IP Library › Granted Patent US 12,478,683

Granted Patent B2

US 12,478,683 · App. 17/072,015 · Granted Nov 25, 2025

Brush prodrugs and uses thereof

Inventors: Jeremiah A. Johnson (Boston, MA); Yivan Jiang (Revere, MA); Hung Vanthanh Nguyen (Cambridge, MA)

Assignee: Massachusetts Institute of Technology

A61K47/60 A61K47/545 C08F4/74 C08G61/08 A61K45/06 C08G2261/1428 C08G2261/1432 C08G2261/418 C08G2261/80 C08G2261/90

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Quick Facts

Patent No.: US 12,478,683
App. No.: 17/072,015
Granted: Nov 25, 2025
Kind: B2

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Abstract

The present disclosure provides, in some aspects, macromonomers of Formula (I), and salts thereof; methods of preparing the macromonomers, and salts thereof; Brush prodrugs (polymers); methods of preparing the Brush prodrugs; compounds of Formula (II); conjugates of Formula (III), and salts thereof; pharmaceutical compositions comprising a Brush prodrug, or a conjugate or a salt thereof; kits comprising: a macromonomer or a salt thereof, a Brush prodrug, a compound, a conjugate or a salt thereof, or a pharmaceutical composition; methods of using the Brush prodrugs, or conjugates or salts thereof; and uses of the Brush prodrugs, and conjugates or salts thereof. These chemical entities may be useful in delivering pharmaceutical agents to a subject or cell.

Claims (159)

1 . A polymer prepared by polymerizing a macromonomer of Formula (I):

or a salt thereof, in the presence of a metathesis catalyst, wherein:

each instance of R A is independently hydrogen, halogen, or substituted or unsubstituted, C 1-6 alkyl;

a is an integer from 1 to 20, inclusive;

each instance of —Y—Z— is independently

each instance of L J is independently substituted or unsubstituted, C 1-12 alkylene or substituted or unsubstituted, C 2-12 heteroalkylene;

each instance of m is independently an integer from 1 to 10, inclusive;

each instance of E is independently —O—, —S—, —NR a —, —C(═O)O—, —C(═NR a )O—, —S(═O)O—, —S(═O) 2 O—, —C(═O)NR a —, —C(═NR a )NR a —, —S(═O)NR a —, —S(═O) 2 NR a —, —OC(═O)—, —OC(═NR a )—, —OS(═O)—, —OS(═O) 2 —, —NR a C(═O)—, —NR a C(═NR a )—, —NR a S(═O)—, —NR a S(═O) 2 —, —OC(═O)O—, —OC(═NR a )O—, —OS(═O)O—, —OS(═O) 2 O—, —NR a C(═O)O—, —NR a C(═NR a )O—, —NR a S(═O)O—, —NR a S(═O) 2 O—, —OC(═O)NR a —, —OC(═NR a )NR a —, —OS(═O)NR a —, —OS(═O) 2 NR a —, —NR a C(═O)NR a —, —NR a C(═NR a )NR a —, —NR a S(═O)NR a —, —NR a S(═O) 2 NR a —, —C(═O)—, —C(═NR a )—, —S(═O)—, —S(═O) 2 —, or a moiety formed by reacting E A with E B ;

each instance of E A is a first reaction handle;

each instance of E B is a second reaction handle, wherein each instance of the first reaction handle and second reaction handle is independently —N 3 , substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted

provided that the second reaction handle is able to react with the first reaction handle;

each instance of L is independently substituted or unsubstituted, C 1-200 alkylene, substituted or unsubstituted, C 2-200 alkenylene, substituted or unsubstituted, C 2-200 alkynylene, substituted or unsubstituted, C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, or substituted or unsubstituted, C 2-200 heteroalkynylene, wherein:

optionally one or more carbons in each instance of the substituted or unsubstituted, C 1-200 alkylene, substituted or unsubstituted, C 2-200 alkenylene, substituted or unsubstituted, C 2-200 alkynylene, substituted or unsubstituted, C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, and substituted or unsubstituted, C 2-200 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

optionally one or more heteroatoms in each instance of the substituted or unsubstituted, C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, and substituted or unsubstituted, C 2-200 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

each instance of W is independently a single bond, —O—, —S—, or —NR E —;

each instance of R E is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, or a nitrogen protecting group;

each instance of W′ is independently —O— or —S—;

each instance of R 1 is independently hydrogen, halogen, or substituted or unsubstituted, C 1-6 alkyl;

each instance of y is independently 0 or 1;

when y is 0, is a single bond;

when y is 1, is a single or double bond;

when is a single bond, R 2 is hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;

each instance of R a is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two instances of R a attached to the same nitrogen atom are joined to form substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, or substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl;

when is a double bond, R 2 is absent;

each instance of R 3 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , -NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;

each instance of R 4 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , -NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;

or, when y is 1 and is a single bond, R 3 and R 4 are joined with their intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

or, when y is 1 and is a double bond, R 3 and R 4 are cis to each other and are joined with their intervening atoms to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

or R 4 and R 6 are joined with their intervening atoms to form substituted or unsubstituted heterocyclyl;

when is a single bond, R 5 is hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;

when is a double bond, R 5 is absent;

each instance of R 6 is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, or a nitrogen protecting group;

each instance of T is independently substituted or unsubstituted methylene;

each instance of M is independently an ammonium salt or iminium salt of a pharmaceutical agent, wherein the attachment point is the N + of the ammonium salt or iminium salt;

each instance of R B is independently hydrogen, halogen, or substituted or unsubstituted, C 1-6 alkyl;

each instance of b is independently an integer from 1 to 20, inclusive;

e is an integer from 1 to 10, inclusive;

X is —OR C or —N(R D ) 2 ;

R C is substituted or unsubstituted, C 50-1000 heteroalkyl;

each instance of R D is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 50-1000 heteroalkyl, or a nitrogen protecting group, provided that at least one instance of R D is substituted or unsubstituted, C 50-1000 heteroalkyl;

each carbon atom substituent is independently halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa —, —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3 + X − , —N(OR cc )R bb , —SH, —SR aa —, —SSR cc , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —OC(═NR bb )R aa , —OC(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —OC(═NR bb )N(R bb ) 2 , —NR bb C(═NR bb )N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —NR bb SO 2 R aa , —SO 2 N(R bb ) 2 , —SO 2 R aa , —SO 2 OR aa , —OSO 2 R aa , —S(═O)R aa , —OS(═O)R aa , —Si(R aa ) 3 , —OSi(R aa ) 3 —C(═S)N(R bb ) 2 , —C(═O)SR aa , —C(═S)SR aa , —SC(═S)SR aa , —SC(═O)SR aa , —OC(═O)SR aa , —SC(═O)OR aa , —SC(═O)R aa , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , —OP(═O)(R aa ) 2 , —OP(═O)(OR cc ) 2 , —P(═O)(N(R bb ) 2 ) 2 , —OP(═O)(N(R bb ) 2 ) 2 , —NR bb P(═O)(R aa ) 2 , —NR bb P(═O)(OR cc ) 2 , —NR bb P(═O)(N(R bb ) 2 ) 2 , —P(R cc ) 2 , —P(OR cc ) 2 , —P(R cc ) 3 + X − , —P(OR cc ) 3 + X − , —P(R cc ) 4 , —P(OR cc ) 4 , —OP(R cc ) 2 , —OP(R cc ) 3 + X − , —OP(OR cc ) 2 , —OP(OR cc ) 3 + X − , —OP(R cc ) 4 , —OP(OR cc ) 4 , —B(R aa ) 2 , —B(OR cc ) 2 , —BR aa (OR cc ), C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, ═O, ═S, ═NN(R bb ) 2 , =NNR bb C(═O)R aa , =NNR bb C(═O)OR aa , =NNR bb S(═O) 2 R aa , =NR bb , or =NOR cc , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each nitrogen atom substituent is independently —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR bb )R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O)(OR cc ) 2 , —P(═O)(R aa ) 2 , —P(═O)(N(R cc ) 2 ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, or a nitrogen protecting group, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each oxygen atom substituent is an oxygen protecting group;

each sulfur atom substituent is a sulfur protecting group;

each instance of R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R bb is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , —P(═O)(N(R cc ) 2 ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; wherein X − is a counterion;

each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R dd is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff ) 2 , —N(R ff ) 3 + X − , —N(OR ee )R ff , —SH, —SR ee , —SSR ee , —C(═O)R ee , —CO 2 H, —CO 2 R ee , —OC(═O)R ee , —OCO 2 R ee , —C(═O)N(R ff ) 2 , —OC(═O)N(R ff ) 2 , —NR ff C(═O)R ee , —NR ff CO 2 R ee , —NR ff C(═O)N(R ff ) 2 , —C(═NR ff )OR ee , —OC(═NR ff )R ee , —OC(═NR ff )OR ee , —C(═NR ff )N(R ff ) 2 , —OC(═NR ff )N(R ff ) 2 , —NR ff C(═NR ff )N(R ff ) 2 , —NR ff SO 2 R ee , —SO 2 N(R ff ) 2 , —SO 2 R ee , —SO 2 OR ee , —OSO 2 R ee , —S(═O)R ee , —Si(R ee ) 3 , —OSi(R ee ) 3 , —C(═S)N(R ff ) 2 , —C(═O)SR ee , —C(═S)SR ee , —SC(═S)SR ee , —P(═O)(OR ee ) 2 , —P(═O)(R ee ) 2 , —OP(═O)(R ee ) 2 , —OP(═O)(OR ee ) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be joined to form ═O or ═S; wherein X − is a counterion;

each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X − , —NH(C 1-6 alkyl) 2 + X − , —NH 2 (C 1-6 alkyl) + X − , —NH 3 + X − , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C(═O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC(═O)(C 1-6 alkyl), —OCO 2 (C 1-6 alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6 alkyl) 2 , —OC(═O)NH(C 1-6 alkyl), —NHC(═O)(C 1-6 alkyl), —N(C 1-6 alkyl)C(═O)(C 1-6 alkyl), —NHCO 2 (C 1-6 alkyl), —NHC(═O)N(C 1-6 alkyl) 2 , —NHC(═O)NH(C 1-6 alkyl), —NHC(═O)NH 2 , —C(═NH)O(C 1-6 alkyl), —OC(═NH)(C 1-6 alkyl), —OC(═NH)OC 1-6 alkyl, —C(═NH)N(C 1-6 alkyl) 2 , —C(═NH)NH(C 1-6 alkyl), —C(═NH)NH 2 , —OC(═NH)N(C 1-6 alkyl) 2 , —OC(NH)NH(C 1-6 alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6 alkyl) 2 , —NHC(═NH)NH 2 , —NHSO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 OC 1-6 alkyl, —OSO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —Si(C 1-6 alkyl) 3 , —OSi(C 1-6 alkyl) 3 —C(═S)N(C 1-6 alkyl) 2 , C(═S)NH(C 1-6 alkyl), C(═S)NH 2 , —C(═O)S(C 1-6 alkyl), —C(═S)SC 1-6 alkyl, —SC(═S)SC 1-6 alkyl, —P(═O)(OC 1-6 alkyl) 2 , —P(═O)(C 1-6 alkyl) 2 , —OP(═O)(C 1-6 alkyl) 2 , —OP(═O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, ═O, or ═S; and

X − is a counterion.

2 . A method of preparing a polymer comprising polymerizing a macromonomer of Formula (I):

or a salt thereof, in the presence of a metathesis catalyst, wherein:

each instance of R A is independently hydrogen, halogen, or substituted or unsubstituted, C 1-6 alkyl;

a is an integer from 1 to 20, inclusive;

each instance of —Y—Z— is independently

each instance of L J is independently substituted or unsubstituted, C 1-12 alkylene or substituted or unsubstituted, C 2-12 heteroalkylene;

each instance of m is independently an integer from 1 to 10, inclusive;

each instance of E A is a first reaction handle;

provided that the second reaction handle is able to react with the first reaction handle;

each instance of W is independently a single bond, —O—, —S—, or —NR E —;

each instance of R E is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, or a nitrogen protecting group;

each instance of W′ is independently —O— or —S—;

each instance of R 1 is independently hydrogen, halogen, or substituted or unsubstituted, C 1-6 alkyl;

each instance of y is independently 0 or 1;

when y is 0, is a single bond;

when y is 1, is a single or double bond;

when is a double bond, R 2 is absent;

each instance of R 3 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;

each instance of R 4 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;

or, when y is 1 and is a single bond, R 3 and R 4 are joined with their intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

or R 4 and R 6 are joined with their intervening atoms to form substituted or unsubstituted heterocyclyl;

when is a double bond, R 5 is absent;

each instance of R 6 is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, or a nitrogen protecting group;

each instance of T is independently substituted or unsubstituted methylene;

each instance of M is independently an ammonium salt or iminium salt of a pharmaceutical agent, wherein the attachment point is the N + of the ammonium salt or iminium salt;

each instance of R B is independently hydrogen, halogen, or substituted or unsubstituted, C 1-6 alkyl;

each instance of b is independently an integer from 1 to 20, inclusive;

e is an integer from 1 to 10, inclusive;

X is —OR C or —N(R D ) 2 ;

R C is substituted or unsubstituted, C 50-1000 heteroalkyl;

each carbon atom substituent is independently halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3 + X − , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —OC(═NR bb )R aa , —OC(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —OC(═NR bb )N(R bb ) 2 , —NR bb C(═NR bb )N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —NR bb SO 2 R aa , —SO 2 N(R bb ) 2 , —SO 2 R aa , —SO 2 OR aa , —OSO 2 R aa , —S(═O)R aa , —OS(═O)R aa , —Si(R aa ) 3 , —OSi(R aa ) 3 —C(═S)N(R bb ) 2 , —C(═O)SR aa , —C(═S)SR aa , —SC(═S)SR aa , —SC(═O)SR aa , —OC(═O)SR aa , —SC(═O)OR aa , —SC(═O)R aa , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , —OP(═O)(R aa ) 2 , —OP(═O)(OR cc ) 2 , —P(═O)(N(R bb ) 2 ) 2 , —OP(═O)(N(R bb ) 2 ) 2 , —NR bb P(═O)(R aa ) 2 , —NR bb P(═O)(OR cc ) 2 , —NR bb P(═O)(N(R bb ) 2 ) 2 , —P(R cc ) 2 , —P(OR cc ) 2 , —P(R cc ) 3 + X − , —P(OR cc ) 3 + X − , —P(R cc ) 4 , —P(OR cc ) 4 , —OP(R cc ) 2 , —OP(R cc ) 3 + X − , —OP(OR cc ) 2 , —OP(OR cc ) 3 + X − , —OP(R cc ) 4 , —OP(OR cc ) 4 , —B(R aa ) 2 , —B(OR cc ) 2 , —BR aa (OR cc ), C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, ═O, ═S, ═NN(R bb ) 2 , =NNR bb C(═O)R aa , =NNR bb C(═O)OR aa , =NNR bb S(═O) 2 R aa , =NR bb , or =NOR cc , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each oxygen atom substituent is an oxygen protecting group;

each sulfur atom substituent is a sulfur protecting group;

each instance of R dd is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff ) 2 , —N(R ff ) 3 + X − , —N(OR ee )R ff , —SH, —SR ee , —SSR ee , —C(═O)R ee , —CO 2 H, —CO 2 R ee , —OC(═O)R ee , —OCO 2 R ee , —C(═O)N(R ff ) 2 , —OC(═O)N(R ff ) 2 , —NR ff C(═O)R ee , —NR ff CO 2 R ee , —NR ff C(═O)N(R ff ) 2 , —C(═NR ff )OR ee , —OC(═NR ff )R ee , —OC(═NR ff )OR ee , —C(═NR ff )N(R ff ) 2 , —OC(═NR ff )N(R ff ) 2 , —NR ff C(═NR ff )N(R ff ) 2 , —NR ff SO 2 R ee , —SO 2 N(R ff ) 2 , —SO 2 R ee , —SO 2 OR ee , —OSO 2 R ee , —S(═O)R ee , —Si(R ee ) 3 , —OSi(R ee ) 3 , —C(═S)N(R ff ) 2 , —C(═O)SR ee , —C(═S)SR ee , —SC(═S)SR ee , —P(═O)(OR ee ) 2 , —P(═O)(R ee ) 2 , —OP(═O)(R ee ) 2 , —OP(═O)(OR ee ) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2 -6alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be joined to form ═O or ═S; wherein X − is a counterion;

each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X − , —NH(C 1-6 alkyl) 2 + X − , —NH 2 (C 1-6 alkyl) + X − , —NH 3 + X − , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C(═O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC(═O)(C 1-6 alkyl), —OCO 2 (C 1-6 alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6 alkyl) 2 , —OC(═O)NH(C 1-6 alkyl), —NHC(═O)(C 1-6 alkyl), —N(C 1-6 alkyl)C(═O)(C 1-6 alkyl), —NHCO 2 (C 1-6 alkyl), —NHC(═O)N(C 1-6 alkyl) 2 , —NHC(═O)NH(C 1-6 alkyl), —NHC(═O)NH 2 , —C(═NH)O(C 1-6 alkyl), —OC(═NH)(C 1-6 alkyl), —OC(═NH)OC 1-6 alkyl, —C(═NH)N(C 1-6 alkyl) 2 , —C(═NH)NH(C 1-6 alkyl), —C(═NH)NH 2 , —OC(═NH)N(C 1-6 alkyl) 2 , —OC(NH)NH(C 1-6 alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6 alkyl) 2 , —NHC(═NH)NH 2 , —NHSO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 OC 1-6 alkyl, —OSO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —Si(C 1-6 alkyl) 3 , —OSi(C 1-6 alkyl) 3 -C(═S)N(C 1-6 alkyl) 2 , C(═S)NH(C 1-6 alkyl), C(═S)NH 2 , —C(═O)S(C 1-6 alkyl), —C(═S)SC 1-6 alkyl, —SC(═S)SC 1-6 alkyl, —P(═O)(OC 1-6 alkyl) 2 , —P(═O)(C 1-6 alkyl) 2 , —OP(═O)(C 1-6 alkyl) 2 , —OP(═O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, ═O, or ═S; and

X − is a counterion.

3 . A pharmaceutical composition comprising a polymer of claim 1 and optionally a pharmaceutically acceptable excipient.

4 . A kit comprising:

a polymer of claim 1 ; and

instructions for using the polymer.

5 . A method of delivering a pharmaceutical agent to a subject in need thereof comprising administering to the subject in need thereof a polymer of claim 1 .

6 . A method of treating a disease in a subject in need thereof comprising administering to or implanting in the subject in need thereof a therapeutically effective amount of:

a polymer of claim 1 ;

wherein at least one instance of the pharmaceutical agent is a therapeutic agent.

7 . A method of preventing a disease in a subject in need thereof comprising administering to or implanting in the subject in need thereof a prophylactically effective amount of:

a polymer of claim 1 ;

wherein at least one instance of the pharmaceutical agent is a prophylactic agent.

8 . A method of diagnosing a disease in a subject comprising administering to or implanting in the subject a diagnostically effective amount of:

a polymer of claim 1 ;

wherein at least one instance of the pharmaceutical agent is a diagnostic agent.

9 . The polymer of claim 1 , wherein e is 1.

10 . The polymer of claim 9 , wherein each instance of m is 1.

11 . The polymer of claim 10 , wherein each instance of E is

12 . The polymer of claim 11 , wherein each instance of L J is unsubstituted C 1-12 alkylene.

13 . The polymer of claim 12 , wherein each instance of L is unsubstituted C 2-20 alkylene.

14 . The polymer of claim 13 , wherein each instance of W is a single bond, and each instance of W′ is —O—.

15 . The polymer of claim 14 , wherein each instance of R 1 is hydrogen.

16 . The polymer of claim 15 , wherein X is —N(R D ) 2 , and each instance of R D is independently hydrogen or unsubstituted C 50-1000 heteroalkyl, provided that at least one instance of R D is unsubstituted C 50-1000 heteroalkyl.

17 . The polymer of claim 16 , wherein y is 0; and is a single bond.

18 . The polymer of claim 16 , wherein the macromonomer is of the formula:

or a salt thereof, wherein:

each instance of R 7 is independently halogen or unsubstituted C 1-6 alkyl; and

z is 0, 1, 2, 3, 4, 5, or 6.

19 . The polymer of claim 16 , wherein the macromonomer is of the formula:

or a salt thereof, wherein:

each instance of R 7 is independently halogen or unsubstituted C 1-6 alkyl; and

z is 0, 1, 2, 3, or 4.

20 . The polymer of claim 16 , wherein the macromonomer is of the formula:

21 . The polymer of claim 16 , wherein at least one instance of M is

(an anionic counterion),

(an anionic counterion), or

(an anionic counterion).

22 . The polymer of claim 1 , wherein macromonomer is of the formula:

or a salt thereof.

23 . The polymer of claim 10 , wherein each instance of E is a moiety formed by reacting E A with E B .

24 . The polymer of claim 23 , wherein each instance of E A is —N 3 , and each instance of E B is independently —C≡CH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted

25 . The polymer of claim 15 , wherein X is

wherein n is an integer from 40 to 100, inclusive; and R F is hydrogen or unsubstituted C 1-6 alkyl.

26 . The polymer of claim 16 , wherein each instance of R A and R B is hydrogen.

27 . The polymer of claim 26 , wherein each instance of —Y—Z— is

28 . The polymer of claim 16 , wherein each instance of R 2 when present, R 3 when present, R 4 , R 5 , and R 6 is hydrogen.

29 . The polymer of claim 16 , wherein each instance of the pharmaceutical agent is an anti-cancer agent.

30 . The polymer of claim 16 , wherein each instance of the pharmaceutical agent is independently abiraterone acetate; afatinib dimaleate; bendamustine hydrochloride; cabozantinib-s-malate; daunorubicin hydrochloride; doxorubicin hydrochloride; epirubicin hydrochloride; erlotinib hydrochloride; fludarabine phosphate; gemcitabine hydrochloride; goserelin acetate; imatinib mesylate; irinotecan hydrochloride; lanreotide acetate; lapatinib ditosylate; leucovorin calcium, leuprolide acetate; mechlorethamine hydrochloride; mitoxantrone hydrochloride; omacetaxine mepesuccinate; pamidronate disodium; pazopanib hydrochloride; pemetrexed disodium; ponatinib hydrochloride; procarbazine hydrochloride; raloxifene hydrochloride; ruxolitinib phosphate; sorafenib tosylate; sunitinib malate; tamoxifen citrate; topotecan hydrochloride; vinblastine sulfate; vinorelbine tartrate; or JQ1, AZD5153, vincristine, ado-trastuzumab emtansine, aldesleukin, alemtuzumab, anastrozole, asparaginase Erwinia chrysanthemi , axitinib, azacitidine, bevacizumab, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, carfilzomib, ceritinib, cetuximab, chlorambucil, cisplatin, clofarabine, crizotinib, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, decitabine, degarelix, denileukin diftitox, denosumab, dinutuximab, gefitinib, ibritumomab tiuxetan, ibrutinib, idelalisib, imiquimod, ipilimumab, ixabepilone, lenalidomide, lenvatinib, letrozole, mercaptopurine, methotrexate, mitomycin c, nelarabine, nilotinib, nivolumab, obinutuzumab, ofatumumab, olaparib, OTX-015, oxaliplatin, palbociclib, panitumumab, panobinostat, pazopanib, pegaspargase, peginterferon alfa-2b, pembrolizumab, pertuzumab, plerixafor, pomalidomide, pralatrexate, ramucirumab, recombinant interferon alfa-2b, regorafenib, rituximab, siltuximab, temozolomide, toremifene, tositumomab, trametinib, trastuzumab, vandetanib, vemurafenib, vismodegib, ziv-aflibercept, zoledronic acid, or a pharmaceutically acceptable salt thereof.

31 . The polymer of claim 16 , wherein y is 1, and is a double bond.

32 . The polymer of claim 16 , wherein the weight average molecular weight of the polymer as determined with static light scattering is between 3,000 and 1,000,000, between 3,000 and 100,000, between 3,000 and 10,000, between 10,000 and 1,000,000, between 10,000 and 100,000, between 100,000 and 1,000,000, or between 30,000 and 30,000,000, g/mol.

33 . The polymer of claim 1 , wherein the polymer is of the formula:

wherein n′ is the polymerization degree.

34 . A method of delivering a pharmaceutical agent to a cell comprising contacting the cell with a polymer of claim 1 .

35 . The method of claim 34 , wherein the cell is in vitro.

36 . The method of claim 6 , wherein the disease is cancer, and at least one instance of the therapeutic agent is an anti-cancer agent.

37 . The method of claim 8 , wherein the disease is cancer.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 9, 2021

From: JOHNSON, JEREMIAH A.; JIANG, YIVAN; NGUYEN, HUNG VANTHANH

To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY

Reel/Frame 057425/0204 →

Continuity (2)

Provisional Application 62916036 · Oct 16, 2019

Related Publication 20210113701A1 · Apr 22, 2021

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