Biologically active compounds and methods thereof

A compound having the structure of formula B:

• or a salt thereof, wherein:
• LR is
• L, —C≡C—, optionally substituted —CH═CH—, —C(O)—, —C(S)—, or —C(NR″)—;
• Lb is L;
• Rb is R″;
• Ring L is an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• each of Rs is independently R″, halogen, —CN, oxo, —NO2, or an optionally substituted group selected from acyl, acylamino, hydroxy, amino acid, amine, amide, carbamate, ester, ether, carboxylic acid, thio, thioalkyl, thioester, thioether, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, alkylsulfonyl, and arylsulfonyl;
• q is 0-10;
• each R″ is independently hydrogen, halogen, -L-R′, -L-OR′, -L-SR′, -L-C(O)OR′, -L-C(O)SR′, -L-C(O)N(R′)2, -L-OC(O)N(R′)2, -L-C(O)R′, -L-N(R′)2, —CN, —OC(R′)2COOH, —SC(R′)2COOH, —N(R′)C(R′)2COOH, or is an optionally substituted group selected from alkylsulfonyl, arylsulfonyl, carboxylate, ester, ether, amide, carbohydrate, amino acid, acyl, alkyloxy-substituted acyl, alditol, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, and thioether;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

A compound having the structure of formula A′:

• or a salt thereof, wherein:
• Ring P is an optionally substituted 5-20 membered, monocyclic, bicyclic or polycyclic ring having 0-5 heteroatoms;
• is a single bond or double bond;
• each of Y and Z is independently C or N;
• each of R2 and R3 is independently R″ or
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• each of Rs and R6 is independently R″ or —C(O)OR″;
• each of R7 and Rs is independently R″;
• Ring A is an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• LA is L;
• each of R9 and R8 is independently R″, halogen, —CN, oxo, —NO2, or an optionally substituted group selected from acyl, acylamino, hydroxy, amino acid, amine, amide, carbamate, ester, ether, carboxylic acid, thio, thioalkyl, thioester, thioether, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, alkylsulfonyl, and arylsulfonyl;
• each of p and q is independently 0-10;
• each R″ is independently hydrogen, halogen, -L-R′, -L-OR′, -L-SR′, -L-C(O)OR′, -L-C(O)SR′, -L-C(O)N(R′)2, -L-OC(O)N(R′)2, -L-C(O)R′, -L-N(R′)2, —CN, —OC(R′)2COOH, —SC(R′)2COOH, —N(R′)C(R′)2COOH, or is an optionally substituted group selected from alkylsulfonyl, arylsulfonyl, carboxylate, ester, ether, amide, carbohydrate, amino acid, acyl, alkyloxy-substituted acyl, alditol, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, and thioether;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.
• X is —O—, —S—, —C(R′)═, —N(R′)—, or optionally substituted —CH═, —CH═CH—, or —NH—;
• t is 0-9;
• and
• R1 is R9;
• or
• a compound having the structure of formula C:
• or a salt thereof, wherein:
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• each of R10, RD, R12, R13, and R14 is independently R″;
• each R″ is independently hydrogen, halogen, -L-R′, -L-OR′, -L-SR′, -L-C(O)OR′, -L-C(O)SR′, -L-C(O)N(R′)2, -L-OC(O)N(R′)2, -L-C(O)R′, -L-N(R′)2, —CN, —OC(R′)2COOH, —SC(R′)2COOH, or —N(R′)C(R′)2COOH;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R is independently halogen, —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms;
• or
• a compound having the structure of formula D:
• or a salt thereof, wherein:
• each of R15 and R16 is independently -Lw-Rw;
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R is independently halogen, —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms;
• or
• a compound having the structure of formula E:
• or a salt thereof, wherein:
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• each of R17 and R18 is independently an optionally substituted 5-20 membered, monocyclic, bicyclic or polycyclic aromatic ring having 0-5 heteroatoms;
• Ring C is an optionally substituted 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-6 heteroatoms.
• L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms;
• or
• a compound having the structure of formula F:
• or a salt thereof, wherein:
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• each of Rs6, Rs7 is independently Rs;
• each of Rs is independently R″, halogen, —CN, oxo, —NO2, or an optionally substituted group selected from acyl, acylamino, hydroxy, amino acid, amine, amide, carbamate, ester, ether, carboxylic acid, thio, thioalkyl, thioester, thioether, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, alkylsulfonyl, and arylsulfonyl;
• each R″ is independently hydrogen, halogen, -L-R′, -L-OR′, -L-SR′, -L-C(O)OR′, -L-C(O)SR′, -L-C(O)N(R′)2, -L-OC(O)N(R′)2, -L-C(O)R′, -L-N(R′)2, —CN, —OC(R′)2COOH, —SC(R′)2COOH, —N(R′)C(R′)2COOH, or is an optionally substituted group selected from alkylsulfonyl, arylsulfonyl, carboxylate, ester, ether, amide, carbohydrate, amino acid, acyl, alkyloxy-substituted acyl, alditol, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, and thioether;
• each of q, x and y is independently 0-4;
• L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, C(O), C(S), C(NR′), —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms;
• or
• a compound having the structure of formula G:
• or a salt thereof, wherein:
• Ring B is an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• R8a is Rm, or
• LA is L;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• Ring A is an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each Rm is independently Rs;
• each of Rs is independently R″, halogen, —CN, oxo, —NO2, or an optionally substituted group selected from acyl, acylamino, hydroxy, amino acid, amine, amide, carbamate, ester, ether, carboxylic acid, thio, thioalkyl, thioester, thioether, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, alkylsulfonyl, and arylsulfonyl;
• each R″ is independently hydrogen, halogen, -L-R′, -L-OR′, -L-SR′, -L-C(O)OR′, -L-C(O)SR′, -L-C(O)N(R′)2, -L-OC(O)N(R′)2, -L-C(O)R′, -L-N(R′)2, —CN, —OC(R′)2COOH, —SC(R′)2COOH, —N(R′)C(R′)2COOH, or is an optionally substituted group selected from alkylsulfonyl, arylsulfonyl, carboxylate, ester, ether, amide, carbohydrate, amino acid, acyl, alkyloxy-substituted acyl, alditol, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, and thioether;
• q is independently 0-10;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms;
• or
• a compound having the structure of formula H:
• or a salt thereof, wherein:
• R4 is or comprises an isourea or isothiourea moiety, or -Lw-Rw;
• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• R5 is independently R″ or —C(O)OR″;
• R2 is independently R″ or
• LA is L;
• Ring A is an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each of R9 and Rs is independently R″, halogen, —CN, oxo, —NO2, or an optionally substituted group selected from acyl, acylamino, hydroxy, amino acid, amine, amide, carbamate, ester, ether, carboxylic acid, thio, thioalkyl, thioester, thioether, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, alkylsulfonyl, and arylsulfonyl;
• each of p and q is independently 0-10;
• each R″ is independently hydrogen, halogen, -L-R′, -L-OR′, -L-SR′, -L-C(O)OR′, -L-C(O)SR′, -L-C(O)N(R′)2, -L-OC(O)N(R′)2, -L-C(O)R′, -L-N(R′)2, —CN, —OC(R′)2COOH, —SC(R′)2COOH, —N(R′)C(R′)2COOH, or is an optionally substituted group selected from alkylsulfonyl, arylsulfonyl, carboxylate, ester, ether, amide, carbohydrate, amino acid, acyl, alkyloxy-substituted acyl, alditol, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, and thioether;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

The compound of any one of the preceding claims, wherein R4 is -Lw-Rw, wherein:

• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rw is -T-C(═NRw1)N(Rw2)(Rw3);
• each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• and
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

The compound of any one of the preceding claims, wherein R4 is -Lw-Rwh, wherein:

• Lw is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• Rwh is -T-H;
• T is O or S;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• and
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

A method for inhibiting an activity of a polypeptide comprising a nucleophilic moiety, comprising contacting the polypeptide with a compound or composition of any one of the preceding claims;

• preferably:
• wherein the nucleophilic moiety is —SH or —SeH or a salt form thereof;
• or
• wherein the polypeptide is GPX4;
• or
• a method for inhibiting cell proliferation in a system, comprising administering to the system a compound or composition of any one of the preceding claims;
• or
• a method for inducing cell death in a system, comprising administering to the system a compound or composition of any one of the preceding claims;
• or
• a method for inducing ferroptosis in a system, comprising administering to the system a compound or composition of any one of the preceding claims.

A method for preventing a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of a compound or composition of any one of the preceding claims;

• or
• a method for preventing a condition, disorder or disease associated with a polypeptide comprising —SeH or a salt form, comprising administering or delivering to a subject susceptible thereto an effective amount of a compound or composition of any one of the preceding claims;
• or
• a method for treating a condition, disorder or disease associated with a polypeptide comprising —SeH or a salt form, comprising administering or delivering to a subject suffering therefrom an effective amount of a compound or composition of any one of the preceding claims.

The compound of any one of the preceding claims, wherein:

• the compound inhibits an activity of a polypeptide comprising a selenocysteine residue;
• compound reacts with selenocysteine or a salt thereof, or a selenocysteine residue in a polypeptide;
• —SeH of a selenocysteine or a salt form thereof replaces the isourea moiety;
• the compound is capable of inhibiting or preventing cell growth or proliferation;
• the compound is capable of inducing cell death;
• the compound is capable of inducing ferroptosis;
• the effect of the compound is reduced in the presence of a ferroptosis inhibitor;
• an observed IC50 for the compound for a capability in the presence of a ferroptosis inhibitor is about or at least about 2-5000, e.g., about or at least about 10-1000, 50-1000, 100-1000, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500 or 1000 fold of that absence of a ferroptosis inhibitor;
• an observed IC50 for the compound for a capability in the presence of a ferroptosis inhibitor is about or at least about 10 fold of that absence of a ferroptosis inhibitor;
• an observed IC50 for the compound for a capability in the presence of a ferroptosis inhibitor is about or at least about 20 fold of that absence of a ferroptosis inhibitor;
• an observed IC50 for the compound for a capability in the presence of a ferroptosis inhibitor is about or at least about 50 fold of that absence of a ferroptosis inhibitor;
• an observed IC50 for the compound for a capability in the presence of a ferroptosis inhibitor is about or at least about 100 fold of that absence of a ferroptosis inhibitor;
• an observed IC50 for the compound for a capability in the presence of a ferroptosis inhibitor is about or at least about 1-100, e.g., about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 uM;
• the concentration of the ferroptosis inhibitor is about or at least about EC50 of the ferroptosis inhibitor when the ferroptosis inhibitor is assessed by itself;
• the concentration of the ferroptosis inhibitor is about or at least about 0.1-100, e.g., about or at least about 1-20, 2-10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 uM;
• the concentration of the ferroptosis inhibitor is about or at least about 1 uM;
• the concentration of the ferroptosis inhibitor is about or at least about 2 uM;
• the compound inhibits an activity of GPX4;
• the compound binds to GPX4;
• or
• wherein the isourea or isothiourea moiety has the structure of Rw, wherein Rw is -T-C(═NRw1)N(Rw2)(Rw3) or a salt thereof, wherein each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• T is O or S;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• and
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

A compound comprising Rw, wherein Rw is -T-C(═NRw1)N(Rw2)(Rw3) or a salt form thereof, wherein each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;

• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• T is O or S;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• and
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms;
• or
• a compound comprising Rw, wherein R″ is —OC(=NRw1)N(Rw2)(Rw3) or a salt thereof, wherein each of Rw1, Rw2 and Rw3 is independently -L-R′ or a detectable moiety;
• each L is independently a covalent bond, or an optionally substituted bivalent C1-10 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• and
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

The compound of claim 71 or 72, comprising -Lw-Rw, wherein LV is a covalent bond, or an optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-6 heteroatoms, wherein one or more methylene unit is optionally and independently replaced with —C(R′)2—, -Cy-, —O—, —S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(S)N(R′)—, —C(NR′)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;

• each -Cy- is independently an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
• each R′ is independently R, —OR, —C(O)R, —C(O)OR, —C(O)N(R)2, —S(O)R, or —S(O)OR;
• and
• each R is independently —H, or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-10 heteroatoms, C6-20 aryl, 5-20 membered heteroaryl having 1-10 heteroatoms, 3-20 membered heterocyclyl having 1-10 heteroatoms and combinations thereof, wherein each combination independently has 1-30 carbon atoms and 0-10 heteroatoms;
• or:
• two R groups are optionally and independently taken together to form a covalent bond, or:
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-20 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
• or:
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.