Compounds and Methods for Treating Toll-Like Receptor 2-Related Diseases and Conditions

A compound having the formula:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein
• a is an integer of 1 to 3;
• b is an integer of 0 to 4, wherein when b is 0, the carbon bonded to X and Y is not bonded to 2 or more heteroatoms;
• each of R1, R2, and R3 is, independently, H or C1-6 alkyl;
• R4 is H, optionally substituted C1-6 alkyl, optionally substituted C7-16 aralkyl, or optionally substituted C2-15 heterocyclylalkyl;
• R5 is CO2H, SO3H, OSO3H, OP(O)(OH)2, or 5-tetrazolyl;
• X is selected from the group consisting of —NRX1V, —N(RX1)C(O)V, —N(RX1)C(S)V, —N(RX1)C(O)N(RX2)V, —N(RX1)C(S)N(RX2)V, —N(RX1)C(O)OV, N(RX1)S(O)2V, —C(O)N(RX1)V, —C(O)OV, —OC(O)V, —OC(O)OV, and —OC(O)N(RX1)V, where each of RX1 and RX2 is, independently, H or C1-6 alkyl, and V is a C1-20 alkyl, C1-20 alkenyl, or C1-20 alkynyl group, optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl and optionally containing 1 or 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain:
• W is selected from the group consisting of H, —C(O)N(RW1)RW2, —C(O)ORW2, —(CH2)cORW3, —(CH2)cSRW3, —(CH)cO(CH2)dCH(ORW3)RW4, —(CH2)cS(CH2)dCH(ORW3)RW4—C(O)N(RW1)(CH2)cCH(ORW3)RW4 and —C(O)N(RW1)(CH2)cCH(ORW3)(CH2)eORW5, wherein each of c and d is, independently, an integer of 1 to 4, e is an integer of 2 to 4, RW1 is H or C1-6 alkyl RW2 is C1-20 alkyl C1-20 alkenyl, or C1-20 alkynyl, each of RW3 and RW5 is, independently, H, C1-20 alkyl C1-21 acyl, C1-20 alkenyl, or C1-20 alkynyl, and RW4 is H, C1-20 alkyl C1-20 alkenyl, or C1-20 alkynyl, wherein each of RW2, RW3, RW4, and RW5 is optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl, optionally contains 1 to 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain, and optionally contains 1 to 4 non-vicinal oxygen atoms in the carbon chain;
• and
• U is selected from the group consisting of
• where
• f is an integer of 1 to 4, g is 0 or 1,
• each of RU1, RU2, and RU3 is, independently, H, optionally substituted C1-6 alkyl, optionally substituted C7-16 aralkyl, or optionally substituted C2-15 heterocyclylalkyl, or RU1 is H or optionally substituted C1-6 alkyl and RU2 and RU3 together with the carbon atom they are bonded to form an optionally substituted C3-6 aliphatic ring, or RU2 is H and RU3 and RU1 together with the carbon atom bonded to RU3 and the nitrogen atom bonded to RU1 form an optionally substituted 4-6-membered heterocyclic ring,
• RU4 is selected from the group consisting of —CH2RU5, —C(O)RU6, —C(O)NH(RU7), and —C(O)O(RU8), wherein each of RU5, RU6, RU7, and RU8 is selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C7-16 aralkyl, optionally substituted C2-15 heterocyclylalkyl, optionally substituted C6-10 aryl, and optionally substituted C1-9 heterocyclyl, or RU4 is a peptide chain of 1 to 10 natural or non-natural amino acids, or mixture thereof, linked via the C-terminal end and substituted at the N-terminal end of the peptide with a group selected from H, —CH2RU5, —C(O)RU6, —C(O)NH(RU7), and —C(O)O(RU5), wherein each of RU5, RU6, RU7, and RU8 is as defined above, and
• RU5 is a peptide chain of 1 to 10 natural or non-natural amino acids, or mixture thereof, linked via the N-terminal end and the C-terminal end is CO2RU9 or CONRU10RU11 wherein each of RU9, RU10, and RU11 is selected from the group consisting of H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C7-16 aralkyl, optionally substituted C2-15 heterocyclylalkyl, optionally substituted C6-10 aryl, and optionally substituted C1-9 heterocyclyl.

A compound having the formula:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein
• i is an integer of 1 to 4
• R6 is H or C1-6 alkyl;
• Z is selected from the group consisting of —NRZ1V, —N(RZ1)C(O)V, —N(RZ1)C(S)V, —N(RZ1)C(O)N(RZ2)V, —N(RZ1)C(S)N(RZ2)V, —N(RZ1)C(O)OV, and —N(RZ1)S(O)2V, where each of RZ1 and RZ2 is, independently, H or C1-6 alkyl, and V is a C1-20 alkyl, C1-20 alkenyl, or C1-20 alkynyl group, optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl and optionally contains 1 to 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain;
• R7 is C1-20 alkyl, C1-20 alkenyl, or C1-20 alkynyl, optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl and optionally contains 1 to 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain;
• each of R8 and R9 is, independently H, optionally substituted C1-6 alkyl, optionally substituted C7-16 aralkyl, or optionally substituted C2-15 heterocyclylalkyl, or R8 and R9 together with the carbon atom they are bonded to form an optionally substituted C3-6 aliphatic ring;
• and
• T is ORT1, NRT2RT3, or a peptide chain of 1 to 10 natural or non-natural amino acids, or mixture thereof, linked via the N-terminal end and the C-terminal end is CORT1, or CONRT2RT3, wherein each of RT1, RT2, and RT3 is selected from the group consisting of H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C7-16 aralkyl, optionally substituted C2-15 heterocyclylalkyl, optionally substituted C6-10 aryl, and optionally substituted C1-9 heterocyclyl.