3-substituted piperidine compounds for Cbl-b inhibition, and use thereof

A method of producing a modified immune cell, comprising culturing a cell population containing an immune cell in the presence of an effective amount of a Cbl-b inhibitor to modulate activity of the immune cell, thereby producing the modified immune cell, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A modified immune cell comprising a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

An isolated modified immune cell, wherein the immune cell has been contacted or is in contact with a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A method of modulating the immune response, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to modulate the immune response in the individual, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to inhibit Cbl-b activity in the individual, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to treat the cancer responsive to inhibition of Cbl-b activity, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a Spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the Spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A method of inhibiting abnormal cell proliferation, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to inhibit abnormal cell proliferation in the individual, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A kit comprising a cell culture composition comprising a cell population containing an immune cell and a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A method for treating or preventing a disease or condition associated with Cbl-b activity, the method comprising administering a Cbl-b inhibitor to an individual in need thereof, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl.

A method of treating cancer, the method comprising administering to an individual with cancer an effective amount of a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl;
• and
• administering to the individual an effective amount of an additional therapeutic agent.

A method of treating cancer, the method comprising administering to an individual with cancer an effective amount of a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl;
• and
• administering to the individual an effective amount of radiation therapy.

A method of immunizing, the method comprising administering to an individual in need thereof an effective amount of a small molecule Cbl-b inhibitor of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl;
• and
• administering to the individual an effective amount of a vaccine.

A method of treating cancer, the method comprising administering to an individual with cancer an effective amount of a small molecule Cbl-b inhibitor of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl;
• and
• administering to the individual an effective amount of an oncolytic virus.

A method of treating cancer, the method comprising:

• administering to an individual with cancer an effective amount of
• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
• wherein
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or
• -(C1-C6 alkylene)—O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5a R5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5aand R5bare taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl, and
• administering to the individual an effective amount of a therapeutic cancer vaccine;
• or
• administering to the individual an effective amount of an oncolytic virus.

A pharmaceutical composition comprising a cancer vaccine and a small molecule Cbl-b inhibitor of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• is
• and Y is a bond;
• W is oxygen or a bond;
• R2a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl, optionally wherein the composition further comprises a pharmaceutically acceptable excipient.

A pharmaceutical composition comprising an oncolytic virus and a small molecule Cbl-b inhibitor of Formula (I)

• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl, optionally wherein the composition further comprises a pharmaceutically acceptable excipient.

A kit for treating cancer, the kit comprising

• (a) a small molecule Cbl-b inhibitor of Formula (I)
• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl;
• (b) an oncolytic virus;
• and
• (c) instructions for administration of an effective amount of the Cbl-b inhibitor and the oncolytic virus to treat cancer in an individual.

A kit for treating cancer, the kit comprising

• (a) a pharmaceutical composition comprising a small molecule Cbl-b inhibitor of Formula (I)
• or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• is
• X is CH or nitrogen;
• Z1 is CH or nitrogen;
• Z2 is CH or nitrogen;
• R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• R2a is —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or —(C1-C6 alkylene)-O—(C1-C6 alkyl);
• R2b is hydrogen, halo, or C1-C6 alkyl;
• or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl,
• wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
• R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl;
• or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl;
• R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• is
• and Y is CR5aR5b or sulfur;
• or
• is
• and Y is a bond;
• W is oxygen or a bond;
• R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl;
• or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl;
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R7 is hydrogen, 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-C6 cycloalkyl);
• R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
• R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH;
• and
• R10 is —CF3 or cyclopropyl, and an oncolytic virus;
• and
• (b) instructions for administration of an effective amount of the pharmaceutical composition comprising the small molecule Cbl-b inhibitor and the oncolytic virus to treat cancer in an individual.