COMPOUNDS AND THERAPEUTIC USES THEREOFThe invention relates to compounds, pharmaceutical compositions and methods useful for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, ischemia, and other complications associated with these diseases and disorders.A compound having a structure according to Formula IFormula Iand pharmaceutically acceptable salts and solvates thereof;wherein:Y is phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, Ci_5 alkyl, nitro, cyano, Ci_5 alkoxy, C-amido, N-amido, C- carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfmyl;Yi is divalent carbocycle, divalent heterocycle, divalent phenyl or divalent heteroaryl, wherein any ring atom is optionally independently substituted with halo, Ci_5 alkyl, nitro, cyano, trihalomethyl, Ci_5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfmyl, orYi is C2-8 alkylene or C2_g alkenylene, optionally interrupted one, two, or three times by -0-, -S-, -S(=0)-, -S(=0)2-, -OC(=0)N(R)-, -N(R)C(=0)0-, -C(=0)N(R)-, -N(R)C(=0)-, - N(R)C(=0)N(R)-, -N(R)-, -C(=0)-, -OC(=0)-, -C(=0)0-, -OS(=0)2N(R)-, -N(R)S(=0)20-, - SC(=0)-, -C(=0)S-, -OC(=S)N(R)-, -N(R)C(=S)0-, -C(=S)N(R)-, -N(R)C(=S)-, -N(R)C(=S)N(R)-, -C(=S)-, -OC(=S)-, -C(=S)0-, -S(=0)2N(R)-, -N(R)S(=0)2-, -S(=0)2N(R)C(=0)-, or - C(=0)N(R)S(=0)2-;Y2 is -OCH2-, -SCH2-, -N(R)CH2-, -N(R)C(=0)-, -C(=0)N(R)-, -S(=0)2CH2-, -S(=0)CH2-, - CH20-, -CH2CH20-, -CH2S-, -CH2N(R)-, -CH2S(=0)2-, -CH2S(=0)-, -C(=0)0-, -OC(=0)-, - S02N(R)-, -N(R)S02-, ethylene, propylene, n-butylene, -0-Ci_4 alkylene-N(R)C(=0)-, -0-Ci_4 alkylene-C(=0)N(R)-, -N(R)C(=0)-Ci_4 alkylene-O-, -C(=0)N(R)-Ci_4 alkylene-O-, -Ci_4 alkylene- S(=0)2-, -C alkylene-S(=0)-, -S(=0)2-Ci_4 alkylene-, -S(=0)-Ci_4 alkylene-, -CM alkylene- S02N(R)-, -Ci_4 alkylene-N(R)S02-, -S02N(R)-Ci_4 alkylene-, -N(R)S02-Ci_4 alkylene-, -Ci_4 alkylene-0-Ci_4 alkylene-, -0-Ci_4 alkylene-, -Ci_4 alkylene-O-, -S-Ci_4 alkylene-, -Ci_4 alkylene-S-, - Ci_4 alkylene-S-Ci_4 alkylene-, -N(R)-Ci_4 alkylene-, -C1-4 alkylene-N(R)-, -C1-4 alkylene-N(R)-Ci_4 alkylene-, -C1-4 alkylene-C(=0)-0-Ci_4 alkylene-, -C1-4 alkylene-0-C(=0)-Ci_4 alkylene-, -C1-4 alkylene-C(=0)-N(R)-Ci_4 alkylene-, -Ci_4 alkylene-N(R)-C(=0)-Ci_4 alkylene-, -C(=0)-N(R)-Ci_4 alkylene-S02N(R)-, or -N(R)-C(=0)-Ci_4 alkylene- S02N(R)-;Z0 is carbocycle, cycloalkyl, cycloalkenyl, heterocycle, heterocyclonoyl, aryl, heteroaryl, carbocycloalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or arylalkynyl,wherein any of the foregoing groups are optionally substituted at least once with alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, carbocycle, cycloalkyl, cycloalkenyl,heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy,heterocycloxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, heterocyclonoyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl, carboxyalkenylene, carboxyalkyl salt, carboxyalkoxy, carboxyalkoxyalkanoyl, amino, aminoalkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,aminothiocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, cyano, nitrile, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfmyl, sulfonyl, sulfonamide, aminosulfonyl,aminosulfonyloxy, sulfonamidecarbonyl, alkanoylaminosulfonyl, trihalomethylsulfonyl, or trihalomethy lsulfonamide ;wherein any alkylene or alkenylene group is optionally independently substituted with Ci_4 alkyl, halo, Ci_4 haloalkyl, or C3 or C4 cycloalkyl;wherein for the purpose of Yi, R is H, halo, Ci_4 alkyl, Ci_4 alkenyl, or Ci_4 alkynyl;wherein for the purpose of Y2, R is H, halo, Ci_5 alkyl, Ci_5 alkenyl, Ci_5 alkynyl, or is methylene or ethylene that forms a 5- or 6- membered heterocycle with a carbon atom of Zo; and with the proviso that the compound is NOT:ethyl 3 -(pyridin-3 -yl)-4-( {4- [(3 - { [(pyridin-3 -ylmethyl)carbamoyl] amino } benzyl)oxy]phenyl} sulfonyl)butanoate;4-({4-[(3-{ [(pyridin-3 -ylmethyl)carbamoyl] amino } benzyl)oxy]phenyl} sulfonyl)-3 - [4-(trifluoromethyl)phenyl]butanoic acid;3 -phenyl-4-( {4- [(3 - { [(pyridin-3 -ylmethyl)carbamoyl] amino } benzyl)oxy]phenyl} sulfonyl)butanoic acid;3 -(4-chloro-3 -fluorophenyl)-4- [(4- { [3 - { [(pyridin-3 -ylmethyl)carbamoyl]amino } -5 -(trifluoromethyl)benzyl]oxy } phenyl)sulfonyl]butanoic acid;3 -phenyl-4-[(4- { [3 - { [(pyridin-3 -ylmethyl)carbamoyl] amino } -5 -(trifluoromethyl)benzy l]oxy } phenyl) sulfonyljbutanoic acid; 3 -(pyridin-3 -yl)-4-( {4-[(3 - { [(pyridin-3 -ylmethyl)carbamoyl] amino } benzyl)oxy]phenyl} sulfonyl)butanoic acid;4-( {4- [(4-fluoro-3 - { [(pyridin-3 -ylmethyl)carbamoyl] amino } benzyl)oxy]phenyl} sulfonyl)-3 -(pyridin-3 -yl)butanoic acid;1 , 1 '-butane- 1 ,4-diylbis[3 -(pyridin-3 -ylmethyl)urea];1 - [(6-methoxypyridin-3 -yl)methyl]-3 - [3 -(3 -methylphenoxy)propyl]urea; or1 - [3 -(2-fluorophenoxy)propyl]-3 - [(6-methoxypyridin-3 -yl)methyl]urea.
화합물 및 그의 치료 용도본 발명은 암, 전신성 또는 만성 염증, 류마티스 관절염, 당뇨병, 비만, T-세포 매개 자가면역 질환, 허혈, 및 이들 질환 및 장애와 관련된 기타 합병증의 치료에 유용한 화합물, 제약 조성물 및 방법에 관한 것이다.화학식 I에 따른 구조를 갖는 화합물 및 그의 제약상 허용되는 염 및 용매화물.<화학식 I>상기 식에서,Y는 페닐, 2-피리디닐, 3-피리디닐 또는 4-피리디닐이고, 여기서 임의의 고리 탄소는 임의로 독립적으로 할로, C1-5 알킬, 니트로, 시아노, C1-5 알콕시, C-아미도, N-아미도, C-카르복시, O-카르복시, 술폰아미드, 아미노, 히드록실, 메르캅토, 알킬티오, 술포닐 또는 술피닐로 치환되고;Y1은 2가 카르보사이클, 2가 헤테로사이클, 2가 페닐 또는 2가 헤테로아릴이고, 여기서 임의의 고리 원자는 임의로 독립적으로 할로, C1-5 알킬, 니트로, 시아노, 트리할로메틸, C1-5 알콕시, C-아미도, N-아미도, 술폰아미드, 아미노, 아미노술포닐, 히드록실, 메르캅토, 알킬티오, 술포닐 또는 술피닐로 치환되거나;Y1은 -O-, -S-, -S(=O)-, -S(=O)2-, -OC(=O)N(R)-, -N(R)C(=O)O-, -C(=O)N(R)-, -N(R)C(=O)-, -N(R)C(=O)N(R)-, -N(R)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OS(=O)2N(R)-, -N(R)S(=O)2O-, -SC(=O)-, -C(=O)S-, -OC(=S)N(R)-, -N(R)C(=S)O-, -C(=S)N(R)-, -N(R)C(=S)-, -N(R)C(=S)N(R)-, -C(=S)-, -OC(=S)-, -C(=S)O-, -S(=O)2N(R)-, -N(R)S(=O)2-, -S(=O)2N(R)C(=O)- 또는 -C(=O)N(R)S(=O)2-가 임의로 1, 2 또는 3회 개입된, C2-8 알킬렌 또는 C2-8 알케닐렌이고;Y2는 -OCH2-, -SCH2-, -N(R)CH2-, -N(R)C(=O)-, -C(=O)N(R)-, -S(=O)2CH2-, -S(=O)CH2-, -CH2O-, -CH2CH2O-, -CH2S-, -CH2N(R)-, -CH2S(=O)2-, -CH2S(=O)-, -C(=O)O-, -OC(=O)-, -SO2N(R)-, -N(R)SO2-, 에틸렌, 프로필렌, n-부틸렌, -O-C1-4 알킬렌-N(R)C(=O)-, -O-C1-4 알킬렌-C(=O)N(R)-, -N(R)C(=O)-C1-4 알킬렌-O-, -C(=O)N(R)-C1-4 알킬렌-O-, -C1-4 알킬렌-S(=O)2-, -C1-4 알킬렌-S(=O)-, -S(=O)2-C1-4 알킬렌-, -S(=O)-C1-4 알킬렌-, -C1-4 알킬렌-SO2N(R)-, -C1-4 알킬렌-N(R)SO2-, -SO2N(R)-C1-4 알킬렌-, -N(R)SO2-C1-4 알킬렌-, -C1-4 알킬렌-O-C1-4 알킬렌-, -O-C1-4 알킬렌-, -C1-4 알킬렌-O-, -S-C1-4 알킬렌-, -C1-4 알킬렌-S-, -C1-4 알킬렌-S-C1-4 알킬렌-, -N(R)-C1-4 알킬렌-, -C1-4 알킬렌-N(R)-, -C1-4 알킬렌-N(R)-C1-4 알킬렌-, -C1-4 알킬렌-C(=O)-O-C1-4 알킬렌-, -C1-4 알킬렌-O-C(=O)-C1-4 알킬렌-, -C1-4 알킬렌-C(=O)-N(R)-C1-4 알킬렌-, -C1-4 알킬렌-N(R)-C(=O)-C1-4 알킬렌-, -C(=O)-N(R)-C1-4 알킬렌-SO2N(R)-, 또는 -N(R)-C(=O)-C1-4 알킬렌-SO2N(R)-이고;Z0는 카르보사이클, 시클로알킬, 시클로알케닐, 헤테로사이클, 헤테로시클로노일, 아릴, 헤테로아릴, 카르보시클로알킬, 헤테로시클릴알킬, 아릴알킬, 아릴알케닐, 헤테로아릴알킬, 헤테로아릴알케닐, 헤테로아릴알키닐 또는 아릴알키닐이고, 여기서 임의의 상기 기는 임의로 알킬, 알킬렌, 알케닐, 알케닐렌, 알키닐, 알키닐렌, 카르보사이클, 시클로알킬, 시클로알케닐, 헤테로사이클, 아릴, 헤테로아릴, 할로, 히드로, 히드록실, 알콕시, 알키닐옥시, 시클로알킬옥시, 헤테로시클로옥시, 아릴옥시, 헤테로아릴옥시, 아릴알콕시, 헤테로아릴알콕시, 메르캅토, 알킬티오, 아릴티오, 아릴알킬, 헤테로아릴알킬, 헤테로아릴알케닐, 아릴알키닐, 할로알킬, 알데히드, 티오카르보닐, 헤테로시클로노일, O-카르복시, C-카르복시, 카르복실산, 에스테르, C-카르복시 염, 카르복시알킬, 카르복시알케닐렌, 카르복시알킬 염, 카르복시알콕시, 카르복시알콕시알카노일, 아미노, 아미노알킬, 니트로, O-카르바밀, N-카르바밀, O-티오카르바밀, N-티오카르바밀, C-아미도, N-아미도, 아미노티오카르보닐, 히드록시아미노카르보닐, 알콕시아미노카르보닐, 시아노, 니트릴, 시아네이토, 이소시아네이토, 티오시아네이토, 이소티오시아네이토, 술피닐, 술포닐, 술폰아미드, 아미노술포닐, 아미노술포닐옥시, 술폰아미드카르보닐, 알카노일아미노술포닐, 트리할로메틸술포닐 또는 트리할로메틸술폰아미드로 1회 이상 치환되고;여기서 임의의 알킬렌 또는 알케닐렌 기는 임의로 독립적으로 C1-4 알킬, 할로, C1-4 할로알킬, 또는 C3 또는 C4 시클로알킬로 치환되고;여기서 Y1의 목적상, R은 H, 할로, C1-4 알킬, C1-4 알케닐 또는 C1-4 알키닐이고;여기서 Y2의 목적상, R은 H, 할로, C1-5 알킬, C1-5 알케닐, C1-5 알키닐이거나 Z0의 탄소 원자와 함께 5- 또는 6-원 헤테로사이클을 형성하는 메틸렌 또는 에틸렌이고;단, 화합물은에틸 3-(피리딘-3-일)-4-({4-[(3-{[(피리딘-3-일메틸)카르바모일]아미노}벤질)옥시]페닐}술포닐)부타노에이트;4-({4-[(3-{[(피리딘-3-일메틸)카르바모일]아미노}벤질)옥시]페닐}술포닐)-3-[4-(트리플루오로메틸)페닐]부탄산;3-페닐-4-({4-[(3-{[(피리딘-3-일메틸)카르바모일]아미노}벤질)옥시]페닐}술포닐)부탄산;3-(4-클로로-3-플루오로페닐)-4-[(4-{[3-{[피리딘-3-일메틸)카르바모일]아미노}-5-(트리플루오로메틸)벤질]옥시}페닐)술포닐]부탄산;3-페닐-4-[(4-{[3-{[(피리딘-3-일메틸)카르바모일]아미노}-5-(트리플루오로메틸)벤질]옥시}페닐)술포닐]부탄산;3-(피리딘-3-일)-4-({4-[(3-{[(피리딘-3-일메틸)카르바모일]아미노}벤질)옥시]페닐}술포닐)부탄산;4-({4-[(4-플루오로-3-{[(피리딘-3-일메틸)카르바모일]아미노}벤질)옥시]페닐}술포닐)-3-(피리딘-3-일)부탄산;1,1'-부탄-1,4-디일비스[3-(피리딘-3-일메틸)우레아];1-[(6-메톡시피리딘-3-일)메틸]-3-[3-(3-메틸페녹시)프로필]우레아; 또는1-[3-(2-플루오로페녹시)프로필]-3-[(6-메톡시피리딘-3-일)메틸]우레아가 아니다.