Cbl-b inhibitors and anti-pd1/anti-pd-l1 for use in the treatment of cancer

A method of treating a disease or condition associated with cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a CBL-B inhibitor wherein the subject has previously been treated with an anti-PD1/anti-PD-L1 agent.

A method of treating a disease or condition associated with cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of an anti-PD1/anti-PD-L1 agent wherein the subject has previously been treated with a CBL-B inhibitor.

The method of any of the previous claims, wherein C is selected from the group consisting of optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted thiadizolyl, optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, and optionally substituted pyridazinyl.

The method of any of the previous claims, wherein the compound is of Formula (B):

• or pharmaceutically acceptable salts thereof.

The method of any of the previous claims, wherein the compound is of Formula (I):

• or pharmaceutically acceptable salts thereof.

The method of any of the previous claims, wherein the compound is of Formula (Ia) or (IIa):

• or a pharmaceutically acceptable salt thereof,
• wherein each W is independently selected from N or C.

The method of any of the previous claims, wherein the compound is of formula (Ia1) or (IIa1):

• or a pharmaceutically acceptable salt thereof.

The method of any of the previous claims, wherein the compound is of Formula (Ia2), (Ia3), or (Ia4):

• or a pharmaceutically acceptable salt thereof.

The method of any of the previous claims, wherein the compound is of formula (Ib) or (IIb):

• or pharmaceutically acceptable salts thereof,
• wherein each W is independently selected from N or C.

The method of any of the previous claims, wherein the compound is of formula (Ic) or (IIc):

• or pharmaceutically acceptable salts thereof.

The method of any of the previous claims, wherein R∘ is optionally substituted C1-C3 aliphatic.

The method of any of the previous claims, wherein each R∘ is independently selected from the group consisting of methyl, —CD3, —CHF2

The method of any of the previous claims, wherein Rc is methyl.

The method of any of the previous claims, wherein X is optionally substituted C1-C2 alkylene.

The method of any of the previous claims, wherein X is

• or optionally substituted C2 alkylene, wherein one methylene unit is replaced with

The method of any of the previous claims, wherein X is selected from the group consisting of

The method of any of the previous claims, wherein Ra is L-A.

The method of any of the previous claims, wherein L is —CH2— or —CH(CH3)—.

The method of any of the previous claims, wherein A is optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S.

The method of any of the previous claims, wherein Ra is selected from halogen, —CN, —C(O)R1, —CO2H, —CONR1R2, optionally substituted C1-C6 aliphatic, and optionally substituted C1-C6 heteroalkyl.

The method of any of the previous claims, wherein each Ra is independently selected from the group consisting of halogen, —CN, —CO2H, —CHO, —CHF2, —CF3, —OMe, —S(O)2NHMe,

The method of any of the previous claims, wherein the compound is

• or a pharmaceutically acceptable salt thereof.

The method of any of the previous claims, wherein the compound is

• or a pharmaceutically acceptable salt thereof.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 60-600 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 60-600 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 60-100 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 100-200 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 200-300 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 300-400 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 400-500 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 500-600 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 60 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 100 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 150 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 200 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 250 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 300 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 350 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 400 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 450 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 500 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 550 mg.

The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 600 mg.

The method of any of the previous claims, wherein the anti-PD1/anti PD-L1 agent is an anti-PD1 antibody.

The method of any of the previous claims, wherein the anti-PD1/anti PD-L1 agent is selected from the group consisting of B0146, nivolumab, pembrolizumab, atezolizumab, dostarlimab, cemiplimab, durvalumab, and avelumab.

The method of any of the previous claims, wherein the disease or condition associated with cell proliferation is hyperplasia or cancer.

The method of 62, the increased NK-cell activation comprises increased production of cytokines.