Piperidinyl derivatives as modulators of chemokine receptor activityThe present application describes substituted piperidinyl modulators of MIP-1 or CCR-1 or stereoisomers or pharmaceutically acceptable salts thereof. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and transplant rejection using said modulators are disclosed.Formula (i) compound or its steric isomer or prodrug or pharmaceutical acceptable salt:whereindotted line is represented two keys of choosing wantonly;t is r 1be alkyl, cycloalkyl, aryl, heterocyclic radical or heteroaryl, whole described groups are optional by 0-5 r 1areplace; r 1awhen occurring, independently be selected from every turn alkyl, haloalkyl, aryl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclic radical, heterocyclic radical alkyl-, halogen ,-nh 2,-cn ,-no 2,-c (=o) oh ,-c (=o) o (cr 8r 8) rr 10,-o (cf 2) rcf 3,-o (cr 8r 8) rr 10,-oh ,-sh ,-s (cr 8r 8) rr 10,-s (o) 3h ,-p (o) 3h 2,-c (=o) nr 9r 9,-nr 9r 9,-s (o) 2nr 9r 9,-nr 9s (o) 2(cf 2) rcf 3,-c (=o) nr 9s (o) 2r 6,-s (o) 2nr 9c (=o) or 6,-s (o) 2nr 9c (=o) nr 9r 9,-c (=o) nr 9s (o) 2(cf 2) rcf 3,-c (=o) (cr 8r 8) rr 10,-nr 9c (=o) h ,-nr 9c (=o) (cr 8r 8) rr 10,-oc (=o) (cr 8r 8) rr 10,-c (=nr 14) nr 9r 9,-nhc (=nr 14) nr 14r 14,-s (=o) (cr 8r 8) rr 10,-s (o) 2(cr 8r 8) rr 10,-nr 9c (=o) or 8,-nr 9s (o) 2r 8,-s (o) 2nr 9c (o) r 6, aryloxy-or arylalkyl-, wherein said aryl, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclic radical, heterocyclic radical alkyl-, aryloxy-and arylalkyl-optional by 0-3 r 1breplace; r 1bwhen occurring, independently be selected from every turn alkyl, haloalkyl, aryl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclic radical, heterocyclic radical alkyl-, halogen ,-nh 2,-cn ,-no 2,-c (=o) oh ,-c (=o) o (cr 8r 8) rr 10,-o (cf 2) rcf 3,-o (cr 8r 8) rr 10,-oh ,-sh ,-s (cr 8r 8) rr 10,-s (o) 3h ,-p (o) 3h 2,-c (=o) nr 9r 9,-nr 9r 9,-s (o) 2nr 9r 9,-nr 9s (o) 2(cf 2) rcf 3,-c (=o) nr 9s (o) 2r 6,-s (o) 2nr 9c (=o) or 6,-s (o) 2nr 9c (=o) nr 9r 9,-c (=o) nr 9s (o) 2(cf 2) rcf 3,-c (=o) (cr 8r 8) rr 10,-nr 9c (=o) h ,-nr 9c (=o) (cr 8r 8) rr 10,-oc (=o) (cr 8r 8) rr 10,-c (=nr 14) nr 9r 9,-nhc (=nr 14) nr 14r 14,-s (=o) (cr 8r 8) rr 10,-s (o) 2(cr 8r 8) rr 10,-nr 9c (=o) or 8,-nr 9s (o) 2r 8, aryloxy-or arylalkyl-; r 2be alkyl, cycloalkyl, cycloalkylalkyl-or thiazolinyl, the optional quilt-oh replacement of wherein said alkyl; r 3it when occurring alkyl at every turn; or any two r that link to each other with same carbon atom 33 to 6 yuan of rings of optional formation; w be hydrogen, f ,-oh ,-cn or-nh 2r 5for halogen ,-cn or-the o alkyl; or w and a r 5and their carbon atoms of being connected separately form 3 to 6 yuan of ether rings together, and wherein said ring is optional by one or more r 5replace; r 6when occurring at every turn independently for alkyl, cycloalkyl, cycloalkylalkyl-, aryl, arylalkyl-, heteroaryl or heteroarylalkyl-; r 8when occurring, independently be hydrogen or alkyl at every turn; r 9when occurring at every turn independently for hydrogen, alkyl, cycloalkyl, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclic radical or heterocyclic radical alkyl-, wherein said aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclic radical or heterocyclic radical alkyl-optional by 0-5 r 9areplace, and described heteroaryl, heteroarylalkyl-, 1-4 heteroatoms that is selected from n, o and s of heterocyclic radical or heterocyclic radical alkyl-contain; r 9awhen occurring, independently be selected from every turn alkyl, haloalkyl, aryl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclic radical, heterocyclic radical alkyl-, halogen ,-nh 2,-cn ,-no 2,-c (=o) oh ,-c (=o) o (cr 8r 8) rr 14,-o (cf 2) rcf 3,-o (cr 8r 8) rr 14,-oh ,-sh ,-s (cr 8r 8) rr 14,-s (o) 3h ,-p (o) 3h 2,-c (=o) nr 14r 14,-nr 14r 14,-s (o) 2nr 14r 14,-nr 14s (o) 2(cf 2) rcf 3,-c (=o) nr 14s (o) 2r 6,-s (o) 2nr 14c (=o) or 6,-s (o) 2nr 14c (=o) nr 14r 14,-c (=o) nr 14s (o) 2(cf 2) rcf 3,-c (=o) (cr 8r 8) rr 14,-nr 14c (=o) h ,-nr 14c (=o) (cr 8r 8) rr 14,-oc (=o) (cr 8r 8) rr 14,-c (=nr 14) nr 14r 14,-nhc (=nr 14) nr 14r 14,-s (=o) (cr 8r 8) rr 14,-s (o) 2(cr 8r 8) rr 14,-nr 14c (=o) or 8,-nr 14s (o) 2r 8, aryloxy-or arylalkyl-; r 10when occurring, independently be selected from every turn alkyl, aryl, arylalkyl-, heterocyclic radical or heterocyclic radical alkyl-, wherein said alkyl, aryl, arylalkyl-, heterocyclic radical or heterocyclic radical alkyl-optional by 0-3 r 10areplace 1-4 heteroatoms that is selected from n, o and s of and described heterocyclic radical and heterocyclic radical alkyl-contain; r 10awhen occurring, independently be selected from every turn alkyl, haloalkyl, aryl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclic radical, heterocyclic radical alkyl-, halogen ,-nh 2,-cn ,-no 2,-c (=o) oh ,-c (=o) o (cr 8r 8) rr 14,-o (cf 2) rcf 3,-o (cr 8r 8) rr 14,-oh ,-sh ,-s (cr 8r 8) rr 14,-s (o) 3h ,-p (o) 3h 2,-c (=o) nr 14r 14,-nr 14r 14,-s (o) 2nr 14r 14,-nr 14s (o) 2(cf 2) rcf 3,-c (=o) nr 14s (o) 2r 6,-s (o) 2nr 14c (=o) or 6,-s (o) 2nr 14c (=o) nr 14r 14,-c (=o) nr 14s (o) 2(cf 2) rcf 3,-c (=o) (cr 8r 8) rr 14...
케모킨 수용체 활성의 조절인자로서의 피페리디닐 유도체 본 출원에는 MIP-1 또는 CCR-1의 치환된 피페리디닐 조절인자, 또는 이의 입체이성질체 또는 제약상 허용되는 염이 기재되어 있다. 또한, 상기 조절인자를 사용한, 천식 및 알레르기성 질환과 같은 염증성 질환, 뿐만 아니라 류마티스성 관절염 및 이식 거부와 같은 자가면역 병상의 치료 및 예방 방법이 개시되어 있다. 하기 화학식 I의 화합물, 또는 이의 입체이성질체, 전구약물 또는 제약상 허용되는 염 형태. <화학식 I> [이미지] 식 중: 파선은 임의적 이중 결합을 나타내고; T는 [이미지], [이미지], [이미지] 또는 [이미지]이고; R1은 알킬, 시클로알킬, 아릴, 헤테로시클릴 또는 헤테로아릴이며, 이들 모두는 0 내지 5개의 R1a로 임의로 치환될 수 있고; R1a는 각각 독립적으로 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)O(CR8R8)rR10, -O(CF2)rCF3, -O(CR8R8)rR10, -OH, -SH, -S(CR8R8)rR10, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR9R9, -S(O)2NR9R9, -NR9S(O)2(CF2)rCF3, -C(=O)NR9S(O)2R6, -S(O)2NR9C(=O)OR6, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2(CF2)rCF3, -C(=O)(CR8R8)rR10, -NR9C(=O)H, -NR9C(=O)(CR8R8)rR10, -OC(=O)(CR8R8)rR10, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)(CR8R8)rR10, -S(O)2(CR8R8)rR10, -NR9C(=O)OR8, -NR9S(O2)R8, -S(O)2NR9C(O)R6, 아릴옥시 또는 아릴알킬로부터 선택되며, 여기서 상기 아릴, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 아릴옥시 및 아릴알킬은 0 내지 3개의 R1b로 임의로 치환될 수 있고; R1b는 각각 독립적으로 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)O(CR8R8)rR10, -O(CF2)rCF3, -O(CR8R8)rR10, -OH, -SH, -S(CR8R8)rR10, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR9R9, -S(O)2NR9R9, -NR9S(O)2(CF2)rCF3, -C(=O)NR9S(O)2R6, -S(O)2NR9C(=O)OR6, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2(CF2)rCF3, -C(=O)(CR8R8)rR10, -NR9C(=O)H, -NR9C(=O)(CR8R8)rR10, -OC(=O)(CR8R8)rR10, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)(CR8R8)rR10, -S(O)2(CR8R8)rR10, -NR9C(=O)OR8, -NR9S(O2)R8, 아릴옥시 또는 아릴알킬로부터 선택되고; R2는 알킬, 시클로알킬, 시클로알킬알킬 또는 알케닐이며, 여기서 상기 알킬은 -OH로 임의로 치환될 수 있고; R3은 각각 알킬이거나; 동일한 탄소 원자에 부착된 임의의 2개의 R3이 3- 내지 6-원 고리를 형성할 수 있고; W는 수소, F, -OH, -CN, -NH2이고; R5는 할로, -CN 또는 -O알킬이거나; W 및 1개의 R5가, 이들 각각이 부착된 탄소 원자와 함께 3- 내지 6-원 산소 함유 고리를 형성하며, 여기서 상기 고리는 1개 이상의 R5로 임의로 치환될 수 있고; R6은 각각 독립적으로 알킬, 시클로알킬, 시클로알킬알킬, 아릴, 아릴알킬, 헤테로아릴 또는 헤테로아릴알킬이고; R8은 각각 독립적으로 수소 또는 알킬이고; R9는 각각 독립적으로 수소, 알킬, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 또는 헤테로시클릴알킬이며, 여기서 상기 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 또는 헤테로시클릴알킬은 0 내지 5개의 R9a로 임의로 치환될 수 있고, 상기 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 또는 헤테로시클릴알킬은 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 함유하고; R9a는 각각 독립적으로 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)O(CR8R8)rR14, -O(CF2)rCF3, -O(CR8R8)rR14, -OH, -SH, -S(CR8R8)rR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2(CF2)rCF3, -C(=O)NR14S(O)2R6, -S(O)2NR14C(=O)OR6, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2(CF2)rCF3, -C(=O)(CR8R8)rR14, -NR14C(=O)H, -NR14C(=O)(CR8R8)rR14, -OC(=O)(CR8R8)rR14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)(CR8R8)rR14, -S(O)2(CR8R8)rR14, -NR14C(=O)OR8, -NR14S(O2)R8, 아릴옥시 또는 아릴알킬로부터 선택되고; R10은 각각 독립적으로 알킬, 아릴, 아릴알킬, 헤테로시클릴 또는 헤테로시클릴알킬로부터 선택되며, 여기서 상기 알킬, 아릴, 아릴알킬, 헤테로시클릴 또는 헤테로시클릴알킬은 0 내지 3개의 R10a로 임의로 치환될 수 있고, 상기 헤테로시클릴 및 헤테로시클릴알킬은 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 함유하고; R10a는 각각 독립적으로 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)O(CR8R8)rR14, -O(CF2)rCF3, -O(CR8R8)rR14, -OH, -SH, -S(CR8R8)rR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2(CF2)rCF3, -C(=O)NR14S(O)2R6, -S(O)2NR14C(=O)OR6, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2(CF2)rCF3, -C(=O)(CR8R8)rR14, -NR14C(=O)H, -NR14C(=O)(CR8R8)rR14, -OC(=O)(CR8R8)rR14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)(CR8R8)rR14, -S(O)2(CR8R8)rR14, -NR14C(=O)OR8, -NR14S(O2)R8, 아릴옥시 또는 아릴알킬로부터 선택되고; R14는 각각 독립적으로 수소, 알킬, 시클로알킬 또는 페닐로부터 선택되고; m은 각각 0 내지 2이고; n은 1 내지 3이고; r은 0 내지 5이다.