PHENYL SUBSTITUTED CARBOXYLIC ACIDS AS INHIBITORS OF PROTEIN TYROSINE PHOSPHATASE-1BDisclosed are compounds and pharmaceutically acceptable salts of formula (A): which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia. Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-1B (PTP-1B), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.A compound of the formula:or a pharmaceutically acceptable salt thereof, wherein, Ri is H, Ci-Cg alkyl, phenyl (Cx-Cg) alkyl , or C2-C6 alkenyl; L2 is a bond or -C(O)NRι0-, -N (R10) C (0) - , - (Cι-C4) alkyl- N(Rιo)C(0)-, -C(0)N(Rio)-(Ci-C4)alkyl-, -N(Rι0)C(O) - (Cx-C4) alkyl-, - (Cι-C4) alkyl-C (0) N (Ri0) - , -O- (Cι-Ce) alkyl- , or - (Ci-Cg) alkyl-O-; L3 is absent, a bond, - (Cι-C4) alkyl-O- , -0- (C1-C4) alkyl, - (C1-C4) alkyl- , -alkenyl- , -phenyl- ; L5 is a bond, -O- (Ci-Cg) alkyl- , - (Ci-Cg) alkyl-O- , -C (0) N (R9) - (d- C4) alkyl-, -N (R9) C (O) - (C^d) alkyl-, - (C1-C4) alkyl- C(0)N(R9) - (C1-C4) alkyl-, - (C1-C4) alkyl-N (R9) C (0) - (C1-C4) alkyl-, -N (R9) - (Ci-Cg) alkyl-, -N (R9) - (Cι-C6) alkyl- wherein - (Ci-Cg) alkyl- is optionally substituted with phenyl, - (C1-C4) alkyl-N (R9) - (C1-C4) alkyl-, -S02N(R9)-,-S02N(R9) - (C1-C4) alkyl-, -N (R9) S02- (C1-C4) alkyl- , -N(R9)S02- , - (C1-C4) alkyl-, -N(R9)C(0)-, -C (0) - (C1-C4) alkyl-, -S- (C1-C4) alkyl-, or - (C1-C4) alkyl-S- (C1-C4) alkyl-, wherein R9 and Rι0 are independently is H, Ci-Cg alkyl, Cι-C3 alkoxycarbonyl, -S02-aryl, heteroarylalkyl, arylalkyl, wherein the aryl or heteroaryl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, OH, N02, NH2, NH (Cι-C6) alkyl, N(CX-Cs) alkyl (Ci-Cg) alkyl, haloalkyl, or haloalkoxy; R20, R21, R22, and R23 are independently selected from H, arylalkoxy, arylalkyl, halogen, alkyl, OH, alkoxy, N02, NH2, CN, NH(Cι-Cg) alkyl, N (d-Cg) alkyl (Ci-Cg) alkyl , NH-aryl, NHC(O) - (C1-C4) alkyl-aryl, N(d-C4 alkyl) C (O) - (Cι-C4) alkyl-aryl, N(d-C4) alkyl-aryl, -NHS02-aryl, -N(CX-C4alkyl) S02aryl, wherein the aryl group is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently d-C6 alkyl, Ci-Cg alkoxy, halogen, OH, N02, haloalkyl, haloalkoxy; the A ring is aryl, heteroaryl, heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently, halogen, Ci-C alkyl, Ci-Cg alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, N02, NH2, NH (Cι-C6) alkyl, or N(d-Cg) alkyl (Ci-Cg) alkyl; Q is H, aryl, -aryl-carbonyl-aryl, -aryl-O-aryl, -aryl-alkyl- aryl, -aryl-heteroaryl, -aryl-heterocycloalkyl, -heteroaryl, -heteroaryl-alkyl-aryl, or -heterocycloalkyl, wherein the aforementioned cyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkoxycarbonyl, Ci-Cg alkyl, Ci-Cg alkoxy, halogen, haloalkyl, haloalkoxy, NRSR7, phenyl, phenyl-Ci-Cg alkyl-, or phenyloxy- ; wherein Rs and R7 are independently H, Ci-Cg alkyl, aryl (Ci-Cg) alkyl, C2- C6 alkanoyl, aryl C2-C6 alkanoyl, Ci-Cg alkoxycarbonyl, aryl Ci-C alkoxycarbonyl, heteroarylcarbonyl, heteroaryl, heterocycloalkylcarbonyl, -C(0)NH2, -C (0) NH (d-C6) alkyl, - C (O)N(Cι-Cg) alkyl (Ci-Cg) alkyl, or -S02-aryl, wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C1-C4 alkyl, d-C4 alkoxy, N02, OH, NH2, NH (Ci-Cg) alkyl, N (Ci-Cg) alkyl (d- Ce) alkyl, haloalkyl or haloalkoxy; andZ is absent, H, -NHC(0)aryl, -N(Cι-C4 alkyl) C (O) aryl, or aryl (phenyl) , wherein the aryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Ci-C alkyl, Ci-Cg alkoxy, halogen, haloalkyl, haloalkoxy, or N02, or Z is -NHC(O) - (Cι-C4) alkyl- (C3-C7) cycloalkyl, -N(d-C4) alkylC (0) - (C1-C4) alkyl- (C3-C7) cycloalkyl .
단백질 티로신 포스파타제-１Ｂ 억제제로서의 페닐 치환된카르복실산인슐린 내성, 렙틴 내성 또는 고지혈증에 관련된 대사 질환을 치료하는데 유용한 하기 화학식(A)의 화합물, 및 약제학적으로 허용되는 염이 기술되어 있다. 본 발명의 화합물에는, 당뇨병 및 기타 PTP 매개된 질환, 예컨대 암, 신경퇴행성 질환 등의 치료에 유용한 단백질 티로신 포스파타제, 특히 단백질 티로신 포스파타제-1B (PTP-1B)의 억제제가 포함된다. 또한, 본 발명의 화합물을 포함하는 약제 조성물, 및 그러한 화합물을 사용하여 상기 언급된 질환을 치료하는 방법이 기술되어 있다: 하기 화학식의 화합물, 또는 이의 약제학적으로 허용되는 염:  상기 식에서, R1은 H, C1-C6 알킬, 페닐 (C1-C6)알킬, 또는 C2-C6 알케닐이며; L2는 결합 또는 -C(O)NR10-, -N(R10)C(O)-, -(C1-C4)알킬-N(R10)C(O)-, -C(O)N (R10)-(C1-C4)알킬-, -N(R10)C(O)-(C1-C4)알킬-, -(C1-C4)알킬-C(O)N(R10)-, -O-(C1-C6)알킬-, 또는 -(C1-C6)알킬-O-이고; L3은 존재하지 않거나, 결합, -(C1-C4)알킬-O-, -O-(C1-C4)알킬, -(C1-C4)알킬-, -알케닐-, -페닐-이며; L5는 결합, -O-(C1-C6)알킬-, -(C1-C6)알킬-O-, -C(O)N(R9)-(Cl-C4)알킬-, -N(R9)C(O)-(C1-C4)알킬-, -(C1-C4)알킬-C(O)N(R9)-(C1-C4)알킬-, -(C1-C4)알킬-N (R9)C(0)-(C1-C4)알킬-, -N(R9)-(C1-C6)알킬-, -N(R9)-(C1-C6)알킬이며, 여기서 -(C1-C6)알킬-은 페닐, -(C1-C4)알킬-N(R9)-(C1-C4)알킬-, -S02N(R9)-, -S02N(R9)-(C1-C4)알킬-, -N(R9)S02-(C1-C4)알킬-, -N(R9)S02-, -(C1-C4)알킬-, -N(R9)C(0)-, -C(0)-(C1-C4)알킬-, -S-(C1-C4)알킬-, 또는 -(C1-C4)알킬-S-(C1-C4)알킬-로 치환되거나 치환되지 않으며, 여기서 R9 및 R10은 독립적으로 H, C1-C6 알킬, C1-C6 알콕시카르보닐, -SO2-아릴, 헤테로아릴알킬, 아릴알킬이며, 여기서 아릴 또는 헤테로아릴 기는 독립적으로 C1-C4 알킬, C1-C4 알콕시, 할로겐, OH, NO2, NH2, NH(C1-C6)알킬, N(C1-C6)알킬(C1-C6)알킬, 할로알킬 또는 할로알콕시인 1, 2, 3 또는 4개의 기로 치환되거나 치환되지 않으며; R20, R21, R22 및 R23은 독립적으로 H, 아릴알콕시, 아릴알킬, 할로겐, 알킬, OH, 알콕시, NO2, NH2, CN, NH(C1-C6)알킬, N(C1-C6)알킬(C1-C6)알킬, NH-아릴, NHC (O)-(C1-C4)알킬-아릴, N(C1-C4 알킬)C(O)-(C1-C4)알킬-아릴, N(C1-C4)알킬-아릴, -NHS02-아릴, -N(C1-C4알킬)S02아릴로부터 선택되며, 여기서 아릴 기는 독립적으로 C1-C6 알킬, C1-C6 알콕시, 할로겐, OH, N02, 할로알킬, 할로알콕시인 1, 2, 3, 4 또는 5개의 기로 치환되거나 치환되지 않으며; A 고리는 아릴, 헤테로아릴, 헤테로시클로알킬이며, 이들 각각은 독립적으로 할로겐, C1-C6 알킬, C1-C6 알콕시, C1-C4 할로알킬, C1-C4 할로알콕시, NO2, NH2, NH(C1-C6)알킬, 또는 N(C1-C6)알킬(C1-C6)알킬인 1, 2 또는 3개의 기로 치환되거나 치환되지 않으며; Q는 H, 아릴, -아릴-카르보닐-아릴, -아릴-0-아릴, -아릴-알킬-아릴, -아릴-헤테로아릴, -아릴-헤테로시클로알킬, -헤테로아릴, -헤테로아릴-알킬-아릴, 또는 -헤테로시클로알킬이며, 여기서 상기 언급된 시클릭 기는 독립적으로 알콕시카르보닐, C1-C6 알킬, C1-C6 알콕시, 할로겐, 할로알킬, 할로알콕시, NR6R7, 페닐, 페닐-(C1-C6)알킬-, 또는 페닐옥시-인 1, 2, 3, 4 또는 5개의 기로 치환되거나 치환되지 않으며, 여기서 R6 및 R7은 독립적으로 H, C1-C6 알킬, 아릴(C1-C6)알킬, C2-C6 알카노일, 아릴 C2-C6 알카노일, C1-C6 알콕시카르보닐, 아릴 C1-C6 알콕시카르보닐, 헤테로아릴카르보닐, 헤테로아릴, 헤테로시클로알킬카르보닐, -C(O)NH2, -C(O)NH(C1-C6)알킬, -C(O)N(C1-C6)알킬(C1-C6)알킬 , 또는 -S02-아릴이며, 여기서 시클릭 기는 독립적으로 할로겐, C1-C4 알킬, C1-C4 알콕시, NO2, OH, NH2, NH(C1-C6)알킬, N(C1-C6)알킬(C1-C6)알킬, 할로알킬 또는 할로알콕시인 1, 2, 3 또는 4개의 기로 치환되거나 치환되지 않으며; Z는 존재하지 않거나, H, -NHC(O)아릴, -N(C1-C4 알킬)C(O)아릴, 또는 아릴(페닐)이며, 여기서 아릴 기는 독립적으로 C1-C6 알킬, C1-C6 알콕시, 할로겐, 할로알킬, 할로알콕시, 또는 NO2인 1, 2, 3, 4 또는 5개의 기로 치환되거나 치환되지 않거나, 또는 Z는 -NHC(O)-(C1-C4)알킬-(C3-C7)시클로알킬, -N(C1-C4)알킬C(O)-(C1-C4)알킬-(C3-C7)시클로알킬이다.