| 主权项 |
1. A compound or stereoisomer thereof having the structure of Formula (I)
wherein: R1 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═CR5R23 or —NHC(═O)R23;R2 is —C1-C6alkyl;R3 is R4 is —N(R6)2 or —NR6R7;R5 is N(R6)2;each R6 is independently selected from H and —C1-C6alkyl;R7 is —(CH2)mN(R12)2, —(CH2)mN(R12)C(═O)OR12 or an unsubstituted C3-C8cycloalkyl;or R7 is a C3-C8cycloalkyl substituted with 1-3 substituents independently selected from C1-C6alkyl, oxo, —C(═O)R18, —(CH2)mOH, —C(═O)(CH2)mOH, —C(═O)((CH2)mO)nR12, —((CH2)mO)nR12 or a C1-C6alkyl which is optionally substituted with 1 to 5 hydroxyl;R8 is an unsubstituted C-linked 5-6 membered heteroaryl having 1-2 N heteroatoms;or R8 is a C-linked 5-6 membered heteroaryl having 1-2 N heteroatoms which is substituted with 1-3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, C1-C6alkoxy, —OH, —CN, —NO2, —C(═O)OR6, —C(═O)N(R6)2, —C(═O)NR6(CH2)mN(R6)C(O)OR6 and —C(═O)NR6(CH2)mN(R6)2;R9 is —OH, C1-C6alkoxy, —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, R10 is LR11 or R11 isNR12C(═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, each R12 is independently selected from H and C1-C6alkyl; R13 is —S(CH2)nCHR14NHC(═O)R12 or R14 is R12 or —C(═O)OR12; R15 is tetrazolyl, —CN, —C(═O)OR12,-LR11 or —X4LR11;
R16 is an N-linked 4-8 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O, S, S(═O) and S(═O)2, which is unsubstituted or substituted with -LR11; R17 is 2-pyridyl or 4-pyridyl; each R18 is independently selected from a C1-C6alkyl, a C1-C6alkyl which is substituted with azido and a C1-C6alkyl which is substituted with 1 to 5 hydroxyl; R19 is an unsubstituted C-linked 5-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N and O; or R19 is a C-linked 5-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N and O which is substituted with 1-3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen and C1-C6alkoxy; R20 is an unsubstituted N-linked 5-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S; or R20 is an N-linked 5-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S, which is substituted with 1-2 substituents independently selected from C1-C6alkyl, —C(═O)OR12, —C(═O)(CH2)mN3, C1-C6haloalkyl, halogen, oxo, —OH and C1-C6alkoxy; R21 is a C-linked 5-6 membered heteroaryl having 1-2 N heteroatoms which is substituted with LR1 and 0-2 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, —CN, NO2, —C(═O)OR6, —C(═O)N(R6)2 and C1-C6alkoxy; R22 is a C-linked 5-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S which is substituted with LR11 and 0-2 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen and C1-C6alkoxy; R23 is an N-linked 5-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N and O which is substituted with LR11 and 0-2 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen and C1-C6alkoxy; each L is independently selected from -L1L2L3L4L5L6-, -L6L5L4L3L2L1-, -L1L2L3L4L5-, -L5L4L3L2L1-, -L1L2L3L4-, -L4L3L2L1-, -L1L2L3-, -L3L2L1-, -L1L2-, -L2L1- and -L1, wherein L1 is 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)O)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)X(═O)NR12(CH2)mX3(CH2)m—, —C(═O)NR12(CH2)mNR12C(═O)(CH2)m—, —C(═O)NR12(CH2)mNR12C(═O)(CH2)mX3(CH2)m—,—(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)—,—((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—, —(CH2)mNR12C(═O)(CH2)mNR12C(═O)(CH2)m—, —C(═O)NR12(CH2)mNR12C(═O)—, —(CH2)mS(CH2)m—, —NR12C(═O)(CH2)m—, —NR12C(═O)(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)mC(═O)NR12—, —(CH2)mC(═O)NR12—, —(CH2)mNR12(CH2)m—, —(CH2)mX3(CH2)m—, —(CH2)mX3—, —X3(CH2)m—, —((CH2)mO)n(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)m(O(CH2)m)n—, —NR12(CH2)m—, —NR12C(R12)2(CH2)m—, —(CH2)mC(R12)2NR12—, —(CH2)mC(═O)NR12(CH2)mNR12—, —(CH2)mC(═O)NR12(CH2)mNR12C(═O)NR12—, —(CH2)mC(═O)NR12(CH2)mNR12C(═O)—, —(CH2)mC(═O)X2X1C(═O)—, —NR12(CH2)mNR12C(═O)(CH2)m—, —NR12C(R12)2(CH2)mNR12C(═O)(CH2)m—, —(CH2)mC(═O)NR12(CH2)m(R12)2NR12, —NR12(CH2)mX3(CH2)m—, —NR12C(R12)2(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)mC(R12)2NR12—, —NR12C(R12)2(CH2)mOC(═O)NR12(CH2)m—, —(CH2)mNR12C(═O)O(CH2)mC(R12)2NR12—, —NR12C(R12)2(CH2)mOC(═O)NR12(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)mNR12C(═O)O(CH2)mC(R12)2NR12—, —NR12C(R12)2(CH2)mOC(═O)NR12((CH2)mO)n(CH2)m—, —(CH2)m(O(CH2)m)nNR12C(═O)O(CH2)mC(R12)2NR12—, —NR12C(R12)2(CH2)mOC(═O)NR12((CH2)mO)n(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)m(O(CH2)m)nNR12C(═O)O(CH2)mC(R12)2NR12—, —(CH2)mX3(CH2)mNR12, —NR12((CH2)mO)n(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)m(O(CH2)m)nNR12—, —(CH2)mNR12, —NR12((CH2)mO)n(CH2)m—, —NR12((CH2)mO)n(CH2)mNR12C(═O)(CH2)m—, —(CH2)mC(═O)NR12(CH2)m(O(CH2)m)nNR12—, —(CH2)m(O(CH2)m)nNR12—, —(C(R12)2)m—, —(CH2CH2O)11, —(OCH2CH2)n—, —(CH2)mO(CH2)m—, —S(═O)2(CH2)m—, —(CH2)mS(═O)2—, —S(═O)2(CH2)mNR12C(═O)(CH2)m—, —(CH2)mC(═O)NR12(CH2)mS(═O)2—, —S(═O)2(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)mS(═O)2—, —(CH2)mX2X1C(═O)—, —C(═O)X1X2(CH2)m—, —(CH2)m(O(CH2)m)nC(═O)X2X1C(═O)—, —C(═O)X1X2C(═O)((CH2)mO)n(CH2)m—, —(CH2)m(O(CH2)m)nX2X1C(═O)—, —(CH2)mX3(CH2)mX2X1C(═O)—, —C(═O)X1X2(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)m(O(CH2)m)nX2X1C(═O)—, —(CH2)mX3(CH2)mC(═O)NR12(CH2)mNR12C(═O)—, —(CH2)mX3(CH2)mC(═O)NR12(CH2)mC(═O)—, —C(═O)(CH2)mNR12C(═O(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)mC(═O)NR12(CH2)m(O(CH2)m)nC(═O)—, —C(═O)((CH2)mO)n(CH2)mNR12C(═O)(CH2)mX3(CH2)m—, —(CH2)mNR12C(═O)X1X2C(═O)(CH2)m—, —(CH2)mC(═O)X2X1C(═O)NR12(CH2)m—, —X4X1X2C(═O)(CH2)m—, —(CH2)mC(═O)X2X1X4—, —X1C(═O)(CH2)mNR12C(═O)(CH2)m—, —(CH2)mC(═O)NR12(CH2)mC(═O)X1—, —C(═O)CHRaaNR12, —NR12CHRaaC(═O)—, —C(═O)NR12—, —C(═O)O—, —S—, —SCH2(C═O)NR12—, —NR12C(═O)CH2S—, —S(═O)2CH2CH2S—, —SCH2CH2S(═O)2—, —(CH2)2S(═O)2CH2CH2S—, —SCH2CH2S(═O)2CH2CH2—, —NR12C(═S)—, —(CH2)mX3(O(CH2)m)nC(═O)—, —C(═O)((CH2)mO)nX3(CH2)m—, —(CH2)mNR12C(═O)((CH2)mO)n(CH2)m—, —(CH2)m(O(CH2)m)nC(═O)NR12(CH2)m—, —(CH2)mNR12C(═O)NR12(CH2)m—, —(CH2)mX3(CH2)mNR12C(═O)—, —C(═O)NR12(CH2)mX3(CH2)m—, —NR12S(═O)2(CH2)mX3(CH2)m—, —(CH2)mX3(CH2)mS(═O)2NR12—, R24 is H or Me; each R25 is independently selected from H or C1-4 alkyl; R26 is Raa is H or a side chain of an amino acid selected from alanine, tryptophan, tyrosine, phenylalanine, leucine, isoleucine, valine, asparagine, glutamic acid, glutamine, aspatic acid, histidine, arginine, lysine, cysteine, methionine, serine, threonine, citrulline, ornithine, phenylglycine and t-butylglycine; R30 is H, —CH3 Or phenyl; R32 is independently selected from H, C1-4 alkyl, phenyl, pyrimidine and pyridine; R33 is independently selected from R34 is independently selected from H, C1-4 alkyl, and C1-6 haloalkyl; X1 is self immolative spacer selected from X2 is dipeptide selected from X3 isand
X4 is L2, L3, L4, L5, and L6 are each independently selected from a bond and L1; each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18,or a pharmaceutically acceptable salt thereof. |
