Dipeptidyl peptidase-iv inhibitorsThe present invention relates generally to pyrrolidine and thiazolidine DPP-IV inhibitor compounds. The present invention also provides synthetic methods for preparation of such compounds, methods of inhibiting DPP-IV using such compounds and pharmaceutical formulations containing them for treatment of DPP-IV mediated diseases, in particular, Type-2 diabetes.Formula (i) compound and all steric isomer, diastereomer, racemic mixture and pharmacologically acceptable salt thereof and all polymorphic forms:a-b-d (i)；wherein a is:b is:and d is:whereine and g are 6 yuan of aryl or 5 yuan of heteroaryls or 6 yuan of heteroaryls independently;e can be by one or more r 1group replaces; g can be by one or more r 2group replaces; x and y be divalence and be independently of one another: key, cr 4r 5, o, nr 4, s, s=o, s (=o) 2, c (=o), (c=o) n (r 4), s (=o) 2n (r 4), c=n-or 4,-c (r 4r 5) c (r 4r 5)-,-c (r 4r 5) c (r 4r 5) c (r 4r 5)-,-c (r 4r 5) c (r 4r 5) c (r 4r 5) c (r 4r 5)-,-c (r 4)=c (r 5)-,-c (r 4r 5) nr 4-,-c (r 4r 5) o-,-c (r 4r 5) s (=o) t-,-(c=o) o-,-(c=nr a) n (r 4)-,-(c=nr an)-, (c=o) nr 4nr 5, n (c=o) r 4, n (c=o) or 4, ns (=o) 2nr 4nr 5, ns (=o) 2r 4or aryl, heteroaryl, cycloalkyl or heterocycle, all can choosing wantonly is substituted; r 1and r 2be independently of one another: halogen, cf 3, cor 4, or 4, nr 4r 5, no 2, cn, so 2or 4, co 2r 4, conr 4r 5, co 2h, so 2nr 4r 5, s (o) tr 4, so 3h, oc (o) r 4, oc (o) nr 4r 5, nr 4c (o) r 5, nr 4co 2r 5, (c 0-c 6)-alkyl-c (=nr a) nhr 4, (c 0-c 6)-alkyl-c (=nr 4) nhr a, (c 0-c 6)-alkyl-nr 4c (=nr 4) nr 4r 5, (c 0-c 6)-alkyl-c (o) or 4, (c 0-c 6)-alkyl-c (o) nr 4r 5, (c 0-c 6)-alkyl-c (o)-nh-cn, o-(c 0-c 6)-alkyl-c (o) nr 4r 5, s (o) t-(c 0-c 6)-alkyl-c (o) or 4, s (o) t-(c 0-c 6)-alkyl-c (o) nr 4r 5, (c 0-c 6)-alkyl-c (o) nr 4-(c 0-c 6)-alkyl-nr 4r 5, (c 0-c 6)-alkyl-nr 4r 5, (c 0-c 6)-alkyl-nr 4-c (o) r 5, (c 0-c 6)-alkyl-nr 4-c (o) or 4, (c 0-c 6)-alkyl-nr 4-c (o)-nr 4r 5, (c 0-c 6)-alkyl-nr 4-so 2nr 4r 5, (c 0-c 6)-alkyl-nr 4-so 2r 4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, fluoroalkyl, heterocyclylalkyl alkyl, alkylhalide group, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl group, can choosing wantonly that wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, fluoroalkyl, heterocyclylalkyl alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl group are all is substituted; r 3do not exist or halogen, cf 3, cor 4, or 4, nr 4r 5, no 2, cn, so 2or 4, co 2r 4, conr 4r 5, co 2h, so 2nr 4r 5, s (o) tr 4, so 3h, oc (o) r 4, oc (o) nr 4r 5, nr 4c (o) r 5, nr 4co 2r 5, (c 0-c 6)-alkyl-c (=nr a) nhr 4, (c 0-c 6)-alkyl-c (=nr 4) nhr a, (c 0-c 6)-alkyl-nr 4c (=nr 4) nr 4r 5, (c 0-c 6)-alkyl-c (o) or 4, (c 0-c 6)-alkyl-c (o) nr 4r 5, (c 0-c 6)-alkyl-c (o)-nh-cn, o-(c 0-c 6)-alkyl-c (o) nr 4r 5, s (o) t-(c 0-c 6)-alkyl-c (o) or 4, s (o) t-(c 0-c 6)-alkyl-c (o) nr 4r 5, (c 0-c 6)-alkyl-c (o) nr 4-(c 0-c 6)-alkyl-nr 4r 5, (c 0-c 6)-alkyl-nr 4r 5, (c 0-c 6)-alkyl-nr 4-c (o) r 5, (c 0-c 6)-alkyl-nr 4-c (o) or 4, (c 0-c 6)-alkyl-nr 4-c (o)-nr 4r 5, (c 0-c 6)-alkyl-nr 4-so 2nr 4r 5, (c 0-c 6)-alkyl-nr 4-so 2r 4, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, fluoroalkyl, heterocyclic radical, heterocyclylalkyl alkyl, alkylhalide group, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl group, can choosing wantonly that wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, fluoroalkyl, heterocyclylalkyl alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkyl group are all is substituted; r abe hydrogen, cn, no 2, alkyl, alkylhalide group, s (o) tnr 4r 5, s (o) tr 4, c (o) or 4, c (o) r 4or c (o) nr 4r 5r 4, r 5, r 20and r 21when occurring be independently of one another: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, fluoroalkyl, heterocyclylalkyl alkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl group at every turn, wherein all optional being substituted of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, fluoroalkyl, heterocyclylalkyl alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl group, or r 4and r 5form comprise carbon atom 3 to 8 yuan rings and can choose wantonly to comprise with the nitrogen that they connected and be selected from o, s or nr 50heteroatoms and 3 to 8 yuan of rings can choose wantonly and be substituted; r 50when occurring r at every turn 20, cn, no 2, s (o) tnr 20r 21, s (o) tr 20, c (o) or 20, c (o) r 20c (=nr a) nr 20r 21, c (=nr 20) nr 21r a, c (=nor 20) r 21or c (o) nr 20r 21r 7and r 8when occurring be independently of one another: halogen, cf at every turn 3, cor 4, or 4, nr 4r 5, no 2, cn, so 2or 4, co 2r 4, conr 4r 5, co 2h, so 2nr 4r 5, s (o) tr 4, so 3h, oc (o) r 4, oc (o) nr 4r 5, nr 4c (o) r 5, nr 4co 2r 5, (c 0-c 6)-alkyl-c (=nr a) nhr 4, (c 0-c 6)-alkyl-c (=nr 4) nhr a, (c 0-c 6)-alkyl-nr 4c (=nr 4) nr 4r 5, (c 0-c 6)-alkyl-c (o) or 4, (c 0-c 6)-alkyl-c (o) nr 4r 5, (c 0-c 6)-alkyl-c (o)-nh-cn, o-(c 0-c 6)-alkyl-c (o) nr 4r 5, s (o) t-(c 0-c 6)-alkyl-c (o) or 4, s (o) t-(c 0-c 6)-alkyl-c (o) nr 4r 5, (c 0-c 6)-alkyl-c (o) nr 4-(c 0-c 6)-alkyl-nr 4r 5, (c 0-c 6)-alkyl-nr 4r 5, (c 0-c...
디펩티딜 펩티다아제-Ⅳ 억제제본 발명은 일반적으로 피롤리딘 및 티아졸리딘 DPP-Ⅳ 억제 화합물에 관한 것이다. 본 발명은 또한 그러한 화합물의 제조를 위한 합성 방법, 그러한 화합물을 사용하여 DPP-IV를 억제하는 방법, 및 DPP-IV 매개 질병, 특히, 제 2형 당뇨병의 치료를 위한 상기 화합물을 포함하는 약제 조성물을 제공한다.하기 화학식 (I)의 화합물 및 이의 모든 입체이성질체, 부분입체이성질체, 라세미 혼합물 및 약제학적으로 허용되는 염 및 모든 다형체: A-B-D (I) 상기 화학식에서, A가 [이미지] 이고; B는 [이미지] [이미지] 이며; D가 [이미지] 이고; E 및 G는 독립적으로 6-원 아릴, 또는 5-원 헤테로아릴 또는 6-원 헤테로아릴이고; E는 하나 이상의 R1기로 치환될 수 있고; G는 하나 이상의 R2기로 치환될 수 있으며; X 및 Y는 이가(divalent)이고 각각 독립적으로 결합(bond), CR4R5, 0, NR4, S, S=O, S(=O)2, C(=O), (C=O)N(R4), S(O)2N(R4), C=N-OR4, -C(R4R5)C(R4R5)-, -C(R4R5)C(R4R5)C(R4R5)-, -C(R4R5)C(R4R5)C(R4R5)C(R4R5)-, -C(R4)=C(R5)-, -C(R4R5)NR4-, -C(R4R5)O-, -C(R4R5)S(=O)t-, -(C=O)O-, -(C=NRa)N(R4)-, -(C=NRa)-, N(C=O)NR4NR5, N(C=O)R4, N(C=O)OR4, NS(=O)2NR4NR5, NS(O)2R4; 또는 치환되거나 치환되지 않은 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클릭 고리이며; R1 및 R2는 각각 독립적으로 할로겐, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-알킬-C(=NRa)NHR4, (C0-C6)-알킬-C(=NR4)NHRa, (C0-C6)-알킬-NR4C(=NR4)NR4R5, (C0-C6)-알킬-C(0)OR4, (C0-C6)-알킬-C(0)NR4R5, (C0-C6)-알킬-C(O)-NH-CN, O-(C0-C6)-알킬-C(O)NR4R5, S(0)t(C0-C6)-알킬-C(0)OR4, S(O)t-(C0-C6)-알킬-C(0)NR4R5, (C0-C6)-알킬-C(0)NR4-(C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4-C(O)R5, (C0-C6)-알킬-NR4-C(O)OR4, (C0-C6)-알킬-NR4-C(O)-NR4R5, (C0-C6)-알킬-NR4-SO2NR4R5, (C0-C6)-알킬-NR4-SO2R4, 수소, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 할로알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 또는 아미노알킬이며, 여기서, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 및 아미노알킬 모두는 치환되거나 치환되지 않으며; R3는 부존재하거나 할로겐, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-알킬-C(=NRa)NHR4, (C0-C6)-알킬-C(=NR4)NHRa, (C0-C6)-알킬-NR4C(=NR4)NR4R5, (C0-C6)-알킬-C(O)OR4, (C0-C6)-알킬-C(O)NR4R5, (C0-C6)-알킬-C(O)-NH-CN, 0-(C0-C6)-알킬-C(0)NR4R5, S(O)t-(C0-C6)-알킬-C(O)OR4, S(O)t-(C0-C6)-알킬-C(O)NR4R5, (C0-C6)-알킬-C(0)NR4-(C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4-C(O)R5, (C0-C6)-알킬-NR4-C(O)OR4, (C0-C6)-알킬-NR4-C(O)-NR4R5, (C0-C6)-알킬-NR4-SO2NR4R5, (C0-C6)-알킬-NR4-SO2R4, 수소, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클릴, 헤테로시클로알킬알킬, 할로알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 또는 아미노알킬이고, 여기서, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 및 아미노알킬은 모두 치환되거나 치환되지 않으며; Ra는 수소, CN, NO2, 알킬, 할로알킬, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, 또는 C(O)NR4R5이고; R4, R5, R20 및 R21은 각각 독립적으로 수소, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬 또는 아미노알킬이거나, 여기서, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬 및 아미노알킬은 모두 치환 또는 비치환되며, R4 및 R5는 이들이 결합된 질소와 함께 탄소원자를 함유하는 3-원 내지 8-원 고리를 형성하고, O, S 또는 NR50로부터 선택된 헤테로원자를 함유하거나 함유하지 않으며, 상기 3-원 내지 8-원 고리는 치환되거나 치환되지 않으며; R50는 각각 R20, CN, NO2, S(O)tNR20R21, S(O)tR20, C(O)OR20, C(O)R20C(=NRa)NR20R21, C(=NR20)NR21Ra, C(=NOR20)R21 또는 C(O)NR20R21이고; R7 및 R8은 각각 독립적으로 할로겐, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-알킬-C(=NRa)NHR4, (C0-C6)-알킬-C(=NR4)NHRa, (C0-C6)-알킬-NR4C(=NR4)NR4R5, (C0-C6)-알킬-C(O)OR4, (C0-C6)-알킬-C(O)NR4R5, (C0-C6)-알킬-C(0)-NH-CN, 0-(C0-C6)-알킬-C(0)NR4R5, S(O)t-(C0-C6)-알킬-C(O)OR4, S(0)t(C0-C6)-알킬-C(0)NR4R5, (C0-C6)-알킬-C(0)NR4-(C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4-C(O)R5, (C0-C6)-알킬-NR4-C(O)OR4, (C0-C6)-알킬-NR4-C(O)-NR4R5, (C0-C6)-알킬-NR4-SO2NR4R5, (C0-C6)-알킬-NR4-SO2R4, 수소, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 할로알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 또는 아미노알킬이고, 여기서, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 및 아미노알킬은 모두가 치환되거나 치환되지 않으며; R9은 H 또는 C1-6 알킬이고; R10은 할로겐, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-알킬-C(=NRa)NHR4, (C0-C6)-알킬-C(=NR4)NHRa, (C0-C6)-알킬-NR4C(=NR4)NR4R5, (C0-C6)-알킬-C(O)OR4, (C0-C6)-알킬-C(O)NR4R5, (C0-C6)-알킬-C(O)-NH-CN, 0-(C0-C6)-알킬-C(O)NR4R5, S(0)t-(C0-C6)-알킬-C(0)OR4, S(O)t-(C0-C6)-알킬-C(O)NR4R5, (C0-C6)-알킬-C(O)NR4-(C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4-C(O)R5, (C0-C6)-알킬-NR4-C(O)OR4, (C0-C6)-알킬-NR4-C(O)-NR4R5, (C0-C6)-알킬-NR4-SO2NR4R5, (C0-C6)-알킬-NR4-S02R4, 수소, B(OH)2, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 할로알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 또는 아미노알킬이고, 여기서, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 알케닐, 알키닐, 아릴, 헤테로아릴, 아릴알킬, 헤테로아릴알킬, 알콕시알킬 및 아미노알킬은 모두 치환되거나 치환되지 않으며; R11 및 R12는 각각 독립적으로 할로겐, CF3, COR4, OR4, NR4R5, NO2, CN, SO2OR4, CO2R4, CONR4R5, CO2H, SO2NR4R5, S(O)tR4, SO3H, OC(O)R4, OC(O)NR4R5, NR4C(O)R5, NR4CO2R5, (C0-C6)-알킬-C(=NRa)NHR4, (C0-C6)-알킬-C(=NR4)NHRa, (C0-C6)-알킬-NR4C(=NR4)NR4R5, (C0-C6)-알킬-C(O)OR4, (C0-C6)-알킬-C(O)NR4R5, (C0-C6)-알킬-C(O)-NH-CN, O-(C0-C6)-알킬-C(O)NR4R5, S(O)t-(C0-C6)-알킬-C(O)OR4, S(O)t-(C0-C6)-알킬-C(O)NR4R5, (C0-C6)-알킬-C(O)NR4-(C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4R5, (C0-C6)-알킬-NR4-C(O)R5, (C0-C6)-알킬-NR4-C(O)OR4, (C0-C6)-알킬-NR4-C(O)-NR4R5, (C0-C6)-알킬-NR4-SO2NR4R5, (C0-C6)-알킬-NR4-SO2R4, 수소, 알킬, 시클로알킬, 시클로알킬알킬, 헤테로시클로알킬, 플루오로알킬, 헤테로시클로알킬알킬, 할로알킬, 알케닐, 알키닐, 아릴, 헤테로아...