Silicon based drug conjugates and methods of using same

A silicon based conjugate represented by the formula:

• and pharmaceutically acceptable salts thereof, wherein:
• L is a targeting moiety that permits selective accumulation of the conjugate within a target cell or tissue;
• P is a payload moiety;
• RP is P, H, or R5;
• Y1 is represented by the formula:
• -LL1-G1-LL2-;
• Y2 is represented by the formula:
• -LL3-G2-LL4-;
• G1 and G2 are each optional catalytic moieties each independently selected from the group consisting of -heteroaryl-, —O-heteroaryl-, —NRa-heteroaryl-, —S(O)w-heteroaryl- (wherein w is 0, 1, or 2), —NRa—SO2-heteroaryl-, —SO2—NRa-heteroaryl-, -phenyl-, —O-phenyl-, —NRa-phenyl-, —S(O)w-phenyl- (wherein w is 0, 1, or 2), —NRa—SO2-phenyl-, —SO2—NRa-phenyl-, —C(O)—C0-6alkyl-, —C(O)—O—C0-6alkyl-, —O—C(O)—C0-6alkyl-, —NRa—C(O)—C0-6alkyl-, —C(O)—NRa—C0-6alkyl-, and —NRa—C0-6alkyl-;
• wherein -heteroaryl-, —O-heteroaryl-, —NRa-heteroaryl-, —S(O)w-heteroaryl-(wherein w is 0, 1, or 2), —NRa—SO2-heteroaryl-, —SO2—NRa-heteroaryl-, -phenyl-, —O-phenyl-, —NRa-phenyl-, —S(O)w-phenyl- (wherein w is 0, 1, or 2), —NRa—SO2-phenyl-, —SO2—NRa-phenyl-, may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6alkoxy, —COOH, —C(O)—O—C1-6alkyl, —C(O)—NRaRb, —NRa—C(O)—C1-6alkyl, —C(O)—NRa—SO2—C1-6alkyl, —SO3H, —SO2—NRaRb, —NRa—SO2—C1-6alkyl, and —SO2—NRa—C1-6alkyl;
• LL1, LL2, LL3 and LL4 are spacer moieties each independently selected from the group consisting of a bond, and C1-20alkylene, wherein one, two, three or four methylene units of C1-20alkylene are optionally and independently replaced by C3-8cycloalkylene, C2-10alkenylene C2-10alkynylene, aryl, heteroaryl, amino acids, polypeptides, —NR1Y—, —N(R1Y)C(O)—, —C(O)N(R1Y)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR1Y)—, —NR1Y—C1-15alkyl-NR1Y—C(O)—;
• —(CH2—CH2—O)s—, —(O—CH2—CH2)s—, —NR1Y—(CH2—CH2—O)s—C1-6alkyl-NR1Y—C(O)—;
• —(O—CH2—CH2)s—NR1Y—C(O)—;
• —S—C0-6alkyl-;
• —NR1Y—C1-6alkyl-;
• —N(C1-3alkyl)-C1-6alkyl-NH—C(O)—;
• —NH—C1-6alkyl-N(C1-3alkyl)-C(O)—;
• —SO2—NR1Y—C0-6alkyl-;
• —N(R1Y)SO2—C0-6alkyl-;
• —SO2-heterocyclyl-C0-6alkyl-;
• -heterocyclyl-C(O)—;
• -heterocyclyl-C0-6alkyl-NR1Y—C(O)—;
• —NR1Y—C0-6alkylene-heterocyclyl-C(O)—;
• —O—C1-6alkylene-C(O)—;
• —O—C1-15alkylene-NR1Y—C(O)—;
• —O—C1-15alkylene-C(O)—NR1Y—;
• —O—C1-6alkylene-;
• a natural or unnatural amino acid;
• a natural or unnatural oligopeptide;
• a natural or unnatural polypeptide;
• photocleavable motifs;
• carbohydrates, and a self-immolating connector;
• wherein LL1, LL2, LL3 and LL4 are optionally substituted;
• wherein, independently for each occurrence, R1Y is selected from the group consisting of H, C1-6alkyl, cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic, wherein the cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic are optionally substituted with one or more substituents selected from —COOH, urea, amidine, guanidine, sulfonamide, acylsulfonamide, and sulfonyl amide;
• s is an integer from 1-15;
• R1, R2, R3, R4 are selected independently for each occurrence from the group consisting of —Y1-L, —Y1—P, H, —OH, ORa, C1-6alkyl, —O—C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, —C1-6alkyl-NRaRb, α- or β-amino acid, heterocyclyl, phenyl, naphthalene, and heteroaryl;
• wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, Ra, Rb, heterocyclyl, phenyl, naphthalene, amino acid, and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —COOH, —C(O)O—C1-6alkyl, —O—C(O)—C1-6alkyl, —NHC(O)C1-6alkyl, —C(O)NH2, —C(O)NHC1-6alkyl, —C(O)N(C1-6alkyl)2, —NHC(O)CF3, —C(O)—NRa—SO2—C1-6alkyl, —SO3H, —SO2—NRaRb, —NRa—SO2—C1-6alkyl, and —SO2—NRa—C1-6alkyl, amidine, guanidine, urea, sulfonamide, acylsulfonamide, sulfonyl amide, C1-6alkyl, heteroaryl, and phenyl;
• R5 is selected independently for each occurrence from the group consisting of H, —OH, ORa, C1-6alkyl, —O—C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, —C1-6alkyl-NRaRb, α- or β-amino acid, heterocyclyl, phenyl, naphthalene, and heteroaryl;
• wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, Ra, Rb, heterocyclyl, phenyl, naphthalene, amino acid and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —COOH, —C(O)O—C1-6, —C(O)NH2, —C(O)NHC1-6alkyl, —C(O)N(C1-6alkyl)2, amidine, guanidine, urea, sulfonamide, acylsulfonamide, sulfonyl amide, C1-6alkyl, heteroaryl, and phenyl;
• or any pairwise combination of Y1, Y2, R1, R2, R3, and R4 may, independently, together with the atoms to which they are attached, each form a 4-10 membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 4-10 membered heterocyclic ring is optionally substituted;
• each ring formed may optionally be fused to another through a single shared atom or single shared bond;
• or R1 and R2, together with the silicon to which they are attached, form a 4-8 membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 4-8 membered heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, amino, and hydroxyl;
• or Y1 and R1, together with the atoms to which they are attached, form a 4-8 membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 4-8 membered heterocyclic ring is optionally substituted;
• or Y1 and R1, and R1 and R2, together with the atoms to which they are attached, form a 7-11 membered bicyclic heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 7-11 membered bicyclic heterocyclic ring is optionally substituted;
• or Y1, R1, and R2, together with the atoms to which they are attached, form an 11-15 membered tricyclic heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 11-15 membered tricyclic heterocyclic ring is optionally substituted;
• Ra and Rb are independently selected, for each occurrence, from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, and phenyl;
• wherein C1-6alkyl, C2-6alkenyl, and phenyl may be optionally substituted;
• or Ra and Rb, together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, or N;
• wherein the 4-7 membered heterocyclic ring is optionally substituted;
• and
• wherein the silicon based conjugate is substantially stable in aqueous solution having a pH of between 7 and 7.5 and hydrolytically cleaves in aqueous solution having a pH less than 7 to release the payload moiety from the conjugate.

A silicon based conjugate having the formula:

• and pharmaceutically acceptable salts thereof, wherein:
• L is a targeting moiety that permits selective accumulation of the conjugate within a target cell or tissue;
• A is an adaptor moiety selected from the group consisting of a carbon atom, a nitrogen atom, C3-6cycloalkyl, C3-6cycloalkenyl, phenyl, aryl, biaryl, heteroaryl, heterobiaryl, and mono or bicyclic heterocyclyl;
• P is a payload moiety;
• RP is P, H, or R5;
• Y1 is represented by the formula:
• -LL2-G1-LL3-;
• Y2 is represented by the formula:
• -LL4-G2-LL5-
• n is an integer from 2 to 15;
• m is an integer from 1 to 12;
• G1 and G2 are each optional catalytic moieties each independently selected for each occurrence from the group consisting of a bond, -heteroaryl-, —O-heteroaryl-, —NRa-heteroaryl-, —S(O)w-heteroaryl- (wherein w is 0, 1, or 2), —NRa—SO2-heteroaryl-, —SO2—NRa-heteroaryl-, -phenyl-, —O-phenyl-, —NRa-phenyl-, —S(O)w-phenyl- (wherein w is 0, 1, or 2), —NRa—SO2-phenyl-, —SO2—NRa-phenyl-, —NRa—C(O)—C0-6alkyl-, —C(O)—NRa—C0-6alkyl-, and —NRa—C0-6alkyl-;
• wherein -heteroaryl-, —O-heteroaryl-, —NRa-heteroaryl-, —S(O)w-heteroaryl- (wherein w is 0, 1, or 2), —NRa—SO2-heteroaryl-, —SO2—NRa-heteroaryl-, -phenyl-, —O-phenyl-, —NRa-phenyl-, —S(O)w-phenyl- (wherein w is 0, 1, or 2), —NRa—SO2-phenyl-, —SO2—NRa-phenyl-, may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6alkoxy, —COOH, —C(O)—NRaRb, —NRa—C(O)—C1-6alkyl, —C(O)—NRa—SO2—C1-6alkyl, —SO3H, —SO2—NRaRb, —NRa—SO2—C1-6alkyl, and —SO2—NRa—C1-6alkyl;
• LL1, LL2, LL3, LL4 and LL5 are spacer moieties each independently selected for each occurrence from the group consisting of a bond and C1-20alkylene, wherein one, two, three or four methylene units of C1-20alkylene are optionally and independently replaced by C3-8cycloalkylene, C2-10alkenylene C2-10alkynylene, aryl, heteroaryl, amino acids, polypeptides, —N(R1)C(O)—, —C(O)N(R1)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR1Y)—, —NR1Y—C1-15alkyl-NR1Y—C(O)—;
• —(CH2—CH2—O)s—, —(O—CH2—CH2)s—, —NR1Y—(CH2—CH2—O)s—C1-6alkyl-NR1Y—C(O)—;
• —(O—CH2—CH2)s—NR1Y—C(O)—;
• —S—C0-6alkyl-;
• —NR1Y—(CH1-6alkyl-;
• —N(C1-3alkyl)-C1-6alkyl-NH—C(O)—;
• —NH—C1-6alkyl-N(C1-3alkyl)-C(O)—;
• —SO2—NR1Y—C0-6alkyl-;
• —N(R1Y)SO2—C0-6alkyl-;
• —SO2-heterocyclyl-C0-6alkyl-;
• -heterocyclyl-C(O)—;
• -heterocyclyl-C0-6alkyl-NR1Y—C(O)—;
• —NR1Y—C0-6alkylene-heterocyclyl-C(O)—;
• —O—C1-6alkylene-C(O)—;
• —O—C1-15alkylene-NR1Y—C(O)—;
• —O—C1-15alkylene-C(O)—NR1Y—;
• —O—C1-6alkylene-;
• a natural or unnatural amino acid;
• a natural or unnatural oligopeptide;
• a natural or unnatural polypeptide;
• photocleavable motifs;
• carbohydrates, and a self-immolating connector;
• wherein LL1, LL2, LL3, LL4 and LL5 are optionally substituted;
• wherein, independently for each occurrence, R1Y is selected from the group consisting of H, C1-6alkyl, cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic, wherein the cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic are optionally substituted with one or more substituents selected from —COOH, urea, amidine, guanidine, sulfonamide, acylsulfonamide, and sulfonyl amide;
• s is an integer from 1-15;
• R1, R2, R3, R4 are selected independently for each occurrence from the group consisting of —Y1-L, —Y1—P, H, —OH, ORa, C1-6alkyl, —O—C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, —C1-6alkyl-NRaRb, α- or β-amino acid, heterocyclyl, phenyl, naphthalene, and heteroaryl;
• wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, Ra, Rb, heterocyclyl, phenyl, naphthalene, amino acid, and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —COOH, —C(O)O—C1-6alkyl, —O—C(O)—C1-6alkyl, —NHC(O)C1-6alkyl, —C(O)NH2, —C(O)NHC1-6alkyl, —C(O)N(C1-6alkyl)2, —NHC(O)CF3, —C(O)—NRa—SO2—C1-6alkyl, —SO3H, —SO2—NRaRb, —NRa—SO2—C1-6alkyl, and —SO2—NRa—C1-6alkyl, amidine, guanidine, urea, sulfonamide, acylsulfonamide, sulfonyl amide, C1-6alkyl, heteroaryl, and phenyl;
• R5 is selected independently for each occurrence from the group consisting of H, —OH, ORa, C1-6alkyl, —O—C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, —C1-6alkyl-NRaRb, α- or β-amino acid, heterocyclyl, phenyl, naphthalene, and heteroaryl;
• wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, Ra, Rb, heterocyclyl, phenyl, naphthalene, amino acid and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —COOH, —C(O)O—C1-6, —C(O)NH2, —C(O)NHC1-6alkyl, —C(O)N(C1-6alkyl)2, amidine, guanidine, urea, sulfonamide, acylsulfonamide, sulfonyl amide, C1-6alkyl, heteroaryl, and phenyl;
• or any pairwise combination of Y1, Y2, R1, R2, R3, and R4 may, independently, together with the atoms to which they are attached, each form a 4-10 membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 4-10 membered heterocyclic ring is optionally substituted;
• each ring formed may optionally be fused to another through a single shared atom or single shared bond;
• or R1 and R2, together with the silicon to which they are attached, form a 4-8 membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 4-8 membered heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, amino, and hydroxyl;
• or Y1 and R1, together with the atoms to which they are attached, form a 4-8 membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 4-8 membered heterocyclic ring is optionally substituted;
• or Y1 and R1, and R1 and R2, together with the atoms to which they are attached, form a 7-11 membered bicyclic heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 7-11 membered bicyclic heterocyclic ring is optionally substituted;
• or Y1, R1, and R2, together with the atoms to which they are attached, form an 11-15 membered tricyclic heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S, or N;
• wherein the 11-15 membered tricyclic heterocyclic ring is optionally substituted;
• Ra and Rb are independently selected, for each occurrence, from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, and phenyl;
• wherein C1-6alkyl, C2-6alkenyl, and phenyl may be optionally substituted;
• or Ra and Rb, together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, or N;
• wherein the 4-7 membered heterocyclic ring is optionally substituted;
• and
• wherein the silicon based conjugate is substantially stable in aqueous solution having a pH of between 7 and 7.5 and hydrolytically cleaves in aqueous solution having a pH less than 7 to release the payload moiety from the conjugate.