CBL-B inhibitors and compositions containing CBL-B inhibitors in methods for treating cell proliferation-related diseases

Abstract

The present disclosure relates to the treatment of a subject having a disease or condition associated with cell proliferation, which comprises administering a therapeutically effective amount of a CBL-B inhibitor.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Patent Application No. 63 / 388,480, filed on Jul. 12, 2022, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Background The E3 ligase Casitas B - lineage lymphoma proto - oncogene B (CBL - B) is an important negative modulator of T - cell receptor and costimulatory control. CBL - B inhibition reduces the threshold of antigen - specific T - cell activation, even in the absence of costimulatory signaling or in the presence of an immunosuppressive environment. Genetic ablation of CBL - B or functional inactivation of its E3 ligase activity in mouse or primary human T - cells enhances immune - mediated tumor growth control. Thus, CBL - B inhibition can address sub - optimal responses to current immunotherapies due to mild inflammation, no / low costimulatory signals, or highly immunosuppressive environments.

Summary of the Invention

[0003] Summary The present disclosure includes a method for treating a disease or condition related to cell proliferation, comprising administering a therapeutically effective amount of a compound disclosed herein, which comprises a compound of formula (A): TIFF2025523056000002.tif36165 or a pharmaceutically acceptable salt thereof, wherein, Y is selected from the group consisting of =C(H)-, =C(R a )-, or =N -; Z is =O or =S; E is an optionally substituted 5 - to 6 - membered heterocyclyl; B is an optionally substituted phenyl, an optionally substituted 8 - to 10 - membered bicyclic ring, or an optionally substituted 5 - to 6 - membered heteroaryl; C is an optionally substituted 5 - to 6 - membered heterocyclyl; X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are -N(H)-, -N(R 1 ), -, -O-, -S-, -SO-, -SO2-, an optionally substituted 3- to 6-membered carbocyclic ring, and an optionally substituted 3- to 6-membered heterosilyl, and X is optionally substituted with a group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3- to 6-membered heteroaryl, 3- to 6-membered heterosilyl, and -(CH2)(3- to 6-membered carbocyclic ring), Each R a is L-A, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted phenyl, and an optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of, and R a is optionally substituted with 1 to 5 R a1 s, L is an optionally substituted C1-C3 alkylene chain, A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, and A is optionally substituted with 1-5 R a1 and is optionally substituted with each R a1 is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , and is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR1 R 2 、 -SO2OH, -SO2OR 1 、 -S(O)R 1 、 -S(O)2R 1 、 -S(O)(NH)R 1 、 -S(O)(NR 1 )R 1 、 optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of, each R c is hydrogen, optionally substituted C1-C6 aliphatic, OR 1 、 -NH2, -NR 1 R 2 、 optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 、 -CO2R 3 、 -C(O)NHR 3 、 and -SO2R 3 、 independently selected from the group consisting of, each R 1 is optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 、 -CO2R 3 、 -C(O)NHR 3 、 and -SO2R 3 、 independently selected from the group consisting of, each R2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, or R 1 and R 2 together with their intervening atom(s) (if any) form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

[0004] The present disclosure is further defined in the appended claims.

Brief Description of the Drawings

[0005]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0006] Detailed Description CBL-B Inhibitor The term "CBL-B inhibitor" refers to a compound that, upon administration to a subject, results in inhibition or downregulation of a biological activity associated with the activation of CBL-B in a patient, including any of the downstream biological effects that would otherwise be caused by the binding of its natural ligand to CBL-B. Such CBL-B inhibitors include any agent that can block either the activation of CBL-B or any of the downstream biological effects of CBL-B activation.

[0007] In some embodiments, the CBL-B inhibitor is a compound of formula (A): TIFF2025523056000003.tif37165 or a pharmaceutically acceptable salt thereof, wherein, Y is selected from the group of =C(H)-, =C(R a )-, or =N-, Z is =O or =S, E is an optionally substituted 5- to 6-membered heterocyclyl, B is an optionally substituted phenyl, an optionally substituted 8- to 10-membered bicyclic ring, or an optionally substituted 5- to 6-membered heteroaryl, C is an optionally substituted 5- to 6-membered heterocyclyl, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units may be replaced by -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, an optionally substituted 3- to 6-membered carbocyclyl, and an optionally substituted 3- to 6-membered heterosilyl, and X may be substituted with an optionally substituted group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3- to 6-membered heteroaryl, 3- to 6-membered heterosilyl, and -(CH2)(3- to 6-membered carbocyclyl), Each R a is L-A, halogen, -CN, -OH, -OR 1, -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of, R a R is optionally substituted with 1-5 R a1 and L is an optionally substituted C1-C3 alkylene chain A is optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, selected from the group consisting of, A is optionally substituted with 1-5 R a1 and each R a1 is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1, -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of each R cis hydrogen, optionally substituted C1-C6 aliphatic, OR 1 , -NH2, -NR 1 R 2 , optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , independently selected from the group consisting of each R 1 is optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , independently selected from the group consisting of each R 2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, alternatively, R 1 and R 2 together with their intervening atom(s) (if any) form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, Each R 3 is independently selected from the group consisting of an optionally substituted C1-C6 aliphatic, an optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted phenyl, and an optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

[0008] In some embodiments, the disclosure encompasses a compound of formula (B): TIFF2025523056000004.tif43165 or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of =C(H)-, =C(R a ), or =N-, Z is =O or =S, B is an optionally substituted phenyl, a substituted 5-6 membered heteroaryl or an optionally substituted 8-10 membered bicyclic, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units may be replaced by -N(H)-, -N(R 1 ), -O-, -S-, -SO-, -SO2-, an optionally substituted 3-6 membered carbocyclyl, and an optionally substituted 3-6 membered heterocyclyl, Each R a is L-A, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2, -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, L is an optionally substituted C1-C3 alkylene chain, A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, Each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1, independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, each R c is hydrogen, optionally substituted C1-C6 aliphatic, -OR 1 , -NH2, -NR 1 R 2 , optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , independently selected from the group consisting of: each R 1 is optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , independently selected from the group consisting of: each R 2is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, or R 1 and R 2 together with their intervening atom(s), form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, or 4.

[0009] In some embodiments, the disclosure provides a compound of formula (I): TIFF2025523056000005.tif42165 or a pharmaceutically acceptable salt thereof, wherein, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2025523056000006.tif may be replaced by 35165, and each methylene unit may be substituted with one or two substituents independently selected from the group consisting of halogen, optionally substituted C1-C3 aliphatic, optionally substituted 5-membered heteroaryl, optionally substituted phenyl, optionally substituted C3-C4 carbosilyl, and optionally substituted C3-C4 heterocyclyl. Each R a is L-A, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group, and R a may be substituted with 1-5 R a1 s, Each Y is independently selected from the group consisting of -C=, -O-, -N=, and -S-. L is an optionally substituted C1-C3 alkylene chain. A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, and A is optionally substituted with 1-5 R a1 and may be substituted with each R a1 is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , and is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, B is optionally substituted phenyl, substituted 5-6 membered heteroaryl or optionally substituted 8-10 membered bicyclic, each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R1 ,-CONH2, -CONR 1 R 2 ,-SO2NH2, -SO2NR 1 R 2 ,-SO2OH, -SO2OR 1 ,-S(O)R 1 ,-S(O)2R 1 ,-S(O)(NH)R 1 ,-S(O)(NR 1 )R 1 ,optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of each R c is hydrogen, optionally substituted C1-C6 aliphatic, optionally deuterated optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , independently selected from the group consisting of each R 1 is optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3selected independently from the group consisting of, each R 2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, alternatively, R 1 and R 2 together with their intervening atom(s) (if any) form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, or 4.

[0010] In some embodiments, the disclosure encompasses a compound of formula (Ia) or (IIa): TIFF2025523056000007.tif49165 or a pharmaceutically acceptable salt thereof, wherein each W is independently selected from N or C, and X, Y, Z, R a 、R b 、R c 、n, and m are as defined above and as described in the classes and subclasses of this specification.

[0011] In some embodiments, the present disclosure relates to a compound of formula (Ia1) or (IIa1): TIFF2025523056000008.tif43165 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a 、R b 、R c 、n, and m are as defined above and as described in the classes and subclasses of this specification.

[0012] In some embodiments, the present disclosure relates to a compound of formula (Ia2), (Ia3), or (Ia4): TIFF2025523056000009.tif81165 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a 、R b 、R c 、n, and m are as defined above and as described in the classes and subclasses of this specification.

[0013] In some embodiments, the present disclosure relates to a compound of formula (Ia1) or (IIa1): TIFF2025523056000010.tif43165 or a pharmaceutically acceptable salt thereof, wherein X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units may be replaced by -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2025523056000011.tif28165, each R a is L-A, halogen, -CN, -OH, -OR 1 、-NH2, -NR 1 R 2 、-SH, -SR 1 、-SF5, -CO2H, -CO2R 1 、-C(O)R 1 、-CONH2, -CONR 1 R 2 、-SO2NH2, -SO2NR 1 R2 、 -SO2OH, -SO2OR 1 、 -S(O)R 1 、 -S(O)2R 1 、 -S(O)(NH)R 1 、 -S(O)(NR 1 )R 1 、 Optionally substituted C1 - C6 aliphatic, optionally substituted C1 - C6 heteroalkyl, optionally substituted 3 - 6 membered heterocyclyl containing 1 - 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5 - 6 membered heteroaryl containing 1 - 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of L is an optionally substituted C1 - C3 alkylene chain, A is selected from the group consisting of optionally substituted C3 - C7 carbosilyl, optionally substituted C1 - C6 heteroalkyl, optionally substituted 3 - 6 membered heterocyclyl containing 1 - 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5 - 6 membered heteroaryl containing 1 - 4 heteroatoms each selected from the group consisting of N, O, and S, Each R b is halogen, -CN, -OH, -OR 1 、 -NH2, -NR 1 R 2 、 -SH, -SR 1 、 -SF5, -CO2H, -CO2R 1 、 -CONH2, -CONR 1 R 2 、 -SO2NH2, -SO2NR 1 R 2 、 -SO2OH, -SO2OR 1 、 -S(O)R 1 、 -S(O)2R 1 、 -S(O)(NH)R 1 、 -S(O)(NR 1 )R 1, independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, each R c is selected independently from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , selected independently from the group consisting of each R 1 is selected independently from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , selected independently from the group consisting of each R 2 is selected independently from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, Alternatively, R 1 and R 2 together with their intervening atom(s), if any, form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl each containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl each containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, or 4.

[0014] In some embodiments, the disclosure includes a compound of formula (Ib) or (IIb): TIFF2025523056000012.tif49165 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a , R b , R c , and m are as defined above and as described in the classes and subclasses of this specification.

[0015] In some embodiments, the disclosure includes a compound of formula (Ib1) or (IIb1): TIFF2025523056000013.tif49165 or a pharmaceutically acceptable salt thereof, wherein X, R a , R b , R c , and m are as defined above and as described in the classes and subclasses of this specification.

[0016] In some embodiments, the disclosure includes a compound of formula (Ib2), (Ib3), or (Ib4): TIFF2025523056000014.tif94165 or a pharmaceutically acceptable salt thereof, wherein X, R a , R b , R c , and m are as defined above and as described in the classes and subclasses of this specification.

[0017] In some embodiments, the present disclosure is a compound of formula (Ic) or (IIc): TIFF2025523056000015.tif56165 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a , R b , R c , and m are as defined above and as described in the classes and subclasses of this specification.

[0018] In some embodiments, the present disclosure is a compound of formula (Ic1) or (IIc1): TIFF2025523056000016.tif49165 or a pharmaceutically acceptable salt thereof, wherein X, R a , R b , R c , and m are as defined above and as described in the classes and subclasses of this specification.

[0019] In some embodiments, the present disclosure is a compound of formula (Id) or (IId): TIFF2025523056000017.tif49165 or a pharmaceutically acceptable salt thereof, wherein X, R b , R c , and m are as defined above and as described in the classes and subclasses of this specification.

[0020] In some embodiments, the present disclosure is a compound of formula (Id1) or (IId1): TIFF2025523056000018.tif49165 or a pharmaceutically acceptable salt thereof, wherein X, R b , R c, and m is as defined above and as described in the classes and subclasses of this specification.

[0021] X In some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are -N(H)-, -N(R 1 ), -, -O-, -S-, -SO-, -SO2-, an optionally substituted 3-6 membered carbocyclyl, and an optionally substituted 3-6 membered heterocyclyl, and X may be substituted with an optionally substituted group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3-6 membered heteroaryl, 3-6 membered heterocyclyl, and -(CH2)(3-6 membered carbocyclyl). In some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are -N(H)-, -N(R 1 ), -, -O-, -S-, -SO-, -SO2-, an optionally substituted 3-6 membered carbocyclyl, and an optionally substituted 3-6 membered heterocyclyl, and X may be substituted with an optionally substituted group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3-6 membered heteroaryl, 3-6 membered heterocyclyl, and -(CH2)(3-6 membered carbocyclyl). In some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are -N(H)-, -N(R 1 ), -, -O-, -S-, -SO-, -SO2-, may be replaced by TIFF2025523056000019.tif35165, and each methylene unit may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, an optionally substituted C1-C3 aliphatic, an optionally substituted 5-membered heteroaryl, an optionally substituted phenyl, an optionally substituted C3-C4 carbocyclyl, and an optionally substituted C3-C4 heterocyclyl. In some embodiments, in some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are -N(H)-, -N(R 1 ), -, -O-, -S-, It may be replaced by TIFF2025523056000020.tif28165. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, It may be replaced by TIFF2025523056000021.tif27165. In some embodiments, X is an optionally substituted C1-C2 alkylene. In some embodiments, X is TIFF2025523056000022.tif22165 or an optionally substituted C2 alkylene, and one methylene unit is replaced by TIFF2025523056000023.tif21165. In some embodiments, X is selected from the group consisting of TIFF2025523056000024.tif201165 and TIFF2025523056000025.tif228165.

[0022] In some embodiments, X is selected from the group consisting of TIFF2025523056000026.tif56165.

[0023] R a In some embodiments, each R a is L-A, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R1 ,-S(O)(NR 1 )R 1 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, are independently selected from the group consisting of. In some embodiments, it is L-A. In some embodiments, R a is halogen, -CN, -C(O)R 1 , -CO2H, -CONR 1 R 2 , optionally substituted C1-C6 aliphatic, and optionally substituted C1-C6 heteroalkyl. In some embodiments, each R a is independently selected from the group consisting of halogen, -CN, -CO2H, -CHO, -CHF2, -CF3, -OMe, -S(O)2NHMe, TIFF2025523056000027.tif207165TIFF2025523056000028.tif227165TIFF2025523056000029.tif213165TIFF2025523056000030.tif239165TIFF2025523056000031.tif192165.

[0024] In some embodiments, R a is selected from the group consisting of halogen, -CN, -CO2H, TIFF2025523056000032.tif148165.

[0025] L In some embodiments, L is an optionally substituted C1-C3 alkylene chain. In some embodiments, L is -CH2- or -CH(CH3)-.

[0026] A In some embodiments, A is selected from the group consisting of optionally substituted C3-C7 carbosilyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, A is optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, A is selected from optionally substituted piperidine, optionally substituted tetrahydropyridine, optionally substituted pyrrolidine, optionally substituted dihydropyrrole, optionally substituted aziridine, and optionally substituted morpholine.

[0027] C In some embodiments, C is an optionally substituted 5-membered heteroaryl. In some embodiments, C is an optionally substituted 5-membered heteroaryl containing 3 nitrogen atoms. In some embodiments, C is an optionally substituted triazolyl. In some embodiments, C is an optionally substituted 1, 2, 4-trizaolyl. In some embodiments, C is an optionally substituted 1, 2, 3-trizaolyl. In some embodiments, C is an optionally substituted 5-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, C is an optionally substituted pyrazolyl. In some embodiments, C is an optionally substituted isoxazolyl. In some embodiments, C is an optionally substituted thiazolyl. In some embodiments, C is an optionally substituted thiadiazolyl. In some embodiments, C is an optionally substituted 1, 3, 4-thiadiazolyl. In some embodiments, C is an optionally substituted pyridinyl. In some embodiments, C is an optionally substituted pyrazinyl. In some embodiments, C is an optionally substituted pyrimidinyl. In some embodiments, C is an optionally substituted pyridazinyl.

[0028] R b In some embodiments, each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R1 Selected independently from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S.

[0029] R c In some embodiments, each R c is hydrogen, optionally substituted C1-C6 aliphatic, -OR 1 , -NH2, -NR 1 R 2 , optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , and is selected independently from the group consisting of. In some embodiments, each R c is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , and is selected independently from the group consisting of. In some embodiments, R c is optionally substituted C1-C3 aliphatic. In some embodiments, R c is methyl.

[0030] R 1 In some embodiments, each R 1 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 . In some embodiments, each R 1 is optionally substituted C1-C6 aliphatic. In some embodiments, each R 1 is methyl.

[0031] R 2 In some embodiments, each R 2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, alternatively, R 1 and R 2 together with their intervening atom(s), if any, form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S.

[0032] In some embodiments, each R 2 is optionally substituted C1-C6 aliphatic. In some embodiments, each R2 is methyl.

[0033] R 3 In some embodiments, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S.

[0034] In some embodiments, the present disclosure includes the compounds described in Table 1.

[0035] (Table 1) TIFF2025523056000033.tif 189165 TIFF2025523056000034.tif 219165 TIFF2025523056000035.tif 219165 TIFF2025523056000036.tif 205165 TIFF2025523056000037.tif 220165 TIFF2025523056000038.tif 215165 TIFF2025523056000039.tif 219165 TIFF2025523056000040.tif 209165 TIFF2025523056000041.tif 210165 TIFF2025523056000042.tif 212165 TIFF2025523056000043.tif 223165 TIFF2025523056000044.tif 215165 TIFF2025523056000045.tif 211165 TIFF2025523056000046.tif 232165 TIFF2025523056000047.tif 227165 TIFF2025523056000048.tif 230165 TIFF2025523056000049.tif 218165 TIFF2025523056000050.tif 226165 TIFF2025523056000051.tif 214165 TIFF2025523056000052.tif 179165 TIFF2025523056000053.tif 231165 TIFF2025523056000054.tif 228165 TIFF2025523056000055.tif 230165 TIFF2025523056000056.tif 238165 TIFF2025523056000057.tif 233165 TIFF2025523056000058.tif 219165 TIFF2025523056000059.tif 223165 TIFF2025523056000060.tif 232165 TIFF2025523056000061.tif 240165 TIFF2025523056000062.tif 220165 TIFF2025523056000063.tif 230165 TIFF2025523056000064.tif 226165 TIFF2025523056000065.tif227165TIFF2025523056000066.tif227165TIFF2025523056000067.tif224165TIFF2025523056000068.tif234165TIFF2025523056000069.tif220165TIFF2025523056000070.tif230165TIFF2025523056000071.tif211165TIFF2025523056000072.tif229165TIFF2025523056000073.tif191165TIFF2025523056000074.tif187165TIFF2025523056000075.tif186165TIFF2025523056000076.tif179165TIFF2025523056000077.tif183165TIFF2025523056000078.tif176165TIFF2025523056000079.tif176165TIFF2025523056000080.tif175165TIFF2025523056000081.tif175165TIFF2025523056000082.tif177165TIFF2025523056000083.tif177165TIFF2025523056000084.tif175165TIFF2025523056000085.tif184165TIFF2025523056000086.tif177165TIFF2025523056000087.tif180165TIFF2025523056000088.tif177165TIFF2025523056000089.tif180165TIFF2025523056000090.tif184165TIFF2025523056000091.tif183165TIFF2025523056000092.tif177165TIFF2025523056000093.tif177165TIFF2025523056000094.tif174165TIFF2025523056000095.tif185165TIFF2025523056000096.tif192165TIFF2025523056000097.tif180165TIFF2025523056000098.tif196165TIFF2025523056000099.tif180165TIFF2025523056000100.tif180165TIFF2025523056000101.tif191165TIFF2025523056000102.tif184165TIFF2025523056000103.tif174165TIFF2025523056000104.tif176165TIFF2025523056000105.tif184165TIFF2025523056000106.tif184165TIFF2025523056000107.tif178165TIFF2025523056000108.tif184165TIFF2025523056000109.tif176165TIFF2025523056000110.tif176165TIFF2025523056000111.tif174165TIFF2025523056000112.tif169165TIFF2025523056000113.tif187165TIFF2025523056000114.tif180165TIFF2025523056000115.tif180165TIFF2025523056000116.tif187165TIFF2025523056000117.tif187165TIFF2025523056000118.tif185165TIFF2025523056000119.tif174165TIFF2025523056000120.tif184165TIFF2025523056000121.tif184165TIFF2025523056000122.tif187165TIFF2025523056000123.tif167165TIFF2025523056000124.tif177165TIFF2025523056000125.tif190165TIFF2025523056000126.tif196165TIFF2025523056000127.tif189165TIFF2025523056000128.tif177165TIFF2025523056000129.tif177165TIFF2025523056000130.tif180165TIFF2025523056000131.tif180165TIFF2025523056000132.tif177165TIFF2025523056000133.tif164165TIFF2025523056000134.tif180165TIFF2025523056000135.tif180165TIFF2025523056000136.tif177165TIFF2025523056000137.tif177165TIFF2025523056000138.tif220165TIFF2025523056000139.tif225165TIFF2025523056000140.tif236165TIFF2025523056000141.tif231165TIFF2025523056000142.tif233165TIFF2025523056000143.tif230165TIFF2025523056000144.tif238165TIFF2025523056000145.tif232165TIFF2025523056000146.tif233165TIFF2025523056000147.tif228165TIFF2025523056000148.tif240165TIFF2025523056000149.tif228165TIFF2025523056000150.tif219165TIFF2025523056000151.tif233165TIFF2025523056000152.tif231165TIFF2025523056000153.tif229165TIFF2025523056000154.tif193165TIFF2025523056000155.tif198165TIFF2025523056000156.tif234165TIFF2025523056000157.tif232165TIFF2025523056000158.tif201165TIFF2025523056000159.tif221165TIFF2025523056000160.tif218165TIFF2025523056000161.tif227165TIFF2025523056000162.tif221165TIFF2025523056000163.tif220165TIFF2025523056000164.tif231165TIFF2025523056000165.tif225165TIFF2025523056000166.tif237165TIFF2025523056000167.tif219165TIFF2025523056000168.tif227165TIFF2025523056000169.tif240165TIFF2025523056000170.tif193165TIFF2025523056000171.tif235165TIFF2025523056000172.tif201165TIFF2025523056000173.tif199165TIFF2025523056000174.tif236165TIFF2025523056000175.tif212165TIFF2025523056000176.tif180165TIFF2025523056000177.tif217165TIFF2025523056000178.tif193165TIFF2025523056000179.tif205165TIFF2025523056000180.tif204165TIFF2025523056000181.tif198165TIFF2025523056000182.tif208165TIFF2025523056000183.tif199165TIFF2025523056000184.tif204165TIFF2025523056000185.tif212165TIFF2025523056000186.tif217165TIFF2025523056000187.tif216165TIFF2025523056000188.tif213165TIFF2025523056000189.tif226165TIFF2025523056000190.tif216165TIFF2025523056000191.tif215165TIFF2025523056000192.tif87165or a pharmaceutically acceptable salt thereof.

[0036] One of ordinary skill in the art will understand that the present disclosure includes compounds having stereochemistry opposite to that depicted. Additionally, the present disclosure contemplates tautomers of the compounds depicted herein.

[0037] This disclosure includes racemates of any of the compounds disclosed herein.

[0038] Definitions As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has one point of attachment to the remainder of the molecule (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl"). Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has one point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and their hybrid groups, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0039] The term "haloaliphatic" refers to an aliphatic group substituted with one or more halogen atoms.

[0040] The term "alkyl" refers to a straight-chain or branched alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0041] The term "haloalkyl" refers to a straight-chain or branched-chain alkyl group substituted with one or more halogen atoms.

[0042] The term "halogen" means F, Cl, Br, or I.

[0043] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring within the system is aromatic and each ring within the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., which may have one or more substituents. Also, when the term "aryl" is used herein, its scope includes groups in which an aromatic ring is fused to one or more non-aromatic rings such as, for example, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0044] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety such as, for example, "heteroalkyl" or "heteroalkoxy" refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 π electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar" also include groups in which one or more aryl rings, cycloaliphatic rings, or heterocyclyl rings are fused to a heteroaromatic ring and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of these terms includes rings which may be substituted. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl portion and the heteroaryl portion may be independently substituted.

[0045] As used herein, the terms "heterocyclic ring", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1 to 4, of the heteroatoms as defined above. When used with respect to the ring atoms of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen can be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or + NR (such as in TV-substituted pyrrolidinyl). The heterocyclic ring can be attached by any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclic ring", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and these terms include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, and the radical or point of attachment is on the heterocyclyl ring. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl portion and the heterocyclyl portion can be independently substituted.

[0046] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially saturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0047] As described herein, the compounds of the invention may contain "optionally substituted" moieties. Generally, the term "substituted" means that one or more hydrogens of the designated moiety are replaced with an appropriate substituent, whether or not preceded by the term "optionally". Unless otherwise specified, an "optionally substituted" group may have an appropriate substituent at each substitutable position of the group, and when two or more positions of any given structure are substituted with two or more substituents selected from the specified groups, the substituents may be the same or different at any position. Combinations of substituents contemplated by the present invention preferably result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that do not substantially change when subjected to the conditions for their manufacture, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0048] Suitable monovalent substituents for the substitutable carbon atoms of an "optionally substituted" group are, independently, halogen; -(CH2) 0-4 R ° ; -(CH2) 0-4 OR ° ; -O(CH2) 0-4 R ° , -O-(CH2) 0-4 C(O)OR ° ; -(CH2) 0-4 CH(OR ° )2; -(CH2) 0-4 SR ° ; R° which may be replaced by -(CH2) 0-4 Ph;R ° which may be replaced by -(CH2) 0-4 O(CH2) 0-1 Ph;R ° which may be replaced by -CH=CHPh;R ° which may be replaced by -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R ° )2; -(CH2) 0-4 N(R ° )C(O)R ° ; -N(R ° )C(S)R ° ; -(CH2) 0-4 N(R ° )C(O)NR ° 2; -N(R ° )C(S)NR ° 2; -(CH2) 0-4 N(R ° )C(O)OR ° ; -N(R ° )N(R ° )C(O)R ° ; -N(R ° )N(R ° )C(O)NR ° 2; -N(R ° )N(R ° )C(O)OR ° ; -(CH2) 0-4 C(O)R ° ; -C(S)R ° ; -(CH2) 0-4 C(O)OR ° ; -(CH2) 0-4 C(O)SR ° ; -(CH2) 0-4 C(O)OSiR ° 3; -(CH2) 0-4 OC(O)R ° ; -OC(O)(CH2) 0-4 SR ° 、SC(S)SR ° ; -(CH2) 0-4 SC(O)R ° ; -(CH2)0-4 C(O)NR ° 2;-C(S)NR ° 2;-C(S)SR ° ;-SC(S)SR ° 、-(CH2) 0-4 OC(O)NR ° 2;-C(O)N(OR ° )R ° ;-C(O)C(O)R ° ;-C(O)CH2C(O)R ° ;-C(NOR ° )R ° ;-(CH2) 0-4 SSR ° ;-(CH2) 0-4 S(O)2R ° ;-(CH2) 0-4 S(O)2OR ° ;-(CH2) 0-4 OS(O)2R ° ;-S(O)2NR ° 2;-(CH2) 0-4 S(O)R ° ;-N(R ° )S(O)2NR ° 2;-N(R ° )S(O)2R ° ;-N(OR ° )R ° ;-C(NH)NR ° 2;-P(O)2R ° ;-P(O)R ° 2;-OP(O)R ° 2;-OP(O)(OR ° )2;SiR ° 3;-(C 1-4 a straight-chain or branched alkylene)O-N(R ° )2; or -(C 1-4 a straight-chain or branched alkylene)C(O)O-N(R ° )2, and each R ° may be substituted as defined hereinafter and is independently hydrogen, C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent Rs ° The occurrence of which, together with their intervening atom(s) (if any), forms a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and may be substituted as defined hereinafter.

[0049] R ○ (or a ring formed by joining two independent occurrences of R ○ ) Suitable monovalent substituents on are, independently, halogen, -(CH2) 0-2 R ● , -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2; -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ●is unsubstituted or, when "halo" precedes, substituted only with one or more halogens, and C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R ○ include =O and =S.

[0050] Suitable divalent substituents on the saturated carbon atoms of a "optionally substituted" group include =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from hydrogen, a C 1-6 aliphatic group optionally substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to an adjacent substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, a C 1-6 aliphatic group optionally substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] Suitable substituents on the aliphatic group of R* include halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, when preceded by "halo", is substituted with only one or more halogens, and independently, C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] Suitable substituents on the nitrogen of the "optionally substituted" group include -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † )2, -C(NH)NR † 2, or -N(R † )S(O)2R † is mentioned, and each R † is independently hydrogen, a C 1~6 aliphatic group that can be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently existing R † together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0053] R † Suitable substituents on the aliphatic group of are independently halogen, -R ● , -(haloR● )、 -OH, -OR ● 、 -O(haloR ● )、 -CN, -C(O)OH, -C(O)OR ● 、 -NH2, -NHR ● 、 -NR ● 2, or -NO2, and each R ● is unsubstituted or, when "halo" precedes, substituted only with one or more halogens, and, independently, is a C 1-4 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that exhibit a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate.

[0055] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4Examples of such salts include (alkyl) salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts are formed using counterions such as halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acids, if appropriate, and include non-toxic ammonium, quaternary ammonium, and amine cations.

[0056] The combinations of substituents and variable elements envisioned by the present disclosure are limited to those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound having sufficient stability to allow for manufacture and to maintain the integrity of the compound over a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0057] The recitation of a list of chemical groups in the definition of a variable element herein includes the definition of that variable element as a single group or a combination of the listed groups. The recitation of embodiments of a variable element herein includes that embodiment as a single embodiment or in combination with any other embodiment or part thereof.

[0058] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from mammals; and blood, saliva, urine, feces, sperm, tears, or other body fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, storage of biological specimens, and biological assays.

[0059] As used herein, "therapeutically effective amount" means an amount of a substance (e.g., therapeutic agent, composition, and / or formulation) that induces a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered as part of a dosing regimen to a subject having or susceptible to having the disease, disorder, and / or condition. As will be appreciated by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, the target cell or tissue, etc. For example, the effective amount of a compound provided in a formulation for treating a disease, disorder, and / or condition is an amount that results in the reduction, improvement, alleviation, suppression, prevention, delay in onset, reduction in severity, and / or decrease in incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. I

[0060] As used herein, the terms "treat", "treating", and "treatment" refer to the partial or complete reduction, suppression, delay in onset, prevention, improvement, and / or alleviation of a disorder or condition described herein or one or more symptoms thereof. In some embodiments, treatment can be administered after one or more symptoms have occurred. In some embodiments, the term "treatment" includes preventing or arresting the progression of a disease or disorder. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a symptom history and / or genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence. Thus, in some embodiments, the term "treatment" includes preventing the relapse or recurrence of a disease or disorder.

[0061] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0062] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound(s) formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the compounds disclosed herein include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin, but are not limited thereto.

[0063] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that, when administered to a recipient, can directly or indirectly provide the compound of the present disclosure or its inhibitory active metabolite or residue.

[0064] As used herein, the expression "dosage unit form" refers to physically discrete dosage units appropriate to the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage levels for a particular patient or organism will depend on various factors including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of the treatment; drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical arts.

[0065] Unless specifically recited or apparent from the context, as used herein, the term "about" is understood to be within the normal tolerances in the art, e.g., within 2 standard deviations of the mean. About can be understood to be within ±10% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term about.

[0066] Alternative embodiments In alternative embodiments, the compounds described herein may also contain one or more isotope substitutions. For example, hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium), and carbon may be, for example, 13 C or 14 C, oxygen may be, for example, 18 O, nitrogen may be, for example, 15 N, etc. In other embodiments, a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound.

[0067] Diseases and disorders In this specification, for example, a method of regulating the activity of immune cells (e.g., T cells, B cells, or NK cells) is provided by contacting an effective amount of a Cbl-b inhibitor or a composition thereof described herein with the immune cells. Also provided is an in vitro method for producing the immune cells having regulated activity, referred to herein as "modified immune cells", in which the modified immune cells can be administered, by an ex vivo method, to an individual in need thereof (e.g., an individual having cancer). Further provided is an in vitro method for regulating a response in an individual in need thereof (e.g., an individual suffering from cancer), the method including administering an effective amount of a Cbl-b inhibitor or a composition thereof described herein. Furthermore, the present disclosure provides an in vitro method for generating a proliferating population of lymphocytes after in vivo lymphomodulation in an individual, the lymphomodulation occurring as a result of administering an effective amount of a Cbl-b inhibitor or a composition thereof described herein to the individual. Furthermore, the proliferated lymphocyte population can then be administered to an individual suffering from cancer. In some embodiments, the modified immune cells or the proliferated lymphocyte population are produced from a biological sample containing immune cells obtained from an individual, such as a blood sample containing peripheral blood mononuclear cells or a tumor biopsy containing tumor infiltrating lymphocytes (TIL).

[0068] Furthermore, a Cbl-b inhibitor for use as a therapeutic agent is provided. A Cbl-b inhibitor for use in treating or preventing a disease or condition associated with Cbl-b activity is provided. Also provided is a Cbl-b inhibitor for use in treating cancer. Furthermore, the use of a Cbl-b inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity is provided. Also provided is the use of a Cbl-b inhibitor in the manufacture of a medicament for treating cancer. Furthermore, the present disclosure provides a treatment method, a medicament, and a use including a Cbl-b inhibitor as part of a combination therapy for treating cancer, the combination therapy including one or more of an immune checkpoint inhibitor, an anti-tumor agent, and radiotherapy.

[0069] In some embodiments of the treatment methods, agents, and uses of the present disclosure, the cancer is a blood cancer such as lymphoma, leukemia, or myeloma. In other embodiments of the treatment methods, agents, and uses of the present disclosure, the cancer is a non-blood cancer such as sarcoma, carcinoma, or melanoma.

[0070] Blood cancers include, but are not limited to, one or more leukemias such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), acute lymphoblastic leukemia (ALL), one or more chronic leukemias including chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia, and "preleukemia" (which is a collection of diverse blood disorders integrated by ineffective production (or dysplasia) of myeloid blood cells), and additional blood cancers or blood disorders not limited thereto.

[0071] Non-blood cancers include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, gastric cancer, brain tumor, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0072] In some embodiments, the efficacy of administering a Cbl-b inhibitor in the treatment of a disease or disorder such as cancer is measured by assessing clinical outcomes such as reduction in tumor size or number of tumors and / or survival rate. In some embodiments, "treatment of cancer" includes evaluating the patient's response to the treatment plan according to the described solid tumor response evaluation criteria in solid tumors (RECIST version 1.1) (see, e.g., Eisenhauer et al., Eur J Cancer, 45:228-247, 2009; and Nishino et al., Am J Roentgenol, 195:281-289, 2010). Response criteria for determining an objective anti-tumor response according to RECIST 1.1 include complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD).

[0073] Formulation The present disclosure also provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0074] The present disclosure also provides an agent comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, as an active ingredient.

[0075] Generally, for pharmaceutical use, the compounds disclosed herein may be formulated as a pharmaceutical preparation comprising at least one disclosed compound, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant, and optionally one or more further pharmaceutically active compounds. Details regarding the presence of further pharmaceutically active compounds are described below.

[0076] As a non-limiting example, such formulations can be in a form suitable for oral administration, parenteral administration (such as intravenous, intramuscular, or subcutaneous injection, or intravenous infusion), topical administration (including eye drops), administration by inhalation, skin patches, implants, suppositories, etc. Such suitable dosage forms (which can be solid, semi-solid, or liquid depending on the mode of administration) and the methods used for their preparation, as well as carriers, diluents, and excipients, will be apparent to those skilled in the art; see the latest edition of Remington’s Pharmaceutical Sciences.

[0077] Preferred but non-limiting examples of such formulations include tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions, and sterile packaged powders for bolus and / or continuous administration (which are usually reconstituted before use), which can be formulated with carriers, excipients, and diluents that are themselves suitable for such formulation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methylhydroxybenzoate and propylhydroxybenzoate, talc, magnesium stearate, edible oils, vegetable oils, and mineral oils, or suitable mixtures thereof. The formulations can optionally include other substances commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, bulking agents, fillers, preservatives, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions can also be formulated to provide rapid, sustained, or delayed release of the active compound(s) contained therein.

[0078] The pharmaceutical preparations of the present disclosure are preferably in unit dosage forms and may be suitably packaged, for example, in boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holders or containers (which may be suitably labeled), and optionally, one or more leaflets containing product information and / or instructions for use may be attached.

[0079] Depending on the condition to be prevented or treated and the route of administration, the disclosed compounds may be administered as a single daily dose, divided into one or more daily doses, or essentially continuously, for example, using intravenous infusion.

[0080] Another object of the present disclosure is the use of the combination as a medicament, i.e., for medical use. Thus, in one embodiment, the present disclosure provides the use of the combination of the present disclosure for the manufacture of a medicament. In particular, the present disclosure provides the use of the combination pharmaceutical composition or the kit of the present disclosure for the manufacture of a medicament.

[0081] Administration In some embodiments, the CBL-B inhibitor is administered at a dose of 60 - 600 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 100 - 500 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 125 - 475 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 150 - 450 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 200 - 400 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 60 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 80 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 100 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 120 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 140 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 160 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 180 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 200 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 220 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 240 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 260 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 300 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 325 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 350 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 375 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 400 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 425 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 450 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 475 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 500 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 525 mg.In some embodiments, the CBL-B inhibitor is administered at a dose of about 550 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 575 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 600 mg.

[0082] In some embodiments, the CBL-B inhibitor is administered at a dose of 2.0 to 60 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 2.0 to 60 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 2.0 to 10 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 10 to 20 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 20 to 30 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 30 to 40 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 40 to 50 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 50 to 60 mg / kg.

[0083] In some embodiments, the CBL-B inhibitor is administered at a dose of about 2.0 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 6.0 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 10 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 20 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 30 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 40 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 50 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of about 60 mg / kg.

[0084] In some embodiments, the compounds or compositions disclosed herein may be administered at specific intervals. For example, during treatment, the compound or composition may be administered to the patient, for example, at intervals of 1 year, 6 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hour, 0.5 hour, or 0.25 hour.

[0085] In some embodiments, the CBL-B inhibitor is administered once daily. In some embodiments, the CBL-B inhibitor is administered twice daily (BID). In some embodiments, the CBL-B inhibitor is administered three times daily (TID). In some embodiments, the CBL-B inhibitor is administered four times daily (QID). In some embodiments, the CBL-B inhibitor is administered once a week. In some embodiments, the CBL-B inhibitor is administered twice a week. In some embodiments, the CBL-B inhibitor is administered three times a week. In some embodiments, the CBL-B inhibitor is administered four times a week. In some embodiments, the CBL-B inhibitor is administered once a month. In some embodiments, the CBL-B inhibitor is administered twice a month. In some embodiments, the CBL-B inhibitor is administered three times a month. In some embodiments, the CBL-B inhibitor is administered four times a month.

Example

[0086] Example 1. Synthesis of Compound 29 TIFF2025523056000193.tif711651. Synthesis of 10b A mixture of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (100 g, 416.627 mmol, 1 equiv) and SeO₂ (92.47 g, 833.254 mmol, 2 equiv) in AcOH (500 mL) was stirred at 120 °C overnight. The resulting mixture was diluted with water (1000 mL). The aqueous layer was extracted with methyl tert-butyl ether (2 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (100 mL) for purification. As a result, 5-bromo-3-(trifluoromethyl)pyridine-2-carbaldehyde (62 g, 58.81%) was obtained as an off-white solid.

[0087] 2. Synthesis of 10c To a stirred solution of 10b (100 g, 395.26 mmol, 1.20 equiv) and I-3 (80 g, 329.38 mmol, 1.00 equiv) in DCE (1000.00 mL), NaBH(OAc)₃ (139.65 g, 658.761 mmol, 3.00 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (2500.00 mL). The aqueous layer was extracted with EtOAc (3 × 1000.00 mL). The organic layer was concentrated under reduced pressure. The residue was triturated with MTBE (2 × 300.00 mL) for purification. As a result, 10c (116 g, 61.01%) was obtained as a white solid.

[0088] 3. Synthesis of 7 To a stirred solution of 10c (130 g, 269.539 mmol, 1 equiv) and pyridine (127.92 g, 1617.234 mmol, 6 equiv) in DCM (2600 mL) was added triphosgene (26.39 g, 94.594 mmol, 0.35 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by adding NaHCO3 (aqueous solution) (1500 mL). The resulting mixture was extracted with CH2Cl2 / MeOH = 10 / 1 (2 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (600 mL) for purification. As a result, 7 (110 g, 80.29%) was obtained as a yellow solid. (ES, m / z): [M+H] + : 508

[0089] 4. Synthesis of 10d To a solution of 7 (110 g, 216.408 mmol, 1 equiv) and TMEDA (50.30 g, 432.816 mmol, 2 equiv) in dioxane (4400 mL) were added bis(adamantan-1-yl)(butyl)phosphane (15.52 g, 43.282 mmol, 0.2 equiv) and Pd(OAc)2 (4.86 g, 21.641 mmol, 0.1 equiv) inside an autoclave. After the autoclave was flushed three times with CO / H2 (1:1), the mixture was pressurized with CO / H2 (1:1) to 10 atm at 80 °C overnight. The resulting mixture was concentrated under vacuum. The residue was eluted with CH2Cl2 / MeOH (20:1) and purified by silica gel column chromatography to give 10d (58 g, 58.59%) as a yellow solid. (ES, m / z): [M+H] + : 458

[0090] 5. Synthesis of 29 To a stirred mixture of 10d (58 g, 126.800 mmol, 1.00 equiv) and (s)-3-methylpiperidine hydrochloride (34.40 g, 253.600 mmol, 2 equiv) in DCE (1600 mL) was added TEA (38.49 g, 380.400 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 2 h. To the above mixture was added NaBH(OAc)3 (53.75 g, 253.600 mmol, 2 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (1000 mL). The resulting mixture was extracted with CH2Cl2 / MEOH = 10 / 1 (2 × 1000 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 15% to 80% in 40 min; detector, UV 254 nm. As a result, 29 (30.9 g, 45.08%) was obtained as a yellow solid. LC-MS-29: (ES, m / z): [M+H] + 541. H-NMR-29: (400 MHz, CD3OD, δ ppm): 0.75 - 0.95 (m, 4H), 1.43 - 1.49 (m, 1H), 1.49 - 1.66 (m, 4H), 1.86 - 1.91 (m, 1H), 2.67 - 2.76 (m, 2H), 2.96 (s, 3H), 3.31 (s, 2H), 3.53 (s, 2H), 4.90 - 4.95 (m, 1H), 6.88 - 9.90 (d, 1H), 7.00 (s, 1H), 7.29 (s, 1H), 7.37 - 7.40 (d, 1H), 7.64 (s, 1H), 7.74 - 7.76 (d, 1H), 8.19 (s, 1H).

[0091] Example 2. Synthesis of Compound 85 Synthesis of 11616585a of TIFF2025523056000194 A mixture of methyl 2-(3-nitrophenyl)acetate (48.1 g, 246.447 mmol, 1 equiv) and Cs2CO3 (401.49 g, 1232.235 mmol, 5 equiv) in DMF (500 mL) was stirred at 0 °C for 3 h under a nitrogen atmosphere. Bromocyclobutane (99.81 g, 739.341 mmol, 3 equiv) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with NH4Cl (aqueous solution) (3 L) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was eluted with PE / EA (150:1) and purified by silica gel column chromatography to give 85a (49 g, 73.38%) as an off-white solid.

[0092] Synthesis of 85b Hydrazine hydrate (98%) (251.04 g, 4914.425 mmol, 25 equiv, 98%) was added to a stirred solution of 85a (49 g, 196.577 mmol, 1 equiv) in EtOH (500 mL) at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was diluted by adding water (500 mL) at room temperature. The aqueous layer was extracted with CH2Cl2 / MeOH (10:1) (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was eluted with CH2Cl2 / MeOH (100:1) and purified by silica gel column chromatography to give 85b (43 g, 79.86%) as a yellow oil.

[0093] Synthesis of 85c Methyl isothiocyanate (33.00 g, 451.317 mmol, 2.5 equiv) was added to a stirred solution of 85b (45 g, 180.527 mmol, 1 equiv) in THF (450 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (280 mL). The resulting mixture was filtered and the filter cake was washed with water (3 × 50 mL). The resulting solid was dried under vacuum. As a result, 85c (55 g, 86.00%) was obtained as a white solid.

[0094] Synthesis of 85d To a stirred solution of NaOH (66 g, 1650.120 mmol, 9.67 eq) in H2O (1.65 L) was added 85c (55 g, 170.606 mmol, 1 eq) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 5 with HCl (1 M). The resulting mixture was filtered and the filter cake was washed with water (3 × 50 mL). The resulting solid was dried under vacuum. As a result, 85d (50 g, 86.66%) was obtained as an off-white solid.

[0095] Synthesis of 85e To a stirred mixture of 85d (50 g, 164.274 mmol, 1 eq) in EtOAc (190 mL) and H2O (760 mL) was added NaNO2 (113.3 g, 1642.74 mmol, 10 eq) at room temperature. HNO3 (1642 mL, 1642.74 mmol, 10.00 eq, 1 M) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was neutralized to pH 7 with saturated NaHCO3 (aqueous solution). The aqueous layer was extracted with CH2Cl2 / MeOH (10:1) (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was eluted with CH2Cl2 / MeOH (50:1) and purified by silica gel column chromatography to give 85e (40 g, 85.84%) as a yellow solid.

[0096] Synthesis of 85f To a solution of 85e (40 g, 146.892 mmol, 1 eq) in 1.2 L of MeOH was added Pd / C (20%, 8 g) in a 2 L round-bottom flask. Using a hydrogen balloon, the mixture was hydrogenated at room temperature overnight under a hydrogen atmosphere, filtered through a celite pad, and concentrated under reduced pressure. As a result, 85f (35 g, 94.39%) was obtained as an off-white solid.

[0097] Synthesis of 85g To a stirred solution of 85f (31.45 g, 123.800 mmol, 1.2 equiv) and I-2g (31.45 g, 123.800 mmol, 1.2 equiv) in DCE (300 mL) was added NaBH(OAc)3 (43.73 g, 206.334 mmol, 2 equiv) and HOAc (6.20 g, 103.167 mmol, 1 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched by adding water (500 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated with MTBE (2 × 50 mL) for purification. As a result, 85 g (34 g, 65.18%) was obtained as a white solid.

[0098] Synthesis of 85h To a stirred solution of 85g (34 g, 70.784 mmol, 1 equiv) and pyridine (33.59 g, 424.704 mmol, 6 equiv) in DCM (400 mL) was added triphosgene (7.35 g, 24.774 mmol, 0.35 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. The reaction was quenched by adding water (500 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 500 mL) and dried over anhydrous CaCl2. After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated with MTBE (2 × 100 mL) for purification. This 85h (33 g, 87.47%) is a yellow solid.

[0099] Synthesis of 85i To a solution of 85h (33 g, 65.175 mmol, 1 equiv) and TMEDA (15.15 g, 130.350 mmol, 2 equiv) in dioxane (1000 mL) were added bis(adamantan-1-yl)(butyl)phosphane (4.67 g, 13.035 mmol, 0.2 equiv) and Pd(OAc)₂ (1.46 g, 6.518 mmol, 0.1 equiv) inside an autoclave. After the autoclave was flushed three times with CO / H₂ (1:1), the mixture was pressurized to 10 atm with CO / H₂ (1:1) and reacted at 80 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting from CH₂Cl₂ / MeOH (20:1) to CH₂Cl₂ / MeOH (5:1) to give 85i (20 g, 67.38%) as a yellow solid.

[0100] Synthesis of 85j To a stirred mixture of 85i (10 g, 21.957 mmol, 1 equiv) and (3S)-3-methylpiperidine hydrochloride (8.93 g, 65.871 mmol, 3 equiv) in DCE (150 mL) was added Et₃N (8.89 g, 87.828 mmol, 4 equiv). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. To the above mixture was added NaBH(OAc)₃ (6.98 g, 32.936 mmol, 1.5 equiv). The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding water (200 mL) at room temperature. The resulting mixture was extracted with CH₂Cl₂ / MeOH = 10 / 1 (2 × 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mol / L NH₄HCO₃), gradient from 15% to 60% in 40 min; detector, UV 254 nm. As a result, 85j (6.5 g, 54.96%) was obtained as a yellow solid.

[0101] Synthesis of 85 85j (6.5 g) was purified by preparative chiral SFC under the following conditions (column: CHIRAL ART Cellulose-SB, 5 × 25 cm, 10 μm; mobile phase A: CO2, mobile phase B: MEOH (0.1% 2M NH3-MeOH); flow rate: 200 mL / min; gradient: isocratic 30% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT2 (min): 6.26; sample solvent: MEOH (0.1% 2M NH3-MEOH); injection volume: 1 mL; number of runs: 30). As a result, compound 85 (3.0062 g) was obtained as a yellow solid. LC-MS: (ES, m / z): [M+H] + 540 1H-NMR: (400 MHz, DMSO-d6, ppm): δ0.84 - 0.91 (m, 4H), δ1.38 - 1.95 (m, 12H), δ2.08 - 2.10 (m, 1H), δ2.68 - 2.77 (m, 2H), δ3.19 - 3.25 (m, 3H), δ3.43 (s, 3H), δ4.25 - 4.28 (d, 1H), δ7.01 (s, 1H), δ7.19 - 7.21 (d 1H), δ7.32 (s, 1H), δ7.43 - 7.46 (t, 1H), δ7.66 - 7.75 (m, 3H), δ8.34 (s, 1H).

[0102] Example 3. Synthesis of Compound 86 Synthesis of TIFF2025523056000195.tif4916586 85j (85.00 mg, 0.158 mmol, 1.00 equivalent) was purified by preparative chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: from 30% B to 30% B in 8.5 minutes; wavelength: 220 / 254 nm; RT1 (min): 5.19), and compound 86 (24.1 mg, 27.90%) was obtained as a yellow solid. LC-MS: (ES, m / z): [M+H] + 539 1H-NMR: (400 MHz, CDCl3, ppm): δ 0.81 - 0.83 (d, 4H), δ 1.66 - 1.78 (m, 11H), δ 2.04 - 2.11 (m, 1H), δ 2.65 - 3.69 (m, 1H), δ 2.72 - 3.73 (m, 1H), δ 3.22 - 3.35 (m, 3H), δ 3.42 (s, 3H), δ 4.24 - 4.28 (d, 1H), δ 7.00 (s, 1H), δ 7.19 - 7.22 (d, 1H), δ 7.33 (s, 1H), δ 7.44 - 7.47 (m, 1H), δ 7.70 - 7.72 (m, 3H), δ 8.32 (s, 1H).

[0103] Example 4. Subcutaneous H22 mouse liver cancer model in female BALB / c mice The purpose of this pharmacological test was to evaluate the anti - tumor growth effect of Compound 85 in the treatment of a subcutaneous H22 mouse liver cancer model in female BALB / c mice. When the average tumor volume reached approximately 80 mm 3 , the test particles of Compound 85 were delivered by oral administration. Compound 85 was evaluated as a single agent at five different dose levels (2 mpk, 6 mpk, 10 mpk, 20 mpk, and 60 mpk once a day). After the start of treatment, the tumor volume and body weight were measured three times a week. The mice were divided into seven groups and summarized in Table 2.

[0104] (Table 2) TIFF2025523056000196.tif113165

[0105] The drugs were prepared as outlined in Table 3.

[0106] (Table 3) TIFF2025523056000197.tif207165

[0107] Cell culture H22 tumor cells were maintained in vitro in RPMI - 1640 medium supplemented with 10% fetal bovine serum at 37 °C in a 5% CO2 atmosphere in air. Cells in the exponential growth phase were harvested and quantified with a cell counter before tumor inoculation.

[0108] Tumor inoculation To generate tumors, 0.1 ml of H22 tumor cells (1×10e6) in PBS was subcutaneously inoculated into the upper right abdominal area of each mouse.

[0109] Randomization Randomization was initiated when the average tumor size reached approximately 79.89 mm^3. A total of 130 mice were enrolled in the study and randomly assigned to 13 test groups of 10 mice each as shown in Table 4. Randomization was performed based on the "Matched distribution" method / "Stratified" method (Study Director™ software, version 3.1.399.19) / randomization block design. The date of randomization was designated as Day 0.

[0110] Observation and data collection After tumor inoculation, the animals were checked daily for morbidity and mortality. During regular monitoring, the animals were examined for tumor growth and the effects of treatment on behavior such as motor ability, food and water intake, weight gain or loss (weight was measured three times a week after randomization), eye / hair entanglement, and other abnormalities. For each individual animal, the mortality rate and observed clinical signs were recorded in detail.

[0111] After randomization, the tumor volume was measured two-dimensionally three times a week using calipers and expressed in mm3 using the formula V=(L×W×W) / 2, where V is the tumor volume, L is the length of the tumor (the longest dimension of the tumor), and W is the width of the tumor (the longest dimension of the tumor perpendicular to L). Administration and tumor and weight measurements were performed in a laminar flow cabinet.

[0112] Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0113] Test endpoint Tumor growth inhibition (TGI): TGI% is an index of antitumor activity expressed as TGI(%) = 100×(1 - T / C). T and C are the average tumor volumes (or weights) of the treatment group and the control group on a given day.

[0114] End of the test The treatment was carried out for 21 days, and the test was terminated on the 20th day after the start of administration.

[0115] Results The test was terminated when the average tumor size in the vehicle group reached 2858.52 mm^3 on the 12th day. In this test, treatment with compound 85 as a single agent showed tumor growth inhibition of 19.56% - 68.53% (P < 0.01, compared with the vehicle control, Table 4) (Figure 1 and Figure 2). The lowest dose showing significant tumor inhibition for the single agent of compound 85 was 6 mpk once a day, and the TGI value was 41.21%.

[0116] (Table 4) TIFF2025523056000198.tif62165

[0117] In conclusion, H22 tumor growth was significantly inhibited by treatment with compound 85. The minimum effective dose observed with compound 85 was 6 mpk once a day, and the TGI was 54.8%. At high doses of compound 85, 20 mpk or 40 mpk once a day, the maximum TGI was nearly 65%.

[0118] Example 5. Subcutaneous CT26 mouse colorectal cancer model in female BALB / c mice The purpose of this test was to evaluate the in vivo antitumor effect of compound 85 in a subcutaneous CT26 mouse colorectal cancer model in female BALB / c mice. The tumor was 80 mm 3When the time point was reached, the test particles of Compound 85 were delivered by oral administration. The compound was evaluated at six different dose levels (3 mpk, 10 mpk, 30 mpk twice a day, and 6 mpk, 20 mpk, and 60 mpk once a day). After the start of treatment, tumor volume and body weight were measured twice a week. The level of Compound 85 was evaluated in plasma and tumors at the end of the study. The mice were divided into nine groups and summarized in Table 5.

[0119] (Table 5) TIFF2025523056000199.tif111165

[0120] The test substance was formulated as outlined in Table 6.

[0121] (Table 6) TIFF2025523056000200.tif215165

[0122] Cell Culture CT26 tumor cells were maintained in vitro using RPMI - 1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 atmosphere. Cells in the exponential growth phase were harvested and quantified using a cell counter before tumor inoculation.

[0123] Tumor Inoculation 0.1 ml of CT26 tumor cells (5×10 5 ) in PBS were subcutaneously inoculated into the lower right abdominal area of each mouse.

[0124] Randomization Randomization was started when the average tumor size reached approximately 80.7 mm 3 . A total of 80 mice were enrolled in the study and randomly assigned to eight test groups, with 10 mice in each group. Randomization was performed based on the "Matched distribution" method (Study Director (trademark) software, version 3.1.399.19). The date of randomization was designated as Day 0.

[0125] Observation and Data Collection After tumor inoculation, the animals were checked daily for morbidity and mortality. During regular monitoring, the animals were examined for tumor growth and the effects of treatment on behavior such as motor ability, food and water intake, weight gain or loss (weight was measured twice a week after randomization), eye / hair entanglement, and other abnormalities. For each individual animal, the mortality rate and observed clinical signs were recorded in detail.

[0126] After randomization, tumor volume was measured two - dimensional using calipers twice a week, and the volume was expressed in mm3 using the formula V=(L×W×W) / 2, where V is the tumor volume, L is the length of the tumor (the longest dimension of the tumor), and W is the width of the tumor (the longest dimension of the tumor perpendicular to L). Administration and tumor and weight measurements were performed in a laminar flow cabinet.

[0127] Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0128] Results In this study, the mean tumor size of the vehicle group reached 2348.26 mm 3 on day 18. Treatment with Compound 85 showed dose - dependent tumor growth inhibition. Treatment with Compound 85 at 30 mpk twice a day or 60 mpk once a day as a single agent resulted in significant tumor growth inhibition in the subcutaneous CT26 model, and the TGI values were 37.9% (P < 0.05, compared to the vehicle control) and 33.9% (P < 0.05, compared to the vehicle control), respectively (Tables 7 and 8).

[0129] During the treatment period, a decrease of less than 5% of the mean body weight was observed on day 3 in the groups of Compound 85 at 30 mpk twice a day and 60 mpk once a day. The body weight recovered rapidly after day 3 (Figure 3).

[0130] The tumor growth inhibition of Compound 85 was evaluated using a CT26 mouse colon cancer model. In the treatment with Compound 85 at 30 mpk twice a day or 60 mpk once a day as a single agent, significant tumor growth inhibition occurred in the subcutaneous CT26 model, and the TGI values were 37.9% (P < 0.05, compared to the vehicle control) and 33.9% (P < 0.05, compared to the vehicle control), respectively (Tables 7 and 8). No deaths were reported.

[0131] (Table 7) Tumor growth inhibition (TGI) on day 18 TIFF2025523056000201.tif53165

[0132] (Table 8) Statistical analysis of tumor volume on day 18 TIFF2025523056000202.tif54165

[0133] Example 6. Subcutaneous CT26 mouse colorectal cancer model in female BALB / c mice The purpose of this study was to preclinically evaluate the in vivo dose of the test compound in the treatment of a subcutaneous CT26 mouse colorectal cancer model in female BALB / c mice.

[0134] The mice were divided into eight groups and summarized in Table 9.

[0135] (Table 9) TIFF2025523056000203.tif81165

[0136] The test substance was formulated as outlined in Table 10.

[0137] (Table 10) TIFF2025523056000204.tif180165

[0138] Cell culture CT26 tumor cells were maintained in vitro using RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 atmosphere in air. Cells in the exponential growth phase were harvested and quantified using a cell counter prior to tumor inoculation.

[0139] Tumor inoculation To generate tumors, 0.1 ml of CT26 tumor cells (5×10 5 ) in PBS were subcutaneously inoculated into the right lower abdomen of each mouse.

[0140] Randomization Randomization was initiated when the average tumor size reached approximately 89.91 mm 3 . A total of 80 mice were enrolled in the study and randomly assigned to 8 test groups of 10 mice each. Randomization was performed based on the "Matched distribution" method (Study Director™ software, version 3.1.399.19). The date of randomization was designated as day 0 (July 8, 2021).

[0141] Observation and data collection After tumor inoculation, the animals were checked daily for morbidity and mortality. During regular monitoring, the animals were examined for tumor growth and the effects of treatment on behavior such as locomotor ability, food and water intake, weight gain or loss (weight was measured twice a week after randomization), eye / coat condition, and other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0142] After randomization, tumor volume was measured two-dimensionally using calipers twice a week and expressed in mm3 using the formula V = (L × W × W) / 2, where V is the tumor volume, L is the length of the tumor (the longest dimension of the tumor), and W is the width of the tumor (the longest dimension of the tumor perpendicular to L). Administration and tumor and weight measurements were performed in a laminar flow cabinet.

[0143] Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0144] Test endpoint Tumor growth inhibition (TGI): TGI% is an indicator of antitumor activity expressed as TGI(%) = 100×(1 - T / C). T and C are the mean tumor volumes (or weights) of the treatment group and the control group, respectively, on a given day.

[0145] Statistical analysis of the difference in mean tumor volume between groups was performed using the following method: Use the data collected on the day when either the treatment group or the control group ended, even if the remaining groups were treated as scheduled.

[0146] End of the test The test was terminated when the mean tumor volume of the control group reached 2000 mm^3. Treatment was carried out for 14 days. There was no extension of treatment, and the test was terminated on the 13th day after the start of administration.

[0147] Statistical analysis To compare the tumor volumes of different groups on a pre-specified day, the Bartlett test was used to confirm the assumption of homogeneity of variance across all groups. When the p-value of the Bartlett test was 0.05 or greater, one-way analysis of variance was performed to test the overall equality of the means of all groups. When the p-value of the one-way analysis of variance was less than 0.05, post hoc tests were performed by conducting Tukey's HSD (honest significant difference) test for all pairwise comparisons and Dunnett's test to compare each treatment group with the vehicle group. When the p-value of the Bartlett test was less than 0.05, the Kruskal-Wallis test was performed to test the overall equality of the medians across all groups. When the p-value of the Kruskal-Wallis test was less than 0.05, post hoc tests were performed by conducting Conover's nonparametric test for all pairwise comparisons or to compare each treatment group with the vehicle group (both with single-step p-value adjustment).

[0148] Furthermore, pairwise comparisons were performed without multiple comparison correction, and nominal / uncorrected p-values were reported directly from the Welch's t-test or the Mann-Whitney U-test. Specifically, the Bartlett's test was used to confirm the assumption of homogeneity of variances for pairs of groups. When the p-value of the Bartlett's test was 0.05 or greater, the Welch's t-test was performed; otherwise, the Mann-Whitney U-test was performed to obtain the nominal p-value.

[0149] All statistical analyses were performed in the R-a language and statistical computing and graphics environment (version 3.3.1). Unless otherwise specified, all tests were two-sided, and p-values less than 0.05 were considered statistically significant.

[0150] Summary of Results In this study, the mean tumor size in the vehicle group reached 2273.48 mm^3.

[0151] Treatment with compound 29 as a single agent at 60 mg / kg (twice daily, group 3) and 100 mg / kg (twice daily, group 04) showed significant antitumor effects (P < 0.01, compared to the control group) against the subcutaneous CT26 colorectal cancer syngeneic model, with TGI values of 41.76% and 50.83%, respectively, indicating a dose-dependent manner of the efficacy of compound 29.

[0152] Treatment with compound 85 as a single agent at 30 mg / kg (twice daily, group 05) showed a significant antitumor effect against the subcutaneous CT26 colorectal cancer syngeneic model, with a TGI value of 43.02% (P < 0.01, compared to the vehicle control).

[0153] Treatment with compound 29 as a single agent at 30 mg / kg (twice daily, group 02) did not show a significant antitumor effect compared to the control group in the designed dosing schedule, with TGI values of 10.78%, -1.82%, 32.71%, and 20.73% (P > 0.05, compared to the vehicle control), respectively.

[0154] (Table 11) TGI TIFF2025523056000205.tif40165

[0155] (Table 12) Statistical analysis of tumor volume on the 13th day TIFF2025523056000206.tif69165

[0156] There are a total of eight groups. Group 01 is used as the control group.

[0157] The p-value of the Bartlett's test was 0.02, which violated the assumption of homogeneity of variance. Therefore, non-parametric tests were performed to compare the groups.

Claims

1. A method for treating a disease or condition associated with cell proliferation, comprising administering a therapeutically effective amount of a CBL-B inhibitor to a subject in need thereof.

2. The CBL-B inhibitor is a compound of formula (A): or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group of =C(H)-, =C(R ａ )-, or =N-, Z is =O or =S, E is an optionally substituted 5- or 6-membered heterocyclyl, B is an optionally substituted phenyl, an optionally substituted 8- to 10-membered bicyclic ring, or an optionally substituted 5- or 6-membered heteroaryl, C is an optionally substituted 5- or 6-membered heterocyclyl, X is optionally substituted C １ -C ３ is an alkylene chain, and one or more methylene units are -N(H)-, -N(R １ ), -O-, -S-, -SO-, -SO ２ -, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, and X is halogen, C １ -C ３ aliphatic, phenyl, 3- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, and -(CH ２ )(3- to 6-membered carbocyclyl), and may be optionally substituted with an optionally substituted group selected from the group consisting of Each R ａ is L-A, halogen, -CN, -OH, -OR １ , -NH ２ , -NR １ R ２ , -SH, -SR １ , -SF ５ , -CO ２ H, -CO ２ R １ , -C(O)R １ , -CONH ２ , -CONR １ R ２ , -SO ２ NH ２ , -SO ２ NR １ R ２ , -SO ２ OH, -SO ２ OR １ , -S(O)R １ , -S(O) ２ R １ , -S(O)(NH)R １ , -S(O)(NR １ )R １ , optionally substituted C １ ~C ６ aliphatic, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of, R ａ is optionally substituted with 1 to 5 R ａ１ s, L is an optionally substituted C １ -C ３ alkylene chain, and A is optionally substituted C ３ -C ７ carbosilyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, and A is optionally substituted with 1 to 5 R ａ１ and may be substituted with Each R ａ１ is halogen, -CN, -OH, -OR １ , -NH ２ , -NR １ R ２ , -SH, -SR １ , -SF ５ , -CO ２ H, -CO ２ R １ , -CONH ２ , -CONR １ R ２ , -SO ２ NH ２ , -SO ２ NR １ R ２ , -SO ２ OH, -SO ２ OR １ , -S(O)R １ , -S(O) ２ R １ , -S(O)(NH)R １ , -S(O)(NR １ )R １ , optionally substituted C １ ~C ６ aliphatic, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of Each R ｂ is halogen, -CN, -OH, -OR １ , -NH ２ , -NR １ R ２ , -SH, -SR １ , -SF ５ , -CO ２ H, -CO ２ R １ , -CONH ２ , -CONR １ R ２ , -SO ２ NH ２ , -SO ２ NR １ R ２ , -SO ２ OH, -SO ２ OR １ , -S(O)R １ , -S(O) ２ R １ , -S(O)(NH)R １ , -S(O)(NR １ )R １ , optionally substituted C １ ~C ６ aliphatic, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of Each R ｃ is hydrogen, optionally substituted C １ to C ６ aliphatic, OR １ , -NH ２ , -NR １ R ２ , optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R ３ , -CO ２ R ３ , -C(O)NHR ３ , and -SO ２ R ３ , and is independently selected from the group consisting of, Each R １ which may be substituted C １ -C ６ aliphatic, optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R ３ , -CO ２ R ３ , -C(O)NHR ３ , and -SO ２ R ３ , and are independently selected from the group consisting of Each R ２ is independently selected from the group consisting of hydrogen, optionally substituted C １ to C ６ aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S Alternatively, R １ and R ２ together with their intervening atom(s), form a 3- to 8-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, Each R ３ which may be substituted C １ ~C ６ aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of, n is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4, The method according to claim 1.

3. The method according to any one of the preceding claims, wherein C is selected from the group consisting of an optionally substituted triazolyl, an optionally substituted pyrazolyl, an optionally substituted isoxazolyl, an optionally substituted thiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazinyl, an optionally substituted pyrimidinyl, and an optionally substituted pyridazinyl.

4. The method according to any one of the preceding claims, wherein the compound is a compound of formula (B): or a pharmaceutically acceptable salt thereof.

5. The method according to any one of the preceding claims, wherein the compound is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

6. The method according to any one of the preceding claims, wherein the compound is a compound of formula (Ia) or (IIa): or a pharmaceutically acceptable salt thereof, wherein each W is independently selected from N or C, The method according to any one of the preceding claims.

7. The method according to any one of the preceding claims, wherein the compound is a compound of formula (Ia1) or (IIa1): or a pharmaceutically acceptable salt thereof.

8. The method according to any one of the preceding claims, wherein the compound is a compound of formula (Ia2), (Ia3), or (Ia4): or a pharmaceutically acceptable salt thereof.

9. The method according to any one of the preceding claims, wherein the compound is a compound of formula (Ib) or (IIb): or a pharmaceutically acceptable salt thereof, wherein each W is independently selected from N or C, The method according to any one of the preceding claims.

10. The compound is a compound of formula (Ic) or (IIc): or a pharmaceutically acceptable salt thereof, the method according to any one of the preceding claims.

11. R ｃ is optionally substituted C １ -C ３ to C, aliphatic, the method according to any one of the preceding claims.

12. Each R ｃ is independently selected from the group consisting of methyl, -CD ３ , -CHF ２ The method according to any one of the preceding claims.

13. R ｃ The method according to any one of the preceding claims, wherein R is methyl.

14. X is optionally substituted C １ - C ２ The method according to any one of the preceding claims, wherein X is alkylene.

15. X is or optionally substituted C ２ is alkylene, and one methylene unit is substituted, the method according to any one of the preceding claims.

16. X is selected from the group consisting of, the method according to any one of the preceding claims.

17. R ａ The method according to any one of the preceding claims, wherein R is L-A.

18. L is -CH ２ - or -CH(CH ３ )-, the method according to any one of the preceding claims.

19. A is each independently a substituted or unsubstituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S is, the method according to any one of the preceding claims.

20. R ａ is halogen, -CN, -C(O)R １ , -CO ２ H, -CONR １ R ２ , optionally substituted C １ to C ６ aliphatic, and optionally substituted C １ to C ６ heteroalkyl, the method according to any one of the preceding claims.

21. Each R ａ is halogen, -CN, -CO ２ H, -CHO, -CHF ２ , -CF ３ , -OMe, -S(O) ２ NHMe, independently selected from the group consisting of, the method according to any one of the preceding claims.

22. The compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof, the method according to any one of the preceding claims.

23. The compound is or a pharmaceutically acceptable salt thereof, the method according to any one of the preceding claims.

24. The compound is or a pharmaceutically acceptable salt thereof, the method according to any one of the preceding claims.

25. The disease or condition related to cell proliferation is hyperplasia or cancer, the method according to any one of the preceding claims.

26. The cancer is a hematological cancer, the method according to claim 25.

27. The hematological cancer is selected from the group consisting of lymphoma, leukemia, and myeloma, the method according to claim 26.

28. The cancer is a non-hematological cancer, the method according to claim 27.

29. The non-hematological cancer is a sarcoma or carcinoma, the method according to claim 28.

30. After administration of the compound according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 16 to the subject, the subject has one or more of an increase in T cell activation, an increase in T cell proliferation, a decrease in T cell exhaustion, a decrease in T cell anergy, and a decrease in T cell tolerance, the method according to any one of claims 1 to 29.

31. The increase in T cell activation includes an increase in cytokine production, the method according to claim 30.

32. The subject has an increase in NK cell activation, the method according to any one of claims 1 to 29.

33. The increase in NK cell activation includes an increase in cytokine production, the method according to claim 32.

34. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 60 to 600 mg.

35. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 60 to 600 mg.

36. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 60 to 100 mg.

37. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 100 to 200 mg.

38. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 200 to 300 mg.

39. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 300 to 400 mg.

40. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 400 to 500 mg.

41. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of 500 to 600 mg.

42. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 60 mg.

43. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 100 mg.

44. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 150 mg.

45. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 200 mg.

46. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 250 mg.

47. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 300 mg.

48. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 350 mg.

49. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 400 mg.

50. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 450 mg.

51. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 500 mg.

52. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 550 mg. **Claim 53** The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered at a dose of about 600 mg.

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