Treatment of cell proliferation-related disorders by combining a CLB-B inhibitor with an additional therapeutic agent

Abstract

The present disclosure relates to treating a subject in need thereof, comprising administering a therapeutically effective amount of a CBL-B inhibitor and a therapeutically effective amount of an additional therapeutic agent.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Patent Application No. 63 / 388,518, filed on July 12, 2022, the content of which is incorporated herein by reference in its entirety.

Background Art

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

Summary of the Invention

[0003] 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 additional therapeutic agent.

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

Brief Description of the Drawings

[0005]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode 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): TIFF2025523058000002.tif37165 or a pharmaceutically acceptable salt thereof, wherein, Y is selected from the group of =C(H)-, =C(R a ), or =N-, Z is =O or =S, E is an optionally substituted 5- to 6-membered heterocyclyl, B is an optionally substituted phenyl, an optionally substituted 8- to 10-membered bicyclic ring, or an optionally substituted 5- to 6-membered heteroaryl, C is an optionally substituted 5- to 6-membered heterocyclyl, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are -N(H)-, -N(R1 )-, -O-, -S-, -SO-, -SO2-, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterosilyl, and X may be replaced by a group optionally substituted by halogen, C1-C3 aliphatic, phenyl, 3- to 6-membered heteroaryl, 3- to 6-membered heterosilyl, and -(CH2)(3- to 6-membered carbocyclyl), Each R a is L-A, halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -C(O)R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , 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, where R a is optionally substituted by 1 to 5 examples of R a1 and 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, wherein A is optionally substituted with 1-5 examples of R a1 and may be substituted with each R a1 is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 and is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, each R b is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR1 R 2 、 -SO2OH, -SO2OR 1 、 -S(O)R 1 、 -S(O)2R 1 、 -S(O)(NH)R 1 、 -S(O)(NR 1 )R 1 、 optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of each R c is hydrogen, optionally substituted C1-C6 aliphatic, OR 1 、 -NH2, -NR 1 R 2 、 optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 、 -CO2R 3 、 -C(O)NHR 3 、 and -SO2R 3 、 independently selected from the group consisting of each R 1 is optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 、 -CO2R 3 、 -C(O)NHR 3 、 and -SO2R 3 、 independently selected from the group consisting of each R2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, or, R 1 and R 2 together with their intervening atom(s) (if any) form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

[0008] In some embodiments, the disclosure encompasses a compound of formula (B): TIFF2025523058000003.tif44165 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 5-6 membered heteroaryl or optionally substituted 8-10 membered bicyclic, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, an optionally substituted 3-6 membered carbocyclyl, and an optionally substituted 3-6 membered heterocyclyl, and may be optionally replaced by, 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 , and is independently selected from the group consisting of an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 heteroalkyl, 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, L is an optionally substituted C1-C3 alkylene chain, A is selected from the group consisting of an optionally substituted C3-C7 carbosilyl, an optionally substituted C1-C6 heteroalkyl, 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, 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 , and is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, Each R c is hydrogen, optionally substituted C1-C6 aliphatic, -OR 1 , -NH2, -NR 1 R 2 , optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 , -CO2R 3 , -C(O)NHR 3 , and -SO2R 3 , and is independently selected from the group consisting of Each R 1is independently selected 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 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 the intervening atom(s) (if any) form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, or 4.

[0009] In some embodiments, the disclosure provides a compound of formula (I): TIFF2025523058000004.tif44165 or a pharmaceutically acceptable salt thereof, and wherein X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2025523058000005.tif34165 may be replaced by, and each methylene unit is 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, and may be substituted with 1-2 substituents independently selected from the group consisting of, 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, where R a is 1-5 examples of R a1may be replaced with, 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 an optionally substituted C3-C7 carbosilyl, an optionally substituted C1-C6 heteroalkyl, 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, wherein A is substituted with 1-5 examples of R a1 may be replaced 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 , an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 heteroalkyl, 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, and are independently selected from the group consisting of; B is an optionally substituted phenyl, a substituted 5-6 membered heteroaryl or an optionally substituted 8-10 membered bicyclic; Each Rb is halogen, -CN, -OH, -OR 1 , -NH2, -NR 1 R 2 , -SH, -SR 1 , -SF5, -CO2H, -CO2R 1 , -CONH2, -CONR 1 R 2 , -SO2NH2, -SO2NR 1 R 2 , -SO2OH, -SO2OR 1 , -S(O)R 1 , -S(O)2R 1 , -S(O)(NH)R 1 , -S(O)(NR 1 )R 1 , and is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, each R 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 , and is independently selected from the group consisting of each R 1is independently selected 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 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 the intervening atom(s) (if any) form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, or 4.

[0010] In some embodiments, the disclosure provides a compound of formula (Ia) or (IIa): TIFF2025523058000006.tif50165 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 disclosure relates to a compound of formula (Ia1) or (IIa1): TIFF2025523058000007.tif45165 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 disclosure relates to a compound of formula (Ia2), (Ia3) or (Ia4): TIFF2025523058000008.tif82165 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 disclosure relates to a compound of formula (Ia1) or (IIa1): TIFF2025523058000009.tif44165 or a pharmaceutically acceptable salt thereof, wherein wherein X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, TIFF2025523058000010.tif23165 may be optionally replaced by, 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 , and is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, 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, -CONR1 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 substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 、 -CO2R 3 、 -C(O)NHR 3 、 and -SO2R 3 、 independently selected from the group consisting of, each R 1 is optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R 3 、 -CO2R 3 、 -C(O)NHR 3 、 and -SO2R 3 、 independently selected from the group consisting of, each R 2is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, or R 1 and R 2 together with their intervening atom(s) form a 3-8 membered heterocyclyl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, or an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S, each R 3 is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, or 4.

[0014] In some embodiments, the disclosure includes a compound of formula (Ib) or (IIb): TIFF2025523058000011.tif50165 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a 、R b 、R c 、and m are as defined above and as described in the classes and subclasses of this specification.

[0015] In some embodiments, the disclosure includes a compound of formula (Ib1) or (IIb1): TIFF2025523058000012.tif50165 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 is a compound of formula (Ib2), (Ib3) or (Ib4): TIFF2025523058000013.tif95165 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): TIFF2025523058000014.tif49165 or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R a , R b , R c , and m are as defined above and as described in the classes and subclasses of this specification.

[0018] In some embodiments, the disclosure is a compound of formula (Ic1) or (IIc1): TIFF2025523058000015.tif51165 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): TIFF2025523058000016.tif50165 or a pharmaceutically acceptable salt thereof, wherein X, R b , Rc and m are as defined above and as described in the classes and subclasses of this specification.

[0020] In some embodiments, the disclosure encompasses a compound of formula (Id1) or (IId1): TIFF2025523058000017.tif51165 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.

[0021] X In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are optionally replaced by -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, an optionally substituted 3-6 membered carbocyclyl, and an optionally substituted 3-6 membered heterocyclyl, and X is optionally substituted by an optionally substituted group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3-6 membered heteroaryl, 3-6 membered heterocyclyl, and -(CH2)(3-6 membered carbocyclyl). In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are optionally replaced by -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, an optionally substituted 3-6 membered carbocyclyl, and an optionally substituted 3-6 membered heterocyclyl. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are optionally replaced by -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, It may be replaced by TIFF2025523058000018.tif34165, 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. In some embodiments, in some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, It may be replaced by TIFF2025523058000019.tif25165. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units are -N(H)-, -N(R 1 )-, -O-, -S-, -SO-, -SO2-, It may be replaced by TIFF2025523058000020.tif22165. In some embodiments, X is optionally substituted C1-C2 alkylene. In some embodiments, X is TIFF2025523058000021.tif23165 or optionally substituted C2 alkylene, wherein one methylene unit is Replaced by TIFF2025523058000022.tif22165. In some embodiments, X is Selected from the group consisting of TIFF2025523058000023.tif230165TIFF2025523058000024.tif224165.

[0022] In some embodiments, X is Selected from the group consisting of TIFF2025523058000025.tif46165.

[0023] R a In some embodiments, each Ra 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, are independently selected from the group consisting of. In some embodiments, it is L-A. In some embodiments, R a is halogen, -CN, -C(O)R 1 , -CO2H, -CONR 1 R 2 , is selected from optionally substituted C1-C6 aliphatic and optionally substituted C1-C6 heteroalkyl. In some embodiments, each R a is independently selected from the group consisting of halogen, -CN, -CO2H, -CHO, -CHF2, -CF3, -OMe, -S(O)2NHMe, TIFF2025523058000026.tif211165TIFF2025523058000027.tif224165TIFF2025523058000028.tif218165TIFF2025523058000029.tif228165TIFF2025523058000030.tif173165

[0024] In some embodiments, R a is selected from the group consisting of halogen, -CN, -CO2H, TIFF2025523058000031.tif154165.

[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 an optionally substituted C3-C7 carbosilyl, an optionally substituted C1-C6 heteroalkyl, 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. In some embodiments, A is an 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 、each 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.

[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 3-6 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 , each 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 3-6 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 , each 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 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 . In some embodiments, each R 1 is optionally substituted C1-C6 aliphatic. In some embodiments, each R 1 is methyl.

[0031] R 2 In some embodiments, each R 2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 3-6 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.

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

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

[0034] In some embodiments, the present disclosure includes a compound described in Table 1 or a pharmaceutically acceptable salt thereof.

Table 1

[0035] One of ordinary skill in the art will understand that the present disclosure includes compounds having a stereochemistry opposite to that depicted. Additionally, the present disclosure contemplates tautomers of the compounds depicted herein.

[0036] The present disclosure includes racemates of any of the compounds disclosed herein.

[0037] Additional therapeutic agents In some embodiments, the additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of pemetrexed, carboplatin, paclitaxel / nab-paclitaxel, cisplatin, 5-fluorouracil, trastuzumab, capecitabine, oxaliplatin, leucovorin, platinum, bevacizumab, and etoposide.

[0038] In some embodiments, the additional therapeutic agent is radiation therapy. In some embodiments, the additional therapeutic agent is SBRT or chemoradiotherapy.

[0039] In some embodiments, the additional therapeutic agent is an angiogenesis inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of axitinib, lenvatinib, bevacizumab, cabozantinib, anlotinib, IBI305, and apatinib.

[0040] In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of ipilimumab, tremelimumab, LY3321367, sabatolimab, relatlimab, COM701, tiragolumab, PF-05082566, APX005M, KY1044, and GWN323.

[0041] In some embodiments, the additional therapeutic agent is a targeted therapy. In some embodiments, the additional therapeutic agent is selected from the group consisting of erlotinib, osimertinib, crizotinib, alectinib, crizotinib, pamiparib, niraparib, olaparib, cobimetinib, AMG510, MK-8353, dabrafenib, trametinib, encorafenib, cetuximab, copanlisib, ipatasertib, pemigatinib, B-701, savolitinib, abemaciclib, and TNO155.

[0042] In some embodiments, the additional therapeutic agent is an antibody-drug conjugate. In some embodiments, the additional therapeutic agent is selected from the group consisting of trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), enfortumab vedotin (EV), and sacituzumab govitecan.

[0043] In some embodiments, the additional therapeutic agent is an antibody product. In some embodiments, the additional therapeutic agent is selected from the group consisting of the following. TIFF2025523058000188.tif147165

[0044] In some embodiments, the additional therapeutic agent is a chimeric antigen receptor T cell (CAR-T). In some embodiments, the CAR-T cells are CD19 / C19CAR-28-ζ T cells, GD2 / iC9-GD2-CD28-OX40 (iC9-GD2) T cells, anti-CD19 CAR T cells, autologous anti-C19CAR-4-1BB-CD3ζ-EGFRt-expressing CD4 + / CD8 + central memory T lymphocyte CAR014 T cells, CD19 / KTE-C19 T cells, JCAR017 T cells, and CART-EGFRvII T cells.

[0045] In some embodiments, the additional therapeutic agent is an oncolytic virus. In some embodiments, the additional therapeutic agent is herpes virus (e.g., HSV1716, G47Δ-mIL-12), adenovirus (e.g., hTertAd, ISF35, D24-RGDOX, ADV-TK, rHu-hDCT, ChAdOx I-STEAP I, ChAdOx I-h5T4), vaccinia virus (e.g., WR-mAb I), and myxoma virus (e.g., vPD1).

[0046] In some embodiments, the methods disclosed herein include administering two or more additional therapeutic agents to a subject in need thereof. In some embodiments, the two or more additional therapeutic agents are selected from the group consisting of the following. TIFF2025523058000189.tif162165

[0047] Definition As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic and has one point of attachment to the remainder of the molecule (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl"). Unless otherwise specified, 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 "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely 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.

[0048] The term "haloaliphatic" refers to an aliphatic group substituted with one or more halogen atoms.

[0049] 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.

[0050] The term "haloalkyl" refers to a straight-chain or branched-chain alkyl group substituted with one or more halogen atoms.

[0051] The term "halogen" means F, Cl, Br, or I.

[0052] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring within the system is aromatic and each ring within the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., which may have one or more substituents. Also, when the term "aryl" is used herein, its scope includes groups in which an aromatic ring is fused to one or more non-aromatic rings such as, for example, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0053] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety such as, for example, "heteroalkyl" or "heteroalkoxy" refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 π electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar" also include groups in which one or more aryl rings, cycloaliphatic rings, or heterocyclyl rings are fused to a heteroaromatic ring and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of these terms includes the rings that are appropriately substituted. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl portion and the heteroaryl portion are independently and optionally substituted.

[0054] 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 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 to its pendant group 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 independently optionally substituted.

[0055] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially saturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0056] 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 of 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 feasible compounds. The term "stable", as used herein, refers to compounds that do not substantially change when subjected to the conditions necessary for their manufacture, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0057] 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) 0-4SR ° ;R ° which may be replaced by -(CH2) 0-4 Ph;R ° which may be replaced by -(CH2) 0-4 O(CH2) 0-1 Ph;R ° which may be replaced by -CH=CHPh;R ° which may be replaced by -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R ° )2; -(CH2) 0-4 N(R ° )C(O)R ° ; -N(R ° )C(S)R ° ; -(CH2) 0-4 N(R ° )C(O)NR ° 2; -N(R ° )C(S)NR ° 2; -(CH2) 0-4 N(R ° )C(O)OR ° ; -N(R ° )N(R ° )C(O)R ° ; -N(R ° )N(R ° )C(O)NR ° 2; -N(R ° )N(R ° )C(O)OR ° ; -(CH2) 0-4 C(O)R ° ; -C(S)R ° ; -(CH2) 0-4 C(O)OR ° ; -(CH2) 0-4 C(O)SR ° ; -(CH2) 0-4 C(O)OSiR ° 3; -(CH2) 0-4 OC(O)R ° ; -OC(O)(CH2) 0-4 SR ° 、SC(S)SR ° ; -(CH2) 0-4 SC(O)R° ;-(CH2) 0-4 C(O)NR ° 2;-C(S)NR ° 2;-C(S)SR ° ;-SC(S)SR ° 、-(CH2) 0-4 OC(O)NR ° 2;-C(O)N(OR ° )R ° ;-C(O)C(O)R ° ;-C(O)CH2C(O)R ° ;-C(NOR ° )R ° ;-(CH2) 0-4 SSR ° ;-(CH2) 0-4 S(O)2R ° ;-(CH2) 0-4 S(O)2OR ° ;-(CH2) 0-4 OS(O)2R ° ;-S(O)2NR ° 2;-(CH2) 0-4 S(O)R ° ;-N(R ° )S(O)2NR ° 2;-N(R ° )S(O)2R ° ;-N(OR ° )R ° ;-C(NH)NR ° 2;-P(O)2R ° ;-P(O)R ° 2;-OP(O)R ° 2;-OP(O)(OR ° )2;SiR ° 3;-(C 1-4 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 below and is independently hydrogen, C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -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 ° appearances, together with their intervening atom(s), form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and may be substituted as defined hereinafter.

[0058] R ○ (or a ring formed by combining two independent occurrences of R ○ with their intervening atom) suitable monovalent substituents on are, independently, halogen, -(CH2) 0-2 R ● , -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2; -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● , or -SSR ● wherein each R ●is unsubstituted or, when "halo" precedes, is substituted only with one or more halogens and C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R ○ include =O and =S.

[0059] Suitable divalent substituents on the saturated carbon atoms of a "optionally substituted" group include =O, =S, =NNR * 2, =NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is hydrogen, a C 1-6 aliphatic group optionally substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to an adjacent substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2-3 O-, where each independent occurrence of R * is hydrogen, a C 1-6 aliphatic group optionally substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] R * Suitable substituents on the aliphatic group of include halogen, -R ● -, -(haloR ● ), -OH, -OR● 、 -O(halo R ● ), -CN, -C(O)OH, -C(O)OR ● 、 -NH2, -NHR ● 、 -NR ● 2, or -NO2, where each R ● is unsubstituted or, when "halo" precedes, is substituted by only one or more halogens, and independently is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0061] 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 † where each R † is independently hydrogen, a C 1~6 aliphatic group that can be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently existing R † together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0062] R † The suitable substituents on the aliphatic group of are independently halogen, -R● 、 -(halo R ● )、 -OH、 -OR ● 、 -O(halo R ● )、 -CN、 -C(O)OH、 -C(O)OR ● 、 -NH2、 -NHR ● 、 -NR ● 2, or -NO2, and each R ● is unsubstituted or, when "halo" precedes, substituted only with one or more halogens, and independently, C 1-4 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that exhibit a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, 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.

[0064] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4Examples of such salts include (alkyl) salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts, where appropriate, are formed using counterions such as halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acids, and include non-toxic ammonium, quaternary ammonium, and amine cations.

[0065] The combinations of substituents and variable elements envisioned by the present disclosure are limited to those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound having sufficient stability to allow for manufacture and to maintain the integrity of the compound over a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0066] 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 an embodiment of a variable element herein includes that embodiment as a single embodiment or in combination with any other embodiment or part thereof.

[0067] 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.

[0068] As used herein, "therapeutically effective amount" means the amount of a substance (e.g., therapeutic agent, composition, and / or formulation) that induces a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered as part of a dosing regimen to a subject 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

[0069] 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 recurrence. Thus, in some embodiments, the term "treatment" includes preventing the relapse or recurrence of a disease or disorder.

[0070] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0071] 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.

[0072] "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.

[0073] 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 level for a particular patient or organism depends 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 simultaneously with the specific compound used, and similar factors well known in the medical arts.

[0074] Unless specifically recited or apparent from the context, as used herein, the term "about" is understood to be within the normal tolerances in the art, e.g., within 2 standard deviations of the mean. About can be understood to be within ±10% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term about.

[0075] Alternative embodiments In alternative embodiments, the compounds described herein may also contain one or more isotope substitutions. For example, hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium), and carbon may be, for example, 13 C or 14 C, oxygen may be, for example, 18 O, nitrogen may be, for example, 15 N, etc. In other embodiments, a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound.

[0076] Diseases and disorders In this specification, for example, a method of regulating the activity of immune cells (e.g., T cells, B cells, or NK cells) is provided by contacting an effective amount of a Cbl-b inhibitor or a composition thereof described herein with the immune cells. Also provided is an in vitro method for producing the immune cells having regulated activity, referred to herein as "modified immune cells", in which, by an ex vivo method, the modified immune cells can be administered to an individual in need thereof (e.g., an individual having cancer). Further provided is an in vitro method for regulating a response in an individual in need thereof (e.g., an individual suffering from cancer), which method comprises administering an effective amount of a Cbl-b inhibitor or a composition thereof described herein. Furthermore, the present disclosure provides an in vitro method for generating a proliferating population of lymphocytes after in vivo lymphomodulation in an individual, the lymphomodulation occurring as a result of administering an effective amount of a Cbl-b inhibitor or a composition thereof described herein to the individual. Furthermore, the proliferated lymphocyte population can then be administered to an individual suffering from cancer. In some embodiments, the modified immune cells or the proliferated lymphocyte population are produced from a biological sample containing immune cells obtained from an individual, such as a blood sample containing peripheral blood mononuclear cells or a tumor biopsy containing tumor infiltrating lymphocytes (TIL).

[0077] Furthermore, a Cbl-b inhibitor for use as a therapeutic agent is provided. A Cbl-b inhibitor for use in treating or preventing a disease or condition associated with Cbl-b activity is provided. Also provided is a Cbl-b inhibitor for use in treating cancer. Furthermore, the use of a Cbl-b inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity is provided. Also provided is the use of a Cbl-b inhibitor in the manufacture of a medicament for treating cancer. Furthermore, the present disclosure provides a treatment method, a medicament, and a use 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.

[0078] 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.

[0079] Blood cancers include, but are not limited to, one or more leukemias such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), acute lymphoblastic leukemia (ALL), one or more chronic leukemias including chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin lymphoma, plasmablastic lymphoma, and additional blood cancers or blood disorders including, but not limited to, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia, and "preleukemia", which are a collection of diverse blood disorders integrated by ineffective production (or dysplasia) of myeloid blood cells.

[0080] 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.

[0081] 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 a reduction in tumor size or number of tumors and / or survival rate. In some embodiments, "treatment of cancer" includes evaluating a 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).

[0082] In some embodiments, the disease or disorder is selected from the group consisting of non-squamous non-small cell lung cancer, squamous non-small cell lung cancer, triple-negative breast cancer (TNBC), esophageal cancer, gastroesophageal junction adenocarcinoma, and HER+ gastric adenocarcinoma. In some embodiments, the disease or disorder is selected from the group consisting of solid tumors, NSCLC, head and neck squamous cell carcinoma (HNSCC), and SCLC. In some embodiments, the disease or disorder is selected from the group consisting of renal cell carcinoma (RCC), solid tumors, endometrial cancer, non-squamous NSCLC, hepatocellular carcinoma (HCC), gastric cancer, SCLC, cervical cancer, TNBC, sarcoma, kidney cancer, and melanoma. In some embodiments, the disease or disorder is selected from the group consisting of urothelial cancer, colorectal cancer, HNSCC, NSCLC, gastric adenocarcinoma or GEJ adenocarcinoma, germ cell tumor, mesothelioma, HCC, pancreatic ductal adenocarcinoma, melanoma, RCC, solid tumors, and lymphoma. In some embodiments, the disease or disorder is NSCLC, solid tumors (e.g., KRAS p.G12C mutant solid tumors), TNBC, ovarian cancer, colorectal cancer, melanoma, breast cancer, and lymphoma. In some embodiments, the disease or disorder is selected from the group consisting of HER2+ metastatic breast cancer, urothelial cancer, and triple-negative metastatic breast cancer. In some embodiments, the disease or disorder is B cell lymphoma, chronic lymphocytic, leukemia, acute lymphocytic leukemia, neuroblastoma, CD19 +It is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, glioblastoma, and non-Hodgkin lymphoma. In some embodiments, the disease or disorder is selected from the group consisting of rhabdomyosarcoma, glioblastoma, brain metastatic melanoma, lung adenocarcinoma, melanoma, and prostate cancer.

[0083] 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.

[0084] The present disclosure also provides a medicament comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, as an active ingredient.

[0085] Generally, for pharmaceutical use, the compounds disclosed herein may be formulated as a pharmaceutical preparation comprising at least one disclosed compound, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant, and optionally one or more further pharmaceutically active compounds. Details regarding the presence of further pharmaceutically active compounds are described below.

[0086] By way of non-limiting example, such formulations may 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 may 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.

[0087] Preferred but non-limiting examples of such formulations include tablets, pills, powders, troches, cachets, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions, and sterile packaged powders for bolus and / or continuous administration (which are usually reconstituted before use), which are formulated with carriers, excipients, and diluents suitable therefor, 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 may optionally contain 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 may also be formulated to provide rapid, sustained, or delayed release of the active compound(s) contained therein.

[0088] The pharmaceutical formulations of the present disclosure are preferably in unit dosage form and may be suitably packaged, for example, in boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holder or container (which may be appropriately labeled), and optionally, one or more leaflets containing product information and / or instructions for use may be attached.

[0089] 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.

[0090] Another object of the present disclosure is the use of the combination as a medicament, i.e., for medical use. Thus, in one embodiment, the present disclosure provides the use of the combination of the present disclosure for the manufacture of a medicament. In particular, the present disclosure provides the use of the combination pharmaceutical composition of the present disclosure or the kit of the present disclosure for the manufacture of a medicament.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] In some embodiments, the additional therapeutic agent is administered once a day. In some embodiments, the additional therapeutic agent is administered twice a day (BID). In some embodiments, the additional therapeutic agent is administered three times a day (TID). In some embodiments, the additional therapeutic agent is administered four times a day (QID). In some embodiments, the additional therapeutic agent is administered once a week. In some embodiments, the additional therapeutic agent is administered twice a week. In some embodiments, the additional therapeutic agent is administered three times a week. In some embodiments, the additional therapeutic agent is administered four times a week. In some embodiments, the additional therapeutic agent is administered once a month. In some embodiments, the additional therapeutic agent is administered twice a month. In some embodiments, the additional therapeutic agent is administered three times a month. In some embodiments, the additional therapeutic agent is administered four times a month.

[0098] In some embodiments, doxorubicin is administered at a dose of 60-75 mg / m 2 In some embodiments, doxorubicin is administered at a dose of 60-75 mg / m every three weeks. 2 In some embodiments, doxorubicin is administered at a dose of 40-75 mg / m 2 In some embodiments, doxorubicin is administered at a dose of 40-75 mg / m every 3-4 weeks. 2 In some embodiments, doxorubicin is administered at a dose of 60 mg / m 2 In some embodiments, doxorubicin is administered at a dose of 60 mg / m every 14 days. 2 In some embodiments, doxorubicin is administered at a dose of 20 mg / m 2 In some embodiments, doxorubicin is administered at a dose of 20 mg / m every week. 2

[0099] In some embodiments, gemcitabine is administered at a dose of about 1000 mg / m 2 In some embodiments, gemcitabine is administered once a week at a dose of about 1000 mg / m 2Administer at a dose of. In some embodiments, gemcitabine is administered at a dose of about 1000 mg / m² on days 1 and 8 of a 21-day cycle, once a week. 2 Administer at a dose of. In some embodiments, gemcitabine is administered at a dose of about 1250 mg / m². 2 Administer at a dose of. In some embodiments, gemcitabine is administered at a dose of about 1250 mg / m² on days 1 and 8 of a 21-day cycle, once a week. 2 Administer at a dose of.

[0100] In some embodiments, oxaliplatin is administered at a dose of about 65 - 100 mg / m². 2 Administer at a dose of. In some embodiments, oxaliplatin is administered at a dose of about 65 mg / m². 2 Administer at a dose of. In some embodiments, oxaliplatin is administered at a dose of about 75 mg / m². 2 Administer at a dose of. In some embodiments, oxaliplatin is administered at a dose of about 85 mg / m². 2 Administer at a dose of.

Example

[0101] Example 1. Synthesis of Compound 29 Synthesis of 10b in TIFF2025523058000190.tif711651. 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), triphosgene (26.39 g, 94.594 mmol, 0.35 equiv) was added 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. The autoclave was flushed three times with CO / H₂ (1:1), and then the mixture was pressurized overnight at 80 °C with CO / H₂ (1:1) up to 10 atm. 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 equiv) and (s)-3-methylpiperidine hydrochloride (34.40 g, 253.600 mmol, 2 equiv) in DCE (1600 mL) was added TEA (38.49 g, 380.400 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 2 h. To the above mixture was added NaBH(OAc)₃ (53.75 g, 253.600 mmol, 2 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (1000 mL). The resulting mixture was extracted with CH₂Cl₂ / MEOH = 10 / 1 (2 × 1000 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH₄HCO₃), gradient from 15% to 80% in 40 min; detector, UV 254 nm. As a result, 29 (30.9 g, 45.08%) was obtained as a yellow solid. LC-MS - 29: (ES, m / z): [M+H] +541. H-NMR-29: (400 MHz, CD3OD, δ ppm): 0.75 - 0.95 (m, 4H), 1.43 - 1.49 (m, 1H), 1.49 - 1.66 (m, 4H), 1.86 - 1.91 (m, 1H), 2.67 - 2.76 (m, 2H), 2.96 (s, 3H), 3.31 (s, 2H), 3.53 (s, 2H), 4.90 - 4.95 (m, 1H), 6.88 - 9.90 (d, 1H), 7.00 (s, 1H), 7.29 (s, 1H), 7.37 - 7.40 (d, 1H), 7.64 (s, 1H), 7.74 - 7.76 (d, 1H), 8.19 (s, 1H).

[0106] Example 2. Synthesis of Compound 85 Synthesis of 11616585a of TIFF2025523058000191.tif 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 To a stirred solution of 85a (49 g, 196.577 mmol, 1 equiv) in EtOH (500 mL) was added hydrazine hydrate (98%) (251.04 g, 4914.425 mmol, 25 equiv, 98%) 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 purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (100:1) to afford 85b (43 g, 79.86%) as a yellow oil.

[0108] Synthesis of 85c To a stirred solution of 85b (45 g, 180.527 mmol, 1 equiv) in THF (450 mL) was added methyl isothiocyanate (33.00 g, 451.317 mmol, 2.5 equiv) 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 equiv) in H2O (1.65 L) was added 85c (55 g, 170.606 mmol, 1 equiv) 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 equiv) in EtOAc (190 mL) and H2O (760 mL), NaNO2 (113.3 g, 1642.74 mmol, 10 equiv) was added at room temperature. To the above mixture, HNO3 (1642 mL, 1642.74 mmol, 10.00 equiv, 1 M) was added dropwise 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 equiv) in 1.2 L of MeOH, Pd / C (20%, 8 g) was added 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 85 g (34 g, 70.784 mmol, 1 equiv) and pyridine (33.59 g, 424.704 mmol, 6 equiv) in DCM (400 mL) was added triphosgene (7.35 g, 24.774 mmol, 0.35 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. The reaction was quenched by adding water (500 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 500 mL) and dried over anhydrous CaCl2. After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated with MTBE (2 × 100 mL) for purification. This 85 h (33 g, 87.47%) is a yellow solid.

[0114] Synthesis of 85i To a solution of 85 h (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 with CO / H2 (1:1) to 10 atm 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 H-NMR: (400 MHz, DMSO-d6, ppm): δ0.84 - 0.91 (m, 4H), δ1.38 - 1.95 (m, 12H), δ2.08 - 2.10 (m, 1H), δ2.68 - 2.77 (m, 2H), δ3.19 - 3.25 (m, 3H), δ3.43 (s, 3H), δ4.25 - 4.28 (d, 1H), δ7.01 (s, 1H), δ7.19 - 7.21 (d 1H), δ7.32 (s, 1H), δ7.43 - 7.46 (t, 1H), δ7.66 - 7.75 (m, 3H), δ8.34 (s, 1H).

[0117] Example 3. Synthesis of Compound 86 Synthesis of TIFF2025523058000192.tif4916586 85j (85.00 mg, 0.158 mmol, 1.00 equivalent) was purified by preparative chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% of 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 30% B from 30% B in 8.5 minutes; wavelength: 220 / 254 nm; RT1 (min): 5.19) to obtain Compound 86 (24.1 mg, 27.90%) as a yellow solid. LC-MS: (ES, m / z): [M + H] + 539 H-NMR: (400 MHz, CDCl3, ppm): δ0.81 - 0.83 (d, 4H), δ1.66 - 1.78(m, 11H), δ2.04 - 2.11 (m, 1H), δ2.65 - 3.69 (m, 1H), δ2.72 - 3.73 (m, 1H), δ3.22 - 3.35 (m, 3H), δ3.42 (s, 3H), δ4.24 - 4.28 (d, 1H), δ7.00 (s, 1H), δ7.19 - 7.22 (d, 1H), δ7.33 (s, 1H), δ7.44 - 7.47 (m, 1H), δ7.70 - 7.72 (m, 3H), δ8.32 (s, 1H).

[0118] Example 4. In Vivo Efficacy Test in the Treatment of Subcutaneous Mouse Colorectal Cancer Model CT26.WT in Female BALB / c Mice The purpose of this study was to preclinically evaluate the in vivo therapeutic efficacy of the test substance of HotSpot Therapeutics in the treatment of subcutaneous mouse colorectal model CT26.WT in female BALB / c mice. The test particles of Compound 29 were delivered via oral administration. Compound 29 was evaluated in combination with oxaliplatin or cabozantinib at various dose levels. After the start of treatment, tumor volume and body weight were measured three times a week. The mice were divided into several groups and summarized in Table 2.

[0119] [Table 2]

[0120] The test substance of this study was formulated as outlined in Table 3.

[0121] [Table 3]

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

[0123] Tumor Inoculation To generate tumors, 5×10 5 cells in 0.1 ml of PBS mixed with Matrigel (1:1) were subcutaneously inoculated into the lower right abdomen of each mouse.

[0124] Randomization The average tumor size was approximately 86.42 mm 3When [the value] reached [a certain point], randomization was started. Sixty mice were enrolled in the study. All animals were randomly assigned to six study groups, with ten mice in each group. Randomization was performed according to the "Matched distribution" method (StudyDirector™ software, version 3.1.399.19).

[0125] The date of randomization was designated as Day 0.

[0126] Test substance administration According to the study design, treatment was started on the same day as randomization (Day 0).

[0127] Observation and data collection After tumor cell inoculation, animals were checked daily for morbidity and mortality. During regular monitoring, animals were examined for tumor growth and the effects of treatment on behavior such as locomotor activity, food and water intake, weight gain or loss (weight was measured twice a week after randomization), eye / coat condition, and other abnormalities. For each individual animal, mortality and observed clinical signs were recorded in detail.

[0128] After randomization, tumor volume was measured two-dimensionally twice 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 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.

[0129] Body weight and tumor volume were measured using StudyDirector™ software (version 3.1.399.19).

[0130] Study termination For Group 01 and Group 03, the study was terminated when the mean tumor volume of the vehicle control group reached 2000 mm^3 on Day 16.

[0131] For groups 02, 04, 05, and 06, the experiment was conducted for 3 weeks. The test was terminated on the 21st day (September 21, 2022).

[0132] Statistical analysis method To compare the tumor volumes of different groups on a pre-specified day, first, the Bartlett's test was used to confirm the assumption of homogeneity of variance across all groups. When the p-value of the Bartlett's test was 0.05 or more, one-way analysis of variance was performed to test the overall equality of the means of all groups. When the p-value of the one-way analysis of variance was less than 0.05, post hoc tests were further performed by conducting Tukey's HSD (honest significant difference) test for all pairwise comparisons and Dunnett's test for comparing each treatment group with the vehicle group. When the p-value of the Bartlett's test was less than 0.05, the Kruskal-Wallis test was performed to test the overall equality of the medians among all groups. When the p-value of the Kruskal-Wallis test was less than 0.05, post hoc tests were further performed by conducting Conover's nonparametric test for all pairwise comparisons or for comparing each treatment group with the vehicle group (both with single-step p-value adjustment).

[0133] Furthermore, the inventors performed pairwise comparisons without multiple comparison correction and reported the nominal / uncorrected p-values directly from the Welch's t-test or Mann-Whitney U-test at each time point. Specifically, first, the Shapiro-Wilk test was used to confirm the assumption of normal distribution for each group. When the p-values of the Shapiro-Wilk test for both groups in a pair were 0.05 or more, the Welch's t-test was performed; otherwise, the Mann-Whitney U-test was performed to obtain the nominal p-value.

[0134] All statistical analyses were performed in the R-a language and the statistical computing and graphics environment (version 3.3.1). Unless otherwise specified, all tests were two-sided, and a p-value less than 0.05 was considered statistically significant. In any survival analysis, the Kaplan-Meier model using the log-rank method was applied.

[0135] Results Tumor volume growth curve The tumor volume growth curves and the end of the test among the random groups are shown below. The mean tumor volume curves (including SEM) of the vehicle group and the treatment group are shown in Figure 1. The treatment was carried out for 21 days. The test was ended on the 21st day.

[0136] The calculations of TGI and T / C are based on the tumor size data on the 16th day, which is the last administration day of the treatment (Table 4).

[0137]

Table 4

[0138]

Table 2

[0139] Overview In this study, the mean tumor size of the vehicle reached 2526.75 mm^3 on the 16th day.

[0140] When oxaliplatin (Group 03, 5 mg / kg, once every 4 days) was used as a single agent for treatment, no statistically significant antitumor effect was shown against the subcutaneous CT26.WT mouse colorectal cancer model, and the TGI value was -3.27%. (P > 0.05 compared to Group 01).

[0141] When treated with Compound 29 (Group 02, 60 mg / kg, twice a day) as a single agent, statistically significant antitumor activity was shown against the subcutaneous CT26.WT mouse colorectal cancer model, and the TGI value was 43.58% (P < 0.05 compared to Group 01). When Compound 29 (Group 05, 60 mg / kg, twice a day) and oxaliplatin (Group 05, 5 mg / kg, once every 4 days) were co-administered, enhanced antitumor effects were shown against the subcutaneous CT26.WT mouse colorectal cancer model, and the TGI value was 64.06% (P < 0.01 compared to Group 01).

[0142] Example 5. In Vivo Efficacy Test in the Treatment of Subcutaneous Mouse Colorectal Cancer Model CT26.WT in Female BALB / c Mice The purpose of this study was to preclinically evaluate the in vivo therapeutic efficacy of the test substance in the treatment of subcutaneous mouse colorectal model CT26.WT in female BALB / c mice. The test particles of Compound 29 were delivered via oral administration. Compound 29 was evaluated at various dose levels in combination with doxorubicin, gemcitabine, or paclitaxel. After the start of treatment, tumor volume and body weight were measured three times a week. The mice were divided into several groups and summarized in Table 3.

[0143]

Table 3

[0144] The test substance of this study was formulated as outlined in Table 4.

[0145]

Table 4

[0146] Experimental Method Cell Culture CT26.WT tumor cells are maintained in vitro using RPMI - 1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 atmosphere in air. Cells in the exponential growth phase are harvested and quantified with a cell counter before tumor inoculation.

[0147] Tumor inoculation To develop tumors, 0.1 ml of CT26 tumor cells (5×10^5) in PBS are subcutaneously inoculated into the lower right abdominal area of each ath mouse.

[0148] Randomization Randomization is initiated when the average tumor size reaches approximately 80 - 100 mm^3. A total of 80 mice for each model are enrolled in the study and randomly assigned to 8 test groups as shown in Table 4, with 10 mice per group. Randomization is performed based on the "Matched distribution" method / "Stratified" method (Study Director™ software, version 3.1.399.19) / randomization block design. The date of randomization is designated as Day 0.

[0149] Test substance administration Treatment is initiated on the same day as randomization (Day 0) according to the study design.

[0150] Observation and data collection After tumor cell inoculation, animals are checked daily for morbidity and mortality. During regular monitoring, animals are examined for tumor growth and the effects of treatment on behavior such as motor ability, food and water intake, weight gain or loss (weight is measured twice a week after randomization), eye / hair entanglement, and other abnormalities. Mortality and observed clinical signs are recorded in detail for each individual animal.

[0151] After randomization, tumor volume is measured two - dimensional with calipers twice a week, and the volume is calculated in mm using the formula V=(L×W×W) / 2 3It is represented by [formula], 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 the tumor and body weight are performed in a laminar flow cabinet.

[0152] The body weight and tumor volume are measured using StudyDirector (trademark) software (version 3.1.399.19).

[0153] End of the test The efficacy test was terminated either when the average tumor volume of the vehicle control group reached 2000 mm^3 or at the earlier of continuing the test until the last administration.

[0154] The treatment was carried out for 21 days. In the absence of an extension of the treatment, the test was terminated on the 20th day.

[0155] Results Overall, in the CT26 tumor model, the combination of the CBL-B inhibitor with doxorubicin, gemcitabine, or paclitaxel shows an improved effect of delaying tumor growth even at limited dosages of chemotherapy.

[0156] The combination of compound 29 and doxorubicin shows an improved tumor inhibitory effect compared to each drug as monotherapy (see Figures 2A and 2B). The combination of compound 29 and gemcitabine shows an improved tumor inhibitory effect compared to each drug as monotherapy (see Figures 3A and 3B). The combination of compound 29 and paclitaxel shows an improved tumor inhibitory effect compared to each drug as monotherapy (see Figures 4A and 4B).

[0157] Example 6. In vivo efficacy test in the treatment of the subcutaneous mouse colorectal cancer model CT26.WT in female BALB / c mice The purpose of this study was to preclinically evaluate the in vivo therapeutic efficacy of the test substance in the treatment of the subcutaneous murine colorectal model CT26.WT in female BALB / c mice. The test particles of Compound 29 were delivered via oral administration. Compound 29 was evaluated at various dose levels in combination with ALT-803. After the start of treatment, tumor volume and body weight were measured three times a week. The mice were divided into several groups and summarized in Table 5.

[0158]

Table 5

[0159] The test substance of this study was formulated as outlined in Table 6.

[0160]

Table 6

[0161] Experimental methods Cell culture CT26.WT tumor cells are maintained in vitro using RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 atmosphere in air. Cells in the exponential growth phase are harvested and quantified with a cell counter before tumor inoculation.

[0162] Tumor inoculation To generate tumors, 0.1 ml of CT26 tumor cells (5×10e5) in PBS are subcutaneously inoculated into the lower right abdomen of each ath mouse.

[0163] Randomization Randomization is initiated when the average tumor size reaches approximately 80 - 100 mm^3. A total of 40 mice per model are enrolled in the study and randomly assigned to four test groups of 10 mice each as shown in Table 4. Randomization is performed based on the "Matched distribution" method / "Stratified" method (Study Director (trademark) software, version 3.1.399.19) / randomization block design. The date of randomization is designated as Day 0.

[0164] Administration of the test substance Treatment is initiated on the same day as randomization (Day 0) according to the study design.

[0165] Observation and data collection After tumor cell inoculation, animals are checked daily for morbidity and mortality. During regular monitoring, animals are examined for tumor growth and the effects of treatment on behavior such as motor ability, food and water intake, weight gain or loss (weight is measured twice a week after randomization), eye / coat entanglement, and other abnormalities. For each individual animal, mortality and observed clinical signs are recorded in detail.

[0166] After randomization, tumor volume is measured two - dimensional using calipers twice a week, and the volume is 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 measurement of tumor and body weight are performed within a laminar flow cabinet. 3 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 are performed within a laminar flow cabinet.

[0167] Body weight and tumor volume are measured using StudyDirector (trademark) software (version 3.1.399.19).

[0168] End of the study The efficacy study is terminated at the earlier of when the average tumor volume of the vehicle control group reaches 2000 mm^3 or until the last administration.

[0169] The treatment is carried out for 21 days. If there is no extension of the treatment, the test is terminated on the 20th day.

[0170] Results Overall, the combination of compound 29 and ALT-803 shows an improved tumor inhibitory effect compared to each drug as monotherapy (see Figures 5A and 5B).

Claims

1. A method of 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 additional therapeutic agent to a subject in need thereof.

2. A method of 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 additional therapeutic agent.

3. A method of treating a disease or condition related to cell proliferation, comprising administering a therapeutically effective amount of an additional therapeutic agent to a subject in need thereof, wherein the subject has been previously treated with a CBL-B inhibitor.

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- or 6-membered heterocyclyl, B is an optionally substituted phenyl, an optionally substituted 8- to 10-membered bicyclic ring, or an optionally substituted 5- or 6-membered heteroaryl, C is an optionally substituted 5- or 6-membered heterocyclyl, X is optionally substituted C １ ~C ３ is an alkylene chain, where one or more methylene units are -N(H)-, -N(R １ ), -O-, -S-, -SO-, -SO ２ -, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, and X is optionally substituted with a group selected from the group consisting of halogen, C １ ~C ３ aliphatic, phenyl, 3- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, and -(CH ２ )(3- to 6-membered carbocyclyl), and is optionally substituted, 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, where R ａ is optionally substituted with 1 to 5 examples of R ａ１ and 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, selected from the group consisting of, where A is 1 to 5 examples of 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 which may be substituted C １ ~C ６ aliphatic, optionally substituted phenyl, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, -C(O)R ３ , -CO ２ R ３ , -C(O)NHR ３ , and -SO ２ R ３ , are independently selected from the group consisting of, Each R ２ is independently selected from the group consisting of hydrogen, optionally substituted C １ -C ６ aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, 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 aliphatic, optionally substituted 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each selected from the group consisting of N, O, and S, independently selected from the group consisting of n is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4, The method according to any one of claims 1 to 3.

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

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

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

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

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

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

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

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

13. R ｃ is optionally substituted C １ -C ３ The method according to any one of the preceding claims, wherein the C 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. X is optionally substituted C １ - C ２ The method according to any one of the preceding claims, wherein X is alkylene.

17. X is or optionally substituted C ２ is alkylene, where one methylene unit is The method according to any one of the preceding claims, wherein is substituted with.

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

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 )-, the method according to any one of the preceding claims.

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

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, the 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, The method according to any one of the preceding claims, wherein is independently selected from the group consisting of.

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

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

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

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

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

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

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

31. The method according to any one of the preceding claims, wherein the CBL-B inhibitor is administered in 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 additional therapeutic agent is selected from the group consisting of pemetrexed, carboplatin, paclitaxel / nab-paclitaxel, cisplatin, 5-fluorouracil, trastuzumab, capecitabine, oxaliplatin, leucovorin, platinum, bevacizumab, and etoposide.

48. The method according to any one of the preceding claims, wherein the additional therapeutic agent is SBRT or chemoradiotherapy.

49. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is selected from the group consisting of axitinib, lenvatinib, bevacizumab, cabozantinib, anlotinib, IBI305, and apatinib.

50. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is selected from the group consisting of ipilimumab, tremelimumab, LY3321367, sabatolimab, relatlimab, COM701, tiragolumab, PF-05082566, APX005M, KY1044, and GWN323.

51. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is selected from the group consisting of erlotinib, osimertinib, crizotinib, alectinib, crizotinib, pamiparib, niraparib, olaparib, cobimetinib, AMG510, MK-8353, dabrafenib, trametinib, encorafenib, cetuximab, copanlisib, ipatasertib, pemigatinib, B-701, savolitinib, abemaciclib, and TNO155.

52. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is selected from the group consisting of trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), enfortumab vedotin (EV), and sacituzumab govitecan.

53. The additional therapeutic agent is selected from the group consisting of, the method according to any one of claims 1 to 46.

54. The additional therapeutic agent is selected from the group consisting of CD19 / C19CAR-28-ζ T cells, GD2 / iC9-GD2-CD28-OX40 (iC9-GD2) T cells, anti-CD19 CAR T cells, autologous anti-C19CAR-4-1BB-CD3ζ-EGFRt-expressing CD4 ＋ / CD8 ＋ The method according to any one of claims 1 to 46, which is selected from the group consisting of CAR-T cells selected from the group consisting of central memory T lymphocyte CAR014 T cells, CD19 / KTE-C19 T cells, JCAR017 T cells, and CART-EGFRvII T cells.

55. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is selected from the group consisting of herpes virus (e.g., HSV1716, G47Δ-mIL-12), adenovirus (e.g., hTertAd, ISF35, D24-RGDox, ADV-TK, rHu-hDCT, ChAdOx I-STEAP I, ChAdOx I-h5T4), vaccinia virus (e.g., WR-mAb I), and myxoma virus (e.g., vPD1).

56. The additional therapeutic agent is selected from the group consisting of, the method according to any one of claims 1 to 46.

57. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is doxorubicin.

58. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is gemcitabine.

59. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is paclitaxel.

60. The method according to any one of claims 1 to 46, wherein the additional therapeutic agent is ALT-803.

61. The method according to any of the preceding claims, wherein the disease or condition associated with cell proliferation is hyperplasia or cancer.

62. The method according to claim 61, wherein the cancer is colorectal cancer.

63. The method according to claim 61, wherein the cancer is a hematological cancer.

64. The method according to claim 63, wherein the hematological cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

65. The method according to claim 64, wherein the cancer is a non-hematological cancer.

66. The method according to claim 65, wherein the non-hematological cancer is a sarcoma or a carcinoma.

67. After administration of the compound according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 16, the subject has one or more of an increase in T cell activation, an increase in T cell proliferation, a decrease in T cell exhaustion, a decrease in T cell anergy, and a decrease in T cell tolerance. The method according to any one of claims 1 to 66.

68. The method according to claim 67, wherein the increase in T cell activation includes an increase in cytokine production.

69. The method according to any one of claims 1 to 66, wherein the subject has an increase in NK cell activation.

70. The method according to claim 69, wherein the increase in NK cell activation includes an increase in cytokine production.

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