Phosphonate linkers and their use to faciliate cellular retention of compounds

A payload-ligand conjugate compound comprising a cell-specific targeting ligand conjugated to a payload wherein said conjugate comprises the formula

• wherein
• V is selected from O and S;
• W is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• X is selected from a covalent bond;
• a carbon atom;
• a heteroatom;
• an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
• nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
• Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• D is a payload;
• Z is a linkage formed between (i) a reactive functional group selected from the group consisting of N-hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, strained cycloalkyne, and heterocycloalkyne, alkyne, diene, azadiene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S, and (ii) an S, NR, or O group on the cell-specific targeting ligand (L);
• Each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
• L is a cell-specific targeting ligand;
• and
• n is 1, 2, 3, or 4.

A payload-ligand conjugate compound comprising a cell-specific targeting ligand conjugated to a drug moiety wherein said conjugate comprises the formula

• where the wavy lines indicate the covalent attachment sites to the cell-specific targeting ligand and the payload and wherein
• V is selected from O and S;
• W is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• X is selected from a covalent bond;
• a carbon atom;
• a heteroatom;
• an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
• nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
• Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• Z is a linkage formed between (i) a reactive functional group selected from the group consisting of N-hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, strained cycloalkyne, and heterocycloalkyne, alkyne, diene, azadiene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S, and (ii) an S, NR, or O group on the cell-specific targeting ligand;
• each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
• and
• n is 1, 2, 3, or 4.

A method for treating a disease or disorder by providing to a subject having the disease or disorder a composition comprising a compound having formula (III)

• wherein V is selected from O and S;
• W is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• X is a tuning element selected from a covalent bond;
• a carbon atom;
• a heteroatom;
• an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
• nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
• Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• D is a payload;
• Z is a linkage formed between (i) a reactive functional group selected from the group consisting of N-hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, strained cycloalkyne, and heterocycloalkyne, alkyne, diene, azadiene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S, and (ii) an S, NR, or O group on L;
• each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
• L is a cell-specific targeting ligand;
• and n is 1, 2, 3, or 4;
• and,
• a pharmaceutically acceptable salt or carrier.

An anti-inflammatory compound comprising the formula

• wherein
• V is selected from O and S;
• W is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• X is selected from a covalent bond;
• a carbon atom;
• a heteroatom;
• an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
• nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
• Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• D is an anti-inflammatory agent;
• Z is a linkage formed between (i) a reactive functional group selected from the group consisting of N-hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, strained cycloalkyne, and heterocycloalkyne, alkyne, diene, azadiene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S, and (ii) an S, NR, or O group on the cell-specific targeting ligand (L);
• Each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
• L is a cell-specific targeting ligand;
• and
• n is 1, 2, 3, or 4.

An anti-cancer compound comprising the formula

• wherein
• V is selected from O and S;
• W is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• X is selected from a covalent bond;
• a carbon atom;
• a heteroatom;
• an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
• nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
• Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• D is a cytotoxic agent;
• Z is a linkage formed between (i) a reactive functional group selected from the group consisting of N-hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, strained cycloalkyne, and heterocycloalkyne, alkyne, diene, azadiene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S, and (ii) an S, NR, or O group on the cell-specific targeting ligand (L);
• Each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
• L is a cell-specific targeting ligand;
• and
• n is 1, 2, 3, or 4.

A method for making an antibody-drug conjugate that has reduced propensity for forming aggregates comprising:

• (a) providing a compound comprising the formula
• wherein
• V is selected from O and S;
• W is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• X is selected from a covalent bond;
• a carbon atom;
• a heteroatom;
• an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
• nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
• Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• Z is a reactive functional group selected from the group consisting of N-hydroxysuccinimidyl ester, para-nitrophenyl carbonate, para-nitrophenyl carbamate, azide, hydrazine, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, strained cycloalkyne, and heterocycloalkyne, alkyne, diene, azadiene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S;
• D is a payload;
• each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
• and
• n is 1, 2, 3, or 4;
• and
• (b) conjugating the compound to an antibody to make the antibody-drug conjugate that has reduced propensity for forming aggregates.

A method for making a composition of antibody-drug conjugates in which the propensity of the antibody-drug conjugates in the composition to form aggregates is reduced comprising:

• (a) providing a multiplicity of compounds comprising the formula
• wherein
• V is selected from O and S;
• W is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• X is selected from a covalent bond;
• a carbon atom;
• a heteroatom;
• an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
• nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
• Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, SO2N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
• Z is a reactive functional group selected from the group consisting of N-hydroxysuccinimidyl ester, para-nitrophenyl carbonate, para-nitrophenyl carbamate, azide, hydrazine, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, strained cycloalkyne, and heterocycloalkyne, alkyne, diene, azadiene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S;
• D is a payload;
• each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
• and
• n is 1, 2, 3, or 4;
• and
• (b) conjugating the compounds to a multiplicity of antibodies to make the composition in which the propensity of the antibody-drug conjugates therein to form aggregates is reduced.