CBL inhibitors and compositions for expansion of immune cells

A method of producing expanded immune cells, comprising the step of:

• expanding immune cells in vitro in the presence of a Cbl inhibitor in culture under conditions wherein at least 109 expanded immune cells are produced in a first expansion,
• wherein the immune cells are tumor infiltrating lymphocytes,
• wherein no expansion steps are performed before the first expansion, and
• wherein the Cbl inhibitor is a compound of Formula (A):
• or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
• R1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, 3-to 6-membered heterocyclyl, C1-C6 alkyl-(C3-C6 cycloalkyl), C1-C6 alkyl-(3-to 6-membered heterocyclyl);
• Z1 is CH or N;
• Z2 is CH or N;
• Z3 is CH or N;
• X is CH or N;
• R2 is H, halo, C3-C6 cycloalkyl, —NH-(3-to 6-membered heterocyclyl), —NH—(C1-C6 alkyl),
• —NH—(C3-C6 cycloalkyl), —O-(3-to 6-membered heterocyclyl), —O—(C1-C6 alkyl), or
• —O—(C3-to C6 cycloalkyl);
• R3a is H, halo, or C1-C6 alkyl;
• R3b is H, halo, C1-C6 alkyl, or C3-C6 cycloalkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form a 4- to 8-membered heterocyclyl or a C3-C6 cycloalkyl, wherein the heterocyclyl or cycloalkyl are optionally substituted by 1-3 R12 groups;
• n is 0 or 1;
• Y is C(R11a)(R11b) or S, with the proviso that if either or both of R3a and R3b are halo, Y is C(R11a)(R11b);
• Q is CH or N;
• R4 is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R10 is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R11a and R11b are independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• or R11a and R11b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• or R3b and R11a are taken together with the carbon atoms to which they are attached to form a C3-C6 cycloalkyl optionally substituted by C1-C6 alkyl;
• and
• each R12 is independently C1-C6 alkyl, halo, hydroxy, —O(C1-C6 alkyl), —CN, C1-C6 alkyl-CN, C1-C6 alkyl-OH, or C1-C6 haloalkyl;
• wherein two geminal R12 groups can be taken together with the carbon atom to which they are attached to form a spiro C3-C4 cycloalkyl.