Rapamycin analogs as MTOR inhibitorsThe present disclosure relates to rapamycin analogs of the general Formula (I). The compounds are inhibitors of mTOR and thus useful for the treatment of cancer, immune-mediated diseases and age related conditions.A compound represented by the formula i-x,or a pharmaceutically acceptable salt or tautomer thereof, wherein:r16is selected from r1、r2、h、(c1-c6) alkyl, -or3、-sr3、＝o、-nr3c(o)or3、-nr3c(o)n(r3)2、-nr3s(o)2or3、-nr3s(o)2n(r3)2、-nr3s(o)2r3、(c6-c10) aryl and 5-to 7-membered heteroaryl, andwherein said aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogenand a hydroxyl group;r26is selected from ═ n-r1、＝n-r2、＝o、-or3and n-or3；r28is selected from r1、r2、-or3、-oc(o)o(c(r3)2)n、-oc(o)n(r3)2、-os(o)2n(r3)2and-n (r)3)s(o)2or3；r32is selected from ═ n-r1、＝n-r2、h、＝o、-or3、＝n-or3、＝n-nhr3and n (r)3)2；r40is selected from r1、r2、-or3、-sr3、-n3、-n(r3)2、-nr3c(o)or3、-nr3c(o)n(r3)2、-nr3s(o)2or3、-nr3s(o)2n(r3)2、-nr3s(o)2r3、-op(o)(or3)2、-op(o)(r3)2、-nr3c(o)r3、-s(o)r3、-s(o)2r3、-os(o)2nhc(o)r3、andwherein the compound comprises one r1or a r2；r1is-a-l1-b；r2is-a-c ≡ ch, -a-n3-a-cooh or-a-nhr3(ii) a and iswhereina is absent or selected from- (c (r)3)2)n-、-o(c(r3)2)n-、-nr3(c(r3)2)n-、-o(c(r3)2)n-[o(c(r3)2)n]o-o(c(r3)2)p-、-c(o)(c(r3)2)n-、-c(o)nr3-、-nr3c(o)(c(r3)2)n-、-nr3c(o)o(c(r3)2)n-、-oc(o)nr3(c(r3)2)n-、-nhso2nh(c(r3)2)n-、-oc(o)nhso2nh(c(r3)2)n-、-o(c(r3)2)n-(c6-c10) arylene-radicals,-o(c(r3)2)n-a heteroarylene group-,-oc(o)nh(c(r3)2)n-(c6-c10) arylene-radicals,-o-(c6-c10) arylene-radicals,-o-heteroarylene-,-heteroarylene- (c)6-c10) arylene-radicals,-o(c(r3)2)n-(c6-c10) arylene radical- (c)6-c10) arylene-radicals,-o(c(r3)2)n-heteroarylene-,-o(c(r3)2)n-(c6-c10) arylene-heteroarylene- (c (r)3)2)n-、-o(c(r3)2)n-(c6-c10) arylene-heteroarylene-o (c (r)3)2)n-、-o(c(r3)2)n-(c6-c10) arylene-heteroarylene-nr3(c(r3)2)n-、-o(c(r3)2)n-heteroarylene-heterocyclylene-c (o) (c (r)3)2)n-、-heteroarylene- (c)6-c10) arylene radical- (c)6-c10) arylene-radicals,-heteroarylene- (c)6-c10) arylene-heteroarylene-o (c (r)3)2)n-、-heteroarylene- (c)6-c10) arylene-heteroarylene- (c (r)3)2)n2-o(c(r3)2)n-、-o(c(r3)2)n-heteroarylene-nr3-(c6-c10) arylene-radicals,-o(c(r3)2)n-heteroarylene-heterocyclylene- (c (r)3)2)n-、-o(c(r3)2)n-heteroarylene-heterocyclylene-c (o) (c (r)3)2)n-、-o(c(r3)2)n-(c6-c10) arylene-heteroarylene-heterocyclylene- (c (r)3)2)n-、-o(c(r3)2)n-(c6-c10) arylene-heteroarylene-heterocyclylene-c (o) (c (r)3)2)n-、-o(c(r3)2)n-(c6-c10) arylene-heteroarylene-heterocyclylene-so2(c(r3)2)n-、-heteroarylene- (c)6-c10) arylene-heteroarylene-heterocyclylene- (c (r)3)2)n-、-heteroarylene- (c)6-c10) arylene-heteroarylene-heterocyclylene-c (o) (c (r)3)2)n-、-heteroarylene- (c)6-c10) arylene-heteroarylene-heterocyclylene-so2(c(r3)2)n-and-o(c(r3)2)n-heteroarylene-heterocyclylene-s (o)2nr3-(c6-c10) an arylene radical-containing a substituted or unsubstituted alkylene group,wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from o, n and s; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from o, n and s;wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, hydroxy, -c (o) or3、-c(o)n(r3)2、-n(r3)2and is-n (r)3)2a substituted alkyl group;l1is selected fromandwherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;b is selected fromb1is selected fromnr3-(c(r3)2)n-、nr3-(c(r3)2)n-(c6-c10) arylene- (c (r)3)2)n-、nr3-(c(r3)2)n-a heteroarylene group-,(c6-c10) arylene-radicals,nr3-(c(r3)2)n-nr3c(o)-、nr3-(c(r3)2)n-heteroarylene-heterocyclylene- (c)6-c10) arylene-radicals,heteroarylene-heterocyclylene- (c)6-c10) arylene-radicals,andnr3-(c(r3)2)n-s(o)2arylene-c (o) -, wherein, as drawn, b1left side of the handbond to l1(ii) a and wherein said heteroaryl, heterocyclyl and arylene are optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen or hydroxy;each r3independently h, (c)1-c6) alkyl, -c (o) (c)1-c6) alkyl, -c (o) nh-aryl or-c (s) nh-aryl, wherein the alkyl is unsubstituted or substituted by-cooh, (c)6-c10) aryl or-oh substitution;each r4independently h, (c)1-c6) alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (c)6-c10) aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-n (r)3)2、-or3halogen, (c)1-c6) alkyl, - (c)1-c6) alkylene-heteroaryl, - (c)1-c6) alkylene-cn, -c (o) nr3-heteroaryl or-c (o) nr3-heterocyclyl substitution;each q is independently c (r)3)2or o;each y is independently c (r)3)2or a bond;each n is independently a number from one to 12;each o is independently a number from zero to 12;each p is independently a number from zero to 12;each q is independently a number from zero to 30; and iseach r is independently 1,2, 3 or 4;with the proviso that when r40is r1wherein r is1is-a-l1-b；l1is thatb isand b1is thatnr3-(c(r3)2)n-time of day; then a is not-o (ch)2)2-o(ch2)-。
mTOR 억제제로서의 파라마이신 유사체본 개시는 화학식 (I)의 라파마이신 유사체에 관한 것이다. 상기 화합물은 mTOR의 저해제이며, 따라서 암, 면역-매개 질환 및 연령 관련 병태의 치료에 유용하다.[이미지] (I)화학식 (I-X)로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염 또는 호변이성질체:[이미지] (I-X)[식 중,R16은 R1, R2, H, (C1-C6)알킬, -OR3, -SR3, =O, -NR3C(O)OR3, -NR3C(O)N(R3)2, -NR3S(O)2OR3, -NR3S(O)2N(R3)2, -NR3S(O)2R3, (C6-C10)아릴 및 5 내지 7-원 헤테로아릴 및 [이미지] (여기서, 아릴 및 헤테로아릴은 알킬, 히드록시알킬, 할로알킬, 알콕시, 할로겐 및 히드록실로부터 각각 독립적으로 선택되는 하나 이상의 치환기로 선택적으로 치환됨)로부터 선택되고;R26은 =N-R1, =N-R2, =O, -OR3 및 =N-OR3로부터 선택되고;R28은 R1, R2, -OR3, -OC(O)O(C(R3)2)n, -OC(O)N(R3)2,-OS(O)2N(R3)2 및 -N(R3)S(O)2OR3로부터 선택되고;R32는 =N-R1, =N-R2, H, =O, -OR3, =N-OR3, =N-NHR3 및 N(R3)2로부터 선택되고;R40은 R1, R2, -OR3, -SR3, -N3, -N(R3)2, -NR3C(O)OR3, -NR3C(O)N(R3)2, -NR3S(O)2OR3, -NR3S(O)2N(R3)2, -NR3S(O)2R3, -OP(O)(OR3)2, -OP(O)(R3)2, -NR3C(O)R3, -S(O)R3, -S(O)2R3, -OS(O)2NHC(O)R3, [이미지], [이미지], [이미지] 및 [이미지]로부터 선택되며;여기서 상기 화합물은 하나의 R1 또는 하나의 R2를 포함하고;R1은 -A-L1-B이고;R2는 -A-C≡CH, -A-N3, -A-COOH 또는 -A-NHR3이며;여기서,A는 존재하지 않거나, -(C(R3)2)n-, -O(C(R3)2)n-, -NR3(C(R3)2)n-, -O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-, -C(O)(C(R3)2)n-, -C(O)NR3-, -NR3C(O)(C(R3)2)n-, -NR3C(O)O(C(R3)2)n-, -OC(O)NR3(C(R3)2)n-, -NHSO2NH(C(R3)2)n-, -OC(O)NHSO2NH(C(R3)2)n-,-O(C(R3)2)n-(C6-C10)아릴렌-,-O(C(R3)2)n-헤테로아릴렌-,-OC(O)NH(C(R3)2)n-(C6-C10)아릴렌-,-O-(C6-C10)아릴렌-,-O-헤테로아릴렌-,-헤테로아릴렌-(C6-C10)아릴렌-,-O(C(R3)2)n-(C6-C10)아릴렌-(C6-C10)아릴렌-,-O(C(R3)2)n-헤테로아릴렌-헤테로아릴렌-,-O(C(R3)2)n-(C6-C10)아릴렌-헤테로아릴렌-(C(R3)2)n-,-O(C(R3)2)n-(C6-C10)아릴렌-헤테로아릴렌-O(C(R3)2)n-,-O(C(R3)2)n-(C6-C10)아릴렌-헤테로아릴렌-NR3(C(R3)2)n-,-O(C(R3)2)n-헤테로아릴렌-헤테로시클릴렌-C(O)(C(R3)2)n-,-헤테로아릴렌-(C6-C10)아릴렌-(C6-C10)아릴렌-,-헤테로아릴렌-(C6-C10)아릴렌-헤테로아릴렌-O(C(R3)2)n-,-헤테로아릴렌-(C6-C10)아릴렌-헤테로아릴렌-(C(R3)2)n2-O(C(R3)2)n-,-O(C(R3)2)n-헤테로아릴렌-헤테로아릴렌-NR3-(C6-C10)아릴렌-,-O(C(R3)2)n-헤테로아릴렌-헤테로아릴렌-헤테로시클릴렌-(C(R3)2)n-,-O(C(R3)2)n-헤테로아릴렌-헤테로아릴렌-헤테로시클릴렌-C(O)(C(R3)2)n-,-O(C(R3)2)n-(C6-C10)아릴렌-헤테로아릴렌-헤테로시클릴렌-(C(R3)2)n-,-O(C(R3)2)n-(C6-C10)아릴렌-헤테로아릴렌-헤테로시클릴렌-C(O)(C(R3)2)n-,-O(C(R3)2)n-(C6-C10)아릴렌-헤테로아릴렌-헤테로시클릴렌-SO2(C(R3)2)n-,-헤테로아릴렌-(C6-C10)아릴렌-헤테로아릴렌-헤테로시클릴렌-(C(R3)2)n-,-헤테로아릴렌-(C6-C10)아릴렌-헤테로아릴렌-헤테로시클릴렌-C(O)(C(R3)2)n-,-헤테로아릴렌-(C6-C10)아릴렌-헤테로아릴렌-헤테로시클릴렌-SO2(C(R3)2)n- 및-O(C(R3)2)n-헤테로아릴렌-헤테로아릴렌-헤테로시클릴렌-S(O)2NR3-(C6-C10)아릴렌-(여기서, 헤테로아릴렌은 5 내지 12-원이고, O, N 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 함유하고; 헤테로시클릴렌은 5 내지 12-원이고, O, N 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 함유하며;아릴렌, 헤테로아릴렌 및 헤테로시클릴렌은 알킬, 히드록시알킬, 할로알킬, 알콕시, 할로겐, 히드록실, -C(O)OR3, -C(O)N(R3)2, -N(R3)2, 및 -N(R3)2로 치환된 알킬로부터 각각 독립적으로 선택되는 하나 이상의 치환기로 선택적으로 치환됨)로부터 선택되고;L1은[이미지], [이미지], [이미지],[이미지], [이미지], [이미지], [이미지],[이미지], [이미지],[이미지], [이미지],[이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지] 및 [이미지](여기서, 트리아졸에서 가변 위치와의 결합은 4-위치 또는 5-위치에 있고, A 고리는 페닐렌 또는 5 내지 8-원 헤테로아릴렌임)로부터 선택되고;B는[이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지] 및 [이미지]로부터 선택되고;B1은 [이미지]NR3-(C(R3)2)n-, [이미지]NR3-(C(R3)2)n-(C6-C10)아릴렌-(C(R3)2)n-, [이미지]NR3-(C(R3)2)n-헤테로아릴렌-, [이미지](C6-C10)아릴렌-, [이미지]NR3-(C(R3)2)n-NR3C(O)-,[이미지]NR3-(C(R3)2)n-헤테로아릴렌-헤테로시클릴렌-(C6-C10)아릴렌-, [이미지]헤테로아릴렌-헤테로시클릴렌-(C6-C10)아릴렌-, [이미지], [이미지],[이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지], [이미지] 및 [이미지]NR3-(C(R3)2)n- S(O)2-아릴렌-C(O)- (여기서, 도시된 바와 같은, B1의 좌측 상의 [이미지] 결합은, L1에 결합되고; 헤테로아릴, 헤테로시클릴 및 아릴렌은 알킬, 히드록시알킬, 할로알킬, 알콕시, 할로겐 또는 히드록실로 선택적으로 치환됨)로부터 선택되고;각각의 R3은 독립적으로 H, (C1-C6)알킬, -C(O)(C1-C6)알킬, -C(O)NH-아릴 또는 -C(S)NH-아릴 (여기서, 알킬은 미치환되거나, -COOH, (C6-C10)아릴 또는 -OH로 치환됨)이고;각각의 R4는 독립적으로 H, (C1-C6)알킬, 할로겐, 5 내지 12-원 헤테로아릴, 5 내지 12-원 헤테로시클릴, (C6-C10)아릴 (여기서, 헤테로아릴, 헤테로시클릴 및 아릴은 -N(R3)2, -OR3, 할로겐, (C1-C6)알킬, -(C1-C6)알킬렌-헤테로아릴, -(C1-C6)알킬렌-CN, -C(O)NR3-헤테로아릴 또는 -C(O)NR3-헤테로시클릴로 선택적으로 치환됨)이고;각각의 Q는 독립적으로 C(R3)2 또는 O이고;각각의 Y는 독립적으로 C(R3)2 또는 결합이고;각각의 n은 독립적으로 1 내지 12의 수이고;각각의 o는 독립적으로 0 내지 12의 수이고;각각의 p는 독립적으로 0 내지 12의 수이고;각각의 q는 독립적으로 0 내지 30의 수이고;각각의 r은 독립적으로 1, 2, 3 또는 4이며;단, R40이 R1인 경우, R1은 -A-L1-B이고; L1은 [이미지]이고; B는 [이미지]이고; B1은 [이미지]NR3-(C(R3)2)n- 이며; A는 -O(CH2)2-O(CH2)- 가 아님].