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1. Compounds of Formula (I) Wherein ---- represents an optional single bond; represents either a single bond or a double bond; It provided that when represents a single bond, U and U′, the same or different, independently represent H, R5, or an amine protecting moiety, or the linking group (L′) with the reactive group or a cell binding agent bonded thereto. V and V′, the same or different, are independently selected from the group consisting of H, OH, —NHOH; —OR5; —OCOR5; —OCOOR5; —NR5R5′, —NR5COR5′, —NR5NR5′NR5″; —OCONR5R5′; —NR5(C═NH)NR5R5″; an amino acid, or peptide represented by —NR5CO(Aa)t, wherein Aa is an amino acid or a polypeptide containing between t=1-100 amino acid units; a optionally substituted 5- or 6-membered nitrogen-containing heterocycle (piperidine, tetrahydropyrrole, pyrazole, morpholine); a cyclic carbamate that U and V, and/or U′ and V′ are a part of the cycle; —NR5CONR5′R5″; —OCSNHR5; a cyclic thiocarbamate such that U and V, and U′ and V′ are a part of the cycle; —SH; —SR5; —SOR5; —SOOR5; —SO3, HSO3−, HSO2−, or a salt of HSO3−, SO32− or —HSO2−; —OSO3−; —NR5SOOR5′; H2S2O5 or a salt of S2O52−; PO3SH3, PO2S2H2, POS3H2, PS4H2 or a salt of PO3S3−, PO2S23−, POS33−, PS43−; —(R5O)2POSR5′; HS2O3 or a salt of S2O32−; HS2O4 or a salt of S2O42−; —P(═S)(OR5)(S)(OH) or a salt thereof form with a cation; optionally cyclic amine such that U and V, and U′ and V′ are a part of the cycle; —NR5OR5′; R5C(═O)NOH or a salt formed with a cation; HOCH2SO2−, or its salts; an —NR5COR5′; N3; a cyano; a halo; a trialkylphosphoramidate (phosphoramidic acid), or triarylphosphonium; an amino acid-derived group; or the linking group (L′) with the reactive group or a cell binding agent bonded thereto. The R5, R5′ and R5″ are described below. and when represents a double bond, U and U′ are absent; V and V′ represent H, a linear or branched alkyl having 1 to 4 carbon atoms l, m, n, l′, m′ and n′ are the number 0, 1, 2, 3, 4, 5 or 6. X, X′, Y and Y′ the same or different, independently, represent N, O, S, CH2, CHR5, ═CH—, ═CR5—, or —C(OR5)H—. Z and Z′ the same or different, independently, represent N, CH, C—R5, COH or COR5. R1, R2, R3, R4, R1′, R2′, R3′, and R4′ are the same or different and independently chosen from —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl, alkynyl or aryl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(OCH2CH2)tR5, halogen, —NH(C═NH)NH2, —OR5, —NR5R5′, —NO2, —NCO, —NR5COR5′, —SR5, —SOR5, —SO2R5, —SO3−M+, —SO3H, —OSO3−M+, OSO3H, —SO2NR5R5′, cyano, an azido, —COR5, —OCOR5, —OCONR5R5′, CF3, OR5, aryl, heterocycle, or P(O)R5R5′R5″ or the linking group (L′) with the reactive group, or a cell binding agent bonded thereto; R5, R5′ and R5″ are independently selected from H, linear, branched or cyclic alkyl, alkenyl alkynyl or aryl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH2CH2O)r-R1, an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P; R5, R5′ and R5′ can further be substituted with at least one substituent selected from —N(R1)(R2), —CO2H, —SO3H, —OR1, —CO2R1, —CONR1, —PO2R1R2, POR1R2R3 or —PO3H, or pharmaceutical salts. q=0, 1 or 2. In addition, R2 and R3 join together, or R2′ and R3′ join together to form a ═ (double bond), ═O (ketone), ═S, ═NR5, —C(═O)R5, or a double bond containing group ═CR5R5′; and R1 and R2 join together, or R1′ and R2′ join together, or R3 and R4 join together, or R3′ and R4′ join together form an aromatic, heterocyclic, or heteroaryl ring. L and L′ are the same or independently a linker or a linker-cell binding molecule (Q) covalently bound cluster, or a linker which has a functional group on the linker that enables reaction with a cell-binding agent (CBA). L, when is a linker, which has the formula of: -Ww-(Aa)r-Tt-; or -Ww-(Aa)r-Tt-Q; or Q-Ww-(Aa)r-Tt-; wherein: W is a Stretcher unit; w is 0 or 1; Aa is independently an Amino Acid unit; r is independently an integer ranging from 0 to 100. The Stretcher unit W independently contains a self-immolative or a non-self-immolative component, peptidyl units, a hydrazone bond, a disulfide, an ester, an oxime, an amide, or a thioether bond. The self-immolative unit include, aromatic compounds that are electronically similar to the para-aminobenzylcarbamoyl (PAB) groups: 2-aminoimidazol-5-methanol derivatives, heterocyclic PAB analogs, beta-glucuronide, and ortho or para-aminobenzylacetals. The self-immolative linker component has any one of the following structures:wherein the (*) atom is the point of attachment of additional spacer or releasable linker units, or the cytotoxic agent, and/or the binding molecule (CBA); X1, Y1, Z2 and Z3 are independently NH, or O, or S; Z1 is H, or NH, or O or S independently. v is 0 or 1; Q1 is independently H, OH, C1-C6 alkyl, (OCH2CH2)n F, Cl, Br, I, OR5, or SR5, NR5R5′, N═NR5, N═R5, NR5R5′, NO2, SOR5R5′, SO2R5, SO3R5, OSO3R5, PR5R5′, POR5R5′, PO2R5R5′, OPO(OR5)(OR5′), or OCH2PO(OR5(OR5′) wherein R5 and R5′ are as defined above, preferably R5 and R5′ are independently selected from H, C1-C8 of alkyl; C2-C8 of alkenyl, alkynyl, heteroalkyl; C3-C8 of aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, alkylcarbonyl; or pharmaceutical cation salts.
The non-self-immolative linker component is any one of the following structures:Wherein the (*) atom is the point of attachment of additional spacer or releaseable linkers, the cytotoxic agents, and/or the binding molecules; X1, Y1, Q1, R5, R5′ are as defined above; r is 0-100; m, n and p are 0-6.
Spacers (T) is a linear, branched or cyclic alkyl, alkenyl, alkynyl or aryl having from 1 to 10 carbon atoms, or polyethylene glycol (—CH2CH2O—) spacer; and t is 0, or 1-100. T can also be that undergo cyclization upon amide bond hydrolysis, substituted and unsubstituted 4-aminobutyric acid amides, appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems, and 2-aminophenylpropionic acid amides. In addition L can be R5, OR5, SR5, NHR5, or NR5R5′, thus R1, R2, R3, R4, R1′, R2′, R3′, or R4′, or U, or U′, or V, or V′ on the Formula (I) can be used to linked to Q via Stretcher units (Ww) or via Spacer units (Tt) when the compound is used for conjugation to a cell binding agent. Q is a cell binding molecule (CBA), or a functional group that enables reaction with a cell-binding agent, or a functional group capable of reacting with a linker attached on a cell binding agent. The function group is chosen from a thiol, an amine, a hydrazine, an alkoxylamino, a disulfide substituent, a maleimido, a haloacetyl group, a carboxy acid, an N-hydroxy succinimide ester, a ketone, an ester, an aldehyde, an alkynyl, an alkenyl, or protected thiol or disulfide group: SAc, SSR1 or SSAr. Ar is aromatic group or hetero aromatic group. or a pharmaceutically acceptable salt, hydrates, or hydrated salt, or the polymorphic crystalline structure of the compounds thereof, or the optical isomers, racemates, diastereomers or enantiomers. |
