Aminopyrimidine amide autophagy inhibitors and methods of use thereof

A compound represented by:

• or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:
• W is CH or N;
• X is CH or N;
• Y is C(R33) or N;
• provided that both X and Y are not N;
• R1 is selected from the group consisting of halogen, cyano, C1-C5alkyl, and C3-C5cycloalkyl, wherein C1-C5alkyl and C3-C5cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine;
• R2 is selected from the group consisting of halogen, cyano, C1-C5alkyl, C3-C6cycloalkyl, C2-C5alkenyl, C2-C5alkynyl, C1-C5alkoxy, and C1-C5alkoxy-C2-C5alkyl, wherein each C1-C5alkyl, C3-C6cycloalkyl, C2-C5alkenyl, C2-C5alkynyl, and C1-C5alkoxy may be optionally substituted by one, two, or three independent occurrences of fluorine or cyano;
• R3 is selected from the group consisting of H, C1-C3alkyl, and C3-C5cycloalkyl, wherein C1-C3alkyl and C3-C5cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
• R33 is selected from the group consisting of H, halogen, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl, and C1-C6alkoxy may be optionally substituted by one or more independent occurrences of fluorine;
• R4 is selected from the group consisting of B, D, NR6R9, NR6—(C(R10)2)p—NR6R9, and C(O)—D;
• B is selected from an N-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein B may be optionally substituted on one or more available carbons by R7 and may be optionally substituted on an available nitrogen by R9;
• D is selected from a C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein D may be optionally substituted on one or more available carbons by R7 and may be optionally substituted on an available nitrogen by R9;
• each occurrence of R7 is independently selected from the group consisting of H, C1-C6alkyl, C3-C6cycloalkyl, cyano, and)(C(R10)2)h—NR6R9, wherein C1-C6alkyl and C3-C6cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R7 are joined together with the atom to which they are attached to form oxo;
• R6 is selected from the group consisting of H, C1-C6alkyl, C3-C6cycloalkyl, C1-C5alkoxy-C2-C5alkyl, C(═O)R5, SO2R5, C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C1-C6alkyl and C3-C6cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
• R9 is selected from the group consisting of H, C1-C6alkyl, C3-C6cycloalkyl, C1-C5alkoxy-C2-C5alkyl, C(═O)R5, SO2R5, C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C1-C6alkyl and C3-C6cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
• R5 is selected from the group consisting of H, C1-C6alkyl, C3-C6cycloalkyl, and heterocyclyl, wherein C1-C6alkyl and C3-C6cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
• each occurrence of R10 is independently selected from the group consisting of H, C1-C3alkyl, and C3-C5cycloalkyl, wherein C1-C3alkyl and C3-C5cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R10 are joined together with the carbon to which they are attached to form a C3-C5cycloalkyl;
• RL is selected from the group consisting of C1-C6alkyl and C3-C6cycloalkyl, NR11R12, and
• wherein each C1-C6alkyl and C3-C6cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine;
• U is N or CR13;
• V is selected from the group consisting of oxygen, C(R34)2, and NR6;
• r is 0, 1, or 2;
• q is 1, 2, or 3;
• R11 is selected from the group consisting of H, C1-C3alkyl, and C3-C5cycloalkyl, wherein C1-C3alkyl and C3-C5cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
• R12 is selected from the group consisting of H, C1-C3alkyl, and C3-C5cycloalkyl, wherein C1-C3alkyl and C3-C5cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
• R13 is selected from H and C1-C3alkyl;
• each occurrence of R34 is independently selected from H, C1-C3alkyl, and C3-C5cycloalkyl, wherein C1-C3alkyl and C3-C5cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R34 are joined together with the carbon to which they are attached to form a C3-C6cycloalkyl;
• L is —(C(R10)2)m—;
• h is 1, 2, or 3;
• m is 0, 1, 2, or 3;
• n is 2, 3, or 4;
• and
• p is 2 or 3;
• provided that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.