Claims for Patent: 9,796,754

Summary for Patent: 9,796,754

Title:	Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives
Abstract:	Disclosed herein are non-natural amino acids and dolastatin analogs that include at least one non-natural amino acid, and methods for making such non-natural amino acids and polypeptides. The dolastatin analogs can include a wide range of possible functionalities, but typically have at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Also disclosed herein are non-natural amino acid dolastatin analogs that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such dolastatin analogs. Typically, the modified dolastatin analogs include at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Further disclosed are methods for using such non-natural amino acid dolastatin analogs and modified non-natural amino acid dolastatin analogs, including therapeutic, diagnostic, and other biotechnology use.
Inventor(s):	Miao; Zhenwei (San Diego, CA), Atkinson; Kyle (Golden, CO), Biroc; Sandra (Alameda, CA), Buss; Timothy (Carlsbad, CA), Neal; Melissa (Vista, CA), Kraynov; Vadim (San Diego, CA), Marsden; Robin (San Diego, CA), Pinkstaff; Jason (San Rafael, CA), Skidmore; Lillian (San Diego, CA), Sun; Ying (San Diego, CA), Szydlik; Agnieszka (San Francisco, CA), Lopez De Valenta; Delia Ianina (Poway, CA)
Assignee:	Ambrx, Inc. (La Jolla, CA)
Application Number:	14/122,672
Patent Claims:	1. A compound, or salt thereof, comprising Formula (I): ##STR00244## wherein: Z has the structure of: ##STR00245## R.sub.5 is H, COR.sub.8, C.sub.1-C.sub.6alkyl, or thiazole; R.sub.8 is OH or --NH-(alkylene-O).sub.n--NH.sub.2; R.sub.6 is OH or H; Ar is phenyl or pyridine; R.sub.7 is C.sub.1-C.sub.6alkyl or hydrogen; Y is selected from the group consisting of an hydroxylamine and a cycloalkyne; L is a linker selected from the group consisting of -alkylene-, -alkylene-C(O)--, -(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-C(O)--, -(alkylene-O).sub.n--(CH.sub.2).sub.n'--NHC(O)--(CH.sub.2).sub.n''--C(Me)- .sub.2-S--S--(CH.sub.2).sub.n'''--NHC(O)-(alkylene-O).sub.n''''-alkylene-, -(alkylene-O).sub.n-alkylene-W--, -alkylene-C(O)--W--, -(alkylene-O).sub.n-alkylene-U-alkylene-C(O)--, and -(alkylene-O).sub.n-alkylene-U-alkylene-; W has the structure of: ##STR00246## U has the structure of: ##STR00247## or L is absent, Y is methyl, R.sub.5 is COR.sub.8, and R.sub.8 is --NH-(alkylene-O).sub.n--NH.sub.2; and each n, n', n'', n''' and n'''' are independently integers greater than or equal to one. 2. The compound of claim 1, wherein R.sub.5 is thiazole. 3. The compound of claim 1, wherein R.sub.6 is H. 4. The compound of claim 1, wherein Ar is phenyl. 5. The compound of claim 1, wherein R.sub.7 is methyl. 6. The compound of claim 1, where n is an integer from 1 to 20. 7. The compound of claim 1, where n is an integer from 1 to 10. 8. The compound of claim 1, where n is an integer from 1 to 5. 9. The compound of claim 1, wherein Y is cyclooctyne. 10. The compound of claim 9, wherein the cyclooctyne has a structure of: ##STR00248## each R.sub.19 is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, ester, ether, thioether, aminoalkyl, halogen, alkyl ester, aryl ester, amide, aryl amide, alkyl halide, alkyl amine, alkyl sulfonic acid, alkyl nitro, thioester, sulfonyl ester, halosulfonyl, nitrile, alkyl nitrile, and nitro; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11. 11. The compound of claim 1, wherein Y is azide. 12. The compound of claim 1, comprising Formula (II): ##STR00249## 13. The compound of claim 12, wherein L is -(alkylene-O).sub.n-alkylene-. 14. The compound of claim 13, wherein each alkylene is --CH.sub.2CH.sub.2--, n is equal to 3, and R.sub.7 is methyl. 15. The compound of claim 12, wherein L is -alkylene-. 16. The compound of claim 15, wherein each alkylene is --CH.sub.2CH.sub.2-- and R.sub.7 is methyl or hydrogen. 17. The compound of claim 12, wherein L is -(alkylene-O).sub.n-alkylene-C(O)--. 18. The compound of claim 17, wherein each alkylene is --CH.sub.2CH.sub.2--, n is equal to 4, and R.sub.7 is methyl. 19. The compound of claim 12, wherein L is -(alkylene-O).sub.n--(CH.sub.2).sub.n'--NHC(O)--(CH.sub.2).sub.n''--C(Me)- .sub.2-S--S--(CH.sub.2).sub.n'''--NHC(O)-(alkylene-O).sub.n''''-alkylene-. 20. The compound of claim 19, wherein each alkylene is --CH.sub.2CH.sub.2--, n is equal to 1, n' is equal to 2, n'' is equal to 1, n''' is equal to 2, n'''' is equal to 4, and R.sub.7 is methyl. 21. A compound, or salt thereof, comprising Formula (III), (IV), (V) or (VI): ##STR00250## ##STR00251## wherein: Z has the structure of: ##STR00252## R.sub.5 is H, COR.sub.8, C.sub.1-C.sub.6alkyl, or thiazole; R.sub.8 is OH; R.sub.6 is OH or H; Ar is phenyl or pyridine; R.sub.7 is C.sub.1-C.sub.6alkyl or hydrogen; Y and V are each selected from the group consisting of an hydroxylamine, methyl, aldehyde, protected aldehyde, ketone, protected ketone, thioester, ester, dicarbonyl, hydrazine, amidine, imine, diamine, azide, keto-amine, keto-alkyne, alkyne, cycloalkyne, and ene-dione; L.sub.1, L.sub.2, L.sub.3, and L.sub.4 are each linkers independently selected from the group consisting of a bond, -alkylene-, -(alkylene-O).sub.n-alkylene-J-, -alkylene'-J-(alkylene-O).sub.n-alkylene-, -J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-(alkylene-O).sub.n'-alkylene-J'-, -(alkylene-O).sub.n-alkylene-J-alkylene'-, --W--, -alkylene-W--, alkylene'-J-(alkylene-NMe).sub.n-alkylene-W--, -J-(alkylene-NMe).sub.n-alkylene-W--, -J-alkylene-NMe-alkylene'-NMe-alkylene''-W--, and -alkylene-J-alkylene'-NMe-alkylene''-NMe-alkylene'''-W--; W has the structure of: ##STR00253## each J and J' independently have the structure of: ##STR00254## and each n and n' are independently integers greater than or equal to one. 22. The compound of claim 21, comprising Formula (VII): ##STR00255## 23. The compound of claim 22, wherein L.sub.1 is -(alkylene-O).sub.n-alkylene-J-, L.sub.2 is -alkylene'-J'-(alkylene-O).sub.n'-alkylene-, L.sub.3 is -J''-(alkylene-O).sub.n''-alkylene-, alkylene is --CH.sub.2CH.sub.2--, alkylene' is --(CH.sub.2).sub.4--, n is 1, n' and n'' are 3, J has the structure of ##STR00256## J' and J'' have the structure of ##STR00257## and R.sub.7 is methyl. 24. The compound of claim 22, comprising Formula (IV) wherein L.sub.1 is -J-(alkylene-O).sub.n-alkylene-, L.sub.2 is -(alkylene-O).sub.n'-alkylene-J'-alkylene'-, L.sub.3 is -(alkylene-O).sub.n''-alkylene-J''-, alkylene is --CH.sub.2CH.sub.2--, alkylene' is --(CH.sub.2).sub.4--, n is 1, n' and n'' are 4, and J, J' and J'' have the structure of ##STR00258## 25. A compound comprising Formula (VIII) or (IX): ##STR00259## wherein: A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, --O--, --O-(alkylene or substituted alkylene)-, --S--, --S-(alkylene or substituted alkylene)-, --S(O).sub.k-- where k is 1, 2, or 3, --S(O).sub.k(alkylene or substituted alkylene)-, --C(O)--, --C(O)-(alkylene or substituted alkylene)-, --C(S)--, --C(S)-(alkylene or substituted alkylene)-, --N(R')--, --NR'-(alkylene or substituted alkylene)-, --C(O)N(R')--, --CON(R')-(alkylene or substituted alkylene)-, --CSN(R')--, --CSN(R')-(alkylene or substituted alkylene)-, --N(R')CO-(alkylene or substituted alkylene)-, --N(R')C(O)O--, --S(O).sub.kN(R')--, --N(R')C(O)N(R')--, --N(R')C(S)N(R')--, --N(R')S(O).sub.kN(R')--, --N(R')--N.dbd., --C(R').dbd.N--, --C(R').dbd.N--N(R')--, --C(R').dbd.N--N.dbd., --C(R').sub.2--N.dbd.N--, and --C(R').sub.2--N(R')--N(R')--, where each R' is independently H, alkyl, or substituted alkyl; R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; R.sub.1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.3 and R.sub.4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R.sub.3 and R.sub.4 or two R.sub.3 groups optionally form a cycloalkyl or a heterocycloalkyl; Z has the structure of: ##STR00260## R.sub.5 is H, COR.sub.8, C.sub.1-C.sub.6alkyl, or thiazole; R.sub.8 is OH; R.sub.6 is OH or H; Ar is phenyl or pyridine; R.sub.7 is C.sub.1-C.sub.6alkyl or hydrogen; L is a linker selected from the group consisting of -alkylene-, -alkylene-C(O)--, -(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-C(O)--, -(alkylene-O).sub.n--(CH.sub.2).sub.n'--NHC(O)--(CH.sub.2).sub.n''--C(Me)- .sub.2-S--S--(CH.sub.2).sub.n'''--NHC(O)-(alkylene-O).sub.n''''-alkylene-, -(alkylene-O).sub.n-alkylene-W--, -alkylene-C(O)--W--, -(alkylene-O).sub.n-alkylene-U-alkylene-C(O)--, and -(alkylene-O).sub.n-alkylene-U-alkylene-; W has the structure of: ##STR00261## U has the structure of: ##STR00262## and each n, n', n'', n''' and n'''' are independently integers greater than or equal to one; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof. 26. The compound of claim 25, wherein R.sub.1 is a polypeptide. 27. The compound of claim 26, wherein the polypeptide is an antibody. 28. The compound of claim 27, wherein the antibody is herceptin. 29. The compound of claim 25, wherein R.sub.2 is a polypeptide. 30. The compound of claim 29, wherein the polypeptide is an antibody. 31. The compound of claim 30, wherein the antibody is herceptin. 32. The compound, or salt thereof, comprising Formula (X), (XI), (XII) or (XIII): ##STR00263## ##STR00264## wherein: A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, --O--, --O-(alkylene or substituted alkylene)-, --S--, --S-(alkylene or substituted alkylene)-, --S(O).sub.k-- where k is 1, 2, or 3, --S(O).sub.k(alkylene or substituted alkylene)-, --C(O)--, --C(O)-(alkylene or substituted alkylene)-, --C(S)--, --C(S)-(alkylene or substituted alkylene)-, --N(R')--, --NR'-(alkylene or substituted alkylene)-, --C(O)N(R')--, --CON(R')-(alkylene or substituted alkylene)-, --CSN(R')--, --CSN(R')-(alkylene or substituted alkylene)-, --N(R')CO-(alkylene or substituted alkylene)-, --N(R')C(O)O--, --S(O).sub.kN(R')--, --N(R')C(O)N(R')--, --N(R')C(S)N(R')--, --N(R')S(O).sub.kN(R')--, --N(R')--N.dbd., --C(R').dbd.N--, --C(R').dbd.N--N(R')--, --C(R').dbd.N--N.dbd., --C(R').sub.2--N.dbd.N--, and --C(R').sub.2--N(R')--N(R')--, where each R' is independently H, alkyl, or substituted alkyl; R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; R.sub.1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.3 and R.sub.4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R.sub.3 and R.sub.4 or two R.sub.3 groups optionally form a cycloalkyl or a heterocycloalkyl; Z has the structure of: ##STR00265## R.sub.5 is H, CO.sub.2H, C.sub.1-C.sub.6alkyl, or thiazole; R.sub.6 is OH or H; Ar is phenyl or pyridine; R.sub.7 is C.sub.1-C.sub.6alkyl or hydrogen; L.sub.1, L.sub.2, L.sub.3, and L.sub.4 are each linkers independently selected from the group consisting of a bond, -alkylene-, -(alkylene-O).sub.n-alkylene-J-, -alkylene'-J-(alkylene-O).sub.n-alkylene-, -J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-(alkylene-O).sub.n'-alkylene-J'-, -(alkylene-O).sub.n-alkylene-J-alkylene'-, --W--, -alkylene-W--, alkylene'-J-(alkylene-NMe).sub.n-alkylene-W--, -J-(alkylene-NMe).sub.n-alkylene-W--, -J-alkylene-NMe-alkylene'-NMe-alkylene''-W--, and -alkylene-J-alkylene'-NMe-alkylene''-NMe-alkylene'''-W--; W has the structure of: ##STR00266## each J and J' independently have the structure of: ##STR00267## and each n and n' are independently integers greater than or equal to one. 33. The compound of claim 32, wherein R.sub.1 is a polypeptide. 34. The compound of claim 33, wherein the polypeptide is an antibody. 35. The compound of claim 34, wherein the antibody is herceptin. 36. The compound of claim 32, wherein R.sub.2 is a polypeptide. 37. The compound of claim 36, wherein the polypeptide is an antibody. 38. The compound of claim 37, wherein the antibody is herceptin. 39. A method for derivatizing a dolastatin analog comprising Formula (I), (III), (IV), (V), or (VI), the method comprising contacting the dolastatin analog with a reagent of Formula (XXXVII), wherein Formula (I), (III), (IV), (V), or (VI) correspond to: ##STR00268## ##STR00269## wherein: Z has the structure of: ##STR00270## R.sub.5 is H, COR.sub.8, C.sub.1-C.sub.6alkyl, or thiazole; R.sub.8 is OH or --NH-(alkylene-O).sub.n--NH.sub.2; R.sub.6 is OH or H; Ar is phenyl or pyridine; R.sub.7 is C.sub.1-C.sub.6 alkyl or hydrogen; Y is NH.sub.2--O-- or methyl; L, L.sub.1, L.sub.2, L.sub.3, and L.sub.4 are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)--, -(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-C(O)--, -(alkylene-O).sub.n--(CH.sub.2).sub.n'--NHC(O)--(CH.sub.2).sub.n''--C(Me)- .sub.2-S--S--(CH.sub.2).sub.n'''--NHC(O)-(alkylene-O).sub.n''''-alkylene-, -(alkylene-O).sub.n-alkylene-W--, -alkylene-C(O)--W--, -(alkylene-O).sub.n-alkylene-J-, -alkylene'-J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-alkylene', -J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-(alkylene-O).sub.n'-alkylene-J'-, --W--, -alkylene-W--, alkylene'-J-(alkylene-NMe).sub.n-alkylene-W--, and J-(alkylene-NMe).sub.n-alkylene-W--, -(alkylene-O).sub.n-alkylene-U-alkylene-C(O)--, -(alkylene-O).sub.n-alkylene-U-alkylene-; -J-alkylene-NMe-alkylene'-NMe-alkylene''-W--, and -alkylene-J-alkylene'-NMe-alkylene''-NMe-alkylene'''-W--; W has the structure of: ##STR00271## U has the structure of: ##STR00272## each J and J' independently have the structure of: ##STR00273## or L is absent, Y is methyl, R.sub.5 is COR.sub.8, and R.sub.8 is --NH-(alkylene-O).sub.n--NH.sub.2; and each n, n', n'', n''' and n'''' are independently integers greater than or equal to one; wherein Formula (XXXVII) corresponds to: ##STR00274## wherein: A is optional, and when present is lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, --O--, --O-(alkylene or substituted alkylene)-, --S--, --S-(alkylene or substituted alkylene)-, --S(O).sub.k-- where k is 1, 2, or 3, --S(O).sub.k(alkylene or substituted alkylene)-, --C(O)--, --C(O)-(alkylene or substituted alkylene)-, --C(S)--, --C(S)-(alkylene or substituted alkylene)-, --N(R')--, --NR'-(alkylene or substituted alkylene)-, --C(O)N(R')--, --CON(R')-(alkylene or substituted alkylene)-, --CSN(R')--, --CSN(R')-(alkylene or substituted alkylene)-, --N(R')CO-(alkylene or substituted alkylene)-, --N(R')C(O)O--, --S(O).sub.kN(R')--, --N(R')C(O)N(R')--, --N(R')C(S)N(R')--, --N(R')S(O).sub.kN(R')--, --N(R')--N.dbd., --C(R').dbd.N--, --C(R').dbd.N--N(R')--, --C(R').dbd.N--N.dbd., --C(R').sub.2--N.dbd.N--, and --C(R').sub.2--N(R')--N(R')--, where each R' is independently H, alkyl, or substituted alkyl; each R' is independently H, alkyl, or substituted alkyl; K is ##STR00275## R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; R.sub.1 is H, an amino protecting group, resin, at least one amino acid, or polynucleotide; R.sub.2 is OH, an ester protecting group, resin, at least one amino acid, or polynucleotide; and R.sub.3 and R.sub.4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R.sub.3 and R.sub.4 or two R.sub.3 groups optionally form a cycloalkyl or a heterocycloalkyl. 40. The method of claim 39, wherein the derivatized dolastatin analog comprises at least one oxime containing amino acid having the structure of Formula (VIII), (IX), (X), (XI), (XII), or (XIII): ##STR00276## ##STR00277## 41. The method of claim 39, wherein the dolastatin analog is contacted with the reagent of Formula (XXXVII) in aqueous solution under mildly acidic conditions. 42. A compound comprising Formula (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), or (XXX): ##STR00278## ##STR00279## wherein: Z has the structure of: ##STR00280## R.sub.5 is H, CO.sub.2H, C.sub.1-C.sub.6alkyl, or thiazole; R.sub.6 is OH or H; Ar is phenyl or pyridine; R.sub.1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.4 is H, halogen, lower alkyl, or substituted lower alkyl; R.sub.7 is C.sub.1-C.sub.6alkyl or hydrogen; L, L.sub.1, L.sub.2, L.sub.3, and L.sub.4 are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)--, -alkylene-J-, -(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-C(O)--, -(alkylene-O).sub.n-J-, -(alkylene-O).sub.n-J-alkylene-, -(alkylene-O).sub.n--(CH.sub.2).sub.n'--NHC(O)--(CH.sub.2).sub.n''--C(Me)- .sub.2-S--S--(CH.sub.2).sub.n'''--NHC(O)-(alkylene-O).sub.n''''-alkylene-, -(alkylene-O).sub.n-alkylene-W--, -alkylene-C(O)--W--, -(alkylene-O).sub.n-alkylene-J-, -alkylene'-J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-alkylene', -J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-(alkylene-O).sub.n'-alkylene-J'-, --W--, -alkylene-W--, alkylene'-J-(alkylene-NMe).sub.n-alkylene-W--, -J-(alkylene-NMe).sub.n-alkylene-W--, -(alkylene-O).sub.n-alkylene-U-alkylene-C(O)--, -(alkylene-O).sub.n-alkylene-U-alkylene-; -J-alkylene-NMe-alkylene'-NMe-alkylene''-W--, and -alkylene-J-alkylene'-NMe-alkylene''-NMe-alkylene'''-W--; W has the structure of: ##STR00281## U has the structure of: ##STR00282## each J and J' independently have the structure of: ##STR00283## each n and n' are independently integers greater than or equal to one; and each R.sub.16 is independently selected from the group consisting of hydrogen, halogen, alkyl, NO.sub.2, CN, and substituted alkyl. 43. The compound of claim 42, wherein R.sub.1 is a polypeptide. 44. The compound of claim 43, wherein the polypeptide is an antibody. 45. The compound of claim 44, wherein the antibody is herceptin. 46. The compound of claim 42, wherein R.sub.2 is a polypeptide. 47. The compound of claim 46, wherein the polypeptide is an antibody. 48. The compound of claim 47, wherein the antibody is herceptin. 49. A compound comprising Formula (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI): ##STR00284## ##STR00285## wherein: A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, --O--, --O-(alkylene or substituted alkylene)-, --S--, --S-(alkylene or substituted alkylene)-, --S(O).sub.k-- where k is 1, 2, or 3, --S(O).sub.k(alkylene or substituted alkylene)-, --C(O)--, --C(O)-(alkylene or substituted alkylene)-, --C(S)--, --C(S)-(alkylene or substituted alkylene)-, --N(R')--, --NR'-(alkylene or substituted alkylene)-, --C(O)N(R')--, --CON(R')-(alkylene or substituted alkylene)-, --CSN(R')--, --CSN(R')-(alkylene or substituted alkylene)-, --N(R')CO-(alkylene or substituted alkylene)-, --N(R')C(O)O--, --S(O).sub.kN(R')--, --N(R')C(O)N(R')--, --N(R')C(S)N(R')--, --N(R')S(O).sub.kN(R')--, --N(R')--N.dbd., --C(R').dbd.N--, --C(R').dbd.N--N(R')--, --C(R').dbd.N--N.dbd., --C(R').sub.2--N.dbd.N--, and --C(R').sub.2--N(R')--N(R')--, where each R' is independently H, alkyl, or substituted alkyl; Z has the structure of: ##STR00286## R.sub.5 is H, CO.sub.2H, C.sub.1-C.sub.6alkyl, or thiazole; R.sub.6 is OH or H; Ar is phenyl or pyridine; R.sub.1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; R.sub.3 and R.sub.4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R.sub.3 and R.sub.4 or two R.sub.3 groups optionally form a cycloalkyl or a heterocycloalkyl; R.sub.7 is C.sub.1-C.sub.6alkyl or hydrogen; L, L.sub.1, L.sub.2, L.sub.3, and L.sub.4 are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)--, -alkylene-J-, -(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-C--(O)--, -(alkylene-O).sub.n-J-, -(alkylene-O).sub.n-J-alkylene-, -(alkylene-O).sub.n--(CH.sub.2).sub.n'--NHC(O)--(CH.sub.2).sub.n''--C(Me)- .sub.2-S--S--(CH.sub.2).sub.n'''--NHC(O)-(alkylene-O).sub.n''''-alkylene-, -(alkylene-O).sub.n-alkylene-W--, -alkylene-C(O)--W--, -(alkylene-O).sub.n-alkylene-J-, -alkylene'-J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-alkylene', -J-(alkylene-O).sub.n-alkylene-, -(alkylene-O).sub.n-alkylene-J-(alkylene-O).sub.n'-alkylene-J'-, --W--, -alkylene-W--, alkylene'-J-(alkylene-NMe).sub.n-alkylene-W--, -J-(alkylene-NMe).sub.n-alkylene-W--, -(alkylene-O).sub.n-alkylene-U-alkylene-C(O)--, -(alkylene-O).sub.n-alkylene-U-alkylene-; -J-alkylene-NMe-alkylene'-NMe-alkylene''-W--, and -alkylene-J-allylene'-NMe-alkylene''-NMe-alkylene'''-W--; ##STR00287## U has the structure of: ##STR00288## each J and J' independently have the structure of: ##STR00289## each n and n' are independently integers greater than or equal to one; D has the structure of: ##STR00290## ##STR00291## each R.sub.17 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, -(alkylene or substituted alkylene)-ON(R'').sub.2, -(alkylene or substituted alkylene)-C(O)SR'', -(alkylene or substituted alkylene)-S--S-(aryl or substituted aryl), --C(O)R'', --C(O).sub.2R'', or --C(O)N(R'').sub.2, wherein each R'' is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; each Z.sub.1 is a bond, CR.sub.17R.sub.17, O, S, NR', CR.sub.17R.sub.17--CR.sub.17R.sub.17, CR.sub.17R.sub.17--O, O--CR.sub.17R.sub.17, CR.sub.17R.sub.17--S, S--CR.sub.17R.sub.17, CR.sub.17R.sub.17--NR', or NR'--CR.sub.17R.sub.17; each R' is H, alkyl, or substituted alkyl; each Z.sub.2 is selected from the group consisting of a bond, --C(O)--, --C(S)--, optionally substituted C.sub.1-C.sub.3 alkylene, optionally substituted C.sub.1-C.sub.3 alkenylene, and optionally substituted heteroalkyl; each Z.sub.3 are independently selected from the group consisting of a bond, optionally substituted C.sub.1-C.sub.4 alkylene, optionally substituted C.sub.1-C.sub.4 alkenylene, optionally substituted heteroalkyl, --O--, --S--, --C(O)--, --C(S)--, and --N(R')--; each T.sub.3 is a bond, C(R'')(R''), O, or S; with the proviso that when T.sub.3 is O or S, R'' cannot be halogen; each R'' is H, halogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; m and p are 0, 1, 2, or 3, provided that at least one of m or p is not 0; M.sub.2 is ##STR00292## where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group; M.sub.3 is ##STR00293## where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group; M.sub.4 is ##STR00294## where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group; each R.sub.19 is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, ester, ether, thioether, aminoalkyl, halogen, alkyl ester, aryl ester, amide, aryl amide, alkyl halide, alkyl amine, alkyl sulfonic acid, alkyl nitro, thioester, sulfonyl ester, halosulfonyl, nitrile, alkyl nitrile, and nitro; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and each R.sub.16 is independently selected from the group consisting of hydrogen, halogen, alkyl, NO.sub.2, CN, and substituted alkyl. 50. The compound of claim 49, wherein R.sub.1 is a polypeptide. 51. The compound of claim 50, wherein the polypeptide is an antibody. 52. The compound of claim 51, wherein the antibody is herceptin. 53. The compound of claim 49, wherein R.sub.2 is a polypeptide. 54. The compound of claim 53, wherein the polypeptide is an antibody. 55. The compound of claim 54, wherein the antibody is herceptin. 56. The compound of claim 49, comprising Formula (XXXI-A): ##STR00295##

Details for Patent 9,796,754

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2031-05-27
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2031-05-27