Asymmetric Bisaminoquinolines And Bisaminoquinolines With Varied Linkers As Autophagy Inhibitors For Cancer And Other Therapy

A compound of Formula IB

• wherein
• R1 and R1 are each independently H, F, Cl, Br, I, CN, N02, optionally substituted C1-C6 alkyl, optionally substituted 0-Ci-C6 alkyl, optionally substituted C2-C7 acyl, an optionally substituted —(NH)-acyl, or optionally substituted C2-C7 ester;
• R and R′ are each independently H, a Q-Q optionally substituted alkyl group, a C1-C7 optionally substituted acyl group, a C2-C7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R′ is bonded);
• R″ is H, Cy′ or (C=0)z-G, where Cy′ is an optionally substituted cycloalkyl, aryl or heteroaryl group G is an optionally substituted C0-C12 alkyl, alkene or alkynyl group (wherein optional substituents include a C1-C12 alkyl, alkene or alkynyl group substituted by (N-J)-(C1-C8 alkyl, alkene or alkynyl group)z-(Cy2)x, where RJ is H or a C1-C8 alkyl, alkene or alkynyl group, z is 0, 1, 2, 3, 4 or 5, x is 0 or 1 and Cy2 is an optionally substituted aryl or heteroaryl group);
• RM is independently at each occurrence H, F, Cl, Br, I, an optionally substituted C0-C12 alkyl, alkene, alkynyl or alkoxy group;
• p and p′ in linker L1B are each independently 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9 or 10),
• and the pharmaceutically acceptable salts, enantiomers, diastereomers, solvates and polymorphs thereof.

A compound of Formula IC:

• wherein
• R1 and R1 are each independently H, F, Cl, Br, I, CN, N02, optionally substituted C1-C6 alkyl, optionally substituted 0-Ci-C6 alkyl, optionally substituted C2-C7 acyl, an optionally substituted —(NH)-acyl, or optionally substituted C2-C7 ester;
• R and R′ are each independently H, a C C6 optionally substituted alkyl group, a C1-C7 optionally substituted acyl group, a C2-C7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R′ is bonded);
• R″ is H, Cy′ or (C=0)z-G, where Cy′ is an optionally substituted cycloalkyl, aryl or heteroaryl group G is an optionally substituted C0-C12 alkyl, alkene or alkynyl group (wherein optional substituents include a C1-C12 alkyl, alkene or alkynyl group substituted by (N—RJ)—(C1-C8 alkyl, alkene or alkynyl group)z-(Cy2)x, where RJ is H or a C C8 alkyl, alkene or alkynyl group, z is 0, 1, 2, 3, 4 or 5, x is 0 or 1 and Cyt is an optionally substituted aryl or heteroaryl group);
• RM is independently at each occurrence H, F, Cl, Br, I, an optionally substituted C0-C12 alkyl, alkene, alkynyl or alkoxy group;
• Each p in linker group L is independently 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);
• and the pharmaceutically acceptable salts, enantiomers, diastereomers, solvates and polymorphs thereof.

A compound of Formula ID:

• wherein
• R1 and R1 are each independently H, F, Cl, Br, I, CN, N02, optionally substituted C1-C6 alkyl, optionally substituted O—C1-C6 alkyl, optionally substituted C2-C7 acyl, optionally substituted —(NH)-acyl, or optionally substituted C2-C7 ester;
• R and R′ are each independently H, a C1-C6 optionally substituted alkyl group, a C1-C7 optionally substituted acyl group, a C2-C7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R′ is bonded);
• R″ is H, Cy′ or (C=0)z-G, where Cy′ is an optionally substituted cycloalkyl, aryl or heteroaryl group G is an optionally substituted C0-C12 alkyl, alkene or alkynyl group (wherein optional substituents include a C1-C12 alkyl, alkene or alkynyl group substituted by (N-J)-(C1-C8 alkyl, alkene or alkynyl group)z-(Cy2)x, where RJ is H or a C1-C6 alkyl, alkene or alkynyl group, z is 0, 1, 2, 3, 4 or 5, x is 0 or 1 and Cy2 is an optionally substituted aryl or heteroaryl group);
• RM is independently at each occurrence H, F, Cl, Br, I, an optionally substituted C0-C12 alkyl, alkene, alkynyl or alkoxy group;
• Linker group L1D is an optionally substituted alkylene group containing from 1-20 methylene groups;
• and the pharmaceutically acceptable salts, enantiomers, diastereomers, solvates and polymorphs thereof.

A compound of formula IE:

• wherein
• R1 and R1 are each independently H, halo (F, Cl, Br or I), CN, N02, optionally substituted C1-C6 alkyl, optionally substituted O—C1-C6 alkyl, optionally substituted —(NH)— acyl, optionally substituted C2-C7 acyl or optionally substituted C2-C7 ester (oxycarbonyl ester or carboxyester, preferably carboxyester);
• RM is independently at each occurrence H, F, Cl, Br, I, an optionally substituted Q-C12 (preferably C1-C8) alkyl, alkene, alkynyl or alkoxy group;
• R and R′ are each independently H, a Ci-C6 optionally substituted alkyl group, a C1-C7 (preferably C2-C7) optionally substituted acyl group, a C2-C7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R′ is bonded);
• Linker group L1E is a {circumflex over ( )}CH2Y{circumflex over ( )}-{circumflex over ( )}Y′CF¾r-{circumflex over ( )} or a {circumflex over ( )}CH, —Z{circumflex over ( )}A′ group wherein at least one of the CH2 groups in L1E is optionally substituted with an optionally substituted C1-C6 alkyl group including a cyclic alkyl group, each of which alkyl groups is optionally substituted, or at least two methylene groups (preferably two adjacent methylene groups) are optionally substituted with alkylene groups to form an optionally substituted C3-C8 cycloalkyl group, or linker group L1E is a (poly)ethylene glycol group having from 1 to 20 ethylene glycol units, each (poly)ethylene glycol group being optionally substituted at one or both of its distal ends with an A group, or L is a linear group containing from 1 to 5 non-contiguous amine groups N—R″, each amine group being separated from an adjacent amine group by an alkylene group containing from 1, 2, 3, 4, 5, 6, 7, or 8 (preferably 2, 3, 4, 5 or 6) methylene groups or an ethylene glycol containing group having from 1 to 6 (preferably 2 to 6, 3 to 6 or 4, 5 or 6) ethylene glycol units;
• X is absent, (CH2)j O, S or N—R″;
• Y is absent, CH2, O, CH20 or N—R″ and Y′ is absent CH2, O, OCH2 or N—R″, with the proviso that when one or more of X, Y and Y′ is present, each of X and Y, X and Y′ or Y and Y′, when present, forms a stable bond;
• R″ is H or an optionally substituted C1-C6 alkyl group or an amine protecting group;
• each j is independently 1, 2, 3, 4, 5 or 6;
• each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 with the proviso that when n is 0, X is (CH2)j where j is at least 1 and at least one CH2 group is optionally substituted, preferably with a C1-C3 alkyl group which itself is optionally substituted with one or two hydroxyl groups or one, two, or three halo groups;
• A is absent, C=0 or (CH2)j and A′ is C=0 or (CH2)j wherein at least one CH2 group in A or A′ is optionally substituted, preferably with a C C3 alkyl group which is itself optionally substituted;
• Z is O or N—Rz;
• Rz is H or an optionally substituted C1-C3 alkyl group,
• or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvent or polymorph thereof.