Calicheamicin derivatives and antibody drug conjugates thereof

A compound of Formula (IIA):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R3 is selected from the group consisting of —CH3, —CH2CH3, and —CH(CH3)2;
• X is selected from the group consisting of:
• (i) —CH3 optionally substituted by one R10;
• (ii) —C2-C8alkyl optionally substituted by one R10;
• (iii) —(C0-C6alkyl)-C3-C10 carbocyclyl,
• wherein said C3-C10 carbocyclyl is optionally substituted by one R10;
• (iv) —(C0-C6alkyl)-3 to 10 membered heterocyclyl,
• wherein said 3 to 10 membered heterocyclyl is optionally substituted by one R10, and
• wherein said 3 to 10 membered heterocyclyl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S;
• (v) —(C0-C6alkyl)-phenyl,
• wherein said phenyl is optionally substituted by one R10;
• and
• (vi) —(C0-C6alkyl)-5 to 10 membered heteroaryl,
• wherein said 5 to 10 membered heteroaryl is optionally substituted by one R10, and
• wherein said 5 to 10 membered heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S;
• and which X is optionally further substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
• R10 is —R10a-R10b, wherein
• R10a is either absent or —(CH2)n—, which R10a is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
• R10b is selected from the group consisting of:
• (i) —OH;
• (ii) —CN;
• (iii) —PO3H;
• (iv) —CO2H;
• (v) —CO2C1-C4alkyl,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (vi) —CO—R11;
• (vii) —NH—R11;
• (viii) —N(C1-C4alkyl)-R11,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (ix) —CONN—R11;
• (x) —CON(C1-C4alkyl)-R11,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xi) —CONHNH—R11;
• (xii) —CONHN(C1-C4alkyl)-R11,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xiii) —CON(C1-C4alkyl)NH—R11,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xiv) —CON(C1-C4alkyl)N(C1-C4alkyl)-R11,
• wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xv) —CON(R11)NH2;
• (xvi) —CON(R11)NH(C1-C4alkyl),
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xvii) —CON(R11)N(C1-C4alkyl)2,
• wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xviii) —CONHN═C(C1-C4alkyl)-C6H4-OC1-C4alkyl,
• wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xix) —CON(C1-C4alkyl)N═C(C1-C4alkyl)-C6H4-OC1-C4alkyl,
• wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xx) —N(R11)CO(C1-C4alkyl),
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xxi) —CH(CO2H)NH—R11;
• (xxii) —CH(CO2C1-C4alkyl)NH—R11,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xxiii) —CH(NH2)CO—R11;
• (xxiv) —CH(NH(C1-C4alkyl))CO—R11,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xxv) —CH(N(C1-C4alkyl)2)CO—R11,
• wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• (xxvi) —CH(CO—R11)NH—R11;
• and
• (xxvii) —CH(CO—R11)N(C1-C4alkyl)-R11,
• wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
• R11 is selected from the group consisting of —R11a-R11b—R11c and —R11d—R11e-R11f, wherein
• R11a is either absent, or is selected from the group consisting of,
• R11b is either absent, or is selected from the group consisting of
• and AAr,
• wherein AA is independently for each occurrence a natural amino acid or a non-natural amino acid;
• R11c is either absent or is selected from the group consisting of —H, —C1-C4alkyl and -COC1-C4alkyl;
• R11d is either absent or —(CH2)t—,
• wherein R11d when present is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
• R11e is either absent or selected from the group consisting of —O— and —NH—;
• R11f is selected from the group consisting of C6-C12 aryl and 5 to 10 membered heteroaryl,
• wherein said 5 to 10 membered heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and
• wherein R11f is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
• n is 1, 2, 3, 4, 5, or 6;
• r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20;
• t is 1, 2, 3, 4, 5, or 6;
• G is selected, independently for each occurrence, from the group consisting of —F, —Cl, —CN, —OH, —NH2, —NH—C1-C4alkyl, —N(C1-C4alkyl)2, —NO2, —CO2H, —C1-C4alkylOH, —C1-C4alkylNH2, —C1-C4alkoxy, ═O, —CO2C1-C4alkyl, —OC(O)C1-C4alkyl, —NHC(O)C1-C4alkyl, —C(O)NHC1-C4alkyl, and —C(O)N(C1-C4alkyl)2;
• E is selected, independently for each occurrence, from the group consisting of —F, —Cl, —CN, —OH, —NH2, —NHCH3, —N(CH3)2, —NO2, —CO2H, —OCH3, —OCF3, and —CF3;
• and
• L is -LB-LA:
• wherein:
• LA is selected from the group consisting of —NHR,
• LB is —LB1—LB2—LB3 wherein:
• LB1 is absent;
• LB2 is either absent, or is selected from the group consisting of
• LB3 is AA0-12, wherein AA is independently for each occurrence a natural amino acid or a non-natural amino acid;
• and
• each R is independently selected from the group consisting of H, —C1-C20 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, halo, hydroxyl, alkoxy, —NH2, —NH(C1-C8 alkyl), —N(C1-C8 alkyl)2, —NO2, —C6-C14 aryl and —C6-C14 heteroaryl,
• wherein two or more R optionally join to form a ring or rings, and
• wherein said —C6-C14 aryl and —C6-C14 heteroaryl are optionally substituted with 1 to 5 substituents independently selected from —C1-C10 alkyl, —C1-C10 alkoxy, -halo, —C1-C10 alkylthio, -trifluoromethyl, —NH2, —NH(C1-C8 alkyl), —N(C1-C8 alkyl)2, —C1-C10 alkyl-N(C1-C8 alkyl)2, —C1-C3 alkylthio, —NO2 or —C1-C10 heterocyclyl, for each ring system in which R appears.