Claims for Patent: 9,169,264

Summary for Patent: 9,169,264

Title:	Spliceostatin analogs and methods for their preparation
Abstract:	The present invention is directed to novel cytotoxic spliceostatin analogs and derivatives, to antibody drug conjugates thereof, and to methods for using the same to treat medical conditions including cancer.
Inventor(s):	Subramanyam; Chakrapani (South Glastonbury, CT), Koehn; Frank Erich (Mystic, CT), Dirico; Kenneth John (Gales Ferry, CT), Eustaquio; Alessandra S. (Old Saybrook, CT), Green; Michael Eric (Boston, MA), He; Haiyin (Mahwah, NJ), He; Min (North Potomac, CT), O\'Donnell; Christopher John (Mystic, CT), Puthenveetil; Sujiet (North Attleboro, MA), Ratnayake; Anokha (Mystic, CT), Teske; Jesse Alexander (Westerly, RI), Yang; Hui Yu (Newton, MA)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	14/069,057
Patent Claims:	1. A compound of formula (I): ##STR00323## wherein: a dashed line represents an optional bond; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; R.sup.1 is selected from the group consisting of: --R, --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15, --OCON(R.sup.14)NR(R.sup.15), .dbd.O (double bond to oxygen) and --NR.sup.14R.sup.15; R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and oxo; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is independently selected from --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--N(R)COR.sup.13, --(C(R).sub.2).sub.m--C(O)--SR, --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15, --(C(R).sub.2).sub.m--NR--C(O)--NR.sup.14R.sup.15 and --(C(R).sub.2).sub.m--NR.sup.14N(R)R.sup.15; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-8carbocyclyl, C.sub.3-8heterocyclyl, C.sub.1-6alkyl-C.sub.6-14aryl, C.sub.1-6alkyl-C.sub.5-14heteroaryl, wherein R.sup.13 is optionally substituted with --NRR or --SO.sub.2NRR; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, --(C(R).sub.2).sub.m--O--NRR and --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alky; and each m is independently 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein: X.sup.1 is --O--; X.sup.2 is --NR--; R.sup.1 is selected from the group consisting of: --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15 and --NR.sup.14R.sup.15; R.sup.2 is C.sub.1-6alkyl; R.sup.3 is C.sub.1-6alkyl; R.sup.4 is hydrogen or --OR; R.sup.5 is hydrogen or --OR; R.sup.6 and R.sup.7 are each independently selected from the group consisting of: hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from and halogen, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen or --OR; R.sup.9 is independently selected from, --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15--(C(R).sub.2).sub.m--NR--- C(O)--NR.sup.14R.sup.15 and --(C(R).sub.2).sub.m--N(R)COR.sup.13; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl; or, each of R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring; wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, --(C(R).sub.2).sub.m--O--NRR and --S--S--C.sub.1-6alkyl-NRR. 3. The compound of claim 1 wherein: X.sup.2 is --NH--, X.sup.1 is --O--, R.sup.1 is --OCOR.sup.13, OH or --OCONR.sup.14R.sup.15, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 together form epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, or --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15, R.sup.13 is C.sub.1-6 alkyl, and R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring. 4. A compound selected from the group consisting of: ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## or a pharmaceutically acceptable salt thereof. 5. A compound having the formula II: L-P (II) or a pharmaceutically acceptable salt thereof, wherein: L is the linker moiety L.sup.1-L.sup.2-L.sup.3, where L.sup.3 is bound to P; P is a radical of formula (I): ##STR00340## wherein: a dashed line represents an optional bond; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X' is CR or N; each X'' is CH--, CR--(C(R).sub.2).sub.m--NR--, CR--(C(R).sub.2).sub.m--O--; CR--(C(R).sub.2).sub.m--C(O)NR--, CR--(C(R).sub.2).sub.m--C(O)NR--NR--, CR--(C(R).sub.2).sub.m--SO.sub.2NR--, CR--(C(R).sub.2).sub.m--NR--NR--, CR--(C(R).sub.2).sub.m--NR--C(O)-- or N-- if X'' binds to L.sup.2 or an additional L.sup.3, or otherwise is O, S, CRR, CR--(C(R).sub.2).sub.m--NRR or NRR; each X''' is --(C(R).sub.2).sub.m--NR-- or CR--(C(R).sub.2).sub.m--O-- if X''' binds to L.sup.2, or otherwise is R; Y is --C(R).sub.2--, --O--, --NR-- or --S--; R.sup.1 is selected from the group consisting of: --R, --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15, --OCON(R.sup.14)NR(R.sup.15), .dbd.O (double bond to oxygen) and --NR.sup.14R.sup.15; R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and OXO; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is --(C(R).sub.2).sub.m--C(O)-- or --(C(R).sub.2).sub.m--; L.sup.1 is selected from: -halogen, --NR.sub.2, ##STR00341## L.sup.2 is L.sup.2A-L.sup.2B-L.sup.2C or L.sup.2C-L.sup.2B-L.sup.2A where: L.sup.2A comprises one or more components selected from: --O--, --C(O)--, --C(O)NR--, --C(O)--C.sub.1-6alkyl-, --C(O)NRC.sub.1-6alkyl-, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C(O)--C.sub.1-6alkyl-NRC(O)--, --C(O)--C.sub.1 -6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--C(O)--, --C.sub.1-6alkyl-S--S--C.sub.1 -6alkyl- NRC(O)CH.sub.2--, --C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)CH.sub.2--, --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1 -6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-C(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)--, --C(O)--C.sub.1-6alkyl-phenyl-(NR--C(O)--C.sub.1-6alkyl).sub.1-4-, --C(O)--C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)C.sub.1-6alkyl-- , --C.sub.1-6alkyl-, --S--, --C(O)--C.sub.1-6alkyl-phenyl-NR-, --O--C.sub.1-6alkyl-S--, --C(O)--O--C.sub.1-6alkyl-S-- and (--CH.sub.2--CH.sub.2--O--).sub.1-20, or L.sup.2A is absent; L.sup.2B is selected from AA.sub.0-aa, where AA is a natural or non-natural amino acid and aa is 12; and L.sup.2C comprises one or more components selected from: -PABA- and -PABC-, or L.sup.2C is absent; L.sup.3 is selected from one or more of: --C.sub.1-6alkyl-, --NR--C.sub.3-C.sub.8heterocyclyl-NR-, --NR--C.sub.3-C.sub.8carbocyclyl-NR-, --NR--C.sub.1-6alkyl-NR-, --NR--C.sub.1-6alkyl-, --S--, --NR--, --NR--NR-- and --NR--C(O)--NR-- where the two R groups optionally join to form a 4-10 membered ring, --NR--C.sub.1-6alkyl-phenyl-NR-, --NR--C.sub.1-6alkyl-phenyl-SO.sub.2--NR--, --SO.sub.2--, --NR--C.sub.1-6alkyl-phenyl-C(O)--, ##STR00342## or L.sup.3 is absent; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-8carbocyclyl, C.sub.3-8heterocyclyl, C.sub.1-6alkyl-C.sub.6-14aryl, C.sub.1-6alkyl-C.sub.5-14heteroaryl, wherein R.sup.13 is optionally substituted with --NRR or --SO.sub.2NRR; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alkyl; and each m is independently 0, 1, 2 or 3. 6. A compound having the formula II': L-P' (II') or a pharmaceutically acceptable salt thereof, wherein: L is the linker moiety L.sup.1-L.sup.2-L.sup.3, where L.sup.3 is bound to P'; P' is a radical of formula (I'): ##STR00343## wherein: a dashed line represents an optional bond; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X' is CR or N; each X'' is CH--, CR--(C(R).sub.2).sub.m--NR--, CR--(C(R).sub.2).sub.m--O--; CR--(C(R).sub.2).sub.m--C(O)NR--, CR--(C(R).sub.2).sub.m--C(O)NR--NR--, CR--(C(R).sub.2).sub.m--SO.sub.2NR--, CR--(C(R).sub.2).sub.m--NR--NR--, CR--(C(R).sub.2).sub.m--NR--C(O)-- or N-- if X'' binds to L.sup.2 or an additional L.sup.3, or otherwise is O, S, CRR, CR--(C(R).sub.2).sub.m--NRR or NRR; each X''' is --(C(R).sub.2).sub.m--NR-- or CR--(C(R).sub.2).sub.m--O-- if X''' binds to L.sup.2, or otherwise is R; Y is --C(R).sub.2--, --O--, --NR-- or --S--; R.sup.1 is selected from the group consisting of: --(C(R).sub.2).sub.m--, --OR'', --OCOR.sup.13', --OC(O)NRR.sup.14', --OCON(R)N(R)--, and --NR-- R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and oxo; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is independently selected from hydrogen, --C.sub.1-6alkyl, --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--C(O)--SR, --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15--(C(R).sub.2).sub.m--NR--- C(O)--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14N(R)R.sup.15 and --(C(R).sub.2).sub.m--N(R)COR.sup.13; wherein R.sup.13 is hydrogen or C.sub.1-6 alkyl. L.sup.1 is selected from: -halogen, --NR.sub.2, ##STR00344## L.sup.2 is L.sup.2A-L.sup.2B-L.sup.2C or L.sup.2C-L.sup.2B-L.sup.2A where: L.sup.2A comprises one or more components selected from: --O--, --C(O)--, --C(O)NR--, --C(O)--C.sub.1-6alkyl-, --C(O)NRC.sub.1-6alkyl-, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C(O)--C.sub.1-6alkyl-NRC(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--C(O)--, --C.sub.1-6alkyl-S--S--C.sub.1-6alkyl-NRC(O)CH.sub.2--, --C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)CH.sub.2--, --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-C(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)--, --C(O)--C.sub.1-6alkyl-phenyl-(NR--C(O)--C.sub.1-6alkyl).sub.1-4-, --C(O)--C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)C.sub.1-6alkyl-- , --C.sub.1-6alkyl-, --S--, --C(O)--C.sub.1-6alkyl-phenyl-NR-, --O--C.sub.1-6alkyl-S--, --C(O)--O--C.sub.1-6alkyl-S-- and (--CH.sub.2--CH.sub.2--O--).sub.1-20, or L.sup.2A is absent; L.sup.2B is selected from AA.sub.0-aa, where AA is a natural or non-natural amino acid and aa is 12; and L.sup.2C comprises one or more components selected from: -PABA- and -PABC-, or L.sup.2C is absent; L.sup.3 is selected from one or more of: --C.sub.1-6alkyl-, --NR--C.sub.3-C.sub.8heterocyclyl-NR-, --NR--C.sub.3-C.sub.8-carbocyclyl-NR-, --NR--C.sub.1-6alkyl-NR-, --NR--C.sub.1-6alkyl-, --S--, --NR--, --NR--NR-- and --NR--C(O)--NR-- where the two R groups optionally join to form a 4-10 membered ring, --NR--C.sub.1-6alkyl-phenyl-NR-, --NR--C.sub.1-6alkyl-phenyl-SO.sub.2--NR--, --SO.sub.2--, --NR--C.sub.1-6alkyl-phenyl-C(O)--, ##STR00345## or L.sup.3 is absent; R.sup.13' is selected from the group consisting of a bond, --C.sub.1-6alkylene-, --C.sub.3-8carbocyclyl-, --C.sub.3-8heteroCyclyl-, --C.sub.1-6alkyl-C.sub.6-14aryl-, --C.sub.1-6alkyl-C.sub.5-14heteroaryl-; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R.sup.14' is independently selected from the group consisting of: a bond, --NR--, --C.sub.3-10carbocyclyl-, --C.sub.3-10heterocyclyl-, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR', -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NR--, and --C.sub.1-6alkylene-, wherein R.sup.14' is optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --NRR or --SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alkyl; each R' is independently selected from --H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 heteroalkyl and aryl; each R'' is independently selected from the group consisting of: a bond and --C.sub.1-6alkylene-; and each m is independently 0, 1, 2 or 3. 7. The compound of claim 5 wherein: L.sup.1 is ##STR00346## and L.sup.2A, L.sup.2B, L.sup.2C and L.sup.3 are all absent. 8. The compound of claim 5 wherein: R.sup.6 is --OH and R.sup.7 is C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from a halogen. 9. The compound of claim 5 wherein: X.sup.2 is --NH--, X.sup.1 is --O--, R.sup.1 is --OCOR.sup.13, --OH or --OCONR.sup.14R.sup.15, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 together form epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, R.sup.13 is C.sub.1-6 alkyl, R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, L.sup.1 is ##STR00347## and L.sup.2A, L.sup.2B, L.sup.2C and L.sup.3 are all absent. 10. The compound of claim 5 wherein: X.sup.2 is --NH--, X.sup.1 is --O--, R.sup.1 is --OCOR.sup.13, --OH or --OCONR.sup.14R.sup.15, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 together form epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, R.sup.13 is C.sub.1-6 alkyl, R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, L.sup.1 is a halogen, L.sup.3 is --NR--C.sub.1-6alkyl-NR, L.sup.2A is --C(O)--C.sub.1-6alkyl- and L.sup.2B and L.sup.2C are absent. 11. The compound of claim 5 wherein: R1 is --OCOR.sup.13 or --OR, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 form an epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, L.sup.3 is --NR--NR-- where each R is hydrogen or methyl or where the two R substituents together form a 6 membered ring, L.sup.1 is a halogen, --NR.sup.2 or ##STR00348## L.sup.2C is PABC, L.sup.2B is -Cit-Val-, and L.sup.2A is --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-. 12. The compound of claim 5 wherein: R.sup.1 is --OCOR.sup.13 or --OR, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 form an epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, L.sup.3 is --NR--NR-- where each R is hydrogen or methyl or the two R substituents together form a 6 membered ring, L.sup.1 is a halogen, --NR.sup.2 or ##STR00349## L.sup.2C is absent; L.sup.2B is -Ala-Val- and L.sup.2A is --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl- or --C(O)--C.sub.1-6alkyl-. 13. The compound of claim 5 wherein L.sup.1 is selected from: -halogen, --NR.sub.2, ##STR00350## 14. The compound of claim 5 wherein: R.sup.1 is --OCOR.sup.13', R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.9 is --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, R.sup.13' is a bond, L.sup.3 is ##STR00351## where m is 0, X' is N, X'' is --N-- and X''' is absent, L.sup.1 is a halogen, L.sup.2C is PABC, L.sup.2B is -Cit-Val- and L.sup.2A is --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-. 15. The compound of claim 5 wherein: X.sup.1 is --O--; X.sup.2 is --NR--; R.sup.1 is selected from the group consisting of: --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15 and --NR.sup.14R.sup.15; R.sup.2 is C.sub.1-6alkyl; R.sup.3 is C.sub.1-6alkyl; R.sup.4 is hydrogen or --OR; R.sup.5 is hydrogen or --OR; R.sup.6 and R.sup.7 are each independently selected from the group consisting of: hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from and halogen, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen or --OR; R.sup.9 is independently selected from, --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15--(C(R).sub.2).sub.m--NR--C(O)- --NR.sup.14R.sup.15 and --(C(R).sub.2).sub.m--N(R)COR.sup.13; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl; or, each of R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10 heterocyclyl ring; wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, --(C(R).sub.2).sub.m--O--NRR and --S--S--C.sub.1-6alkyl-NRR. 16. A compound selected from the group consisting of: ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## or a pharmaceutically acceptable salt thereof. 17. A compound having the formula III: (AB)-(L-P).sub.b (III) or a pharmaceutically acceptable salt thereof, wherein: L is the linker moiety L.sup.1-L.sup.2-L.sup.3, where L.sup.3 is bound to P; P is a radical of formula (I): ##STR00366## wherein: a dashed line represents an optional bond; AB is an antibody; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X' is CR or N; each X'' is CH--, CR--(C(R).sub.2).sub.m--NR--, CR--(C(R).sub.2).sub.m--O--; CR--(C(R).sub.2).sub.m--C(O)NR--, CR--(C(R).sub.2).sub.m--C(O)NR--NR--, CR--(C(R).sub.2).sub.m--SO.sub.2NR--, CR--(C(R).sub.2).sub.m--NR--NR--, CR--(C(R).sub.2).sub.m--NR--C(O)-- or N-- if X'' binds to L.sup.2 or an additional L.sup.3, or otherwise is O, S, CRR, CR--(C(R).sub.2).sub.m--NRR or NRR; each X''' is --(C(R).sub.2).sub.m--NR-- or CR--(C(R).sub.2).sub.m--O-- if X''' binds to L.sup.2, or otherwise is R; Y is --C(R).sub.2--, --O--, --NR-- or --S--; R.sup.1 is selected from the group consisting of: --R, --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15, --OCON(R.sup.14)NR(R.sup.15), .dbd.O (double bond to oxygen) and --NR.sup.14R.sup.15; R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and OXO; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is --(C(R).sub.2).sub.m--C(O)-- or --(C(R).sub.2).sub.m--; L.sup.1 is selected from: a bond to AB, --NR-(bond to AB) and ##STR00367## L.sup.2 is L.sup.2A-L.sup.2B-L.sup.2C or L.sup.2C-L.sup.2B-L.sup.2A where: L.sup.2A comprises one or more components selected from: --O--, --C(O)--, --C(O)NR--, --C(O)--C.sub.1-6alkyl-, --C(O)NRC.sub.1-6alkyl-, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C(O)--C.sub.1-6alkyl-NRC(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--C(O)--, --C.sub.1-6alkyl-S--S--C.sub.1-6alkyl- NRC(O)CH.sub.2--, --C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)CH.sub.2--, --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-C(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)--, --C(O)--C.sub.1-6alkyl-phenyl-(NR--C(O)--C.sub.1-6alkyl).sub.1-4-, --C(O)--C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)C.sub.1-6alkyl-- , --C.sub.1-6alkyl-, --S--, --C(O)--C.sub.1-6alkyl-phenyl-NR-, --O--C.sub.1-6alkyl-S--, --C(O)--O--C.sub.1-6alkyl-S-- and (--CH.sub.2--CH.sub.2--O--).sub.1-20, or L.sup.2A is absent; L.sup.2B is selected from AA.sub.0-aa, where AA is a natural or non-natural amino acid and aa is 12; and L.sup.2C comprises one or more components selected from: -PABA- and -PABC-, or L.sup.2C is absent; L.sup.3 is selected from one or more of: --C.sub.1-6alkyl-, --NR--C.sub.3-C.sub.8heterocyclyl-NR-, --NR--C.sub.3-C.sub.8carbocyclyl-NR-, --NR--C.sub.1-6alkyl-NR-, --NR--C.sub.1-6alkyl-, --S--, --NR--, --NR--NR-- and --NR--C(O)--NR-- where the two R groups optionally join to form a 4-10 membered ring, --NR--C.sub.1-6alkyl-phenyl-NR-, --NR--C.sub.1-6alkyl-phenyl-SO.sub.2--NR--, --SO.sub.2--, --NR--C.sub.1-6alkyl-phenyl-C(O)--, ##STR00368## or L.sup.3 is absent; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-8carbocyclyl, C.sub.3-8heterocyclyl, C.sub.1-6alkyl-C.sub.6-14aryl, C.sub.1-6alkyl-C.sub.5-14heteroaryl, wherein R.sup.13 is optionally substituted with --NRR or --SO.sub.2NRR; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alkyl; and b is 1-20; and each m is independently 0, 1, 2 or 3. 18. A compound having the formula III': (AB)-(L-P').sub.b (III') or a pharmaceutically acceptable salt thereof, wherein: L is the linker moiety L.sup.1-L.sup.2-L.sup.3, where L.sup.3 is bound to P'; P' is a radical of formula (I'): ##STR00369## wherein: a dashed line represents an optional bond; AB is an antibody; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X' is CR or N; each X'' is CH--, CR--(C(R).sub.2).sub.m--NR--, CR--(C(R).sub.2).sub.m--O--; CR--(C(R).sub.2).sub.m--C(O)NR--, CR--(C(R).sub.2).sub.m--C(O)NR--NR--, CR--(C(R).sub.2).sub.m--SO.sub.2NR--, CR--(C(R).sub.2).sub.m--NR--NR--, CR--(C(R).sub.2).sub.m--NR--C(O)-- or N-- if X'' binds to L.sup.2 or an additional L.sup.3, or otherwise is O, S, CRR, CR--(C(R).sub.2).sub.m--NRR or NRR; each X''' is --(C(R).sub.2).sub.m--NR-- or CR--(C(R).sub.2).sub.m--O-- if X''' binds to L.sup.2, or otherwise is R; Y is --C(R).sub.2--, --O--, --NR-- or --S--; R.sup.1 is selected from the group consisting of: --(C(R).sub.2).sub.m--C(O)--, --(C(R).sub.2).sub.m--, --OR'', --OCOR.sup.13', --OCONRR.sup.14', --OCON(R.sup.14)N(R.sup.15)--, and --NR.sup.14-- R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and oxo; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is independently selected from hydrogen, --C.sub.1-6alkyl, --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--C(O)--SR, --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15, --(C(R).sub.2).sub.m--NR--C(O)--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14N(R)R.sup.15 and --(C(R).sub.2).sub.m--N(R)COR.sup.13; wherein R.sub.13 is hydrogen or C.sub.1-6 alkyl. L.sup.1 is selected from: a bond to AB, --NR-(bond to AB) and ##STR00370## L.sup.2 is L.sup.2A-L.sup.2B-L.sup.2C or L.sup.2C-L.sup.2B-L.sup.2A where: L.sup.2A comprises one or more components selected from: --O--, --C(O)--, --C(O)NR--, --C(O)--C.sub.1-6alkyl-, --C(O)NRC.sub.1-6alkyl-, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C(O)--C.sub.1-6alkyl-NRC(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--C(O)--, --C.sub.1-6alkyl-S--S--C.sub.1-6alkyl-NRC(O)CH.sub.2--, --C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)CH.sub.2--, --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-C(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)--, --C(O)--C.sub.1-6alkyl-phenyl-(NR--C(O)--C.sub.1-6alkyl).sub.1-4-, --C(O)--C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)C.sub.1-6alkyl-- , --C.sub.1-6alkyl-, --S--, --C(O)--C.sub.1-6alkyl-phenyl-NR-, --O--C.sub.1-6alkyl-S--, --C(O)--O--C.sub.1-6alkyl-S-- and (--CH.sub.2--CH.sub.2--O--).sub.1-20, or L.sup.2A is absent; L.sup.2B is selected from AA.sub.0-aa, where AA is a natural or non-natural amino acid and aa is 12; and L.sup.2C comprises one or more components selected from: -PABA- and -PABC-, or L.sup.2C is absent; L.sup.3 is selected from one or more of: --C.sub.1-6alkyl-, --NR--C.sub.3-C.sub.8heterocyclyl-NR-, --NR--C.sub.3-C.sub.8-carbocyclyl-NR-, --NR--C.sub.1-6alkyl-NR-, --NR--C.sub.1-6alkyl-, --S--, --NR--, --NR--NR-- and --NR--C(O)--NR-- where the two R groups optionally join to form a 4-10 membered ring, --NR--C.sub.1-6alkyl-phenyl-NR-, --NR--C.sub.1-6alkyl-phenyl-SO.sub.2--NR--, --SO.sub.2--, --NR--C.sub.1-6alkyl-phenyl-C(O)--, ##STR00371## or L.sup.3 is absent; R.sup.13' is selected from the group consisting of a bond, --C.sub.1-6alkylene-, --C.sub.3-8carbocyclyl-, --C.sub.3-8heteroCyclyl-, --C.sub.1-6alkyl-C.sub.6-14aryl-, --C.sub.1-6alkyl-O.sub.5-14heteroaryl-; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R.sup.14' is independently selected from the group consisting of: a bond, --NR--, --C.sub.3-10carbocyclyl-, --C.sub.3-10heterocyclyl-, -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR', -(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NR--, and --C.sub.1-6alkylene-, wherein R.sup.14' is optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --NRR or --SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alkyl; each R' is independently selected from --H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 heteroalkyl and aryl; each R'' is independently selected from the group consisting of: a bond and --C.sub.1-6alkylene-; and b is 1-20; and each m is independently 0, 1, 2 or 3. 19. The compound of claim 17 wherein: X.sup.1 is --O--; X.sup.2 is --NR--; R.sup.1 is selected from the group consisting of: --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15 and --NR.sup.14R.sup.15; R.sup.2 is C.sub.1-6alkyl; R.sup.3 is C.sub.1-6alkyl; R.sup.4 is hydrogen or --OR; R.sup.5 is hydrogen or --OR; R.sup.6 and R.sup.7 are each independently selected from the group consisting of: hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from and halogen, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen or --OR; R.sup.9 is independently selected from, --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15, --(C(R).sub.2).sub.m--NR--C(O)--NR.sup.14R.sup.15 and --(C(R).sub.2).sub.m--N(R)COR.sup.13; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl; or, each of R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring; wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, --(C(R).sub.2).sub.m--O--NRR and --S--S--C.sub.1-6alkyl-NRR. 20. The compound of claim 17 wherein: X.sup.2 is --NH--, X.sup.1 is --O--, R.sup.1 is --OCOR.sup.13, OH or --OCONR.sup.14R.sup.15, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 together form epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, R.sup.13 is C.sub.1-6 alkyl, R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, L.sup.1 is selected from: a bond to AB and --NR-- (bond to AB), and L.sup.2A, L.sup.2B, L.sup.2C and L.sup.3 are all absent. 21. The compound of claim 17 wherein: X.sup.2 is --NH--, X.sup.1 is --O--, R.sup.1 is --OCOR.sup.13, OH or --OCONR.sup.14R.sup.15, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 together form epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, R.sup.13 is C.sub.1-6 alkyl, R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, L.sup.1 is selected from: a bond to AB and --NR-(bond to AB), and L.sup.3 is --NR--C.sub.1-6alkyl-NR with R being hydrogen and the alkyl group being ethyl, L.sup.2A is --C(O)--C.sub.1-6alkyl- and L.sup.2B and L.sup.2C are absent. 22. The compound of claim 17 wherein: X.sup.2 is --NH--, X.sup.1 is --O--, R.sup.1 is --OCOR.sup.13, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 together form epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, R.sup.13 is C.sub.1-6 alkyl, R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, L.sup.1 is selected from: a bond to AB and --NR-(bond to AB), L.sup.3 is --NR--C.sub.1-6alkyl-NR with R being hydrogen and the alkyl group being ethyl, L.sup.2A is --C(O)--C.sub.1-6alkyl- and L.sup.2B and L.sup.2C are absent. 23. The compound of claim 17 wherein: R.sup.1 is --OCOR.sup.13 or --OR, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 form an epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, L.sup.3 is --NR--NR-- where each R is hydrogen or methyl or the two R substituents together form a 6 membered ring, L.sup.1 is selected from: a bond to AB, L.sup.2C is PABC, L.sup.2B is -Cit-Val-, and L.sup.2A is --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-. 24. The compound of claim 17 wherein: R.sup.1 is --OCOR.sup.13 or --OR, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is --OH, R.sup.5 is hydrogen, R.sup.8 is hydrogen, R.sup.6 and R.sup.7 form an epoxide, R.sup.9 is --(C(R).sub.2).sub.m--C(O)--, L.sup.3 is --NR--NR-- where each R is hydrogen or methyl or the two R substituents together form a 6 membered ring, L.sup.1 is selected from: a bond to AB and --NR-(bond to AB), L.sup.2C is PABC, L.sup.2B is -Cit-Val-, and L.sup.2A is --C(O)--C.sub.1-6alkyl-C(O)-- or --C(O)--C.sub.1-6alkyl-. 25. The compound of claim 17 wherein: L.sup.2C is absent; L.sup.2B is -Ala-Val- and L.sup.2A is --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-. 26. The compound of claim 17 wherein: L.sup.1 is selected from: a bond to AB, --NR-- (bond to AB) and ##STR00372## 27. The compound of claim 17 wherein the antibody is selected from trastuzumab and the K392C+L443C trastuzumab mutant. 28. The compound of claim 17 wherein the antibody bound via an Fc-containing or Fab-containing polypeptide engineered with an acyl donor glutamine-containing tag or an endogenous glutamine made reactive by polypeptide engineering in the presence of transglutaminase. 29. The compound of claim 17, selected from the group consisting of: ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## where --NH-X, --NH-C(O)-X or --S--X represents the antibody AB; or a pharmaceutically acceptable salt thereof. 30. The compound or salt of claim 17, wherein the antibody AB is selected from: trastuzumab, trastuzumab mutants, oregovomab, edrecolomab, cetuximab, a humanized monoclonal antibody to the vitronectin receptor (.alpha..sub.v.beta..sub.3), alemtuzumab, a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin's lymphoma, 131I Lym-1, a murine anti-HLA-Dr10 antibody for the treatment of non-Hodgkin's lymphoma, a humanized anti-CD2 mAb for the treatment of Hodgkin's Disease or non-Hodgkin's lymphoma, labetuzumab, bevacizumab, ibritumomab tiuxetan, ofatumumab, panitumumab, rituximab, tositumomab, ipilimumab, gemtuzumab, a humanized monoclonal antibody to the oncofecal protein receptor 5T4, and an antibody to CD11b receptor. 31. The compound or salt of claim 17, wherein P represents a radical of the compound of claim 1. 32. The compound or salt of claim 17, wherein L comprises one or more independently selected amino acid diradicals selected from the group consisting of valine, citrulline, phenylalanine, lysine, alanine and glycine. 33. The compound or salt of claim 17, wherein L is capable of being cleaved from P, or a radical comprising P, by an intracellular protease. 34. The compound or salt of claim 17, wherein AB is attached to an amino acid di-radical via a cysteine residue of AB via a sulphur or sulphur-sulphur bond. 35. The compound or salt of claim 17, wherein AB is attached to an amino acid di-radical via a lysine residue. 36. The compound or salt of claim 17, wherein AB is attached to an amino acid di-radical via a glutamine residue of AB via an amide bond. 37. The compound or salt of claim 17, wherein said antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody or an antibody fragment. 38. A pharmaceutical composition comprising an effective amount of the compound or salt of claim 17, or a pharmaceutically acceptable diluent, carrier or excipient. 39. The pharmaceutical composition of claim 38, further comprising a therapeutically effective amount of a chemotherapeutic agent selected from the group consisting of a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder.

Details for Patent 9,169,264

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2032-11-05
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2032-11-05
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2032-11-05
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2032-11-05
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2032-11-05
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2032-11-05
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2032-11-05