9 reduced the aggregation-induced phenomenon by compound C9 (Fig. 6). This confirmed that compound C9 induces SOX9 aggregation through interaction with a region where aromatic amino acids are clustered in the structureless region of the SOX9 C-terminus.

[0327] Experimental Example 5: Identification of proteins within aggregation-induced SOX9 aggregates.

[0328] Since aggregates are often formed by multiple proteins rather than a single protein, we wanted to identify the proteins that aggregate with SOX9 upon treatment with compound C9. To do this, we labeled SOX9 with TurboID and attached biotin to proteins within 10 nm of SOX9 upon treatment with compound C9. Biotin-bound proteins were separated using streptavidin-beads and subjected to liquid chromatography-mass spectrometry (LC / MS) (Fig. 7a). Each mass spectrometry experiment was repeated three times for one condition. Through mass spectrometry, proteins such as Pol2, as YTHDF3, CCAR2, MBNL1, NDUFA10, MYO1C, TAF5, and chromatin remodelers (KAT6A, KAT8), which are statistically significantly more frequently observed in the C9-treated group compared to DMSO, were detected, and proteins known to act together with SOX9, such as SOX5 and SOX6, were also detected (Fig. 7b).

[0329] Experimental Example 6: Confirmation of protein amorphism and evaluation of similarity with SOX9-C-IDR through spatial frequency analysis.

[0330] Sequence information for proteins significantly detected in C9 and DMSO was used to identify IDR regions using Metapredict. It was confirmed that the proteins detected with compound C9 treatment had a higher concentration of IDRs compared to DMSO (Figure 8a). Since IDRs are known to play a crucial role in aggregation, this indirectly suggests that compound C9 induces SOX9 aggregation.

[0331] Since compound C9 induced aggregation by targeting aromatic amino acids of SOX9 IDR, we confirmed whether the IDRs of proteins detected through mass spectrometry contained sites targeted by compound C9. A one-dimensional binary vector was created, where aromatic amino acids present in the IDRs of the proteins were 1 and other amino acids were 0, and this was wavelet transformed. The transformed information includes information on the degree of aromatic amino acid density according to time (position) and frequency. The degree of similarity to the C-IDR of SOX9 was compared through cross-correlation analysis between the wavelet transformed data of the proteins detected in this way and the data corresponding to the C-IDR of SOX9. This revealed that in the samples treated with compound C9, IDRs with similar patterns to the SOX9 C-IDR were more likely to have high similarity scores (Fig. 8b). To rule out the possibility that the number of proteins with high similarity to the SOX9 C-IDR pattern was low, conditional probabilities were calculated by considering the number of proteins corresponding to each similarity score. This revealed that IDRs with high similarity scores were more likely to be found in samples treated with compound C9 (Fig. 8c). These results support the notion that compound C9 specifically induces aggregate formation in a specific pattern (spatial frequency) created by aromatic amino acids in the C-IDR of SOX9.

[0332] Experimental Example 7: Analysis of SOX9 aggregates using super-resolution fluorescence microscopy (dSTORM).

[0333] To investigate the effect of drugs on changes in SOX9 aggregates within cells, SOX9 was labeled using IF (Immunofluorescence staining) and fluorescence imaging was performed. Since transcription factor aggregates such as SOX9 aggregates have sizes on the order of 100 nm to 1 μm, changes in SOX9 aggregates cannot be detected at the level of a general fluorescence microscope. Therefore, dSTORM (direct stochastic optical reconstruction microscopy), one of the super-resolution microscopes, was used to obtain the fluorescence image in Figure 9.

[0334] Experimental Example 8: Evaluation of mRNA levels of genes involved in osteoarthritis and RNA-FISH analysis.

[0335] To determine the relationship between the observed changes in SOX9 aggregates and transcriptional activity, RNA FISH (Fluorescence In Situ Hybridization) was performed with dSTORM on Col9a1, Acan, and SOX9, which showed a high degree of increase in mRNA levels compared to DMSO among the transcripts in which compound C9 increased transcriptional activity, to obtain the mRNA level graph in Fig. 10 and the dSTORM fluorescence image in Fig. 11.

[0336] RNA-FISH confirmed that the locations of each RNA foci and SOX9 aggregates observed within the nucleus were well colocalized (Fig. 11). Image analysis showed that the size of SOX9 aggregates observed near RNA foci increased by approximately 30% to 50% in C9 compared to DMSO (Fig. 12a, Fig. 12b). This was a high level compared to the 2% change in the size of SOX9 aggregates present in the nucleus. Therefore, it was found that compound C9 is specifically involved in the change in the size of SOX9 aggregates near RNA, which is related to transcriptional activity.

[0337] Experimental Example 9: Confirming the Effect of Compounds on the Binding Degree of SOX9 and DNA Using Cut&Tag

[0338] To determine whether drug-induced SOX9 aggregates are actually involved in transcriptional activity, Cut&Tag experiments were conducted to identify DNA sites to which SOX9 binds at the genome-wide level. As shown below, drug treatment increased the extent to which SOX9 binds to DNA (Fig. 13).

[0339] Experimental Example 10: Confirmation of changes in the degree of SOX9 binding to the DNA of genes that play a role in osteoarthritis according to compound treatment.

[0340] When we checked the information on the degree of DNA binding of SOX9 obtained through Cut&Tag for each of the genes involved in cartilage production, SOX9, Col2a1, Col9a1, Chad, Acan, and Comp, we could confirm that when the drug C9 was treated, SOX9 binding increased throughout the DNA (SOX9, Col2a1, Chad) or increased binding at a specific region of the DNA (red square) (Col9a1, Acan, Comp) (data with DMSO subtracted from C9 data, yellow) compared to when DMSO was treated (Figs. 14a to 14f). These results show that compound C9 affected the size change of SOX9 aggregates and the degree of DNA binding.

[0341] Experimental Example 11: Evaluation of the degree of cartilage tissue recovery in a rat model of osteoarthritis.

[0342] To determine whether compound C9 helps in cartilage formation, we performed an experiment in which compound C9 was injected intra-articularly at a concentration of 750 μM at one-week intervals into a rat model of osteoarthritis (OA) induced by destabilization of the medial meniscus (DMM) surgery for a total of seven injections (Fig. 15a). In contrast to the tissues of DMM-operated rats treated with DMSO, which did not recover and appeared damaged (yellow triangles), the damaged cartilage tissues were recovered when the drug was treated (Fig. 15b). To objectively evaluate the recovery of cartilage tissues, the OARSI Grade (a higher score indicates greater cartilage tissue damage) was assigned in a blinded test by individual researchers. When compound C9 was treated, the OARSI grade was statistically significantly lower (Fig. 15c). This suggests that compound C9 can help in the recovery of damaged cartilage tissues.

[0343] Experimental Example 12: Evaluation of the Degree of Alleviation of Osteoarthritis Through Behavioral Experiments

[0344] To confirm the recovery of osteoarthritis at the behavioral level, weight bearing and Von-Frey behavioral experiments were conducted. In the weight bearing experiment, the degree of force loading on the operated or non-operated limb was measured according to the drug treatment, and the experiment was conducted to determine what changes in the degree of force loading occurred when compound C9 was treated (Fig. 16). When compound C9 was treated, it was confirmed that the level was almost similar to that of non-induced OA mice in mice with OA (DMM surgery), and the degree of change was confirmed to be significant compared to when DMSO was treated (Fig. 16).

[0345] In the Von-Frey behavioral experiment, a weak stimulus was applied to the sole of the mouse's paw. As the stimulus became stronger, the intensity of the stimulus was measured at the moment the paw was lifted, thereby assessing the degree of cartilage recovery in the mouse (Fig. 17). As cartilage recovery improved, the tolerable stimulus intensity increased. Compared to mice without OA, it was confirmed that the tolerable stimulus intensity increased in mice with OA following compound C9 treatment (Fig. 17).

[0346] These behavioral experimental results confirmed that Compound C9 alleviates osteoarthritis at the behavioral level. Therefore, the present invention validates the ability to screen for osteoarthritis-inducing substances, such as Compound C9, that can exhibit osteoarthritis-inducing effects by aggregating SOX9.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, Y 1 and Y 2 One is N and the other is S, O or NR a1 and; X 1 and X 2 are each independently O, S or NR a2 and; U is NR n2 , a 5- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms N or these linked to each other; Z 1 Silver C 1-6 is alkylene; Z 2 is a direct bond, C 1-6 Alkylene, -NR n3 A 5- to 7-membered heteroaryl comprising 1 to 3 heteroatoms selected from CO- or N, O and S; R a1 and R a2 are each independently H or C 1-6 It is alkyl; R n1 , R n2 and R n3 are each independently H or C 1-6 It is alkyl; Z 2 Go C 1-6 In the case of alkylene, any carbon of the alkylene can be halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, cyano, nitro, oxo or C 6-12 optionally substituted with aryl; Z 3 is a direct bond or -C(=O)-; Ring A is a fused benzoheterocyclyl in which a benzene ring is fused to a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a 5- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S; Ring A has 1 to 3 R A is arbitrarily substituted with ; R A is halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 selected from the group consisting of alkyl, cyano, nitro and oxo; Ring E is a 6-14 membered aryl, a partially unsaturated 9-14 membered bicyclic carbocyclyl, a 5-12 membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5-12 membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5-7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl; Ring E has 1 to 3 R E is arbitrarily substituted with ; R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; Carboxy; C 1-6 Alkoxycarbonyl; carbamoyl; C 1-6 Alkylcarbamoyl; di(C 1-6 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-6 Selected from the group consisting of alkyl.

2. In paragraph 1, A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, selected from compounds represented by the following chemical formula 2 or 3; [Chemical formula 2] [Chemical Formula 3] In the above chemical formulas 2 and 3, Z 1 , Z 2 , X 1 , X 2 , U, R n1 , R n2 , ring A and ring E are as described in claim 1.

3. In paragraph 2, Y of chemical formula 2 1 and Y of chemical formula 3 2 A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein each of said compounds is independently S or O.

4. In paragraph 1, U is NR n2 ; piperidine diyl; piperazine diyl; or NR 2n A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of piperidinediyl and piperazinediyl.

5. In paragraph 1, U is NR n2 and is selected from the group consisting of the following structures, and among the following structures: * 1 Silver -C(=X 2 ) is connected to a carbon atom of * 2 is Z 2 A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, which is linked to: .

6. In paragraph 1, A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, biphenylyl, tetrahydronaphthyl, pyranyl, pyranonyl, benzopyranyl or benzopyronyl.

7. In paragraph 1, Ring A is or and the above ring A comprises 1 to 3 R A A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with .

8. In paragraph 7, Z 3 is a direct bond, and ring A is , or Either; or Z 3 is -C(=O)-, and ring A is or A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, R A A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of F, Cl, Br, hydroxy, methoxy, dimethylamino, methyl or oxo.

10. In paragraph 1, Ring A is a compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, selected from the following chemical structures: .

11. In paragraph 1, A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein ring E is phenyl, naphthalenyl, indanyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholinyl, thiomorpholinyl, piperidinyl, hexahydroxypyridazinyl, hexahydroxypyrimidinyl, piperazinyl, indolyl, indazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl or benzodioxolyl.

12. In paragraph 1, Ring E is selected from the following chemical structures; Ring E comprises 1 to 3 R E A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, optionally substituted with: .

13. In paragraph 1, R E A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of methoxy, hydroxy, amino, F, Cl, Br, trifluoromethyl, cyano, hydroxymethyl, methyl, fluorosulfonyl, nitro, and oxo.

14. In paragraph 1, Ring E is a compound selected from the following chemical structures, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: .

15. In paragraph 1, A compound represented by any of the following chemical formulae I to III, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; [Chemical Formula I] In the above chemical formula I, Y 1 is S, O or NR a1 and; R a1 is H or C 1-6 It is alkyl; R n1 and R n2 are each independently H or C 1-6 It is alkyl; Z 4 is a direct bond or C 1-4 is alkylene; R 1 Silver H, Halo, Hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, cyano, nitro, oxo or C 6-12 It's aryl; Ring A is a fused benzoheterocyclyl in which a benzene ring is fused to a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 6- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a 5- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S; Ring A has 1 to 3 R A is arbitrarily substituted with ; R A is halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 selected from the group consisting of alkyl, cyano, nitro and oxo; Ring E is a 6-14 membered aryl, a partially unsaturated 9-14 membered bicyclic carbocyclyl, a 5-12 membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5-12 membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5-7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl; Ring E has 1 to 3 R E is arbitrarily substituted with ; R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; Carboxy; C 1-6 Alkoxycarbonyl; carbamoyl; C 1-6 Alkylcarbamoyl; di(C 1-6 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-6 is selected from the group consisting of alkyl; [Chemical Formula II] In the above chemical formula II, Y 2 is S, O or NR a1 and; R a1 is H or C 1-6 It is alkyl; R n1 and R n2 are each independently H or C 1-6 It is alkyl; Z 4 is a direct bond or C 1-4 is alkylene; R 1 Silver H, Halo, Hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, cyano, nitro, oxo or C 6-12 It's aryl; Ring A 1 is a 6- to 14-membered aryl or a partially unsaturated 9- to 14-membered bicyclic carbocyclyl; Ring A 1 Silver 1 to 3 R A is arbitrarily substituted with ; R A is halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 selected from the group consisting of alkyl, cyano, nitro and oxo; Ring E is a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5- to 7-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl; Ring E has 1 to 3 R E is arbitrarily substituted with ; R E is halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl, carboxy, C 1-6 Alkoxycarbonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 Alkyl)carbamoyl, halosulfonyl, sulfoxy, C 1-6 selected from the group consisting of alkylsulfonyl, cyano, nitro and oxo; [Chemical Formula III] In the above chemical formula III, U 1 is a direct bond or NR n2 and; Y 3 and Y 4 At least one of them is N and the rest are CH; Z 5 is a direct bond, C 1-6 Alkylene, -NR n3 A 5- to 7-membered heteroaryl comprising 1 to 3 heteroatoms selected from CO- or N, O and S; R n1 , R n2 and R n3 are each independently H or C 1-6 It is alkyl; Ring A is a fused benzoheterocyclyl in which a benzene ring is fused to a 6- to 14-membered aryl, a partially unsaturated 9- to 14-membered bicyclic carbocyclyl, a 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5- to 8-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a 5- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S; Ring A has 1 to 3 R A is arbitrarily substituted with ; R A is halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 selected from the group consisting of alkyl, cyano, nitro and oxo; Ring E is a 6-14 membered aryl, a partially unsaturated 9-14 membered bicyclic carbocyclyl, a 5-12 membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N or S, a 5-12 membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N or S, or a fused heterocycloaryl in which a 5-7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N or S is fused to phenyl; Ring E has 1 to 3 R E is arbitrarily substituted with ; R E is halo; hydroxy; C 1-6 Alkoxy; Amino; C 1-6 Alkylamino; di(C 1-6 Alkyl)amino; Carboxy; C 1-6 Alkoxycarbonyl; carbamoyl; C 1-6 Alkylcarbamoyl; di(C 1-6 Alkyl)carbamoyl; halosulfonyl; sulfoxy; C 1-6 Alkylsulfonyl; cyano; nitro; oxo; or halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 C optionally substituted with one or more of alkyl)amino, nitro and cyano 1-6 Selected from the group consisting of alkyl; s is 0 or 1.

16. In paragraph 15, A compound represented by Formula IA, Formula IB, Formula IC, Formula ID, Formula IE or Formula IIA, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; [Chemical Formula IA] [Chemical Formula IB] [Chemical Formula IC] [chemical formula ID] [chemical formula IE] [chemical formula IIA] In the above chemical formulas IA, IB, IC, ID, IE and IIA, R A is halo, hydroxy, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 selected from the group consisting of alkyl, cyano, nitro and oxo; n, m1, m2, o1, o2, p and q are each independently an integer from 0 to 3; The sum of m1 and m2 and o1 and o2 is each less than or equal to 3; Y 1 , Y 2 , R n1 , R n2 , Z 4 , R 1 and ring E is as described in claim 13.

17. In paragraph 1, A compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, selected from compounds represented by the following chemical formula: .

18. A pharmaceutical composition for preventing or treating a disease associated with decreased expression of SOX9 (SRY-Box Transcription Factor 9), comprising a compound of any one of claims 1 to 17, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

19. In paragraph 18, A pharmaceutical composition, wherein the disease associated with the decreased expression of the above SOX9 is osteoarthritis.

20. A method for treating a disease associated with decreased expression of SOX9, comprising administering to a subject a compound of any one of claims 1 to 17, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

21. Use of a compound according to any one of claims 1 to 17, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a disease associated with decreased expression of SOX9.

22. Use of a compound according to any one of claims 1 to 17, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with decreased expression of SOX9.

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