Auristatin derivatives and conjugates thereofDisclosed herein are novel compounds of formula (I) as described herein, and the use of such peptides in making immunoconjugates (i.e Antibody Drug Conjugates) Also described herein are immunoconjugates (i.e Antibody Drug Conjugates) comprising such novel compound linked to an antigen binding moiety, such as an antibody; where such immunoconjugates are useful for treating cell proliferative disorders. The invention further provides pharmaceutical compositions comprising these immunoconjugates, compositions comprising the immunoconjugates with a therapeutic co-agent, and methods to use these immunoconjugates and compositions for treating cell proliferation disorders.There is the compound or its stereoisomer of formula (i) structure,wherein,r1it is-n=cr4r5,-n=r19,-n=cr5r20,-n=cr5nr12(ch2)mn(r12)c(o)or12,-n=cr5nr12 (ch2)mn(r12)2,-nhc (=nr6)r4,-nhc (=o) r4,-nhc (=o) r20、–nhr8、-nhlr11、-nhr21,-n= cr5r10,-n=r22,-n=cr5r23or-nhc (=o) r23；r2it is-c1-c6alkyl；r3it isr4it is-n (r6)2or-nr6r7；r5it is n (r6)2；r6it is each independently selected from h and-c1-c6alkyl；r7it is-(ch2)mn(r12)2、-(ch2)mn(r12) c (=o) or12or unsubstituted c3-c8cycloalkyl；or r7it is c3-c8cycloalkyl, it is replaced by 1-3 independently selected from following substituent group：c1-c6alkyl, oxo ,-c (= o)r18、-(ch2)moh ,-c (=o) (ch2)moh ,-c (=o) ((ch2)mo)nr12、-((ch2)mo)nr12or optionally by 1-5 hydroxyl the c that base replaces1-c6alkyl；r8it is unsubstituted c- connection comprising the heteroatomic 5-6 unit's heteroaryls of 1-2 n；or r8be c- connections comprising the heteroatomic 5-6 unit's heteroaryls of 1-2 n, it is individual independently selected from following replacement by 1-3 base replaces：c1-c6alkyl, c1-c6haloalkyl, halogen, c1-c6alkoxyl ,-oh ,-cn ,-no2,-c (=o) or6,-c (=o) n (r6)2,-c (=o) nr6(ch2)mn(r6)c(o)or6with-c (=o) nr6(ch2)mn(r6)2；r9it is-oh, c1-c6alkoxyl ,-nhs (o)2(ch2)mn3、-nhs(o)2(ch2)mnh2、-n(r12)2、-r16、-nr12(ch2)mn(r12)2、-nr12(ch2)mr16、-lr11、-nhs(o)2r18,-nhs (=o)2lr11、r10it is lr11orr11it is-nr12c (=o) ch=ch2、-n3、sh、-ssr17,-s (= o)2(ch=ch2)、-(ch2)2s (=o)2(ch=ch2)、-nr12s (=o)2(ch=ch2)、-nr12c (=o) ch2r13、-nr12c (=o) ch2br、-nr12c (=o) ch2i ,-nhc (=o) ch2br ,-nhc (=o) ch2i、-onh2、-c(o)nhnh2、- co2h、-nh2、-nco、-ncs、r12it is each independently selected from h and c1-c6alkyl；r13it is-s (ch2)nchr14nhc (=o) r12orr14it is r12or-c (=o) or12；r15it is tetrazole radical ,-cn ,-c (=o) or12、-lr11 or-x4lr11；r16be n- connection comprising independently selected from n, o, s, s (=o) and s (=o)21-2 heteroatomic 4-8 circle heterocycles alkane base, it is unsubstituted or by-lr11replace；r17it is 2- pyridine radicals or 4- pyridine radicals；r18it is each independently selected from c1-c6alkyl, the c replaced by azido1-c6alkyl and the c replaced by 1-5 hydroxyl1-c6alkane base；r19it is unsubstituted c- connection comprising the 1-2 heteroatomic 5-6 circle heterocycles alkyl independently selected from n and o；or r19be c- connections comprising the 1-2 heteroatomic 5-6 circle heterocycles alkyl independently selected from n and o, its by 1-3 solely on the spot replace selected from following substituent group：c1-c6alkyl, c1-c6haloalkyl, halogen and c1-c6alkoxyl；r20it is unsubstituted n- connection comprising the 1-2 heteroatomic 5-6 circle heterocycles alkyl independently selected from n, o and s；or r20be n- connections comprising the 1-2 heteroatomic 5-6 circle heterocycles alkyl independently selected from n, o and s, it is by 1-2 replace independently selected from following substituent group：c1-c6alkyl ,-c (=o) or12,-c (=o) (ch2)mn3、c1-c6haloalkyl, halogen, oxo ,-oh and c1-c6alkoxyl；r21be c- connections comprising the heteroatomic 5-6 unit's heteroaryls of 1-2 n, it is by lr11with 0-2 independently selected from following substituent group replaces：c1-c6alkyl, c1-c6haloalkyl, halogen ,-cn, no2,-c (=o) or6,-c (=o) n (r6)2and c1-c6 alkoxyl；r22be c- connections comprising the 1-2 heteroatomic 5-6 circle heterocycles alkyl independently selected from n, o and s, it is by lr11and 0-2 it is individual to replace independently selected from following substituent group：c1-c6alkyl, c1-c6haloalkyl, halogen and c1-c6alkoxyl；r23be n- connections comprising the 1-2 heteroatomic 5-6 circle heterocycles alkyl independently selected from n and o, it is by lr11with 0-2 replace independently selected from following substituent group：c1-c6alkyl, c1-c6haloalkyl, halogen and c1-c6alkoxyl；l is each independently selected from-l1l2l3l4l5l6-、-l6l5l4l3l2l1-、-l1l2l3l4l5-、-l5l4l3l2l1-、- l1l2l3l4-、-l4l3l2l1-、-l1l2l3-、-l3l2l1-、-l1l2-、-l2l1- and-l1,wherein l1it is to be selected from：-(ch2)m- ,-c (=o) (ch2)m-、-nr12c (=o) (ch2)m- ,-c (=o) x1x2c (=o) (ch2)m- ,-c (=o) x1x2c (=o) (ch2)mnr12c (=o) (ch2)m- ,-c (=o) x1x2c (=o) (ch2)mx3(ch2)m- ,-c (=o) x1x2c (= o)((ch2)mo)n(ch2)m- ,-c (=o) x1x2c (=o) ((ch2)mo)n(ch2)mnr12c (=o) (ch2)m- ,-c (=o) x1x2c (=o) ((ch2)mo)n(ch2)mnr12c (=o) (ch2)mx3(ch2)m- ,-c (=o) x1x2c (=o) ((ch2)mo)n(ch2)mx3 (ch2)m- ,-c (=o) x1x2c (=o) (ch2)mnr12c (=o) ((ch2)mo)n(ch2)m- ,-c (=o) x1x2c (=o) (ch2)mnr12c (=o) ((ch2)mo)n(ch2)mx3(ch2)m- ,-c (=o) x1x2(ch2)mx3(ch2)m- ,-c (=o) x1x2((ch2)mo)n (ch2)m- ,-c (=o) x1x2((ch2)mo)n(ch2)mnr12c (=o) (ch2)m- ,-c (=o) x1x2((ch2)mo)n(ch2)mnr12c (=o) (ch2)mx3(ch2)m- ,-c (=o) x1x2((ch2)mo)n(ch2)mx3(ch2)m- ,-c (=o) x1x2(ch2)mnr12 ((ch2)mo)n(ch2)m- ,-c (=o) x1x2c (=o) (ch2)mnr12((ch2)mo)n(ch2)mx3(ch2)m-、-(ch2)mnr12c (=o) (ch2)m- ,-c (=o) ((ch2)mo)n(ch2)m-、-(ch2)ms (=o)2((ch2)mo)n(ch2)m- ,-c (=o) (ch2)mnr12(ch2)m- ,-c (=o) nr12(ch2)m- ,-c (=o) nr12(ch2)mx3(ch2)m- ,-c (=o) nr12(ch2)mnr12c (= o)x1x2c (=o) (ch2)m- ,-c (=o) x1c (=o) nr12(ch2)mnr12c (=o) (ch2)m- ,-c (=o) x1c (=o) nr12 (ch2)mx3(ch2)m- ,-c (=o) n...
아우리스타틴 유도체 및 그의 접합체본원에 기재된 바와 같은 화학식 I의 신규 화합물 및 면역접합체 (즉 항체 약물 접합체)를 제조하는데 있어서 이러한 펩티드의 용도가 본원에 개시된다. 또한, 항원 결합 모이어티, 예컨대 항체에 연결된 이러한 신규 화합물을 포함하는 면역접합체 (즉 항체 약물 접합체)가 본원에 기재되며; 여기서 이러한 면역접합체는 세포 증식성 장애를 치료하는데 유용하다. 본 발명은 추가로 이들 면역접합체를 포함하는 제약 조성물, 치료 공동-작용제와 함께 면역접합체를 포함하는 조성물, 및 세포 증식 장애를 치료하기 위해 이들 면역접합체 및 조성물을 사용하는 방법을 제공한다. <화학식 I>화학식 I의 구조를 갖는 화합물 또는 그의 입체이성질체, 또는 그의 호변이성질체, 수화물, 또는 제약상 허용되는 염.<화학식 I>[이미지]여기서,R1은 -N=CR4R5, -N=R19, -N=CR5R20, -N=CR5NR12(CH2)mN(R12)C(O)OR12, -N=CR5NR12(CH2)mN(R12)2, -NHC(=NR6)R4, -NHC(=O)R4, -NHC(=O)R20, -NHR8, -NHLR11, -NHR21, -N=CR5R10, -N=R22, -N=CR5R23 또는 -NHC(=O)R23이고;R2는 -C1-C6알킬이고;R3은 [이미지]이고;R4는 -N(R6)2 또는 -NR6R7이고;R5는 N(R6)2이고;각각의 R6은 독립적으로 H 및 -C1-C6알킬로부터 선택되고;R7은 -(CH2)mN(R12)2, -(CH2)mN(R12)C(=O)OR12 또는 비치환된 C3-C8시클로알킬이거나;또는 R7은 C1-C6알킬, 옥소, -C(=O)R18, -(CH2)mOH, -C(=O)(CH2)mOH, -C(=O)((CH2)mO)nR12, -((CH2)mO)nR12, 또는 1 내지 5개의 히드록실로 임의로 치환된 C1-C6알킬로부터 독립적으로 선택된 1-3개의 치환기로 치환된 C3-C8시클로알킬이고;R8은 1-2개의 N 헤테로원자를 갖는 비치환된 C-연결된 5-6원 헤테로아릴이거나;또는 R8은 C1-C6알킬, C1-C6할로알킬, 할로겐, C1-C6알콕시, -OH, -CN, -NO2, -C(=O)OR6, -C(=O)N(R6)2, -C(=O)NR6(CH2)mN(R6)C(O)OR6 및 -C(=O)NR6(CH2)mN(R6)2로부터 독립적으로 선택된 1-3개의 치환기로 치환된, 1-2개의 N 헤테로원자를 갖는 C-연결된 5-6원 헤테로아릴이고;R9는 -OH, C1-C6알콕시, -NHS(O)2(CH2)mN3, -NHS(O)2(CH2)mNH2, -N(R12)2, -R16, -NR12(CH2)mN(R12)2, -NR12(CH2)mR16, -LR11, -NHS(O)2R18, -NHS(=O)2LR11,[이미지]이고;R10은 LR11 또는 [이미지]이고;R11은[이미지], -NR12C(=O)CH=CH2, -N3, [이미지], SH, -SSR17, -S(=O)2(CH=CH2), -(CH2)2S(=O)2(CH=CH2), -NR12S(=O)2(CH=CH2), -NR12C(=O)CH2R13, -NR12C(=O)CH2Br, -NR12C(=O)CH2I, -NHC(=O)CH2Br, -NHC(=O)CH2I, -ONH2, -C(O)NHNH2, [이미지], -CO2H, -NH2, -NCO, -NCS,[이미지][이미지]이고;각각의 R12는 독립적으로 H 및 C1-C6알킬로부터 선택되고;R13은 -S(CH2)nCHR14NHC(=O)R12 또는[이미지]이고;R14는 R12 또는 -C(=O)OR12이고;R15는 테트라졸릴, -CN, -C(=O)OR12,[이미지],-LR11 또는 -X4LR11이고;R16은 비치환되거나 또는 -LR11로 치환된, N, O, S, S(=O) 및 S(=O)2로부터 독립적으로 선택된 1-2개의 헤테로원자를 함유하는 N-연결된 4-8원 헤테로시클로알킬이고;R17은 2-피리딜 또는 4-피리딜이고;각각의 R18은 독립적으로 C1-C6알킬, 아지도로 치환된 C1-C6알킬, 및 1 내지 5개의 히드록실로 치환된 C1-C6알킬로부터 선택되고;R19는 N 및 O로부터 독립적으로 선택된 1-2개의 헤테로원자를 갖는 비치환된 C-연결된 5-6원 헤테로시클로알킬이거나;또는 R19는 C1-C6알킬, C1-C6할로알킬, 할로겐 및 C1-C6알콕시로부터 독립적으로 선택된 1-3개의 치환기로 치환된, N 및 O로부터 독립적으로 선택된 1-2개의 헤테로원자를 갖는 C-연결된 5-6원 헤테로시클로알킬이고;R20은 N, O 및 S로부터 독립적으로 선택된 1-2개의 헤테로원자를 갖는 비치환된 N-연결된 5-6원 헤테로시클로알킬이거나;또는 R20은 C1-C6알킬, -C(=O)OR12, -C(=O)(CH2)mN3, C1-C6할로알킬, 할로겐, 옥소, -OH 및 C1-C6알콕시로부터 독립적으로 선택된 1-2개의 치환기로 치환된, N, O 및 S로부터 독립적으로 선택된 1-2개의 헤테로원자를 갖는 N-연결된 5-6원 헤테로시클로알킬이고;R21은 LR11 및 C1-C6알킬, C1-C6할로알킬, 할로겐, -CN, NO2, -C(=O)OR6, -C(=O)N(R6)2 및 C1-C6알콕시로부터 독립적으로 선택된 0-2개의 치환기로 치환된, 1-2개의 N 헤테로원자를 갖는 C-연결된 5-6원 헤테로아릴이고;R22는 LR11 및 C1-C6알킬, C1-C6할로알킬, 할로겐 및 C1-C6알콕시로부터 독립적으로 선택된 0-2개의 치환기로 치환된, N, O 및 S로부터 독립적으로 선택된 1-2개의 헤테로원자를 갖는 C-연결된 5-6원 헤테로시클로알킬이고;R23은 LR11 및 C1-C6알킬, C1-C6할로알킬, 할로겐 및 C1-C6알콕시로부터 독립적으로 선택된 0-2개의 치환기로 치환된, N 및 O로부터 독립적으로 선택된 1-2개의 헤테로원자를 갖는 N-연결된 5-6원 헤테로시클로알킬이고;각각의 L은 독립적으로 -L1L2L3L4L5L6-, -L6L5L4L3L2L1-, -L1L2L3L4L5-, -L5L4L3L2L1-, -L1L2L3L4-, -L4L3L2L1-, -L1L2L3-, -L3L2L1-, -L1L2-, -L2L1- 및 -L1로부터 선택되고,여기서 L1은-(CH2)m-, -C(=O)(CH2)m-, -NR12C(=O)(CH2)m-, -C(=O)X1X2C(=O)(CH2)m-, -C(=O)X1X2C(=O)(CH2)mNR12C(=O)(CH2)m-, -C(=O)X1X2C(=O)(CH2)mX3(CH2)m-, -C(=O)X1X2C(=O)((CH2)mO)n(CH2)m-, -C(=O)X1X2C(=O)((CH2)mO)n(CH2)mNR12C(=O)(CH2)m-, -C(=O)X1X2C(=O)((CH2)mO)n(CH2)mNR12C(=O)(CH2)mX3(CH2)m-, -C(=O)X1X2C(=O)((CH2)mO)n(CH2)mX3(CH2)m-, -C(=O)X1X2C(=O)(CH2)mNR12C(=O)((CH2)mO)n(CH2)m-, -C(=O)X1X2C(=O)(CH2)mNR12C(=O)((CH2)mO)n(CH2)mX3(CH2)m-, -C(=O)X1X2(CH2)mX3(CH2)m-, -C(=O)X1X2((CH2)mO)n(CH2)m-, -C(=O)X1X2((CH2)mO)n(CH2)mNR12C(=O)(CH2)m-, -C(=O)X1X2((CH2)mO)n(CH2)mNR12C(=O)(CH2)mX3(CH2)m-, -C(=O)X1X2((CH2)mO)n(CH2)mX3(CH2)m-, -C(=O)X1X2(CH2)mNR12((CH2)mO)n(CH2)m-, -C(=O)X1X2C(=O)(CH2)mNR12((CH2)mO)n(CH2)mX3(CH2)m-, -(CH2)mNR12C(=O)(CH2)m-, -C(=O)((CH2)mO)n(CH2)m-,-(CH2)mS(=O)2((CH2)mO)n(CH2)m-, -C(=O)(CH2)mNR12(CH2)m-, -C(=O)NR12(CH2)m-, -C(=O)NR12(CH2)mX3(CH2)m-, -C(=O)NR12(CH2)mNR12C(=O)X1X2C(=O)(CH2)m-, -C(=O)X1C(=O)NR12(CH2)mNR12C(=O)(CH2)m-, -C(=O)X1C(=O)NR12(CH2)mX3(CH2)m-, -C(=O)NR12(CH2)mNR12C(=O)(CH2)m-, -C(=O)NR12(CH2)mNR12C(=O)(CH2)mX3(CH2)m-, [이미지], -(CH2)mC(=O)NR12(CH2)mNR12C(=O)(CH2)m-, -(CH2)mC(=O)-, -C(=O)(CH2)mNR12(CH2)mC(=O)X2X1C(=O)-, -(CH2)mX3(CH2)mC(=O)X2X1C(=O)-, -(CH2)mC(=O)NR12(CH2)m-, -(CH2)mC(=O)NR12(CH2)mX3(CH2)m-, -(CH2)mX3(CH2)mNR12C(=O)(CH2)m-, -(CH2)mC(=O)NR12(CH2)mX3-, -X3(CH2)mNR12C(=O)(CH2)m-, -(CH2)mX3(CH2)mC(=O)NR12(CH2)m-, -(CH2)mNR12C(=O)(CH2)mX3(CH2)m-, -(CH2)mO)n(CH2)mNR12C(=O)(CH2)m-, -(CH2)mC(=O)NR12(CH2)m(O(CH2)m)n-, -((C(R12)2)mOC(=O)NR12(CH2)mO(CH2)m-, -(CH2)m(O(CH2)m)nNR12C(=O)O(C(R12)2)m-, -(CH2)m(O(CH2)m)nC(=O)-, -(CH2)m(O(CH2)m)nS(=O)2(CH2)m-, -(CH2)mNR12(CH2)mC(=O)-, -(CH2)mO(CH2)mNR12C(=O)O((C(R12)2)m-, -(CH2)mNR12C(=O)-, -(CH2)mC(=O)X2X1C(=O)NR12(CH2)mNR12C(=O)-, -(CH2)mC(=O)NR12(CH2)mNR12C(=O)X1-, -(CH2)mC(=O)NR12(CH2)mNR12C(=O)-, [이미지], -((CH2)mO)n(CH2)m-,-(CH2)m(O(CH2)m)n-, -(CH2)m(O(CH2)m)nX3(CH2)m-, -(CH2)mX3((CH2)mO)n(CH2)m-, -(CH2)mX3(CH2)mC(=O)-, -C(=O)(CH2)mX3(CH2)m-, -(CH2)mC(=O)NR12(CH2)mO)n(CH2)mX3-, -X3(CH2)m(O(CH2)m)nNR12C(=O)(CH2)m-, -(CH2)mC(=O)NR12(CH2)mO)n(CH2)mX3(CH2)m-, -(CH2)mX3(CH2)m(O(CH2)m)nNR12C(=O)(CH2)m-, -(CH2)mX3(CH2)m(O(CH2)m)nC(=O)-, -C(=O)((CH2)mO)n(CH2)mX3(CH2)m-, -(CH2)mC(=O)NR12(CH2)mC(=O)-, -C(=O)(CH2)mNR12C(=O)(CH2)m-, -(CH2)mC(=O)NR12(CH2)m(O(CH2)m)nC(=O)-, -C(=O)((CH2)mO)n(CH2)mNR12C(=O)(CH2)m-, -(CH2)mC(=O)NR12(CH2)mC(=O)NR12(CH2)m-...