Compounds, compositions and methods of treatment thereof

Abstract

The present disclosure relates to treatment of a subject in need thereof of comprising administering a therapeutically effective amount of a CBL-B inhibitor and a therapeutically effective amount of bispecific antibody.

Description

[0001] Attorney Docket No. HOT-020WO COMPOUNDS, COMPOSITIONS AND METHODS OF TREATMENT THEREOF BACKGROUND

[0001] E3 ligase Casitas B-Lineage Lymphoma Proto-Oncogene B (CBL-B) is a key negative modulator of T-cell receptor and co-stimulatory regulation. CBL-B inhibition lowers the threshold of antigen-specific T cell activation, even in the absence of co-stimulatory signaling or in the presence of an immune suppressive environment. Genetic ablation of CBL-B or functional inactivation of its E3 ligase activity in mice or primary human T cells enhances immune-mediated tumor growth control. Therefore, CBL-B inhibition may address the suboptimal response to current immunotherapies due to low inflammation, no / low co- stimulation signal or a high immune suppressive environment. SUMMARY

[0002] The present disclosure includes a method of treating a disease or condition associated with cell proliferation comprising administering a therapeutically effective amount of a CBL- B inhibitor in combination with one more bispecific antibodies.

[0003] The present disclosure is further defined in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0004] FIG. 1 is 5 graphs showing improved effect on % tumor killed of a combination of compound 85 with as compared voxalatamab to each of the agents as monotherapies.

[0005] FIG. 2 is 4 graphs showing improved effect on % tumor killed of a combination of compound 85 with as compared pavurutamab to each of the agents as monotherapies. DETAILED DESCRIPTION CBL-B Inhibitors

[0006] An “CBL-B Inhibitor” refers to a compound that, upon administration to a subject, results in inhibition or down-regulation of a biological activity associated with activation of CBL-B in the patient, including any of the downstream biological effects otherwise resulting from the binding to CBL-B of its natural ligand. Such CBL-B Inhibitors include any agent that can block activation of CBL-B or any of the downstream biological effects of CBL-B activation. 1 IPTS / 200089477.1

[0002] Attorney Docket No. HOT-020WO

[0007] In some embodiments, a CBL-B inhibitor is a compound of formula (A): or pharmaceutic wherein Y is selected from the group =C(H)-, =C(Ra)- or =N-; Z is =O or =S; E is optionally substituted 5-6 membered heterocyclyl; B is optionally substituted phenyl, optionally substituted 8-10 membered bicyclyl, or optionally substituted 5-6 membered heteroaryl; C is optionally substituted 5-6 membered heterocyclyl; X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units is optionally replaced by -N(H)-, -N(R1)-, -O-, -S-, -SO-, -SO2-, optionally substituted 3-6- membered carbocyclyl, and optionally substituted 3-6-membered heterocylyl, wherein X is optionally substituted with an optionally substituted group selected from a group consisting of halogen, C1-C3 aliphatic, phenyl, 3-6-membered heteroaryl, 3-6-membered heterocylyl, and -(CH2)(3-6-membered carbocyclyl); each Rais independently selected from the group consisting of L-A, halogen, -CN, -OH, - OR1, -NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -C(O)R1, -CONH2, -CONR1R2, - SO2NH2, -SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, - S(O)(NR1)R1, 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, wherein Rais optionally substituted with 1-5 instances of Ra1; L is an optionally substituted C1-C3 alkylene chain; A is selected from the group consisting of optionally substituted C3-C7 carbocylyl, 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, 2 IPTS / 200089477.1

[0003] Attorney Docket No. HOT-020WO 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 instances of Ra1; each Ra1is independently selected from the group consisting of halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, -S(O)(NR1)R1, 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 Rbis independently selected from the group consisting of, halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, -S(O)(NR1)R1, 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 Rcis independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, OR1, -NH2, -NR1R2, 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R1is 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R2is 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 3 IPTS / 200089477.1

[0004] Attorney Docket No. HOT-020WO 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 R1and R2are taken together with their intervening atom(s) to 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 R3is 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, 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 present disclosure includes a compound of Formula (B): Rc N N , or pharmaceutically acceptable salts thereof, wherein Y is selected from the group =C(H)-, =C(Ra)- or =N-; Z is =O or =S; B is optionally substituted phenyl, substituted 5-6 membered heteroaryl or optionally substituted 8-10 membered bicyclyl; X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units is optionally replaced by -N(H)-, -N(R1)-, -O-, -S-, -SO-, -SO2-, optionally substituted 3-6- membered carbocyclyl, and optionally substituted 3-6-membered heterocylyl, each Rais independently selected from the group consisting of L-A, halogen, -CN, -OH, - OR1, -NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -C(O)R1, -CONH2, -CONR1R2, - SO2NH2, -SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, - S(O)(NR1)R1, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 4 IPTS / 200089477.1

[0005] Attorney Docket No. HOT-020WO 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 carbocylyl, 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 Rbis independently selected from the group consisting of, halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - SO2NR1R2-SO2OH -SO2OR1-S(O)R1-S(O)2R1-S(O)(NH)R1-S(O)(NR1)R1, 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 Rcis independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, -OR1, -NH2, -NR1R2, 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R1is 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R2is 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 5 IPTS / 200089477.1

[0006] Attorney Docket No. HOT-020WO 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 R1and R2are taken together with their intervening atom(s) to 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 R3is 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, 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 present disclosure includes a compound of formula (I): Rc Y N or pharmaceutically a , wherein X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units is , nit nsisting of halogen, optionally substituted C1-C3 aliphatic, optionally substituted 5-membered 6 IPTS / 200089477.1

[0007] Attorney Docket No. HOT-020WO heteroaryl, optionally substituted phenyl, optionally substituted C3-C4 carbocylyl, and optionally substituted C3-C4 heterocyclyl; each Rais independently selected from the group consisting of L-A, halogen, -CN, -OH, - OR1, -NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -C(O)R1, -CONH2, -CONR1R2, - SO2NH2, -SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, - S(O)(NR1)R1, 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, wherein Rais optionally substituted with 1-5 instances of Ra1; each Y is independently selected from the group consisting of -C=, -O-, -N=, and -S-; L is an optionally substituted C1-C3 alkylene chain; A is selected from the group consisting of optionally substituted C3-C7 carbocylyl, 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 instances of Ra1; each Ra1is independently selected from the group consisting of halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, -S(O)(NR1)R1, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted phenyl, and optionally substituted 5-6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O and S; B is optionally substituted phenyl, substituted 5-6 membered heteroaryl, or optionally substituted 8-10 membered bicyclyl; each Rbis independently selected from the group consisting of halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, -S(O)(NR1)R1, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroalkyl, 7 IPTS / 200089477.1

[0008] Attorney Docket No. HOT-020WO 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 Rcis independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, wherein the – 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R1is 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R2is 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 R1and R2are taken together with their intervening atom(s) to 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 R3is 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, 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. 8 IPTS / 200089477.1

[0009] Attorney Docket No. HOT-020WO

[0010] In some embodiments, present disclosure includes a compound is of formula (Ia) or (IIa): wherein each W is independently selected from N or C; and X, Y, Z, Ra, Rb, Rc, n, and m are defined above and described in classes and subclasses herein.

[0011] In some embodiments, present disclosure includes a compound is of formula (Ia1) or (IIa1): , or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, Ra, Rb, Rc, n, and m are defined above and described in classes and subclasses herein.

[0012] In some embodiments, present disclosure includes a compound is of formula (Ia2), (Ia3), or (Ia4): IPTS / 200089477.1

[0010] Attorney Docket No. HOT-020WO or pharmaceutically acceptable salts thereof, wherein X, Y, Z, Ra, Rb, Rc, n, and m are defined above and described in classes and subclasses herein.

[0013] In some embodiments, present disclosure includes a compound is of formula (Ia1) or (IIa1): o wherein X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units is optionally replace ; each Rais independently selected from the group consisting of L-A, halogen, -CN, -OH, - OR1, -NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -C(O)R1, -CONH2, -CONR1R2, - 12 1 1 1 1 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 carbocylyl, 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 Rbis independently selected from the group consisting of, halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - 10 IPTS / 200089477.1

[0011] Attorney Docket No. HOT-020WO SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, -S(O)(NR1)R1, 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 Rcis independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O and S, -C(O)R3, -CO2R3, - C(O)NHR3, and -SO2R3; each R1is 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R2is 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 R1and R2are taken together with their intervening atom(s) to 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 R3is 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, 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. 11 IPTS / 200089477.1

[0012] Attorney Docket No. HOT-020WO

[0014] In some embodiments, present disclosure includes a compound is of formula (Ib) or (IIb): or pharma m are defined above and described in classes and subclasses herein.

[0015] In some embodiments, present disclosure includes a compound of formula (Ib1) or (IIb1): , or a pharmaceutically acceptable salt thereof, wherein X, Ra, Rb, Rcand m are defined above and described in classes and subclasses herein.

[0016] In some embodiments, present disclosure includes a compound of formula (Ib2), (Ib3), or (Ib4): IPTS / 200089477.

[0013] Attorney Docket No. HOT-020WO (Ib4) or a pharmaceutically acceptable salt thereof, wherein X, Ra, Rb, Rcand m are defined above and described in classes and subclasses herein.

[0017] In some embodiments, present disclosure includes a compound of formula (Ic) or (IIc): or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, Ra, Rb, Rcand m are defined above and described in classes and subclasses herein.

[0018] In some embodiments, present disclosure includes a compound of formula (Ic1) or (IIc1): or a pharm y p , , , , efined above and described in classes and subclasses herein.

[0019] In some embodiments, present disclosure includes a compound of formula (Id) or (IId): 13 IPTS / 200089477.1

[0014] Attorney Docket No. HOT-020WO or a pharmaceutically acceptable salt thereof, wherein X, Rb, Rcand m are defined above and described in classes and subclasses herein.

[0020] In some embodiments, present disclosure includes a compound of formula (Id1) or (IId1): or a pharmaceutically acceptable salt thereof, wherein X, Rb, Rcand m are defined above and described in classes and subclasses herein. X

[0021] In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units is optionally replaced by -N(H)-, -N(R1)-, -O-, -S-, -SO-, -SO2-, optionally substituted 3-6-membered carbocyclyl, and optionally substituted 3-6-membered heterocylyl, wherein X is optionally substituted with an optionally substituted group selected from the group consisting of halogen, C1-C3 aliphatic, phenyl, 3-6-membered heteroaryl, 3-6- membered heterocylyl, and -(CH2)(3-6-membered carbocyclyl). In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more methylene units is optionally replaced by -N(H)-, -N(R1)-, -O-, -S-, -SO-, -SO2-, optionally substituted 3-6- membered carbocyclyl, and optionally substituted 3-6-membered heterocylyl. In some embodiments, X is an optionally substituted C1-C3 alkylene chain, wherein one or more h l i i i ll l d b N H N R1O S SO SO ne consisting of halogen, optionally substituted C1-C3 aliphatic, optionally substituted 5- membered heteroaryl, optionally substituted phenyl, optionally substituted C3-C4 carbocylyl, 14 IPTS / 200089477.1

[0015] Attorney Docket No. HOT-020WO 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 is optionally replaced me embodiments, X is methylene units is optionally replaced by -N(H)-, -N(R1)-, -O-, -S-, -SO-, -SO2-, , , and . In some embodiments, X is optionally substituted C1-C2 alkylene. In some embodiments, X i or optionally substituted C2 alkylene, wherein one methylene unit is replaced with . In some embodiments, X is selected from the group consisting of , . Attorney Docket No. HOT-020WO ,

[0016] Attorney Docket No. HOT-020WO , ,

[0022] , g p ing of ,

[0023] In some embodiments, each Rais independently selected from the group consisting of L-A, halogen, -CN, -OH, -OR1, -NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -C(O)R1, - CONH2, -CONR1R2, -SO2NH2, -SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, - S(O)(NH)R1, -S(O)(NR1)R1, 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. In some embodiments, L-A. In some embodiments, Rais selected from halogen, -CN, -C(O)R1, -CO2H, -CONR1R2, optionally substituted C1-C6 aliphatic, and optionally substituted C1-C6 heteroalkyl. In some embodiments each Rais independently selected from the group consisting of halogen, -CN, -CO2H, -CHO, -CHF2, -CF3, -OMe, -S(O)2NHMe, 17 IPTS / 200089477.1

[0017] Attorney Docket No. HOT-020WO , , , IPTS / 2000

[0018] Attorney Docket No. HOT-020WO , , , , , , , IPTS / 2000 .

[0019] Attorney Docket No. HOT-020WO , , IPTS / 2000

[0020] Attorney Docket No. HOT-020WO IPTS / 2000 .

[0021] Attorney Docket No. HOT-020WO , , , 22 IPTS / 200089477.1

[0022] Attorney Docket No. HOT-020WO , ,

[0024] , g p g alogen, -CN, - CO2H, , , 23 IPTS / 200089477.1

[0023] Attorney Docket No. HOT-020WO and L

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

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

[0027] In some embodiments, C is optionally substituted 5-membered heteroaryl. In some embodiments, C is optionally substituted 5-membered heteroaryl containing 3 nitrogen atoms. In some embodiments, C is optionally substituted triazolyl. In some embodiments, C is optionally substituted 1,2,4 trizaolyl. In some embodiments, C is optionally substituted 1,2,3 trizaolyl. In some embodiments, C is optionally substituted 5-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, C is optionally substituted pyrazolyl. In some embodiments, C is optionally substituted isoxazolyl. In some embodiments, C is optionally substituted thiazolyl. In some embodiments, C is optionally substituted thiadizolyl. In some embodiments, C is optionally substituted 1,3,4 thiadizolyl. In some embodiments, C is optionally substituted pyridinyl. In some embodiments, C is optionally substituted pyrazinyl. In some embodiments, C is optionally substituted pyrimidinyl. In some embodiments, C is optionally substituted pyridazinyl. 24 IPTS / 200089477.1

[0024] Attorney Docket No. HOT-020WO Rb

[0028] Im some embodiments, each Rbis independently selected from the group consisting of, halogen, -CN, -OH, -OR1, -NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, - CONR1R2, -SO2NH2, -SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, - S(O)(NR1)R1, 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. Rc

[0029] In some embodiments, each Rcis independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, -OR1, -NH2, -NR1R2, 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3. In some embodiments, each Rcis independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl containing 1- 4 heteroatoms each selected from the group consisting of N, O, and S, optionally substituted 5-6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O and S, -C(O)R3, -CO2R3, -C(O)NHR3, and -SO2R3. In some embodiments, Rcis optionally substituted C1-C3 aliphatic. In some embodiments, Rcis methyl. R1

[0030] In some embodiments, each R1is 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)R3, -CO2R3, -C(O)NHR3, and - SO2R3. In some embodiments, each R1is optionally substituted C1-C6 aliphatic. In some embodiments, each R1is methyl. R2

[0031] In some embodiments, each R2is independently selected from the group consisting of 25 IPTS / 200089477.1

[0025] Attorney Docket No. HOT-020WO 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 R1and R2are taken together with their intervening atom(s) to 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 R2is optionally substituted C1-C6 aliphatic. In some embodiments, each R2is methyl. R3

[0033] In some embodiments, each R3is 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, 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 compounds described in Table 1. Table 1 Cmpd Structure N 26 IPTS / 200089477.1

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[0151] Attorney Docket No. HOT-020WO or a p armaceu ca y accep a e sa ereo .

[0035] A person of skill in the art will understand the present disclosure includes compounds with the stereochemistry which are the opposite of how they have been drawn. Additionally, the present disclosure contemplates tautomers of the compounds as drawn herein.

[0036] The present disclosure includes the racemate of any compound disclosed herein. Bispecific Antibodies

[0037] In some embodiments, a bispecific antibody is a CD3 antibody. In some embodiments, a bispecific antibody is selected from the group consisting of a CD3 / CD19 antibody, GP100 / CD3 antibody, a CD3 / CD20 antibody, a CD3 / BCMA antibody, a CD3 / GPRC5D antibody, MUC16 / CD3, and a CD3 / PMSA antibody.

[0038] In some embodiments, a bispecific antibody is selected from the group consisting of blinatumomab, tebentafusp-tebn, mosunetuzumab, glofitamab, epcoritamab, pavurutamab, teclistamab, elranatamab, talquetamab-tgvs, and voxalatamab.

[0039] In some embodiments, a bispecific antibody is a CD3 / CD19 antibody. In some embodiments, a CD3 / CD19 antibody is blinatumomab.

[0040] In some embodiments, a bispecific antibody is a GP100 / CD3 antibody. In some embodiments, a GP100 / CD3 antibody is tebentafusp-tebn.

[0041] In some embodiments, a bispecific antibody is a CD3 / CD20 antibody. In some embodiments, a CD3 / CD20 antibody is selected from the group consisting of mosunetuzumab, glofitamab, odronextamab, and epcoritamab. In some embodiments, a CD3 / CD20 antibody is mosunetuzumab. In some embodiments, a CD3 / CD20 antibody is glofitamab. In some 152 IPTS / 200089477.1

[0152] Attorney Docket No. HOT-020WO embodiments, a CD3 / CD20 antibody is odronextamab. In some embodiments, a CD3 / CD20 antibody is epcoritamab.

[0042] In some embodiments, a bispecific antibody is a CD3 / BCMA antibody. In some embodiments, a CD3 / BCMA antibody is selected from the group consisting of pavurutamab, teclistamab, REGN5459, linvoseltamab, and elranatamab. In some embodiments, a CD3 / BCMA antibody is pavurutamab. In some embodiments, a CD3 / BCMA antibody is teclistamab. In some embodiments, a CD3 / BCMA antibody is REGN5459. In some embodiments, a CD3 / BCMA antibody is linvoseltamab. In some embodiments, a CD3 / BCMA antibody is elranatamab.

[0043] In some embodiments, a bispecific antibody is a CD3 / GPRC5D antibody. In some embodiments, a CD3 / GPRC5D is talquetamab-tgvs.

[0044] In some embodiments, a bispecific antibody is a CD3 / PSMA antibody. In some embodiments, a CD3 / PSMA antibody is voxalatamab or REGN4336. In some embodiments, a CD3 / PSMA antibody is voxalatamab. In some embodiments, a CD3 / PSMA antibody is REGN4336.

[0045] In some embodiments, a bispecific antibody is a MUC16 / CD3 antibody. In some embodiments, a MUC16 / CD3 antibody is ubamatamab. Definitions

[0046] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or 153 IPTS / 200089477.1

[0153] Attorney Docket No. HOT-020WO unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0047] The term "haloaliphatic" refers to an aliphatic group that is substituted with one or more halogen atoms.

[0048] The term "alkyl" refers to a straight or branched alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0049] The term "haloalkyl" refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.

[0050] The term "halogen" means F, Cl, Br, or I.

[0051] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0052] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, 154 IPTS / 200089477.1

[0154] Attorney Docket No. HOT-020WO acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4Η)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0053] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in TV-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at 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, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0054] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. 155 IPTS / 200089477.1

[0155] Attorney Docket No. HOT-020WO

[0055] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0056] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH2)0-4R∘; —(CH2)0-4OR∘; —O(CH2)0-4R∘, —O—(CH2)0-4C(O)OR∘; —(CH2)0-4CH(OR∘)2; —(CH2)0-4SR∘; —(CH2)0-4Ph, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1Ph which may be substituted with R∘; —CH═CHPh, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R∘; —NO2; —CN; —N3; —(CH2)0-4N(R∘)2; —(CH2)0-4N(R∘)C(O)R∘; —N(R∘)C(S)R∘; —(CH2)0-4N(R∘)C(O)NR∘2; —N(R∘)C(S)NR∘2; —(CH2)0-4N(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)0-4C(O)R∘; — C(S)R∘; —(CH2)0-4C(O)OR∘; —(CH2)0-4C(O)SR∘; —(CH2)0-4C(O)OSiR∘3; —(CH2)0- 4OC(O)R∘; —OC(O)(CH2)0-4SR∘, SC(S)SR∘; —(CH2)0-4SC(O)R∘; —(CH2)0-4C(O)NR∘2; — C(S)NR∘2; —C(S)SR∘; —SC(S)SR∘, —(CH2)0-4OC(O)NR∘2; —C(O)N(OR∘)R∘; — C(O)C(O)R∘; —C(O)CH2C(O)R∘; —C(NOR∘)R∘; —(CH2)0-4SSR∘; —(CH2)0-4S(O)2R∘; — (CH2)0-4S(O)2OR∘; —(CH2)0-4OS(O)2R∘; —S(O)2NR∘2; —(CH2)0-4S(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; —(C1-4 straight or branched alkylene)O—N(R∘)2; or — (C1-4 straight or branched alkylene)C(O)O—N(R∘)2, wherein each R∘may be substituted as defined below and is independently hydrogen, C1-6 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, notwithstanding the definition above, two independent occurrences of R∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl 156 IPTS / 200089477.1

[0156] Attorney Docket No. HOT-020WO mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0057] Suitable monovalent substituents on R∘(or the ring formed by taking two independent occurrences of R∘together with their intervening atoms), are independently halogen, — (CH2)0-2R●, -(haloR●), —(CH2)0-2OH, —(CH2)0-2OR●, —(CH2)0-2CH(OR●)2; —O(haloR●), — CN, —N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, —(CH2)0-2SR●, — (CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR●, —(CH2)0-2NR●2, —NO2, —SiR●3, — OSiR●3, —C(O)SR●, —(C1-4 straight or branched alkylene)C(O)OR●, or —SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R∘include ═O and ═S.

[0058] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2- 3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0059] Suitable substituents on the aliphatic group of R* include halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR●2, or —NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R†, —NR† 2, —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH2C(O)R†, — 157 IPTS / 200089477.1

[0157] Attorney Docket No. HOT-020WO S(O)2R†, —S(O)2NR†2, —C(S)NR†2, —C(NH)NR†2, or —N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0061] Suitable substituents on the aliphatic group of R†are independently halogen, —R●, - (haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, — NR●2, or —NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0- 1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group 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 by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, 158 IPTS / 200089477.1

[0158] Attorney Docket No. HOT-020WO persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0063] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0064] Combinations of substituents and variables envisioned by this disclosure are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0065] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0066] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0067] As used herein, a "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or 159 IPTS / 200089477.1

[0159] Attorney Docket No. HOT-020WO more symptoms or features of the disease, disorder, and / or condition. I

[0068] As used herein, the terms "treatment," "treat," and "treating" refer to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and / or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing relapse or recurrence of a disease or disorder.

[0069] The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[0070] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound(s) with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the compounds disclosed herein include, but are not limited to, 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0071] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.

[0072] The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that total 160 IPTS / 200089477.1

[0160] Attorney Docket No. HOT-020WO daily usage of compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. Specific effective dose level for any particular patient or organism will depend upon a variety of factors including disorder being treated and severity of the disorder; activity of specific compound employed; specific composition employed; age, body weight, general health, sex and diet of the patient; time of administration, route of administration, and rate of excretion of a specific compound employed; duration of treatment; drugs used in combination or coincidental with a specific compound employed, and like factors well known in the medical arts.

[0073] Unless specifically stated or otherwise apparent from context, as used herein the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within ±10% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about. Alternative Embodiments In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) 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 an element that occupies a specific site of the compound. Diseases and Disorders

[0074] Provided herein are methods for modulating activity of an immune cell (e.g., a T- cell, a B-cell, or a NK-cell) such as by contacting the immune cell with an effective amount of a Cbl-b inhibitor described herein or a composition thereof. Also provided are in vitro methods of producing said immune cells with modulated activity, referred to herein as “modified immune cells,” wherein said modified immune cells can be administered to an individual in need thereof (e.g., an individual having cancer) by ex vivo methods. Further provided are in vivo methods of modulating a response in an individual in need thereof (e.g., an individual with cancer), wherein the method comprises administration of an effective amount of a Cbl-b 161 IPTS / 200089477.1

[0161] Attorney Docket No. HOT-020WO inhibitor described herein or a composition thereof. Moreover, the present disclosure provides in vitro methods of producing an expanded population of lymphocytes after in vivo lympho- conditioning in an individual, wherein the lympho-conditioning occurs as a result of administration of an effective amount of a Cbl-b inhibitor described herein or a composition thereof to the individual. In addition, the expanded population of lymphocytes can then be administered to the individual with cancer. In some embodiments, the modified immune cells or the expanded population of lymphocytes are produced from a biological sample comprising immune cells obtained from the individual, such as a blood sample comprising peripheral blood mononuclear cells or a tumor biopsy comprising tumor infiltrating lymphocytes (TILs).

[0075] Additionally, provided are Cbl-b inhibitors for use as therapeutic active substances. A Cbl-b inhibitor for use in treating or preventing a disease or condition associated with Cbl-b activity is provided. Also, a Cbl-b inhibitor for use in treating cancer is provided. Further provided is 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. Also provided is the use of a Cbl-b inhibitor in the manufacture of a medicament for treating cancer. Moreover, the present disclosure provides treatment methods, medicaments, and uses comprising a Cbl-b inhibitor as part of a combination therapy for treating cancer involving one or more of bispecific antibodies.

[0076] In some embodiments of the treatment methods, medicaments, and uses of the present disclosure, the cancer is a hematologic cancer such as lymphoma, a leukemia, or a myeloma. In other embodiments of the treatment methods, medicaments, and uses of the present disclosure, the cancer is a non-hematologic cancer such as a sarcoma, a carcinoma, or a melanoma.

[0077] Hematologic cancers include, but are not limited to, one or more leukemias such as B- cell acute lymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia (“TALL”), acute lymphoid leukemia (ALL); one or more chronic leukemias including, but not limited to, chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and“preleukemia,” which are a 162 IPTS / 200089477.1

[0162] Attorney Docket No. HOT-020WO diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells.

[0078] Non-hematologic cancers include but are not limited to, a neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, 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.

[0079] In some aspects, the effectiveness of administration of a Cbl-b inhibitor in the treatment of a disease or disorder such as cancer is measured by assessing clinical outcome, such as reduction in tumor size or number of tumors, and / or survival. In some embodiments, “treating cancer” comprises assessing a patient’s response to the treatment regimen according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) as described (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 to determine objective anti-tumor responses per RECIST 1.1 include: complete response (CR); partial response (PR); progressive disease (PD); and stable disease (SD).

[0080] In some embodiments, a disease or disorder is selected from the group consisting of non-squamous NSCLC, squamous NSCLC, triple negative breast cancer (TNBC), esophageal cancer, gastroesophageal junction adenocarcinoma, and HER+ gastric adenocarcinoma. In some embodiments, a disease or disorder is selected from the group consisting of a solid tumor, NSCLC, head and neck squamous cell carcinoma (HNSCC), and SCLC. In some embodiments, a disease or disorder is selected from the group consisting of renal cell cancer (RCC), a solid tumor, endometrial cancer, non-squamous NSCLC, hepatocellular carcinoma (HCC), gastric cancer, SCLC, cervical cancer, TNBC, ostreosarcoma, kidney cancer, and melanoma. In some embodiments, a disease or disorder is selected from the group consisting of urothelial cancer, colorectal cancer, HNSCC, NSCLC, gastric or GEJ adenocarcinoma, germ cell tumors, mesothelioma, HCC, pancreatic ductal adenocarcinoma, melanoma, RCC, a solid tumor, and lymphoma. In some embodiments, a disease or disorder is NSCLC, a solid tumor (e.g. KRAS p.G12C mutant solid tumor), TNBC, ovarian cancer, colorectal cancer, melanoma, breast cancer, and lymphoma. In some embodiments, a 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, a disease or disorder is selected from the group consisting of B cell lymphoma, chronic lymphocytic, leukemia, acute lymphocytic leukemia, 163 IPTS / 200089477.1

[0163] Attorney Docket No. HOT-020WO neurobastoma, CD19+diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, glioblastoma, and non-Hodgkin lymphoma. . In some embodiments, a disease or disorder is selected from the group consisting of rhabdomyosarcoma, glioblastoma, melanoma brain metastases, lung adenocarcinoma, melanoma, and prostate cancer.

[0081] In some embodiments, a disease or disorder is leukemia. In some embodiments, leukemia is cell acute lymphoblastic leukemia (ALL). In some embodiments, leukemia is relapsed or refractory precursor B-cell acute lymphoblastic leukemia.

[0082] In some embodiments, a disease or disorder is skin cancer. In some embodiments, skin cancer is melanoma. In some embodiments, skin cancer is uveal melanoma. In some embodiments, skin cancer is unresectable or metastatic uveal melanoma.

[0083] In some embodiments, a disease or disorder is lymphoma. In some embodiments, lymphoma is follicular lymphoma. In some embodiments, lymphoma is relapsed or refractory follicular lymphoma. In some embodiments, lymphoma is non-Hodgkin lymphoma. In some embodiments, non-Hodgkin lymphoma is diffuse large B cell lymphoma.

[0084] In some embodiments, a disease or disorder is multiple myeloma. In some embodiments, a disease or disorder is relapsed and refractory multiple myeloma. Formulations

[0085] The present disclosure also provides pharmaceutical compositions 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.

[0086] The present disclosure also provides a medicament comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, as active ingredient.

[0087] Generally, for pharmaceutical use, a compound disclosed herein may be formulated as a pharmaceutical preparation comprising at least one compound disclosed 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 provided hereafter.

[0088] By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms – which may be solid, semi-solid or liquid, depending on the manner of administration – as well as methods and carriers, diluents and excipients for use in 164 IPTS / 200089477.1

[0164] Attorney Docket No. HOT-020WO the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

[0089] Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and / or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. Formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. Compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.

[0090] Pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and / or instructions for use.

[0091] Depending on the condition to be prevented or treated and the route of administration, a compound disclosed may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.

[0092] Another object of this disclosure is the use of the combination as a medicament, i.e. for medical use. Thus, in one embodiment, the disclosure provides the use of the combination of the disclosure for the manufacturing of a medicament. Especially, the disclosure provides the use of the combined pharmaceutical composition of the disclosure or the kit of the disclosure for the manufacturing of a medicament. EXEMPLIFICATION Compounds of the present disclosure can be prepared as described in WO 2022 / 221704, the entirety of which incorporated in its entirety. 165 IPTS / 200089477.1

[0165] Attorney Docket No. HOT-020WO Example 1. Synthesis of Compound 85

[0093] 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 for 3h at 0°C under nitrogen atmosphere. To the above mixture was added bromocyclobutane (99.81 g, 739.341 mmol, 3 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was diluted with NH4Cl (aq.) (3L) at 0°C.The aqueous layer was extracted with EtOAc (3x500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (150:1) to afford 85a (49 g, 73.38%) as a off-white solid Synthesis of 85b

[0094] 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 overnight at 80°C.The reaction was diluted by the addition of water (500mL) at room temperature. The aqueous layer was extracted with CH2Cl2 / MEOH (10:1) (3x500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (100:1) to afford 85b (43 g, 79.86%) as a yellow oil. Synthesis of 85c 166 IPTS / 200089477.1

[0166] Attorney Docket No. HOT-020WO

[0095] 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 nitrogen atmosphere. The resulting mixture was stirred for 3h at room temperature. The resulting mixture was diluted with water (280 mL). The resulting mixture was filtered, the filter cake was washed with water (3x50 mL). The resulting solid was dried under vacuum. This resulted in 85c (55 g, 86.00%) as a white solid. Synthesis of 85d

[0096] 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 overnight at room temperature. The mixture was acidified to pH 5 with HCl (1 M). The resulting mixture was filtered, the filter cake was washed with water (3x50 mL). The resulting solid was dried under vacuum. This resulted in 85d (50 g, 86.66%) as a off-white solid. Synthesis of 85e

[0097] To a stirred mixture of 85d (50 g, 164.274 mmol, 1 equiv) in EtOAc (190 mL) and H2O (760 mL) was added NaNO2 (113.3 g 1642.74 mmol, 10 equiv) at room temperature. To the above mixture was added HNO3 (1642 mL, 1642.74 mmol, 10.00 equiv, 1 M) dropwise at 0 degrees C. The resulting mixture was stirred overnight at room temperature. The mixture was neutralized to pH 7 with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 / MeOH(10:1) (3x500 mL).The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (50:1) to afford 85e (40 g, 85.84%) as a yellow solid. Synthesis of 85f

[0098] To a solution of 85e (40 g, 146.892 mmol, 1 equiv) in 1.2L MeOH was added Pd / C (20%, 8g) in a 2L round-bottom flask. The mixture was hydrogenated at room temperature overnight under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. This resulted in 85f (35 g, 94.39%) as a off- white solid. Synthesis of 85g

[0099] 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) were added NaBH(OAc)3 (43.73 g, 206.334 mmol, 2 equiv) and HOAc (6.20 g, 103.167 mmol, 1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under 167 IPTS / 200089477.1

[0167] Attorney Docket No. HOT-020WO nitrogen atmosphere. The reaction was quenched by the addition of water (500 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MTBE (2x 50 mL). This resulted in 85g (34 g, 65.18%) as a white solid. Synthesis of 85h

[0100] To a stirred solution of 85g (34 g, 70.784 mmol, 1 equiv) and pyridine (33.59 g, 424.704 mmol, 6 equiv) in DCM (400 mL) were added Triphosgene (7.35 g, 24.774 mmol, 0.35 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (500 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 500 mL) and dried over anhydrous CaCl2. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MTBE (2x 100 mL). This 85h (33 g, 87.47%) as a yellow solid. Synthesis of 85i

[0101] To a solution of 85h (33 g, 65.175 mmol, 1 equiv) and TMEDA (15.15 g, 130.350 mmol, 2 equiv) in dioxane (1000 mL) was 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) in an autoclave. After flushing the autoclave three times with CO / H2 (1:1), the mixture was pressurized to 10 atm with CO / H2 (1:1) and run overnight at 80 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to CH2Cl2 / MeOH (5:1) to afford 85i (20 g, 67.38%) as a yellow solid. Synthesis of 85j

[0102] 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 for 2 h at room temperature under nitrogen atmosphere. To the above mixture was added NaBH(OAc)3 (6.98 g, 32.936 mmol, 1.5 equiv). The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of water (200 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 / MeOH=10 / 1 (2 x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN 168 IPTS / 200089477.1

[0168] Attorney Docket No. HOT-020WO in water(10 mol / L NH4HCO3), 15% to 60% gradient in 40 min; detector, UV 254 nm. This resulted in 85j (6.5 g, 54.96%) as a yellow solid. Synthesis of 85

[0103] The 85j (6.5 g) was purified by Prep-Chiral-SFC with 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(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT2(min): 6.26; Sample Solvent: MEOH(0.1% 2M NH3-MEOH); Injection Volume: 1 mL; Number Of Runs: 30). This resulted in Compound 85 (3.0062g) 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). Example 2. Bispecific antibody-mediated cytotoxicity assay

[0104] Target cell lines (LNCaP, 22Rv1, HCC1500, LK-2 and PC-3) expressing different levels of PSMA antigen were labeled with CFSE and seeded at a density of 1X10^5 cells / ml, 100ul per well in a 96-well flat-bottom plate. The next day, human peripheral blood mononuclear cells (PBMCs) were added at a ratio of 5:1 (effector to target) with a concentration of 1x10^6 cells / ml, 50ul per well. The tumor and PBMC cocultures were treated with serial dilutions (1 μg / mL, 0.1 μg / mL, 0.01 μg / mL, or 0.001 μg / mL) of the bispecific antibody Voxalatamab or a vehicle control, in the presence or absence of 10nM or 100nM of compound 85. After 24 hours of incubation, cells were collected and stained with a live / dead marker (FVS780). The percentage of dead tumor cells (CFSE+FVS780+) was determined by flow cytometry. Results from these experiments are summarized in Table 2 and FIG.1.

[0105] Target cell lines (U266B1, Ramos.2G6.4C10 (Ramos), Daudi, and OCI-LY3) expressing different levels of BCMA antigen were labeled with CFSE and seeded at a density of 2X10^5 cells / ml, 50ul per well in a 96-well flat-bottom plate. Human peripheral blood mononuclear cells (PBMCs) were added at a ratio of 5:1 (effector to target) with a concentration of 1x10^6 cells / ml, 50ul per well. The tumor and PBMC cocultures were treated with serial dilutions (1 μg / mL, 0.1 μg / mL, 0.01 μg / mL, or 0.001 μg / mL) of the bispecific antibody Pavurutamab or a vehicle control, in the presence or absence of 10nM or 100nM of compound 85. After 24 hours of incubation, cells were collected and stained with a live / dead 169 IPTS / 200089477.1

[0169] Attorney Docket No. HOT-020WO marker (FVS780). The percentage of dead tumor cells (CFSE+FVS780+) was determined by flow cytometry. Results from these experiments are summarized in Table 2 and FIG.2. Table 2 E / T ration 5:1 Dead tumor cell percentage (%) Bispecific Tumor antibody (ug / ml) DMSO +100 nM Compound 85 +10 nM Compound 85 170 IPTS / 200089477.1

Claims

1. Attorney Docket No. HOT-020WO CLAIMS We claim:

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

2. A method of treating a disease or condition associated with cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a CBL-B inhibitor wherein the subject has previously been treated with a bispecific antibody.

3. A method of treating a disease or condition associated with cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody wherein the subject has previously been treated with a CBL-B inhibitor.

4. The method of any of claims 1-3, wherein the CBL-B inhibitor is a compound of formula (A): or pharmaceutic , wherein Y is selected from the group =C(H)-, =C(Ra)- or =N-; Z is =O or =S; E is optionally substituted 5-6 membered heterocyclyl; B is optionally substituted phenyl, optionally substituted 8-10 membered bicyclyl, or optionally substituted 5-6 membered heteroaryl; C is optionally substituted 5-6 membered heterocyclyl; X is an optionally substituted C1-C3alkylene chain, wherein one or more methylene units is optionally replaced by -N(H)-, -N(R1)-, -O-, -S-, -SO-, -SO2-, optionally substituted 3-6- membered carbocyclyl, and optionally substituted 3-6-membered heterocylyl, wherein X is optionally substituted with an optionally substituted group selected from a group 171 IPTS / 200089477.1Attorney Docket No. HOT-020WO consisting of halogen, C1-C3 aliphatic, phenyl, 3-6-membered heteroaryl, 3-6-membered heterocylyl, and -(CH2)(3-6-membered carbocyclyl); each Rais independently selected from the group consisting of L-A, halogen, -CN, -OH, - OR1, -NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -C(O)R1, -CONH2, -CONR1R2, - SO2NH2, -SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, -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 Rais optionally substituted with 1-5 instances of Ra1; L is an optionally substituted C1-C3 alkylene chain; A is selected from the group consisting of optionally substituted C3-C7 carbocylyl, 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 instances of Ra1; each Ra1is independently selected from the group consisting of halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - 12 1 1 1 1 1R1,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 Rbis independently selected from the group consisting of, halogen, -CN, -OH, -OR1, - NH2, -NR1R2, -SH, -SR1, -SF5, -CO2H, -CO2R1, -CONH2, -CONR1R2, -SO2NH2, - SO2NR1R2, -SO2OH, -SO2OR1, -S(O)R1, -S(O)2R1, -S(O)(NH)R1, -S(O)(NR1)R1, 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 172 IPTS / 200089477.1Attorney Docket No. HOT-020WO optionally substituted 5-6-membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O and S; each Rcis independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, OR1, -NH2, -NR1R2, 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R1is 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)R3, -CO2R3, -C(O)NHR3, and -SO2R3; each R2is 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 R1and R2are taken together with their intervening atom(s) to 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 R3is 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, 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.

5. The method of any of the previous claims, wherein C is selected from the group consisting of optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally 173 IPTS / 200089477.1Attorney Docket No. HOT-020WO substituted thiadizolyl, optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, and optionally substituted pyridazinyl.

6. The method of any of the previous claims, wherein the compound is of Formula (B): or pharmaceutically a7. The method of any of the previous claims, wherein the compound is of Formula (I):or pharmaceutically acceptable salts thereof.

8. The method of any of the previous claims, wherein the compound is of Formula (Ia) or (IIa): or apharmaceutically acceptable salt thereof, wherein each W is independently selected from N or C. 174 IPTS / 200089477.1Attorney Docket No. HOT-020WO 9. The method of any of the previous claims, wherein the compound is of formula (Ia1) or (IIa1): o10. The method of any of the previous claims, wherein the compound is of Formula (Ia2), (Ia3), or (Ia4): or ap y p .

11. The method of any of the previous claims, wherein the compound is of formula (Ib) or (IIb): IPTS / 2000894.Attorney Docket No. HOT-020WO (Ib) (IIb), or pharmaceutically acceptable salts thereof, wherein each W is independently selected from N or C.

12. The method of any of the previous claims, wherein the compound is of formula (Ic) or (IIc): or13. The method of any of the previous claims, wherein Rcis optionally substituted C1- C3 aliphatic.

14. The method of any of the previous claims, wherein each Rcis independently selected from the group consisting of methyl, -CD3, -CHF2 15. The method of any of the previous claims, wherein Rcis methyl.

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

17. The method of any of the previous claims, wherein X or optionallysubstituted C2 alkylene, wherein one methylene unit is replaced wit .

18. The method of any of the previous claims, wherein X is selected from the group consisting of 176 IPTS / 200089477.1Attorney Docket No. HOT-020WO , , ,177 IPTS / 200089477.1Attorney Docket No. HOT-020WO ,19. The method of any of the previous claims, wherein Rais L-A. 178 IPTS / 200089477.1Attorney Docket No. HOT-020WO 20. The method of any of the previous claims, wherein L is -CH2- or -CH(CH3)-.

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

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

23. The method of any of the previous claims, wherein each Rais independently selected from the group consisting of halogen, -CN, -CO2H, -CHO, -CHF2, -CF3, - OMe, -S(O)2NHMe, , ,179 IPTS / 200089477.1Attorney Docket No. HOT-020WO , , , ,180 IPTS / 200089477.1Attorney Docket No. HOT-020WO ,181 IPTS / 200089477.1Attorney Docket No. HOT-020WO O N182 IPTS / 200089477.1Attorney Docket No. HOT-020WO , , ,183 IPTS / 200089477.1Attorney Docket No. HOT-020WO , , 24.e meto o any o te prevous cams, weren te compound is selected from the group consisting of Cmpd Structure NoIPTS / 200089477.1Attorney Docket No. HOT-020WO185 IPTS / 200089477.1Attorney Docket No. HOT-020WO186 IPTS / 200089477.1Attorney Docket No. HOT-020WO187 IPTS / 200089477.1Attorney Docket No. HOT-020WO188 IPTS / 200089477.1Attorney Docket No. HOT-020WO189 IPTS / 200089477.1Attorney Docket No. HOT-020WO190 IPTS / 200089477.1Attorney Docket No. HOT-020WO191 IPTS / 200089477.1Attorney Docket No. HOT-020WOIPTS / 200089477.1Attorney Docket No. HOT-020WO193 IPTS / 200089477.1Attorney Docket No. HOT-020WO194 IPTS / 200089477.1Attorney Docket No. HOT-020WO195 IPTS / 200089477.1Attorney Docket No. HOT-020WO196 IPTS / 200089477.1Attorney Docket No. HOT-020WO197 IPTS / 200089477.1Attorney Docket No. HOT-020WO198 IPTS / 200089477.1Attorney Docket No. HOT-020WO199 IPTS / 200089477.1Attorney Docket No. HOT-020WO200 IPTS / 200089477.1Attorney Docket No. HOT-020WO201 IPTS / 200089477.1Attorney Docket No. HOT-020WO202 IPTS / 200089477.1Attorney Docket No. HOT-020WO203 IPTS / 200089477.1Attorney Docket No. HOT-020WO204 IPTS / 200089477.1Attorney Docket No. HOT-020WO205 IPTS / 200089477.1Attorney Docket No. HOT-020WO206 IPTS / 200089477.1Attorney Docket No. HOT-020WO207 IPTS / 200089477.1Attorney Docket No. HOT-020WO208 IPTS / 200089477.1Attorney Docket No. HOT-020WO209 IPTS / 200089477.1Attorney Docket No. HOT-020WO210 IPTS / 200089477.1Attorney Docket No. HOT-020WO211 IPTS / 200089477.1Attorney Docket No. HOT-020WO212 IPTS / 200089477.1Attorney Docket No. HOT-020WO213 IPTS / 200089477.1Attorney Docket No. HOT-020WO214 IPTS / 200089477.1Attorney Docket No. HOT-020WO215 IPTS / 200089477.1Attorney Docket No. HOT-020WO216 IPTS / 200089477.1Attorney Docket No. HOT-020WO217 IPTS / 200089477.1Attorney Docket No. HOT-020WO218 IPTS / 200089477.1Attorney Docket No. HOT-020WO219 IPTS / 200089477.1Attorney Docket No. HOT-020WO220 IPTS / 200089477.1Attorney Docket No. HOT-020WO221 IPTS / 200089477.1Attorney Docket No. HOT-020WO222 IPTS / 200089477.1Attorney Docket No. HOT-020WO223 IPTS / 200089477.1Attorney Docket No. HOT-020WO224 IPTS / 200089477.1Attorney Docket No. HOT-020WO225 IPTS / 200089477.1Attorney Docket No. HOT-020WO226 IPTS / 200089477.1Attorney Docket No. HOT-020WO227 IPTS / 200089477.1Attorney Docket No. HOT-020WO228 IPTS / 200089477.1Attorney Docket No. HOT-020WO229 IPTS / 200089477.1Attorney Docket No. HOT-020WO230 IPTS / 200089477.1Attorney Docket No. HOT-020WO231 IPTS / 200089477.1Attorney Docket No. HOT-020WO232 IPTS / 200089477.1Attorney Docket No. HOT-020WO233 IPTS / 200089477.1Attorney Docket No. HOT-020WO234 IPTS / 200089477.1Attorney Docket No. HOT-020WO235 IPTS / 200089477.1Attorney Docket No. HOT-020WO236 IPTS / 200089477.1Attorney Docket No. HOT-020WO237 IPTS / 200089477.1Attorney Docket No. HOT-020WO238 IPTS / 200089477.1Attorney Docket No. HOT-020WO239 IPTS / 200089477.1Attorney Docket No. HOT-020WO240 IPTS / 200089477.1Attorney Docket No. HOT-020WO241 IPTS / 200089477.1Attorney Docket No. HOT-020WO242 IPTS / 200089477.1Attorney Docket No. HOT-020WO243 IPTS / 200089477.1Attorney Docket No. HOT-020WO244 IPTS / 200089477.1Attorney Docket No. HOT-020WO245 IPTS / 200089477.1Attorney Docket No. HOT-020WO246 IPTS / 200089477.1Attorney Docket No. HOT-020WO247 IPTS / 200089477.1Attorney Docket No. HOT-020WO248 IPTS / 200089477.1Attorney Docket No. HOT-020WO249 IPTS / 200089477.1Attorney Docket No. HOT-020WO250 IPTS / 200089477.1Attorney Docket No. HOT-020WO251 IPTS / 200089477.1Attorney Docket No. HOT-020WO252 IPTS / 200089477.1Attorney Docket No. HOT-020WO253 IPTS / 200089477.1Attorney Docket No. HOT-020WO254 IPTS / 200089477.1Attorney Docket No. HOT-020WO255 IPTS / 200089477.1Attorney Docket No. HOT-020WO256 IPTS / 200089477.1Attorney Docket No. HOT-020WO257 IPTS / 200089477.1Attorney Docket No. HOT-020WO258 IPTS / 200089477.1Attorney Docket No. HOT-020WO259 IPTS / 200089477.1Attorney Docket No. HOT-020WO260 IPTS / 200089477.1Attorney Docket No. HOT-020WO261 IPTS / 200089477.1Attorney Docket No. HOT-020WO262 IPTS / 200089477.1Attorney Docket No. HOT-020WO263 IPTS / 200089477.1Attorney Docket No. HOT-020WO264 IPTS / 200089477.1Attorney Docket No. HOT-020WO265 IPTS / 200089477.1Attorney Docket No. HOT-020WO266 IPTS / 200089477.1Attorney Docket No. HOT-020WO267 IPTS / 200089477.1Attorney Docket No. HOT-020WO268 IPTS / 200089477.1Attorney Docket No. HOT-020WO F FF269 IPTS / 200089477.1Attorney Docket No. HOT-020WO 403 P270 IPTS / 200089477.1Attorney Docket No. HOT-020WO271 IPTS / 200089477.1Attorney Docket No. HOT-020WO272 IPTS / 200089477.1Attorney Docket No. HOT-020WO273 IPTS / 200089477.1Attorney Docket No. HOT-020WO274 IPTS / 200089477.1Attorney Docket No. HOT-020WO275 IPTS / 200089477.1Attorney Docket No. HOT-020WO276 IPTS / 200089477.1Attorney Docket No. HOT-020WO277 IPTS / 200089477.1Attorney Docket No. HOT-020WO278 IPTS / 200089477.1Attorney Docket No. HOT-020WO279 IPTS / 200089477.1Attorney Docket No. HOT-020WO280 IPTS / 200089477.1Attorney Docket No. HOT-020WO281 IPTS / 200089477.1Attorney Docket No. HOT-020WO282 IPTS / 200089477.1Attorney Docket No. HOT-020WO283 IPTS / 200089477.1Attorney Docket No. HOT-020WO284 IPTS / 200089477.1Attorney Docket No. HOT-020WO285 IPTS / 200089477.1Attorney Docket No. HOT-020WO286 IPTS / 200089477.1Attorney Docket No. HOT-020WO287 IPTS / 200089477.1Attorney Docket No. HOT-020WO288 IPTS / 200089477.1Attorney Docket No. HOT-020WO289 IPTS / 200089477.1Attorney Docket No. HOT-020WOIPTS / 200089477.1Attorney Docket No. HOT-020WO291 IPTS / 200089477.1Attorney Docket No. HOT-020WO292 IPTS / 200089477.1Attorney Docket No. HOT-020WO293 IPTS / 200089477.1Attorney Docket No. HOT-020WO294 IPTS / 200089477.1Attorney Docket No. HOT-020WO295 IPTS / 200089477.1Attorney Docket No. HOT-020WO296 IPTS / 200089477.1Attorney Docket No. HOT-020WO297 IPTS / 200089477.1Attorney Docket No. HOT-020WO298 IPTS / 200089477.1Attorney Docket No. HOT-020WO299 IPTS / 200089477.1Attorney Docket No. HOT-020WO300 IPTS / 200089477.1Attorney Docket No. HOT-020WO301 IPTS / 200089477.1Attorney Docket No. HOT-020WO302 IPTS / 200089477.1Attorney Docket No. HOT-020WO303 IPTS / 200089477.1Attorney Docket No. HOT-020WO304 IPTS / 200089477.1Attorney Docket No. HOT-020WO305 IPTS / 200089477.1Attorney Docket No. HOT-020WO306 IPTS / 200089477.1Attorney Docket No. HOT-020WO307 IPTS / 200089477.1Attorney Docket No. HOT-020WO308 IPTS / 200089477.1Attorney Docket No. HOT-020WO25. The method of any of the previous claims, wherein the compound isor a pharmaceutically acceptable salt thereof. 309 IPTS / 200089477.1Attorney Docket No. HOT-020WO 26. The method of any of the previous claims, wherein the compound is or a pharmaceutica27. The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of 60-600 mg.

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

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

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

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

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

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

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

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

36. The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 100 mg. 310 IPTS / 200089477.1Attorney Docket No. HOT-020WO 37. The method of any of the previous claims, wherein the CBL-B inhibitor is administered at a dose of about 150 mg.

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

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

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

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

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

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

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

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

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

47. The method of any of the previous claims, wherein the bispecific antibody is an anti-CD3 bispecific antibody.

48. The method of claim 47, wherein the bispecific antibody is a CD3 / CD19 antibody.

49. The method of claim 48, wherein the CD3 / CD19 antibody is blinatumomab.

50. The method of claim 47, wherein the bispecific antibody is a GP100 / CD3 antibody. 311 IPTS / 200089477.1Attorney Docket No. HOT-020WO 51. The method of claim 50, wherein the GP100 / CD3 antibody is tebentafusp-tebn.

52. The method of claim 47, wherein the bispecific antibody is a CD3 / CD20 antibody.

53. The method of claim 52, wherein the CD3 / CD20 antibody is selected from the group consisting of mosunetuzumab, glofitamab, odronextamab, and epcoritamab.

54. The method of claim 47, wherein the bispecific antibody is a CD3 / BCMA antibody.

55. The method of claim 54, wherein the CD3 / BCMA antibody is selected from the group consisting of pavurutamab, teclistamab, REGN5459, linvoseltamab, and elranatamab.

56. The method of claim 47, wherein the bispecific antibody is a CD3 / GPRC5D antibody.

57. The method of claim 56, wherein the CD3 / GPRC5D is talquetamab-tgvs.

58. The method of claim 47, wherein the bispecific antibody is a CD3 / PSMA antibody.

59. The method of claim 58, wherein the CD3 / PSMA antibody is voxalatamab or REGN4336.

60. The method of claim 47, wherein the bispecific antibody is a MUC16 / CD3 antibody.

61. The method of claim 60, wherein the MUC16 / CD3 antibody is ubamatamab.

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

63. The method of claim 60, wherein cancer is colorectal cancer.

64. The method of claim 60, wherein cancer is a hematologic cancer.

65. The method of claim 64, wherein the hematologic cancer is selected from a group consisting of lymphoma, leukemia, and myeloma. 312 IPTS / 200089477.1Attorney Docket No. HOT-020WO 66. The method of claim 65, wherein cancer is a non-hematologic cancer.

67. The method of claim 66, wherein the non-hematologic cancer is a sarcoma or a carcinoma.

68. The method of any one of claims 1-67, wherein the subject has one or more of increased T-cell activation, increased T-cell proliferation, decreased T-cell exhaustion, decreased T-cell anergy and decreased T-cell tolerance after administration of compound of any of claims 1-15 or a pharmaceutical composition of claim 16.

69. The method of claim 68, wherein increased T-cell activation comprises increased production of a cytokines.

70. The method of claims 1-67, wherein the subject has increased NK-cell activation.

71. The method of 70, the increased NK-cell activation comprises increased production of cytokines. 313 IPTS / 200089477.1

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