Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolizationPresently provided are inhibitors of IDO and TDO and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase and tryptophan 2,3 dioxygenase; treating immunosuppression; treating a medical conditions that benefit from the inhibition of tryptophan degradation; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosupression associated with an infectious disease.The compound of following formula(i)its tautomer or pharmacologically acceptable salt, whereinn is 0,1,2,3 or 4;key α is singly-bound or double bondring a is aromatic ring, whereini) v and x is n, w and z be ch, y is c; orii) v, y and z are n, w be ch, x is c; oriii) v, w and y are n, x be c, z is ch; oriv) v and w is n or nh, x and y be c, z is ch;each r 1independent is halogen, cyano group, nitro, c 1-6alkyl, c 1-6haloalkyl ,-or ,-n (r) 2,-sr ,-c (o) or ,-c (o) n (r) 2,-c (o) r ,-s (o) r ,-s (o) or ,-s (o) n (r) 2,-s (o) 2r ,-s (o) 2or ,-s (o) 2n (r) 2,-oc (o) r ,-oc (o) or ,-oc (o) n (r) 2,-n (r) c (o) r ,-n (r) c (o) or or-n (r) c (o) n (r) 2; when key α is singly-bound, r 2-c 1-4alkyl-r aor-c 2-4thiazolinyl-r 3; with when key α is double bond, r 2=c (h) r a; whereinr a-cn ,-c (o) r 3,-c (o) or 3,-c (o) n (r 3) (r c) ,-c (or b) (r 3) (r c) ,-c (nhr b) (r 3) (r c) or-c (=n-or c) r 3, wherein r bhydrogen, c 1-6alkyl, c 1-6haloalkyl ,-c 1-6alkyl-r b1,-c (o) r 3or-s (o) 2r 3,-c (o) (ch 2) 1-4coor ,-c (o) ch (nh 2) (r d),--s (o) 2or 3,-s (o) 2n (r 3) 2,-ch 2-op (o) 2(or) 2or-p (o) (or 3) 2, wherein r b1cyano group, nitro, c 1-6alkyl, c 1-6haloalkyl ,-or ,-n (r) 2,-sr ,-c (o) or ,-c (o) n (r) 2,-c (o) r ,-s (o) r ,-s (o) or ,-s (o) n (r) 2,-s (o) 2r ,-s (o) 2or ,-s (o) 2n (r) 2,-oc (o) r ,-oc (o) or ,-oc (o) n (r) 2,-n (r) c (o) r ,-n (r) c (o) or or-n (r) c (o) n (r) 2; r dhydrogen, methyl ,-ch (ch 3) 2,-ch 2ch (ch 3) 2,-ch (ch 3) (ch 2ch 3), benzyl, 4-hydroxybenzyl ,-ch 2(3-indyl) ,-ch 2sh ,-ch 2ch 2sch 3,-ch 2oh ,-ch (ch 3) oh ,-(ch 2) 4-nh 2,-(ch 2) 3-n (h) c (=nh) nh 2,-ch 2(4-imidazolyl) ,-ch 2cooh ,-ch 2ch 2cooh ,-ch 2conh 2,-ch 2ch 2conh 2; each r 3independent is hydrogen, c 1-6alkyl, c 1-6haloalkyl, aryl, heteroaryl, c 3-8cycloalkyl, c 3-8cycloalkenyl group, 3-10 unit heterocyclic radical, aryl c 1-6alkyl-, heteroaryl c 1-6alkyl-, c 3-8cycloalkyl c 1-6alkyl-, c 3-8cycloalkenyl group c 1-6alkyl-, or (3-10 unit heterocyclic radical) c 1-6alkyl-, whereindescribed alkyl, c 3-8cycloalkyl, c 3-8cycloalkenyl group, 3-10 unit heterocyclic radical, c 3-8cycloalkyl c 1-6alkyl-, c 3-8cycloalkenyl group c 1-6alkyl-and (3-10 unit heterocyclic radical) c 1-6alkyl-optional independently by one=r separately 32group replaces, and optional independently by one, two, three or four r separately 31group replaces; described aryl, heteroaryl, aryl c 1-6alkyl-and heteroaryl c 1-6alkyl-radical is separately optionally by one, two, three or four r 31group replaces; whereineach r 31independent is halogen, cyano group, nitro, c 1-6alkyl ,-c 1-6alkyl-r 33, c 1-6haloalkyl ,-or ,-n (r) 2,-sr ,-c (o) or ,-c (o) n (r) 2,-c (o) r ,-s (o) r ,-s (o) or ,-s (o) n (r) 2,-s (o) 2r ,-s (o) 2or ,-s (o) 2n (r) 2,-oc (o) r ,-oc (o) or ,-oc (o) n (r) 2,-n (r) c (o) r ,-n (r) c (o) or ,-n (r) c (o) n (r) 2, wherein r 33cyano group ,-or ,-n (r) 2,-sr ,-c (o) or ,-c (o) n (r) 2,-c (o) r ,-s (o) r ,-s (o) or ,-s (o) n (r) 2,-s (o) 2r ,-s (o) 2or ,-s (o) 2n (r) 2,-oc (o) r ,-oc (o) or ,-oc (o) n (r) 2,-n (r) c (o) r ,-n (r) c (o) or or-n (r) c (o) n (r) 2; r 32=o ,=s ,=n (r) ,=n (or) ,=c (r 34) 2,=(spiral shell-c 3-8cycloalkyl) or=(spiral shell-(3-10 unit heterocyclic radical)), wherein each r 34independent is hydrogen, halogen, c 1-6alkyl, c 1-6haloalkyl, c 3-8cycloalkyl or 3-10 unit heterocyclic radical; or two r 34the atom be jointly connected with it forms monocycle c jointly 3-8cycloalkyl or monocycle 3-8 unit heterocyclic radical; r chydrogen or c 1-6alkyl; witheach r is independently hydrogen or r 10, wherein r 10c 1-6alkyl, c 1-6haloalkyl, aryl, heteroaryl, c 3-8cycloalkyl, c 3-8cycloalkenyl group, 3-10 unit heterocyclic radical, aryl c 1-6alkyl, heteroaryl c 1-6alkyl-, c 3-8cycloalkyl c 1-6alkyl-, c 3-8cycloalkenyl group c 1-6alkyl-or (3-10 unit heterocyclic radical) c 1-6alkyl-, each r 10optionally replaced by one, two, three or four groups, described group is independently halogen, cyano group, nitro, c separately 1-6alkyl, c 1-6haloalkyl ,-or 11,-n (r 11) 2,-sr 11,-c (o) or 11,-c (o) n (r 11) 2,-c (o) r 11,-s (o) r 11,-s (o) or 11,-s (o) n (r 11) 2,-s (o) 2r 11,-s (o) 2or 11,-s (o) 2n (r 11) 2,-oc (o) r 11,-oc (o) or 11,-oc (o) n (r 11) 2,-n (r 11) c (o) r 11,-n (r 11) c (o) or 11,-n (r 11) c (o) n (r 11) 2, wherein each r 11independent is hydrogen or c 1-6alkyl.
트립토판 대사로 인한 면역억제의 억제제로서의 삼환식 화합물본 발명은 인돌아민 2,3-디옥시게나제 및 트립토판 2,3 디옥시게나제의 활성을 조절하고; 면역억제를 치료하며; 트립토판 저해를 억제하여 유익을 얻을 질병을 치료하고; 항암제를 투여하는 것을 포함하는 항암 치료의 유효성을 증진시키고; 암과 관련된 종양-특이적 면역억제를 치료하며; 감염성 질환과 관련된 면역억제를 치료하는데 유용한 IDO 및 TDO 억제제 및 이의 약학적 조성물을 제공합니다.하기 화학식의 화합물, 이의 토토머 또는 약학적으로 수용 가능한 염:[이미지]여기서n은 0, 1, 2, 3, 또는 4이고; 결합 α는 단일 또는 이중 결합이고, 고리 A는 방향족 고리이고, 여기서 i) V 및 X는 N이고, W 및 Z는 CH이고 Y는 C이거나; ii) V, Y 및 Z는 N이고, W는 CH이고, X는 C이거나; iii) V, W 및 Y는 N이고, X는 C이고 Z는 CH이거나; iv) V 및 W는 N 또는 NH이고, X 및 Y는 C이고, Z는 CH이고;각각의 R1은 독립적으로 할로겐, 시아노, 니트로, C1-6알킬, C1-6할로알킬, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, N(R)C(O)OR, 또는 -N(R)C(O)N(R)2이고;R2는 결합 α가 단일 결합인 경우 -C1-4알킬-RA 또는 -C2-4알케닐-R3이고;R2는 결합 α가 이중 결합인 경우 =C(H)RA이고;여기서RA는 -CN, -C(O)R3, -C(O)OR3, -C(O)N(R3)(RC), -C(ORB)(R3)(RC), C(NHRB)(R3)(RC), 또는 -C(=N-ORC)R3이고, 여기서RB는 수소, C1-6알킬, C1-6할로알킬, -C1-6알킬-RB1, -C(O)R3, 또는 S(O)2R3, -C(O)(CH2)1-4COOR, -C(O)CH(NH2)(RD), -S(O)2OR3,S(O)2N(R3)2,-CH2-OP(O)2(OR)2, 또는 -P(O)(OR3)2이고, 여기서RB1는 시아노, 니트로, C1-6알킬, C1-6할로알킬, -OR, -N(R)2, -SR, C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, 또는 -N(R)C(O)N(R)2이고;RD는 수소, 메틸, -CH(CH3)2, -CH2CH(CH3)2, CH(CH3)(CH2CH3), 벤질, 4-하이드록시벤질, -CH2(3-인돌일), -CH2SH, -CH2CH2SCH3, -CH2OH, -CH(CH3)OH, -(CH2)4-NH2, -(CH2)3-N(H)C(=NH)NH2, -CH2(4-이미다졸릴), -CH2COOH, -CH2CH2COOH, -CH2CONH2, CH2CH2CONH2이고;각각의 R3은 독립적으로 수소, C1-6알킬, C1-6할로알킬, 아릴, 헤테로아릴, C3-8사이클로알킬, C3-8사이클로알케닐, 3-10원 헤테로사이클릴, 아릴C1-6알킬, 헤테로아릴C1-6 알킬, C3-8사이클로알킬C1-6알킬, C3-8사이클로알케닐C1-6알킬, 또는 (3-10원 헤테로사이클릴)C1-6알킬이고,여기서상기 알킬, C3-8사이클로알킬, C3-8사이클로알케닐, 3-10원 헤테로사이클릴, C3-8사이클로알킬C1-6알킬, C3-8사이클로알케닐C1-6알킬, 및 (3-10원 헤테로사이클릴)C1-6알킬은 각각 임의적 및 독립적으로 하나의 =R32기로 치환되고 각각 임의적으로 및 독립적으로 하나, 둘, 셋, 또는 네개의 R31기로 치환되고;상기 아릴, 헤테로아릴, 아릴C1-6알킬, 및 헤테로아릴C1-6알킬기는 각각 임의적으로 하나, 둘, 셋, 또는 네개의 R31기로 치환되며;여기서각각의 R31은 독립적으로 할로겐, 시아노, 니트로, C1-6알킬, C1-6알킬-R33, C1-6할로알킬, -OR, -N(R)2, -SR, -C(O)OR, C(O)N(R)2, -C(O)R,- -S(O)R, -S(O)OR, -S(O)N(R)2, S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, N(R)C(O)N(R)2이고, 여기서R33은 시아노, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, 또는 N(R)C(O)N(R)2이고;R32는 =O, =S, =N(R), =N(OR), =C(R34)2, =(스피로-C3-8사이클로알킬), 또는 =(스피로-(3-10원 헤테로사이클릴))이고, 여기서각각의 R34는 독립적으로 수소, 할로겐, C1-6알킬, C1-6할로알킬, C3-8사이클로알킬, 또는 3-10원 헤테로사이클릴이거나;두 R34 모두는 이들에 결합된 원자와 함께 단환식 C3-8사이클로알킬 또는 단환식 3-8원 헤테로사이클릴을 형성하고;RC는 수소 또는 C1-6알킬이고;각각의 R은 독립적으로 수소 또는 R10이고, 여기서R10은 C1-6알킬, C1-6할로알킬, 아릴, 헤테로아릴, C3-8사이클로알킬, C3-8사이클로알케닐, 3-10원 헤테로사이클릴, 아릴C1-6알킬, 헤테로아릴C1-6알킬, C3-8 사이클로알킬C1-6알킬, C3-8사이클로알케닐C1-6알킬, 또는 (3-10원 헤테로사이클릴)C1-6알킬이고, 각각의 R10은 각각 독립적으로 할로겐, 시아노, 니트로, C1-6알킬, C1-6할로알킬, -OR11, -N(R11)2, -SR11, -C(O)OR11, -C(O)N(R11)2, -C(O)R11, S(O)R11, -S(O)OR11, -S(O)N(R11)2, -S(O)2R11, -S(O)2OR11, -S(O)2N(R11)2, OC(O)R11, -OC(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)R11, N(R11)C(O)OR11, -N(R11)C(O)N(R11)2인 하나, 둘, 셋, 또는 네개의 기로 임의적으로 치환되고, 여기서 각각의 R11은 독립적으로 수소 또는 C1-6알킬이다.