Peptide conjugates of peptidic tubulin inhibitors as therapeutics

A compound of Formula (I):

• R2-L- R1 (I)
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is a peptide;
• R2 is a radical of an auristatin compound;
• and
• L is a linker having a structure selected from:
• wherein the terminal S atom of the linker is bonded with a cysteine residue of the peptide to form a disulfide bond;
• and wherein:
• G1 is selected from a bond, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein said C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of G1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(═NRe)NRcRd, NRcC(═NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORd, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl substituent of G1 are optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(═NR)NRcRd, NRcC(═NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORd, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
• G2 is selected from —NRGC(O)—, —NRG—O—, —S—, —C(O)—, —OC(O)—, —NRGC(O)—, —OC(O)NRG—, and —S(O2)—;
• G3 is selected from C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein said C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of G3 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRcC(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl substituent of G3 are optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
• G4 is selected from —C(O)—, —NRGC(O)—, —NRG—, —O—, —OC(O)—, —NRGC(O)—, and —S(O2)—;
• G5 is selected from a bond, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein said C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of G5 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(═NRe)NRcRd, NRcC(═NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORd, NRcC(O)NRcRd, NRS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl substituent of G5 are optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(═NR)NRcRd, NRcC(═NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
• G6 is selected from —NRGC(O)—, —NRG—, —O—, —C(O)—, —OC(O)—, —NRGC(O)—, —OC(O)NRG—, and —S(O2)—;
• G7 is selected from —NRGC(O)—, —NRG—O—, —S—, —C(O)O—, —OC(O)—, —NRGC(O)—, —OC(O)NRG—, and —S(O2)—;
• each Rs and Rt are independently selected from H, halo, C1-6 alkyl, and C1-6 haloalkyl;
• or each Rs and Rt, together with the C atom to which they are attached, form a C3-6 cycloalkyl ring;
• Ru and Rv are independently selected from H, halo, C1-6 alkyl, and C1-6 haloalkyl;
• each RG is independently selected from H and C1-4 alkyl;
• each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2 NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, C(═NRe2)NRc2Rd2, NRc2C(═NRe2)NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, NR2S(O)2NRc2Rd2, and S(O)2NRc2Rd2;
• each Ra1, Rb2, Rc2, and Rd2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra2, Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• each Re, Re1, and Re2 is independently selected from H and C1-4 alkyl;
• m is 0, 1, 2, 3, or 4;
• n is 0 or 1;
• o is 0 or 1;
• p is 1, 2, 3, 4, 5, or 6;
• and
• q is 0 or 1.