Methods for treatment of diseases involving acidic or hypoxic diseased tissues

A method of reducing bone marrow toxicity associated with administration of an ionizing radiation or cytotoxic agent, which comprises administering to a human or other mammal a therapeutically-effective amount of a compound of formula (I)

• R8-Q-R7 (I)
• or a pharmaceutically acceptable salt thereof, wherein:
• R7 is a peptide comprising at least one of the following sequences:
• ADDONPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:
• 1;
• Pv1), AEONPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:
• 2;
• Pv2), and ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:
• 3;
• Pv3),
• and wherein R7 is attached to Q through a cysteine residue of R7;
• R8 is selected from the group consisting of:
• Q is selected from the group consisting of
• R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12 are each independently selected from H, C1-4 alkyl, C1-4 alkenyl, C6-10 aryl, 5-10 membered heteroaryl, halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, and NRc1C(O)NRc1Rd1, wherein said C1-4 alkyl, C1-4 alkenyl, C6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, and NRc1C(O)NRc1Rd1;
• or R1 and R2 together with the carbon atom to which they are attached form a C3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, and NRc1C(O)NRc1Rd1;
• or R1 and R3 together with the carbon atom to which they are attached form a C3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, and NRc1C(O)NRc1Rd1;
• or R3 and R4 together with the carbon atom to which they are attached form an C3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, and NRc1C(O)NRc1Rd1;
• or R5 and R6 together with the carbon atom to which they are attached form an C3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, and NRc1C(O)NRc1Rd1;
• R13 is H or C1-6 alkyl;
• A is H or C1-4 alkyl;
• is C6-10 aryl or 5-10 membered heteroaryl;
• wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S;
• [N, O, S] is NH, O, or S;
• [N, O] is NH or 0;
• [C, N, O] is CRXRY, NH, or O;
• each RX and RY is independently selected from H and C1-4 alkyl;
• [AA]X is a peptide that may be cleaved by enzymatic action;
• S1 is
• each Ra, Rb, Rc, and Rd is independently selected from H, C1-4 alkyl, ORa2, CO2Ra2 and OC(═O)Ra2, wherein said C1-4 alkyl is optionally substituted with ORa2, CO2Ra2, and OC(═O)Ra2;
• Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, OH, CN, NO2, and CO2CH3;
• wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with OH, CN, NO2, or CO2CH3;
• Ra2 is H or C1-4 alkyl;
• and
• n is 0 or 1,
• in combination with the ionizing radiation or cytotoxic agent.