CBL-B inhibitors and anti-PD1 / anti-PD-L1 for use in cancer treatment

Abstract

The present disclosure relates to the treatment of a subject in need thereof, comprising administering a therapeutically effective amount of a CBL-B inhibitor and a therapeutically effective amount of an anti-PD-1 / anti-PD-L1 agent.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit and priority of U.S. Patent Application No. 63 / 388,506, filed on July 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 resulting from mild inflammation, no / low costimulatory signals, or highly immunosuppressive environments.

Summary of the Invention

[0003] Summary The present disclosure includes a method of treating a disease or condition related to cell proliferation, comprising administering a therapeutically effective amount of a CBL - B inhibitor in combination with an anti - PD1 / anti - PD - L1 agent.

[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): TIFF2025523057000002.tif31165 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 substituted by -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 may be optionally substituted by 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 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 , 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 is optionally substituted with 1-5 R a1 and, L is an optionally substituted C1-C3 alkylene chain, A is an 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, -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 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 Rc 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 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, or, R 1 and R 2together with the intervening atom(s), form a 3- to 8-membered heterocyclic 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 heterocyclic 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, m is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

[0008] In some embodiments, the present disclosure provides a compound of formula (B): TIFF2025523057000003.tif35165 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 optionally substituted phenyl, substituted 5- to 6-membered heteroaryl or optionally substituted 8- to 10-membered bicyclic, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units may be substituted by -N(H)-, -N(R 1 ), -O-, -S-, -SO-, -SO2-, optionally substituted 3- to 6-membered carbocyclic, and optionally substituted 3- to 6-membered heterosilyl, 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, 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 , optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered ring 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 ring 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 ring heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered ring 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 ring heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered ring 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 encompasses a compound of formula (I): TIFF2025523057000004.tif35165 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-, It may be replaced by TIFF2025523057000005.tif33165, 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, and R a may be substituted with 1 - 5 R a1 groups, 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 heterocyclic ring 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 heterocyclic ring 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 ring, 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 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 3 is independently selected from the group consisting of each R 2 is 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, and is independently selected from the group consisting of alternatively, 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 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, and is independently selected from the group consisting of n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, or 4

[0010] In some embodiments, the disclosure includes a compound of formula (Ia) or (IIa): TIFF2025523057000006.tif41165 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): TIFF2025523057000007.tif36165 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): TIFF2025523057000008.tif72165 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): TIFF2025523057000009.tif36165 or a pharmaceutically acceptable salt thereof, wherein X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are optionally substituted by -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2025523057000010.tif16165, and 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, -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, 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 , and is 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 , and is 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 any intervening atom(s), form a 3- to 8-membered heterocyclic 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 encompasses a compound of formula (Ib) or (IIb): TIFF2025523057000011.tif41165 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 encompasses a compound of formula (Ib1) or (IIb1): TIFF2025523057000012.tif41165 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 encompasses a compound of formula (Ib2), (Ib3), or (Ib4): TIFF2025523057000013.tif82165 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 disclosure is a compound of formula (Ic) or (IIc): TIFF2025523057000014.tif42165 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 disclosure is a compound of formula (Ic1) or (IIc1): TIFF2025523057000015.tif42165 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 disclosure is a compound of formula (Id) or (IId): TIFF2025523057000016.tif42165 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 disclosure is a compound of formula (Id1) or (IId1): TIFF2025523057000017.tif42165 or a pharmaceutically acceptable salt thereof, wherein X, R b , R cand m are 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 substituted by -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 substituted by 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 carbocyclic ring). In some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are substituted by -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. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are substituted by -N(H)-, -N(R 1 ), -, -O-, -S-, -SO-, -SO2-, may be substituted by TIFF2025523057000018.tif33165, and each methylene unit may be substituted by one or two 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 carbosilyl, and an optionally substituted C3-C4 heterocyclic ring. In some embodiments, in some embodiments, X is an optionally substituted C1-C3 alkylene chain, and one or more methylene units are substituted by -N(H)-, -N(R 1 ), -, -O-, -S-, It may be replaced by TIFF2025523057000019.tif19165. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, where one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, It may be replaced by TIFF2025523057000020.tif16165. In some embodiments, X is an optionally substituted C1-C2 alkylene. In some embodiments, X is TIFF2025523057000021.tif14165 or an optionally substituted C2 alkylene, and one methylene unit is TIFF2025523057000022.tif14165 substituted. In some embodiments, X is TIFF2025523057000023.tif195165TIFF2025523057000024.tif202165 selected from the group consisting of.

[0022] In some embodiments, X is TIFF2025523057000025.tif40165 selected from the group consisting of.

[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, 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 halogen, -CN, -CO2H, -CHO, -CHF2, -CF3, -OMe, -S(O)2NHMe, TIFF2025523057000026.tif182165TIFF2025523057000027.tif211165TIFF2025523057000028.tif212165TIFF2025523057000029.tif206165TIFF2025523057000030.tif144165and is independently selected from the group consisting of.

[0024] In some embodiments, R a is halogen, -CN, -CO2H, TIFF2025523057000031.tif140165and is selected from the group consisting of.

[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 Independently selected 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 , independently selected 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 , independently selected 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 an optionally substituted C1-C6 aliphatic, an optionally substituted phenyl, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an 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 an 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, an optionally substituted C1-C6 aliphatic, an optionally substituted 3- to 6-membered heterocyclyl 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, alternatively, R 1 and R 2 together with any intervening atoms, 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 2is an optionally substituted C1-C6 aliphatic. In some embodiments, each R 2 is methyl.

[0033] R 3 In some embodiments, 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.

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

[0035]

Table 1

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

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

[0038] Anti-PD1 / anti-PD-L1 agentAs used herein, an "anti-PD1 / anti-PD-L1 agent" is an agent that can interfere with the interaction between PD-1 and its ligand PD-L1. Without being bound by any theory, in some embodiments, interfering with the interaction between PD-1 and PD-L1 stimulates an anti-tumor immune response. In some embodiments, the anti-PD1 / anti-PD-L1 agent is an anti-PD1 antibody. In some embodiments, the antibody or antigen-binding portion thereof specifically binds to PD-1. In some embodiments, examples of anti-PD-1 antibodies include, but are not limited to, nivolumab (BMS-936558, Bristol-Myers Squibb), pembrolizumab (lambrolizumab, MK03475 or MK-3475, Merck), humanized anti-PD-1 antibody JS001 (ShangHai JunShi), monoclonal anti-PD-1 antibody TSR-042 (Tesaro, Inc.), pidilizumab (anti-PD-1 mAb CT-011, Medivation), anti-PD-1 monoclonal antibody BGB-A317 (BeiGene), and / or anti-PD-1 antibody SHR-1210 (ShangHai HengRui), human monoclonal antibody REGN2810 (semiplimab, Regeneron), human monoclonal antibody MDX-1106 (Bristol-Myers Squibb), and / or humanized anti-PD-1 IgG4 antibody PDR001 (Novartis). In some embodiments, the anti-PD-1 antibody is derived from clone: RMP1-14 (rat IgG)-BioXcell catalog number BP0146. Other suitable antibodies include the anti-PD-1 antibodies disclosed in U.S. Patent No. 8,008,449, which is incorporated herein by reference. In some embodiments, the antibody or antigen-binding portion thereof specifically binds to PD-L1, inhibits the interaction with PD-L1, thereby enhancing immune activity. Any antibody known in the art that binds to PD-L1, interferes with the interaction between PD-1 and PD-L1, and stimulates an anti-tumor immune response is suitable in the methods disclosed herein.For example, antibodies targeting PD-L1 include BMS-936559 (Bristol-Myers Squibb) and MPDL3280A (Genetech). See the method described in U.S. Patent No. 7,943,743 for other suitable antibodies targeting PD-L1. It will be understood by those skilled in the art that any antibody that binds to PD-1 or PD-L1, interferes with the PD-1 / PD-L1 interaction, and stimulates an anti-tumor immune response is suitable for use in the methods disclosed herein. In some embodiments, the anti-PD1 / anti-PD-L1 agent is BP0146. In some embodiments, the anti-PD1 / anti-PD-L1 agent is nivolumab. In some embodiments, the anti-PD1 / anti-PD-L1 agent is pembrolizumab. In some embodiments, the anti-PD1 / anti-PD-L1 agent is atezolizumab. In some embodiments, the anti-PD1 / anti-PD-L1 agent is dostarlimab. In some embodiments, the anti-PD1 / anti-PD-L1 agent is semiprimab. In some embodiments, the anti-PD1 / anti-PD-L1 agent is durvalumab. In some embodiments, the anti-PD1 / anti-PD-L1 agent is avelumab.

[0039] Definitions As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted hydrocarbon chain that is either fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is either 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 a "carbocycle", "alicyclic" or "cycloalkyl"). Unless otherwise specified, aliphatic groups contain from 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain from 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain from 1 to 3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain from 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is either 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-chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrid groups thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0040] The term "haloaliphatic" refers to an aliphatic group substituted with one or more halogen atoms.

[0041] The term "alkyl" refers to a straight-chain or branched-chain alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0042] The term "haloalkyl" refers to a straight-chain or branched-chain alkyl group substituted with one or more halogen atoms.

[0043] The term "halogen" means F, Cl, Br, or I.

[0044] 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 an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., which may have one or more substituents. Further, 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.

[0045] 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 from 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 from 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" 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 the rings that are appropriately substituted. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, where the alkyl portion and the heteroaryl portion are each independently and optionally substituted.

[0046] 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 are each independently optionally substituted.

[0047] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0048] As described herein, the compounds of the invention may contain "optionally substituted" moieties. Generally, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens on the designated moiety are replaced by an appropriate substituent. 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 realizable compounds. The term "stable", as used herein, refers to compounds that do not substantially change when subjected to the conditions necessary for their production, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0049] Suitable monovalent substituents for a substitutable carbon atom 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 substituted with -(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 linear or branched alkylene)O-N(R ° )2; or -(C 1-4 linear 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) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R° The appearance, together with their intervening atom(s), forms a 3- to 12-membered saturated ring, a partially unsaturated ring, or an aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and may be substituted as defined hereinafter.

[0050] R ○ (or a ring formed by combining two independent occurrences of R ○ with their intervening atom) Preferred 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 ● wherein each R ● is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens, and C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1It is independently selected from a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from Ph, or nitrogen, oxygen, or sulfur. R ○ Suitable divalent substituents on the saturated carbon atoms of R include =O and =S.

[0051] Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" group include the following: =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- is included, and each independent occurrence of R* is hydrogen, C which may be substituted as defined below 1-6 aliphatic, 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 the adjacent substitutable carbon of the "optionally substituted" group include -O(CR*2) 2-3 O- is included, and each independent occurrence of R* is hydrogen, C which may be substituted as defined below 1-6 aliphatic, 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.

[0052] R * 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 is included, and each of R ● is unsubstituted or, when "halo" precedes, is substituted only with one or more halogens and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1It is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from Ph, or nitrogen, oxygen, or sulfur.

[0053] 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 included, and each R † is independently hydrogen, C 1-6 aliphatic which may 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 independent occurrences of R † together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] 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, is substituted only with one or more halogens, and is independently C 1-4aliphatic, -CH2Ph, -O(CH2) 0-1 a 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0055] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of reasonable medical judgment, and that are commensurate with 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 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.

[0056] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N(C 1-4Examples of the (alkyl)4 salts include. 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.

[0057] 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 maintain the integrity of the compound for a period of time sufficient to enable manufacture and to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0058] 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.

[0059] 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.

[0060] As used herein, "therapeutically effective amount" means the amount of a substance (e.g., a 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 suffering from or susceptible to the disease, disorder, and / or condition. As will be understood 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

[0061] 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.

[0062] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0063] 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.

[0064] "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.

[0065] 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 the severity of the disorder; 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.

[0066] Unless specifically recited or clear 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 the context clearly dictates otherwise, all numerical values provided herein are modified by the term about.

[0067] 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) may 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.

[0068] Diseases and disorders In this specification, for example, a method of modulating 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 modulated activity, referred to herein as "modified immune cells", wherein 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 modulating the response in an individual in need thereof (e.g., an individual suffering from cancer), the method comprising administering an effective amount of a Cbl-b inhibitor or a composition thereof described herein. Furthermore, the present invention 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).

[0069] 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. Further,

[0070] 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 comprising a Cbl-b inhibitor as part of a combination therapy for treating cancer, the combination therapy comprising one or more of an immune checkpoint inhibitor, an anti-tumor agent, and radiation therapy.

[0071] 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.

[0072] 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 myelogenous 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, and additional blood cancers or blood disorders including, but not limited to, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia, and “pre-leukemia”.

[0073] Plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia, and “pre-leukemia” are a collection of diverse blood disorders integrated by ineffective production (or dysplasia) of myeloid blood cells.

[0074] 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.

[0075] 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 evaluating 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 a treatment plan according to the described solid tumor response evaluation criteria (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 antitumor response according to RECIST 1.1 include complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD).

[0076] 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.

[0077] 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.

[0078] 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 additional pharmaceutically active compounds. Details regarding the presence of additional pharmaceutically active compounds are described below.

[0079] 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.

[0080] 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, drip solutions, 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, methyl hydroxybenzoate and propyl hydroxybenzoate, 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.

[0081] 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 appropriately labeled), and optionally, one or more leaflets containing product information and / or instructions for use may be attached.

[0082] 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.

[0083] Another object of the present disclosure is the use of the combination as a medicament, that is, 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 of the present disclosure or the kit of the present disclosure for the manufacture of a medicament.

[0084] Administration In some embodiments, the CBL-B inhibitor is administered at a dose of 60 to 600 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 100 to 500 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 125 to 475 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 150 to 450 mg. In some embodiments, the CBL-B inhibitor is administered at a dose of 200 to 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.

[0085] In some embodiments, the CBL-B inhibitor is administered at a dose of 2.0 - 60 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 2.0 - 60 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 2.0 - 10 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 10 - 20 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 20 - 30 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 30 - 40 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 40 - 50 mg / kg. In some embodiments, the CBL-B inhibitor is administered at a dose of 50 - 60 mg / kg.

[0086] 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.

[0087] 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 at intervals of, for example, 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.

[0088] In some embodiments, the CBL-B inhibitor is administered once a day. In some embodiments, the CBL-B inhibitor is administered twice a day (BID). In some embodiments, the CBL-B inhibitor is administered three times a day (TID). In some embodiments, the CBL-B inhibitor is administered four times a day (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.

[0089] In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 60 to 2000 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 1000 to 2000 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 60 to 1000 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 500 to 1000 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 100 to 500 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 125 to 475 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 150 to 450 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 200 to 400 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 60 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 80 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 100 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 120 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 140 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 160 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 180 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 200 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 220 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 240 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 260 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 300 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 325 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 350 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 375 mg.In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 400 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 425 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 450 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 475 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 500 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 525 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 550 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 575 mg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 600 mg.

[0090] In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 2.0 - 60 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 2.0 - 60 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 2.0 - 10 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 10 - 20 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 20 - 30 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 30 - 40 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 40 - 50 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of 50 - 60 mg / kg.

[0091] In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 2.0 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 6.0 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 10 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 20 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 30 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 40 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 50 mg / kg. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered at a dose of about 60 mg / kg.

[0092] 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 at intervals of, for example, 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.

[0093] In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered once daily. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered twice daily (BID). In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered three times daily (TID). In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered four times daily (QID). In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered once a week. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered twice a week. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered three times a week. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered four times a week. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered once a month. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered twice a month. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered three times a month. In some embodiments, the anti-PD1 / anti-PD-L1 agent is administered four times a month.

[0094] In some embodiments, pembrolizumab is administered at a dose of about 200 mg. In some embodiments, pembrolizumab is administered at a dose of about 400 mg. In some embodiments, pembrolizumab is administered at a dose of about 200 mg every three weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg every six weeks.

[0095] In some embodiments, nivolumab is administered at a dose of about 240 mg. In some embodiments, pembrolizumab is administered at a dose of about 480 mg. In some embodiments, pembrolizumab is administered at a dose of about 240 mg every two weeks. In some embodiments, pembrolizumab is administered at a dose of about 480 mg every four weeks.

[0096] In some embodiments, semiprimab is administered at a dose of about 350 mg. In some embodiments, semiprimab is administered at a dose of about 350 mg every three weeks.

[0097] In some embodiments, atezolizumab is administered at a dose of about 840 mg. In some embodiments, atezolizumab is administered at a dose of about 840 mg every two weeks. In some embodiments, atezolizumab is administered at a dose of about 1200 mg. In some embodiments, atezolizumab is administered at a dose of about 1200 mg every three weeks. In some embodiments, atezolizumab is administered at a dose of about 1680 mg. In some embodiments, atezolizumab is administered at a dose of about 1680 mg every four weeks.

[0098] In some embodiments, dostarlimab is administered at a dose of about 500 mg. In some embodiments, dostarlimab is administered at a dose of about 500 mg every three weeks. In some embodiments, dostarlimab is administered at a dose of about 1000 mg. In some embodiments, dostarlimab is administered at a dose of about 1000 mg every six weeks.

[0099] In some embodiments, durvalumab is administered at a dose of about 1500 mg. In some embodiments, durvalumab is administered at a dose of about 1500 mg every four weeks. In some embodiments, durvalumab is administered at a dose of about 10 mg / kg. In some embodiments, durvalumab is administered at a dose of about 10 mg / kg every two weeks. In some embodiments, durvalumab is administered at a dose of about 1500 mg. In some embodiments, durvalumab is administered at a dose of about 1500 mg every four weeks. In some embodiments, durvalumab is administered at a dose of about 20 mg / kg.

[0100] In some embodiments, avelumab is administered at a dose of about 800 mg. In some embodiments, avelumab is administered at a dose of about 800 mg every two weeks.

Example

[0101] Example 1. Synthesis of Compound 29 Synthesis of TIFF2025523057000189.tif661651.10b 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.

[0102] 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.

[0103] 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

[0104] 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

[0105] 5. Synthesis of 29 To a stirred mixture of 10d (58 g, 126.800 mmol, 1.00 eq) and (s)-3-methylpiperidine hydrochloride (34.40 g, 253.600 mmol, 2 eq) in DCE (1600 mL) was added TEA (38.49 g, 380.400 mmol, 3 eq). 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 eq). 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).

[0106] Example 2. Synthesis of Compound 85 Synthesis of 10916585a of TIFF2025523057000190 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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), NaBH(OAc)3 (43.73 g, 206.334 mmol, 2 equiv) and HOAc (6.20 g, 103.167 mmol, 1 equiv) were added 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, 85g (34 g, 65.18%) was obtained as a white solid.

[0113] 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), triphosgene (7.35 g, 24.774 mmol, 0.35 equiv) was added 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.

[0114] 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 eluted from CH2Cl2 / MeOH (20:1) to CH2Cl2 / MeOH (5:1) and purified by silica gel column chromatography to obtain 85i (20 g, 67.38%) as a yellow solid.

[0115] 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 at room temperature overnight. 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.

[0116] 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): δ 0.84 - 0.91 (m, 4H), δ 1.38 - 1.95 (m, 12H), δ 2.08 - 2.10 (m, 1H), δ 2.68 - 2.77 (m, 2H), δ 3.19 - 3.25 (m, 3H), δ 3.43 (s, 3H), δ 4.25 - 4.28 (d, 1H), δ 7.01 (s, 1H), δ 7.19 - 7.21 (d 1H), δ 7.32 (s, 1H), δ 7.43 - 7.46 (t, 1H), δ 7.66 - 7.75 (m, 3H), δ 8.34 (s, 1H).

[0117] Example 3. Synthesis of Compound 86 Synthesis of TIFF2025523057000191.tif4216586 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 H-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).

[0118] Example 4. Subcutaneous H22 mouse hepatocarcinoma model in female BALB / c mice The purpose of this pharmacological test was to evaluate the antitumor growth effect by the combined use of Compound 85 and anti-PD1 antibody (BP0146) in the treatment of a subcutaneous H22 mouse hepatocarcinoma model in female BALB / c mice. When the average tumor volume reached about 80 mm 3 Compound 85 test particles were delivered via oral administration. Compound 85 was evaluated at four different dose levels (QD was 2 mpk, 6 mpk, 10 mpk, and 20 mpk) in combination with an anti-PD1 antibody (10 mpk, BIW). After the start of treatment, tumor volume and body weight were measured three times a week. The mice were divided into six groups and summarized in Table 2.

[0119]

Table 2

[0120] As outlined in Table 2, the drugs were prepared.

[0121]

Table 3

[0122] Cell culture H22 tumor cells were maintained in vitro using RPMI - 1640 medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2. Cells in the exponential growth phase were harvested and quantified using a cell counter prior to tumor inoculation.

[0123] Tumor inoculation To induce tumors, 0.1 ml of H22 tumor cells (1×10e6) in PBS were subcutaneously inoculated into the right flank of each mouse.

[0124] Observation and data collection After tumor inoculation, animals were checked daily for morbidity and mortality. During regular monitoring, animals were examined for tumor growth and the impact 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 / nasal discharge / hair condition, and other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0125] After randomization, tumor volume was measured two - dimensionally three times a week using calipers. 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 measurement of tumor and body weight were performed in a laminar flow cabinet.

[0126] Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0127] Test endpoint Tumor growth inhibition (TGI): The percentage of 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 on a given day.

[0128] Test termination Treatment was carried out for 21 days, and the test was terminated on the 20th day after the start of administration.

[0129] Results The test was terminated when the average tumor size of the vehicle group reached 2858.52 mm^3 on the 12th day. In this test, a TGI of 64.15% was shown with anti-PD1 alone. Treatment with the combination of compound 85 and anti-PD1 further enhanced tumor inhibition to 74.8% - 87.73% (P < 0.01 compared to the vehicle control, Tables 4 and 5) (Figures 1 and 2). In the combinations of compound 85 (10 mpk once a day and 20 mpk once a day) and anti-PD1, a statistically significant increase in tumor inhibition was shown compared to anti-PD1 alone. On the 20th day, tumor regression was shown in 7 out of 40 mice in the combination group of compound 85 and anti-PD1. Complete regression was observed in one of the combination groups of compound 85 (20 mpk once a day) and anti-PD1. The combination groups of compound 85 at four dose levels (2 mpk, 6 mpk, 10 mpk, and 20 mpk in combination with anti-PD-1) showed an increase in antitumor effect against the subcutaneous H22 mouse liver cancer model in the designed dosing schedule compared to monotherapy.

[0130] During treatment, a decrease of less than 5% of the average body weight was observed on the 2nd day of treatment with the combination of compound 85 (20 mpk once a day) and anti-PD1. The body weight recovered rapidly after the 2nd day.

[0131] Treatment with the combination of compound 85 and anti-PD1 further enhanced the TGI from 74.8% to 87.73%. In the combinations of compound 85 and anti-PD1 (10 mpk once a day or 20 mpk once a day), a statistically significant increase was shown compared to anti-PD1 alone. At the end of the test, it was observed that tumor regression was shown in 7 mice in the combination group of compound 85 and anti-PD1. No tolerance issues were observed during treatment with the combination of compound 85 up to 20 mpk once a day and anti-PD1. Additive or synergistic effects were observed in combination with anti-PD1.

[0132]

Table 4

[0133]

Table 5

[0134] As a conclusion, by combining compound 85 with anti-PD1, the inhibition of tumor growth of H22 tumors was further enhanced. The highest TGI was observed at two dose levels (combination of 10 mpk and 20 mpk with anti-PD-1), tumor regression was shown, and the advantages of combination treatment were shown.

[0135] Example 5. Subcutaneous syngeneic colorectal cancer model CT26 in female BALB / c mice The purpose of this pharmacological test was to evaluate the anti-tumor growth effect by the combined use of compound 29 and anti-PD1 antibody (BP0146) or isotype IgG2a (BP0089) in the treatment of subcutaneous CT26 mouse colorectal cancer model in female BALB / c mice.

[0136] When the average tumor volume reached about 80 mm 3 it was delivered via oral administration of the test particles. The test substances were evaluated at the dose levels described in Table 6. Tumor volume and body weight were measured after the start of treatment. The mice were divided into six groups and summarized in Table 6.

[0137]

Table 6

[0138] The test substances were prepared as outlined in Table 7.

[0139]

Table 77

[0140] Cell culture CT26 tumor cells were cultured in 5% CO in air 2In an atmosphere of 37°C, it was maintained in vitro using RPMI-1640 medium supplemented with 10% fetal bovine serum. Cells in the exponential growth phase were collected and quantified using a cell counter before tumor inoculation.

[0141] Tumor inoculation To induce tumors, 0.1 ml of CT26 tumor cells (5×10 5 ) in PBS were subcutaneously inoculated into the right lower abdomen of each mouse.

[0142] Randomization Randomization was initiated when the average tumor size reached approximately 90.52 mm 3 . A total of 60 mice were enrolled in the study and randomly assigned to 6 test groups of 10 mice each. 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.

[0143] Observation and data collection After tumor inoculation, animals were checked daily for morbidity and mortality. During regular monitoring, animals were examined for tumor growth and the effects of treatment on locomotor ability, food and water intake, weight gain or loss (weight was measured three times a week after randomization), eye / nasal discharge / hair condition, and other abnormalities in behavior. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0144] After randomization, tumor volume was measured two-dimensionally three times a week using calipers, and the volume was expressed in mm 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. 3 Weight and tumor volume were measured using Study Director (trademark) software (version 3.1.399.19).

[0145] ​

[0146] Test endpoint Tumor growth inhibition (TGI): The percentage of TGI is an indicator of antitumor activity and is 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, respectively, on a given day.

[0147] Statistical analysis of the difference in average tumor volume between groups was performed using the following method: Data collected on the day when either the treatment group or the control group ended was used (even if the remaining groups were treated as scheduled).

[0148] End of the test The test was ended on the 13th day after the start of administration.

[0149] Results As shown in Figure 3, in the combination of Compound 29 and anti-PD1, the tumor growth inhibition of CT26 tumors was further enhanced, indicating the advantages of combination treatment.

Claims

**Claim 1** A method for treating a disease or condition related to cell proliferation, comprising administering a therapeutically effective amount of a CBL-B inhibitor and a therapeutically effective amount of an anti-PD1 / anti-PD-L1 agent to a subject in need thereof. **Claim 2** A method for treating a disease or condition related to cell proliferation, comprising administering a therapeutically effective amount of a CBL-B inhibitor to a subject in need thereof, wherein the subject has been previously treated with an anti-PD1 / anti-PD-L1 agent. **Claim 3** A method for treating a disease or condition related to cell proliferation, comprising administering a therapeutically effective amount of an anti-PD1 / anti-PD-L1 agent to a subject in need thereof, wherein the subject has been previously treated with a CBL-B inhibitor. **Claim 4** 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- 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 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 carbocyclic, and optionally substituted 3- to 6-membered heterosilyl, and X is halogen, C １ ~C ３ aliphatic, phenyl, 3- to 6-membered heteroaryl, 3- to 6-membered heterosilyl, and -(CH ２ )(3- to 6-membered carbocyclic), 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, and R ａ is optionally substituted with 1 to 5 R ａ１ s, L is an optionally substituted C １ -C ３ alkylene chain, A is optionally substituted C ３ -C ７ carbocyclyl, 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, A is selected from the group consisting of 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, -COR 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 , is independently selected from the group consisting of, Each R １ is optionally substituted C １ to 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 to C ６ an aliphatic group, an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, an optionally substituted phenyl group, 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 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 any one of claims 1 to 3. **Claim 5** 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, The method according to any one of the preceding claims. **Claim 6** The compound is a compound of formula (B): or a pharmaceutically acceptable salt thereof, The method according to any one of the preceding claims. **Claim 7** The compound is a compound of formula (I): or a pharmaceutically acceptable salt thereof, The method according to any one of the preceding claims. **Claim 8** 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. **Claim 9** The compound is a compound of formula (Ia1) or (IIa1): or a pharmaceutically acceptable salt thereof, the method according to any one of the preceding claims.

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

11. 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.

12. 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.

13. R ｃ is optionally substituted C １ to C ３ The method according to any one of the preceding claims, wherein the aliphatic group is aliphatic.

14. 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.

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

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

17. 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.

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

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

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

21. A is an optionally substituted 3- to 6-membered heterocyclic group containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, the method according to any one of the preceding claims.

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

23. 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.

24. 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.

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

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

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

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

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

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

31. 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.

32. 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.

33. 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.

34. 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.

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

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

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

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

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

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

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

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

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

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

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

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

47. The method according to any one of the preceding claims, wherein the anti-PD1 / anti-PD-L1 agent is an anti-PD1 antibody.

48. The method according to any one of the preceding claims, wherein the anti-PD1 / anti-PD-L1 agent is selected from the group consisting of B0146, nivolumab, pembrolizumab, atezolizumab, dostarlimab, semiprimab, durvalumab, and avelumab.

49. The method according to claim 48, wherein the anti-PD1 / anti-PD-L1 agent is B0146.

50. The method according to claim 49, wherein B0146 is administered at a dose of 10 mg / kg.

51. The method according to claim 50, wherein B0146 is administered every other week at a dose of 10 mg / kg.

52. The method according to claim 50, wherein B0146 is administered every other week for 3 weeks at a dose of 10 mg / kg.

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

54. The method according to claim 53, wherein the cancer is a hematological cancer.

55. The method according to claim 54, wherein the hematological cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

56. The method according to claim 55, wherein the cancer is a non-hematological cancer.

57. The method according to claim 56, wherein the non-hematological cancer is a sarcoma or a carcinoma.

58. The method according to claim 53, wherein the cancer is liver cancer.

59. The method according to claim 53, wherein the cancer is colorectal cancer.

60. The method according to any one of claims 1 to 57, wherein the subject has 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, after administration of the compound according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 16.

61. The method according to claim 60, wherein the increase in T cell activation includes an increase in cytokine production.

62. The method according to any one of claims 1 to 57, wherein the subject has an increase in NK cell activation.

63. The method according to claim 62, wherein the increase in NK cell activation includes an increase in cytokine production.

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