Pyrididine-3(2H)-one derivatives

Abstract

Provided herein is a compound of formula 1, TIFF2024539252000188.tif40128 A variety of substituents are described herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 273,071, filed on 28 October 2021, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Adenosine diphosphate (ADP)-ribosylation is a well-conserved post-translational modification found in viruses, bacteria, and eukaryotes. It is catalyzed by members of the ADP-ribosyltransferase (ART) superfamily of proteins, which transfer ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to a substrate via N-, O-, or S-glycosidic bonds on a target molecule. One subset of ART is poly(adenosine diphosphate-ribose) polymerase (PARP). PARP is a family of 17 known enzymes that regulate fundamental cellular processes, including gene expression, proteolysis, and multiple cellular stress responses (MS. Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. (Nat. Chem Biol 14, 236-243 (2018))). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and a novel approach for new therapeutics.

[0003] Of particular interest is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TIPARP), a CCCH-type zinc finger domain-containing protein (Proc.Nat.Acad.Sci.114(10)2681-2686(2017)). TIPARP is also known as PARP7 and ARTD14. PARP7 acts as a negative regulator of certain aryl hydrocarbon receptor (AHR) transcriptional targets. AHRs are then activated by many substrates, including tobacco smoke. PARP7 inhibitors have been shown to restore type I interferon (IFN) signaling responses to nucleic acids and induce tumor regression in an immune-responsive BALB / c mouse model with CT26 tumors (Gozgit, et al., Cancer Cell 39, 1214-1226(2021)). Currently, there are no approved PARP7 inhibitor drugs. Therefore, it would be useful to provide PARP7 inhibitor compounds with properties suitable for administration as pharmaceuticals to mammals, particularly humans. International Publications 2007 / 138351 and 2009 / 063244 are intended to describe PARP inhibitors. International Publications 2019 / 212937, 2021 / 087018 and 2021 / 087025 are also intended to describe PARP7 inhibitors. PARP7 inhibitors are needed for cancer treatment. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2007 / 138351 [Patent Document 2] International Publication No. 2009 / 063244 [Patent Document 3] International Publication No. 2019 / 212937 [Patent Document 4] International Publication No. 2021 / 087018 [Patent Document 5] International Publication No. 2021 / 087025 [Non-patent literature]

[0005] [Non-Patent Document 1] MSCohen,P.Chang,Insights into the biogenesis,function,and regulation of ADP-ribosylation.(Nat.Chem Biol 14,236-243(2018) [Non-Patent Document 2] Proc.Nat.Acad.Sci.114(10)2681-2686(2017) [Non-Patent Document 3] Gozgit,et al.,Cancer Cell 39,1214-1226(2021) [Overview of the Initiative]

[0006] Compounds and pharmaceutical compositions useful as PARP7 inhibitors are provided herein. Some of the compounds of this disclosure can be found in pharmaceutical compositions with at least one pharmaceutically acceptable excipient to treat subjects requiring such treatment.

[0007] Provided herein are compounds of formula (I),

[0008] [ka] During the ceremony, n is either 0 or 1. X is C, CH, CR 11 , O, N One or more R 5 3- to 10-membered cycloalkyl groups optionally substituted with; or One or more R 5 A 4- to 11-member heterocycline that has been selectively substituted; Selected from, R 1 teeth, One or more R 5 C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl optionally substituted with one or more R; O-R 6 , NHR 7 , NR 7 R 8 ; One or more R 5 C cycloalkyl optionally substituted with one or more R; 3~10 ; One or more R 5 4-11 membered heterocyclyl optionally substituted with one or more R; One or more R 5 C alkylaryl optionally substituted with one or more R; 2~6 ; One or more R 5 C alkylheteroaryl optionally substituted with one or more R; 1~6 ; One or more R 5 5-10 membered heteroaryl optionally substituted with one or more R; One or more R 5 5-11 membered alkyl spiro ring optionally substituted with one or more R; One or more R 5 5-11 membered hetero spiro ring optionally substituted with one or more R; One or more R 5 C aryl optionally substituted with one or more R; or 6~10 ; C(O), C(O)O, C(O)NR 7 , S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 ; Selected from, provided that When X is O, n is 0, and R 1 is One or more R 5 C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl optionally substituted with one or more R; One or more R 5 C optionally substituted with one or more R3~10 Cycloalkyl; One or more R 5 A 4- to 11-member heterocycline that has been selectively substituted; One or more R 5 C is optionally replaced by 1~6 alkylheteroaryl; One or more R 5 5-10 member heteroaryls optionally substituted with; One or more R 5 C is optionally replaced by 6~10 Ariel; One or more R 5 5-11 member alkyl spiro rings optionally substituted with; One or more R 5 A 5- to 11-membered heterospiro ring optionally substituted with; C(O), or C(O)NR 7 ; Selected from, If X is N, then R 1 teeth, One or more R 5 C1-5 alkyl, C1-5 alkenyl, and C1-5 alkynyl molecules optionally substituted with; One or more R 5 C is optionally replaced by 3~10 Cycloalkyl; One or more R 5 A 4- to 11-member heterocycline that has been selectively substituted; One or more R 5 C is optionally replaced by 1~6 Alkylaryl; One or more R 5 C is optionally replaced by 1~6 alkylheteroaryl; One or more R 5 5-10 member heteroaryls optionally substituted with; One or more R 5 5-11 member alkyl spiro rings optionally substituted with; One or more R 5 A 5- to 11-membered heterospiro ring optionally substituted with; One or more R 5C optionally replaced with 6~10 aryl; or C(O), C(O)O, C(O)NR 7 , S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ one or more R 5 4- to 12-member heterocyclyl optionally substituted with one or more R; or one or more R 5 C 3~10 cycloalkyl optionally substituted with one or more R; selected from, or when X is CH and CR 11 R 2 is H, halo, NO2, CN, O-R 6 C(O)-R 5 C(O)-N(R 7 )(R 8 ) N(R 7 )(R 8 ) N(R 7 )C(O)-R 5 N(R 7 )C(O)O-R 6 N(R 7 )S(O)2(R 6 ) -N(R 7 )C(O)-N(R 7 )(R 8 ) S(O)2R 9 S(O)2N(R 7 )(R 8 ) S(O)(NH)R 7 S(O)(NR 7 )NR 8 one or more R 5 C 1~9 alkyl optionally substituted with one or more R; one or more R 5 C 2~9 alkynyl optionally substituted with one or more R; one or more R 5 C 2~9 alkenyl optionally substituted with one or more R; one or more R 5 5- to 10-member heteroaryl optionally substituted with one or more R; one or more R 5 C 6~10 aryl optionally substituted with one or more R; one or more R 5 4- to 12-member heterocyclyl optionally substituted with one or more R; or One or more R 5 C is optionally replaced by 3~10 Cycloalkyl; Selected from, or If X is N, then R 2 teeth, H, -C(O)-R 5 -C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 One or more R 5 C is optionally replaced by 1~9 alkyl; One or more R 5 C is optionally replaced by 2~9 Alkinnil; One or more R 5 C is optionally replaced by 2~9 Alkenil; One or more R 5 5-10 member heteroaryls optionally substituted with; One or more R 5 C is optionally replaced by 6~10 Ariel; One or more R 5 A 4-12 member heterocycline optionally substituted with; or One or more R 5 C is optionally replaced by 3~10 Cycloalkyl; Selected from, or R 1 and R 2 They, together with the atoms to which they are bonded, One or more R 10 C is optionally replaced by 3~11 Cycloalkyl; One or more R 10 A 4- to 8-membered monocyclic heterocycline optionally substituted with; One or more R 10A 6-12 membered bicyclic heterocycline optionally substituted with; One or more R 5 5- to 11-member heteroaryl compounds optionally substituted with; One or more R 5 C is optionally replaced by 6~10 Ariel; Forming, Any 3-11 member cycloalkyl or 4-11 member heterocyclil is monocyclic, bicyclic, condensed bicyclic, spirocyclic, or crosslinked, and one or more R 9 It is optionally replaced by Any 6-12 member heteroaryl or C 6~10 The aryl group can be monocyclic, bicyclic, or fused bicyclic. L is :C(O), OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 6 , N(R 7 )C(O)OR 6 , N(R 7 )S(O)2(R 6 ), N(R 7 )C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 , R 6 (CO), R 6 S(O)2, R 6 S(O)2N(R 7 ); One or more R 9 C, which is optionally replaced by 1~6 Alkilen, C 2~6 Alkenylene, C 2~6 Alkinylene; One or more R 5 C is optionally replaced by 3~10Cycloalkyl; One or more R 5 A 4- to 7-membered monocyclic heterocycline optionally substituted with; One or more R 9 A 6-12 membered bicyclic heterocycline optionally substituted with; One or more R 5 Selected from 5-10 member heteroaryls that are optionally substituted with; or R 1 And L, together with the atoms to which they are bonded, One or more R 9 C is optionally replaced by 3~11 Cycloalkyl; One or more R 5 A 4-11 member monocyclic heterocycline optionally substituted with; One or more R 9 A 6-12 membered bicyclic heterocycline optionally substituted with; One or more R 5 5- to 11-member heteroaryl compounds optionally substituted with; Forming, A 3-11 membered cycloalkyl or 4-11 membered heterocyclil is monocyclic, bicyclic, condensed bicyclic, spirocyclic, or cross-linked, and one or more R 9 It is optionally replaced by R 3 and R 4 teeth, H, Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3,OCHF2, NO2, CN, OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 5 , N(R 7 )C(O)OR 5 , N(R 7 )S(O)2(R 5 ), N(R 7 )C(O)-N(R 7 )(R 8), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 One or more R 5 C is optionally replaced by 1~5 Alkyl; or One or more R 5 C is optionally replaced by 3~10 Cycloalkyl; One or more R 5 5-10 member heteroaryls optionally substituted with; One or more R 5 C is optionally replaced by 6~10 Ariel; or One or more R 5 A 4- to 7-member heterocycline that has been selectively substituted; Selected independently of, or R 2 and R 3 Together with the atoms to which they are bonded, R 10 Forms a 4-10 member cycloalkyl or 4-10 member heterocycle which may be substituted with one or more of the following: A 4-11 membered cycloalkyl or 4-11 membered heterocyclil is monocyclic, bicyclic, condensed bicyclic, spirocyclic, or cross-linked, and one or more R 10 It is optionally replaced by, or R 3 and R 4 These, together with the atoms to which they are bonded, form a 4-12 cycloalkyl or 4-12 membered heterocycline, R 10 It may be substituted with one or more R groups, and the 4-12 membered cycloalkyl or 4-12 membered heterocyclil is monocyclic, bicyclic, condensed bicyclic, spirocyclic, or crosslinked, and one or more R groups 10 It is optionally replaced by Q is selected from 3-12 membered cycloalkyls and 4-12 membered heterocycles, any cycloalkyl and heterocycle is monocyclic or bicyclic, any bicyclic cycloalkyl and heterocycle is bridged, condensed, or spiro, and one or more R 9 It may also be replaced with Z is One or more R 13 5-10 member heteroaryls optionally substituted with; One or more R 13 C is optionally replaced by 6~10 Ariel; One or more R 13 C is optionally replaced by 3~12 Cycloalkyl; One or more R 13 A 4- to 12-membered heterocycline that has been selectively substituted; Selected from, Any 5-12 member heteroaryl, C 6~10 Ariel, C 3~12 Cycloalkyls, or 4-12 membered heterocyclines, are monocyclic, bicyclic, fused bicyclic, or spirocyclic, and contain one or more R 9 It may also be replaced with R 5 H, oxo, hydroxy, halo, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C) 1~9 Alkyl), -O(C 2~6 Alkenyl), -O(C 2~6 Alkinyl), -O(C 3~15 Cycloalkyl), -O(C 1~8 Haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 Alkyl), -NH(C 2~6 Alkenyl), -NH(C 2~6 Alkinyl), -NH(C 3~15 Cycloalkyl), -NH(C 1~8Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C 1~9 Alkyl)2-N(C 3~15 Cycloalkyl)2-N(C 2~6 Alkenyl)2-N(C 2~6 Alkinyl)2,-N(C) 3~15 Cycloalkyl)2,-N(C 1~8 Haloalkyl)2,-N(aryl)2,N(heteroaryl)2,N(heterocyclyl)2,-N(C 1~9 Alkyl)(C 3~15 Cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 Alkenyl), -N(C 1~9 Alkyl)(C 2~6 Alkinyl), -N(C 1~9 Alkyl)(C 3~15 Cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 Haloalkyl), -N(C 1~9 Alkyl)(aryl), -N(C 1~9 Alkyl)(heteroaryl), -N(C 1~9 Alkyl)(heterocyclyl), -C(O)(C 1~9 Alkyl), -C(O)(C 2~6 Alkenyl), -C(O)(C 2~6 Alkinyl), -C(O)(C 3~15 Cycloalkyl), -C(O)(C 1~8 Haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 Alkyl), -C(O)O(C 2~6 Alkenyl), -C(O)O(C 2~6 Alkinyl), -C(O)O(C 3~15 Cycloalkyl), -C(O)O(C 1~8 Haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 Alkyl), -C(O)NH(C 2~6 Alkenyl), -C(O)NH(C 2~6Alkinyl), -C(O)NH(C 3~15 Cycloalkyl), -C(O)NH(C 1~8 Haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 Alkyl)2,-C(O)N(C 3~15 Cycloalkyl)2,-C(O)N(C 2~6 Alkenyl)2,-C(O)N(C) 2~6 Alkinyl)2,-C(O)N(C) 3~15 Cycloalkyl)2,-C(O)N(C 1~8 Haloalkyl)2-C(O)N(aryl)2-C(O)N(heteroaryl)2-C(O)N(heterocyclyl)2,-NHC(O)(C 1~9 Alkyl), -NHC(O)(C 2~6 Alkenyl), -NHC(O)(C 2~6 Alkinyl), -NHC(O)(C 3~15 Cycloalkyl), -NHC(O)(C 1~8 Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) 1~9 Alkyl), -NHC(O)O(C 2~6 Alkenyl), -NHC(O)O(C 2~6 Alkinyl), -NHC(O)O(C 3~15 Cycloalkyl), -NHC(O)O(C 1~8 Haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 Alkyl), -NHC(O)NH(C 2~6 Alkenyl), -NHC(O)NH(C 2~6 Alkinyl), -NHC(O)NH(C 3~15 Cycloalkyl), -NHC(O)NH(C 1~8 Haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 Alkyl), -S(C 2~6Alkenyl), -S(C 2~6 Alkinyl), -S(C 3~15 ) independently selected, where any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2-NH(C) 1~9 Alkyl), -NH(C 3~15 Cycloalkyl), -NH(C 1~8 Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C 1~9 Alkyl)2-N(C 3~15 Cycloalkyl)2,-NHC(O)(C 3~15 Cycloalkyl), -NHC(O)(C 1~8 Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) 1~9 Alkyl), -NHC(O)O(C 2~6 Alkinyl), -NHC(O)O(C 3~15 Cycloalkyl), -NHC(O)O(C 1~8 Haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 Alkyl), -S(O)(NH)(C 1~9 Alkyl), -S(O)(NH)(C 3~9 Cycloalkyl), -S(O)(NC 1~9 Alkyl)(C 1~9 Alkyl), -S(O)(NH)(aryl), -S(O)(NH)(heteroaryl), S(O)2(C 1~9 Alkyl), -S(O)2(C 3~15 Cycloalkyl), -S(O)2(C 1~8 Haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C) 1~9 Alkyl), -S(O)2N(C 1~9 Alkyl) 2.-S(O)2NH(aryl), -S(O)2NH(heteroaryl), -O(C 3~15 Cycloalkyl), -O(C 1~8 Haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 Optionally substituted with alkyl, R 6 These are independently C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Selected from cycloalkyl, aryl, heteroaryl, or heterocyclyl, any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more R 9 It is optionally substituted in the base, R 7 and R 8 H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Independently selected from cycloalkyl, aryl, heteroaryl, or heterocyclyl, Any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more R 9 It is optionally substituted in the base, R 9 H, oxo, hydroxy, halo, -C(O)-, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C) 1~9 Alkyl), -O(C 2~6 Alkenyl), -O(C 2~6 Alkinyl), -O(C 3~15 Cycloalkyl), -O(C 1~8 Haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 Alkyl), -NH(C 2~6 Alkenyl), -NH(C 2~6Alkinyl), -NH(C 3~15 Cycloalkyl), -NH(C 1~8 Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C 1~9 Alkyl)2,-N(C 3~15 Cycloalkyl)2,-N(C 2~6 Alkenyl)2,-N(C) 2~6 Alkinyl)2,-N(C) 3~15 Cycloalkyl)2,-N(C 1~8 Haloalkyl)2,-N(aryl)2,N(heteroaryl)2,N(heterocyclyl)2,-N(C 1~9 Alkyl)(C 3~15 Cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 Alkenyl), -N(C 1~9 Alkyl)(C 2~6 Alkinyl), -N(C 1~9 Alkyl)(C 3~15 Cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 Haloalkyl), -N(C 1~9 Alkyl)(aryl), -N(C 1~9 Alkyl)(heteroaryl), -N(C 1~9 Alkyl)(heterocyclyl), -C(O)(C 1~9 Alkyl), -C(O)(C 2~6 Alkenyl), -C(O)(C 2~6 Alkinyl), -C(O)(C 3~15 Cycloalkyl), -C(O)(C 1~8 Haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 Alkyl), -C(O)O(C 2~6 Alkenyl), -C(O)O(C 2~6 Alkinyl), -C(O)O(C 3~15 Cycloalkyl), -C(O)O(C 1~8 Haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9Alkyl), -C(O)NH(C 2~6 Alkenyl), -C(O)NH(C 2~6 Alkinyl), -C(O)NH(C 3~15 Cycloalkyl), -C(O)NH(C 1~8 Haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 Alkyl)2,-C(O)N(C 3~15 Cycloalkyl)2,-C(O)N(C 2~6 Alkenyl)2,-C(O)N(C) 2~6 Alkinyl)2,-C(O)N(C) 3~15 Cycloalkyl)2,-C(O)N(C 1~8 Haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclyl)2, -NHC(O)(C 1~9 Alkyl), -NHC(O)(C 2~6 Alkenyl), -NHC(O)(C 2~6 Alkinyl), -NHC(O)(C 3~15 Cycloalkyl), -NHC(O)(C 1~8 Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) 1~9 Alkyl), -NHC(O)O(C 2~6 Alkenyl), -NHC(O)O(C 2~6 Alkinyl), -NHC(O)O(C 3~15 Cycloalkyl), -NHC(O)O(C 1~8 Haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 Alkyl), -NHC(O)NH(C 2~6 Alkenyl), -NHC(O)NH(C 2~6 Alkinyl), -NHC(O)NH(C 3~15 Cycloalkyl), -NHC(O)NH(C 1~8Haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 Alkyl), -S(C 2~6 Alkenyl), -S(C 2~6 Alkinyl), -S(C 3~15 Cycloalkyl), -S(C 1~8 Haloalkyl), -S (aryl), -S (heteroaryl), -S (heterocyclyl), -NHS(O)(C 1~9 Alkyl), -N(C 1~9 Alkyl)(S(O)(C 1~9 Alkyl), -S(O)N(C 1~9 Alkyl)2,-S(O)(C 1~9 Alkyl), -S(O)(NH)(C 1~9 Alkyl), -S(O)(NH)(C 3-9 Cycloalkyl), -S(O)(NC 1~9 Alkyl)(C 1~9 Alkyl), -S(O)(NH)(aryl), -S(O)(NH)(heteroaryl), -S(O)(C 2~6 Alkenyl), -S(O)(C 2~6 Alkinyl), -S(O)(C 3~15 Cycloalkyl), -S(O)(C 1~8 Haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C) 1~9 Alkyl), -S(O)2(C 2~6 Alkenyl), -S(O)2(C) 2~6 Alkinyl), -S(O)2(C) 3~15 Cycloalkyl), -S(O)2(C 1~8 Haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C) 1~9 Alkyl), or -S(O)2N(C 1~9 Selected independently from alkyl)2, Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more halos, C 1~9 Alkyl, C 1~8Haloalkyl, -OH, -NH2, -NH(C) 1~9 Alkyl), -NH(C 3~15 Cycloalkyl), -NH(C 1~8 Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C 1~9 Alkyl)2,-N(C 3~15 Cycloalkyl)2,-NHC(O)(C 3~15 Cycloalkyl), -NHC(O)(C 1~8 Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) 1~9 Alkyl), -NHC(O)O(C 2~6 Alkinyl), -NHC(O)O(C 3~15 Cycloalkyl), -NHC(O)O(C 1~8 Haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 Alkyl), -S(O)(NH)(C 1~9 Alkyl), S(O)2(C 1~9 Alkyl), -S(O)2(C 3~15 Cycloalkyl), -S(O)2(C 1~8 Haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C) 1~9 Alkyl), -S(O)2N(C 1~9 Alkyl) 2、 -O(C 3~15 Cycloalkyl), -O(C 1~8 Haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 It is optionally substituted with alkyl, R 10 H, oxo, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 5 , N(R 7 )C(O)OR 5 , N(R 7 )S(O)2(R 5 ), N(R 7 )C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 , C 1-6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, one or more R 5 A 3- to 11-membered alkyl spiro ring optionally substituted with, or one or more R 5 Selected from 4- to 11-membered heterospiro rings, which are optionally substituted with R 11 H, Halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 5 , N(R 7 )C(O)OR 5 , N(R 7 )S(O)2(R 5 ), N(R 7 )C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 , C1-6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, one or more R 5 A 3- to 11-membered alkyl spiro ring optionally substituted with, or one or more R 5 Selected from 4- to 11-membered heterospiro rings, which are optionally substituted with R 13 H, oxo, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 5 , N(R 7 )C(O)OR 5 , N(R 7 )S(O)2(R 5 ), N(R 7 )C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 C is optionally substituted with an alkenyl or one or more R9 groups. 2~6 Selected from Alkinir, R 14 H, oxo, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 5, N(R 7 )C(O)OR 5 , N(R 7 )S(O)2(R 5 ), N(R 7 )C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Selected from Alkinir, R 15 H, oxo, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 5 , N(R 7 )C(O)OR 5 , N(R 7 )S(O)2(R 5 ), N(R 7 )C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 4-12 membered heterocyclyl, one or more R 5 A 3- to 11-membered alkyl spiro ring optionally substituted with, or one or more R5 Independently selected from 4- to 11-membered heterospiro rings, which are optionally substituted, R 16 H, oxo, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 6 , C(O)-R 6 , C(O)-N(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )C(O)-R 5 , N(R 7 )C(O)OR 5 NHR 7 , S(O)2(R 5 ), N(R 7 )C(O)-N(R 7 )(R 8 ), S(O)2R 9 , S(O)2N(R 7 )(R 8 ), S(O)(NH)R 7 , S(O)(NR 7 )NR 8 C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~5 Cycloalkyl, or one or more R 5 It is selected from 4- to 12-membered heterocyclines that have been optionally substituted.

[0009] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog, R 4 This is CF3.

[0010] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, X is NH.

[0011] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog, where X is N and R 1 And L is one or more R 5 It is being replaced by an arbitrary choice.

[0012] [ka] In the formula, m is between 0 and 5 (inclusive).

[0013] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, are X, R 1 , R 2 And L are given by the following equations.

[0014] [ka]

[0015] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, are X, R 1 , R 2 And L are given by the following equations.

[0016] [ka]

[0017] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, X is C, CH, or CH2.

[0018] In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog, X is C or CH, and R 1 And L is one or more R 5 It is optionally replaced by

[0019] [ka] In the formula, m is between 0 and 5 (inclusive).

[0020] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, are X, R 1 , R 2 And L are given by the following equations.

[0021] [ka]

[0022] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, are X, R 1 , R 2 And L are given by the following equations.

[0023] [ka]

[0024] In some embodiments of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, X is one or more R 5 Optionally substituted 3- to 7-membered cycloalkyl groups; or one or more R 5 A 4- to 7-membered heterocycloalkyl group is optionally substituted with R 1 And L is one or more R 5 It is optionally replaced.

[0025] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, R 1 and R 2These condense to form pyrrologine, and the pyrrologine contains one or more R 10 It is optionally replaced.

[0026] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, the compound is of formula Ia:

[0027] [ka] Ia is given by m being between 0 and 5 (inclusive).

[0028] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog, the compound is of formula Ib:

[0029] [ka] Represented by Ib, In the formula, m is between 0 and 5 (inclusive), and p is between 0 and 5 (inclusive).

[0030] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, the compound is of formula Ic:

[0031] [ka] It is expressed by Ic., where n is between 0 and 5 (inclusive).

[0032] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, are X, R 1 , R 2 L, Q, and Z are given by the following equations.

[0033] [ka]

[0034] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, the compound is represented by formula Id, Ie, If, or Ig.

[0035] [ka]

[0036] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog, the compound is of formula Ih:

[0037] [ka] It is expressed by Ih., where s is between 0 and 6 (inclusive).

[0038] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, the compound is of formula Ii:

[0039] [ka] It is expressed by Ii., where s is between 0 and 6 (inclusive).

[0040] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog, R 2 and R 3 These atoms, together with the atoms to which they are bonded, form condensed cycloalkyl or condensed heterocyclines.

[0041] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, the compound is of formula Ij or Ik

[0042] [ka] It is expressed as Ij Ik; where q is independently between 0 and 6.

[0043] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, the compound is of formula Il, Im, In, Io, or Ip

[0044] [ka] It is expressed as follows, where q is between 0 and 6 and t is between 0 and 4.

[0045] In some embodiments, for compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof, the compounds are selected from the group consisting of the following formulas:

[0046] [ka]

[0047] In some embodiments, for compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof, the compounds are selected from the group consisting of the following formulas:

[0048] [ka] In the formula, q is between 0 and 6 (inclusive), m is between 0 and 5 (inclusive), and t is between 0 and 4 (inclusive).

[0049] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, R 3 The expression is as follows:

[0050] [ka]

[0051] In some embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog, Q is

[0052] [ka] In the formula, r is between 0 and 8 (inclusive).

[0053] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Q is

[0054] [ka] In the formula, r is between 0 and 8 (inclusive).

[0055] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Q is

[0056] [ka] In the equation, u is between 0 and 7 (inclusive), and v is between 0 and 9 (inclusive).

[0057] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, L is C 1~6It is an alkylene, and the C 1~6 Alkylene is one or more R 10 It is optionally replaced.

[0058] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is,

[0059] [ka] Selected from the given set, where w is between 0 and 3 (inclusive) and t is between 0 and 4 (inclusive).

[0060] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is,

[0061] [ka]

[0062] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is selected from the following formulas.

[0063] [ka]

[0064] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is selected from the following formulas.

[0065] [ka]

[0066] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is selected from the following formulas.

[0067] [ka]

[0068] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is,

[0069] [ka] The result is selected from the given options, and in the formula, v is between 0 and 9 (inclusive).

[0070] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is selected from the following formulas.

[0071] [ka]

[0072] In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog, Q is

[0073] [ka] The following is selected, and in the formula, r is between 0 and 8 (inclusive).

[0074] In some embodiments of the compound of formula I, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, Z is,

[0075] [ka] Selected from, each A is independently either CH or N, or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the compound of formula I, or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog, the compound is of formula Iq:

[0077] [ka] It is expressed by Iq., where v is between 0 and 9 (inclusive).

[0078] In another embodiment, a pharmaceutical composition is provided comprising a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog, together with a pharmaceutically acceptable carrier.

[0079] In another embodiment, a method for treating cancer is provided, comprising administering to a patient in need of such treatment a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers or deuterated analog thereof, or a pharmaceutical composition of formula I. [Modes for carrying out the invention]

[0080] I. Definition The following description clarifies exemplary methods, parameters, etc. However, such description should be understood not as limiting the scope of this disclosure, but rather as a description of exemplary embodiments.

[0081] The following description clarifies exemplary methods, parameters, etc. However, such description should be understood not as limiting the scope of this disclosure, but rather as a description of exemplary embodiments.

[0082] A dash ("-") without a space between two letters or symbols is used to indicate bonding points for substituents. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn across a line in a structure indicates bonding points of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply direction.

[0083] wavy line

[0084] [ka] The symbol indicates a connection point.

[0085] "C u~v The prefix "" indicates that the following groups have carbon atoms from u to v. For example, "C 1~6 The term "alkyl group" indicates that the alkyl group has 1 to 6 carbon atoms.

[0086] In this specification, references to values ​​or parameters "about" include (and describe) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, "about X" for that term includes a description of "X". Also, the singular forms "a" and "the" include plural references unless otherwise clearly indicated in the context. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0087] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1~20 Alkyl), 1 to 8 carbon atoms (i.e., C 1~8 Alkyl), 1 to 6 carbon atoms (i.e., C 1~6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1~4 Alkyl compounds include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbon atoms is designated by its chemical name or identified by its molecular formula, all positional isomers having that number of carbon atoms can be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0088] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 Alkenyl) or having 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0089] "Alkynyl" contains at least one carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkynyl), 2 to 8 carbon atoms (i.e., C2~8 Alkynyl), 2-6 carbon atoms (i.e., C 2~6 Alkynyl) or having 2 to 4 carbon atoms (i.e., C 2~4 Alkynyl refers to an alkyl group. The term "alkynyl" also includes alkynyl groups that have one triple bond and one double bond.

[0090] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0091] A "haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0092] "Alkylthio" refers to the "alkyl-S-" group.

[0093] "Amino" is the base -NR y R y This refers to each R y The elements are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0094] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or a polycyclic (e.g., bicyclic or tricyclic) system including a condensed system. As used herein, aryl has 6 to 20 carbocyclic atoms (i.e., C 6~20 (aryl), having 6 to 12 carbocyclic atoms (i.e., C 6~12 (aryl), or having 6 to 10 carbon ring atoms (i.e., C 6~10Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl groups do not in any way encompass, nor overlap with, heteroaryl groups as defined below. When one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. When one or more aryl groups are fused with a heterocyclyl group, the resulting ring system is a heterocyclyl group.

[0095] "Cyano" refers to the group -CN.

[0096] "Keto" or "oxo" refers to the base = oxygen.

[0097] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group and -NR refer to the group. y C(O)OR z It refers to both the "N-carbamoyl group" and the group, and in the formula, R y and R z Each of these is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, and each of them can be optionally substituted.

[0098] "Carboxyl" refers to -C(O)OH.

[0099] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent, and each of these may be optionally substituted as defined herein.

[0100] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures, including condensed ring systems, bridged ring systems, and spirocyclic systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl refers to a ring containing 3 to 20 carbon atoms (i.e., C 3~20 Cycloalkyl), 3-12 ring carbon atoms (i.e., C 3~12Cycloalkyl), 3-10 ring carbon atoms (i.e., C 3~10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3~6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0101] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodine. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogens. For example, if a residue is substituted with two or more halogens, it may be referred to by using a prefix corresponding to the number of halogenated moieties. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may but are not necessarily the same halogen. Examples of haloalkyls include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0102] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, a heteroalkyl group comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0103] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 Heteroaryls), or 3 to 8 carbon ring atoms (i.e., C 3~8A heteroaryl group comprises a heteroaryl group and, independently, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridadinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bonded via any of the rings in the fused system. Any aromatic ring having one or more fused rings containing at least one heteroatom is considered a heteroaryl regardless of its bond to the rest of the molecule (i.e., via any one of the fused rings). As defined earlier, a heteroaryl does not contain an aryl and does not overlap with an aryl.

[0104] A "heterocyclyl" independently refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bicyclic heterocyclyl groups, bridged heterocyclyl groups, condensed heterocyclyl groups, and spiro-heterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, and polycyclics may be condensed, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl regardless of bonding (i.e., it can be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, regardless of bonding to the rest of the molecule, which may be condensed with an aryl ring or a heteroaryl ring. As used herein, a heterocyclyl has 2 to 20 ring atoms (i.e., a 4 to 20-membered heterocyclyl), 2 to 12 ring atoms (i.e., a 4 to 12-membered heterocyclyl), 4 to 10 ring atoms (i.e., a 4 to 10-membered heterocyclyl), 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclyl), or 4 to 6 ring carbon atoms (i.e., a 4 to 6-membered heterocyclyl), and independently has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, sulfur, or oxygen. A heterocyclyl may contain one or more oxo groups and / or thioxo groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 4- to 7-membered ring sultams, 4- to 7-membered cyclic carbamates, 4- to 7-membered cyclic carbonates, 4- to 7-membered cyclic sulfides, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4- to 10-membered cyclic moiety in which, at two non-adjacent atoms of a heterocyclyl having one or more (e.g., one or two) 4- to 10-membered cyclic moieties, each heteroatom is independently linked to at least one heteroatom selected from nitrogen, oxygen, and sulfur.As used herein, crosslinked heterocyclyls include bicyclic and tricyclic ring systems. Furthermore, as used herein, the term “spiroheterocyclyl” refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, where the one or more additional rings are 3- to 10-membered cycloalkyls or 3- to 10-membered heterocyclyls, and where a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bonded via any of the rings in the condensation system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group bonded at two points to another cyclic group, and the other cyclic group may itself be a heterocyclic or carbocyclic group.

[0105] As used herein, the term “nitrogen- or sulfur-containing heterocyclil” means a heterocyclil moiety containing at least one nitrogen atom or at least one sulfur atom, or both nitrogen and sulfur atoms, within its ring structure. It should be understood that other heteroatoms, including oxygen, may be present in addition to nitrogen, sulfur, or combinations thereof. Examples of nitrogen- or sulfur-containing heterocyclils include morpholinyl, thiomorpholinyl, thiazolyl, isothiazolyl, oxazolidinone 1,2-dithiolyl, piperidinyl, and piperazinyl.

[0106] "Hydroxy" or "hydroxyl" refers to an -OH group. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0107] "Nitro" refers to the -NO2 group.

[0108] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0109] "Alkylsulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0110] "Alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or a defined group.

[0111] "Thiocyanate" - SCN.

[0112] "Thiol" refers to the group -SR, where R is a substituent or a defined group.

[0113] "Thioxo" or "thion" refers to a (=S) group or a (S) group.

[0114] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" or "alkylenyl" groups, or "arylene" or "aryrenyl" groups, respectively. Also, unless otherwise expressly indicated, when a combination of groups is referred to herein as one part, for example, arylalkyl, the last group mentioned contains the atom to which that part is bonded to the remainder of the molecule.

[0115] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both cases in which such event or situation occurs and cases in which it does not occur. The term “optionally substituted” refers to one or more hydrogen atoms on a specified atom or group that may or may not be substituted by a non-hydrogen portion. “Optionally substituted” may range from zero to the maximum number of possible substitutions, and each occurrence is independent. Where the term “substituted” is used, the substitution must be made on a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from (mandatory) substitutions.

[0116] If a part is "optionally substituted" and any general term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl" is referenced, then this general term is (C 1~3 (Alkyl), (C 4~6 Alkyl), -O(C 1~4 (Alkyl), (C 3~10 Cycloalkyl), O-(C 3~10 The term can refer to any preceding, specifically enumerated term such as cycloalkyl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryls such as phenyl or naphthyl. Similarly, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyls such as oxetanyl, tetrahydropyranil, morpholino, and piperidinyl. Likewise, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteryl)," as well as certain heteroaryls such as pyridine.

[0117] Some of the compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imido acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound contains both amides and imido acid tautomers. Therefore, amide-containing compounds are understood to contain their imido acid tautomers. Similarly, imido acid-containing compounds are understood to contain their amide tautomers.

[0118] Any formula or structure given herein is also intended to represent both the unlabeled and isotope-labeled forms of the compounds. An isotope-labeled compound has the structure represented by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Examples of isotope-labeled compounds in this disclosure include, but are not limited to, I. 3 H, 13 C and 14 These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation therapy for patients.

[0119] This disclosure also includes “deuterated analogues” of the compounds of formula I, in which 1 to n hydrogens bonded to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of formula I when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0120] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to greater metabolic stability, such as extended half-life in vivo, reduced dose requirements, and / or improved therapeutic index. 18 1F-labeled compounds may be useful in PET or SPECT testing. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting readily available isotope-labeling reagents with non-isotope-labeling reagents, by performing the procedures disclosed in the scheme or the examples and preparations described below. In this context, deuterium is understood to be a substituent in the compounds of formula I.

[0121] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in the isotopic composition of the natural abundance of hydrogen. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0122] In many cases, the compounds of this disclosure can form acidic salts and / or basic salts in the presence of an amino group and / or a carboxyl group or a similar group.

[0123] pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human medicinal uses.

[0124] The term “pharmaceutically acceptable salt” of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. “pharmaceutically acceptable salt” or “physiologically acceptable salt” includes, for example, salts containing inorganic acids and salts containing organic acids. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acidic salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating this solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl This includes, but is not limited to, primary, secondary, and tertiary amines such as N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0125] The term "substituted" means that one or more hydrogen atoms on any of the specified atoms or groups are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar non-specific structures obtained by defining substituents with an infinitely many additional substituents (e.g., substituted aryls having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., methyl substituted with five fluorine or heteroaryl groups having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as defined herein. Unless otherwise specified, if a group is described as optionally substituted, any substituent on the group is itself unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to alkyl groups having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted, and those skilled in the art will recognize that the substituents and other parts of the compounds of the general formula herein should be selected to provide compounds that are stable enough to provide pharmaceutically useful compounds that can be formulated into acceptablely stable pharmaceutical compositions. Compounds having such stability are considered to be within the scope of the present invention. Those skilled in the art should understand that the above definitions and any combination of substituents should not result in unmanipulable species or compounds.

[0126] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all kinds of solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in therapeutic compositions, provided that it is not incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the composition.

[0127] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0128] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" or "alkylenyl" groups, or "arylene" or "aryrenyl" groups, respectively. Also, unless otherwise expressly indicated, when a combination of groups is referred to herein as one part, for example, arylalkyl, the last group mentioned contains the atom to which that part is bonded to the remainder of the molecule.

[0129] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both cases in which such event or situation occurs and cases in which it does not occur. The term “optionally substituted” refers to one or more hydrogen atoms on a specified atom or group that may or may not be substituted by a non-hydrogen portion. “Optionally substituted” may range from zero to the maximum number of possible substitutions, and each occurrence is independent. Where the term “substituted” is used, the substitution must be made on a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from (mandatory) substitutions.

[0130] If a part is "optionally substituted" and any general term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl" is referenced, then this general term is (C 1~3 (Alkyl), (C 4~6 Alkyl), -O(C 1~4 (Alkyl), (C 3~10 Cycloalkyl), O-(C 3~10The term can refer to any preceding, specifically enumerated term such as cycloalkyl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryls such as phenyl or naphthyl. Similarly, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyls such as oxetanyl, tetrahydropyranil, morpholino, and piperidinyl. Likewise, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteryl)," as well as certain heteroaryls such as pyridine.

[0131] Some of the compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imido acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound contains both amides and imido acid tautomers. Therefore, amide-containing compounds are understood to contain their imido acid tautomers. Similarly, imido acid-containing compounds are understood to contain their amide tautomers.

[0132] Any formula or structure given herein is also intended to represent both the unlabeled and isotope-labeled forms of the compounds. An isotope-labeled compound has the structure represented by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125Examples of isotope-labeled compounds in this disclosure include, but are not limited to, I. 3 H, 13 C and 14 These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation therapy for patients.

[0133] This disclosure also includes “deuterated analogues” of the compounds of formula I, in which 1 to n hydrogens bonded to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful in extending the half-life of any compound of formula I when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0134] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to greater metabolic stability, such as extended half-life in vivo, reduced dose requirements, and / or improved therapeutic index. 181F-labeled compounds may be useful in PET or SPECT testing. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting readily available isotope-labeling reagents with non-isotope-labeling reagents, by performing the procedures disclosed in the scheme or the examples and preparations described below. In this context, deuterium is understood to be a substituent in the compounds of formula I.

[0135] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in the isotopic composition of the natural abundance of hydrogen. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0136] In many cases, the compounds of this disclosure can form acidic salts and / or basic salts in the presence of an amino group and / or a carboxyl group or a similar group.

[0137] pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human medicinal uses.

[0138] The term “pharmaceutically acceptable salt” of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. “pharmaceutically acceptable salt” or “physiologically acceptable salt” includes, for example, salts containing inorganic acids and salts containing organic acids. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acidic salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating this solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl This includes, but is not limited to, primary, secondary, and tertiary amines such as N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0139] The term "substituted" means that one or more hydrogen atoms on any of the specified atoms or groups are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar non-specific structures obtained by defining substituents with an infinitely many additional substituents (e.g., substituted aryls having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., methyl substituted with five fluorine or heteroaryl groups having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as defined herein. Unless otherwise specified, if a group is described as optionally substituted, any substituent on the group is itself unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to alkyl groups having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted, and those skilled in the art will recognize that the substituents and other parts of the compounds of the general formula herein should be selected to provide compounds that are stable enough to provide pharmaceutically useful compounds that can be formulated into acceptablely stable pharmaceutical compositions. Compounds having such stability are considered to be within the scope of the present invention. Those skilled in the art should understand that the above definitions and any combination of substituents should not result in unmanipulable species or compounds.

[0140] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all kinds of solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in therapeutic compositions, provided that it is not incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the composition.

[0141] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all kinds of solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in therapeutic compositions, provided that it is not incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the composition.

[0142] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0143] II. Combinations Patients being treated with the PARP7 inhibitors of this disclosure often exhibit diseases or conditions that would benefit from treatment with other therapeutic agents. These diseases or conditions may be of an oncological nature or may be associated with inflammation, metabolic disorders, gastrointestinal disorders, etc. Accordingly, one aspect of this disclosure is a method for treating cancer, comprising administering a compound in combination with one or more compounds useful for treating such diseases to a subject in need, in particular a human subject.

[0144] In some embodiments, the compounds of the Disclosure are co-formulated with one or more additional active ingredients. In some embodiments, the other active ingredients are administered in separate dosage forms at approximately the same time. In some embodiments, the other active ingredients may be administered sequentially and at different times with respect to the compounds of the Disclosure.

[0145] In some embodiments, the compounds or pharmaceutical compositions provided herein are administered together with one or more additional therapeutic agents (e.g., 1, 2, 3, or 4). In some embodiments, additional therapeutic agents include, for example, inhibitory immune checkpoint blockers or inhibitors, stimulative immune checkpoint stimulants, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapy agents, antineoplastic agents, antiproliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapy agents, therapeutic antigen-binding molecules (e.g., monospecific and multispecific antibodies of any form, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and their fragments), bispecific antibodies, non-immunoglobulin antibody mimics (e.g., adnectin, afibody molecules, affin, affimer, afitin, alphabody, antikalin, peptide aptamers, armadillo repeat proteins (ARM), atrimers, avimers, designed ankyrin repeat proteins) Examples include proteins (including DARPin®), finomers, Notchin, Knitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editing agents, cells containing chimeric antigen receptors (CARs), modified T cell receptors (TCR-T) including T cell immunotherapy agents, NK cell immunotherapy agents, or macrophage immunotherapy agents, or any combination thereof.

[0146] Exemplary target In some embodiments, one or more additional therapeutic agents include, for example, inhibitors, agonists, antagonists, ligands, modulators, stimulants, blockers, activators, or suppressors of targets (e.g., polypeptides or polynucleotides), such as: 2'-5'-oligoadenylate synthetase (OAS1; NCBI gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI gene ID: 54464); 5'-nucleotidase ecto (NT5E, CD73; NCBI gene ID: 4907); ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI gene ID: 25); and Absent-in melanoma 2 (AIM2; NCBI gene ID: 9447). ;Acetyl-CoA acyltransferase 2 (ACAA2; NCBI gene ID: 10499); Acid phosphatase 3 (ACP3; NCBI gene ID: 55); Adenosine deaminase (ADA, ADA1; NCBI gene ID: 100); Adenosine receptor (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI gene ID: 134, 135, 136, 137); AKT serine / thre Onion kinase 1 (AKT1, AKT, PKB; NCBI gene ID: 207); alanylaminopeptidase, membrane (ANPEP, CD13; NCBI gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI gene ID: 238); alpha-fetoprotein (AFP; NCBI gene ID: 174); copper-containing amine oxidase (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI gene IDs: 26, 314, 8639) Androgen receptor (AR; NCBI gene ID: 367); Angiopoietin (ANGPT1, ANGPT2; NCBI gene IDs: 284, 285); Angiotensin II receptor type 1 (AGTR1, NCBI gene ID: 185); Angiotensinogen (AGT; NCBI gene ID: 183); Apolipoprotein A1 (APOA1; NCBI gene ID: 335); Apoptosis-inducing factor mitochondrial-related 1 (AIFM1, AIF; NCBI gene ID: 9131);Arachidonic acid 5-lipoxygenase (ALOX5; NCBI gene ID: 240); asparaginase (ASPG; NCBI gene ID: 374569); Astalade homolog 1 (ASTE1; NCBI gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI gene ID: 472); ATP-binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI gene ID: 5243); ATP-dependent Clp-protease (CLPP; NCBI gene ID: 8192); ATR serine / Threonine kinase (ATR; NCBI gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI gene ID: 558); B and T lymphocyte-related (BTLA, CD272; NCBI gene ID: 151888); Baculovirus IAP repeat-containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (Survivin); NCBI gene IDs: 329, 330, 331, 332); Basidine (Ok blood group) (BSG, CD147; NCBI gene ID: 68 2); B-cell lymphoma 2 (BCL2; NCBI gene ID: 596); BCL2-binding protein 3 (BBC3, PUMA; NCBI gene ID: 27113); Bcl2-like (e.g., Bcl2L1 (Bcl-x), Bcl2L2 (BIM); Bcl-x; NCBI gene ID: 598, 10018); Beta-3-adrenergic receptor (ADRB3; NCBI gene ID: 155); Bone gamma-carboxyglutamate protein (BGLAP; NCBI gene ID: 632); Bone morphogenesis protein-10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI gene IDs: 623, 624); B-RAF (BRAF; NCBI gene ID: 273); breakpoint cluster regions (BCR; NCBI gene ID: 613); bromodomain and extradomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI gene ID: 695);Cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI gene IDs: 1001, 1004); cancer / testicular antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI gene ID: 51363); carbonic anhydrase (CA1, CA2, CA3, CA4, CA5A, CA5 B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677); carcinoembryonic antigen-associated cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK 2);NCBI gene IDs: 1452, 1457);Caspase (e.g., CASP3, CASP7, CASP8;NCBI gene IDs: 836, 840, 841, 864);Catenin β1 (CTNNB1;NCBI gene ID: 1499);Cathepsin G (CTSG;NCBI gene ID: 1511);Cbl proto-oncogene B (CBLB, Cbl-b;NCBI gene ID: 868);CC motif chemokine ligand 21 (CCL21;NCBI gene ID: 6366);CC motif chemokine receptor 2 (CCR2;NCBI gene ID: 72923 0); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer-binding protein alpha (CEBPA, CEBP; NCBI gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI gene ID: 23705); cell division cycle 7 (CDC7; NCBI gene ID: 8317); cell communication network factor 2 (CCN2; NCBI gene ID: 1490);Cerebron (CRBN; NCBI gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI gene ID: 887); chorionic somatomammotropin hormone 1 (CSH1; NCBI gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI gene IDs: 9074, 51208); differentiation marker clusters —(For example, CD1A, CD1C, CD1D, CD1E, CD2, CD3 Alpha (TRA), CD Beta (TRB), CD Gamma (TRG), CD Delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 ( BLAST1), CD52, CD55(DAF), CD58(LFA3), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CS F1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 (IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), CD194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2) R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902 , 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI gene IDs: 2155, 2159); collagen type IV alpha chains (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily members -10 (COLEC10; NCBI gene ID: 10584); Colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI gene IDs: 1435, 1437, 1440); Complement factors (e.g., C3, C5; NCBI gene IDs: 718, 727); COP9 signalosome subunit 5 (COPS5; NCBI gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD3 71); CD371, NCBI gene IDs: 160364, 170482, 283420); CXC motif chemokine ligand 12 (CXCL12; NCBI gene ID: 6387); CXC motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI gene IDs: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI gene ID: 595);Cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); Cyclin G1 (CCNG1; NCBI gene ID: 900); Cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); Cytochrome P450 oxidoreductases (P; OR; NCBI gene ID: 5447); Cytokine-inducible SH2-containing protein (CISH; NCBI gene ID: 1154); Cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI gene ID: 1493); DEAD-box helicase (e.g., DDX5, DDX6, DDX58; NCBI gene ID: 1655, 1656, 23586); Delta-like canonical Notch ligand (e.g., DLL3, DLL4; NCBI gene ID: 10683, 54567); Diabetic IAP-binding mitochondrial protein (Dia blo, SMAC; NCBI gene ID: 56616); diacylglycerol kinase (e.g., DGKA, DGKZ; NCBI gene ID: 1606, 8525); dickkopfWNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI gene ID: 22943, 27122); dihydrofolate reductase (DHFR; NCBI gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI gene ID: 1803); discoidyl Domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167, NCBI gene IDs: 780, 4921); DNA-dependent protein kinases (PRKDC; NCBI gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI gene IDs: 7150, 7153, 7155, 7156, 8940); Dopachrome tautomers (DCT; NCBI gene ID: 1638); Dopamine receptor D2 (DRD2; NCBI gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI gene ID: 5169); EMAP-like 4 (EML4; NCBI gene ID: 27436); endoglin (ENG; NCBI gene ID: 2022); endoplasmic reticulum aminopeptidase (e.g., ERAP1, ERAP2; NCBI gene IDs: 51752, 64167); zeste2 polycomb repression complex 2 subunit enhancer (EZH2;NCBI gene ID: 2146); Ephrin receptor (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); Ephrin (e.g., EFNA1, EFNA4, EFNB2; NCBI gene IDs: 1942, 1945, 1948); Epidermal growth factor receptor (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), E RBB3 (HER3), ERBB4 (HER4) NCBI gene IDs: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI gene ID: 4072); epithelial mitotic factor (EPGN; NCBI gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI gene IDs: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI gene IDs: 1973, 1984); exopolitin-1 (XPO1; NCBI gene ID: 7514); fal Nesoid X receptor (NR1H4, FXR; NCBI gene ID: 9971); Fa ligand (FASLG, FASL, CD95L, CD178, TNFSF6; NCBI gene ID: 356); Fatty acid amide hydrolase (FAAH; NCBI gene ID: 2166); Fatty acid synthase (FASN; FAS; NCBI gene ID: 2194); Ig receptor Fc fragment (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI gene ID: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI gene ID: 9971); Gene ID: 83416); Fibroblast-activating protein α (FAP; NCBI gene ID: 2191); Fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI gene IDs: 2260, 2261, 2263, 2264); Fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI gene IDs: 2246, 2247, 2249, 2250); Fibronectin 1 (FN1, MSF;NCBI gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI gene IDs: 2321, 2322, 2324); fms-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI gene ID: 2323); lesion adhesion kinase 2 (PTK2, FAK1; NCBI gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI gene ID: 2346); folate receptor 1 (FOLR1; NCBI gene ID: 2 348); Forkhead box protein M1 (FOXM1; NCBI gene ID: 2305); Flurin (Furin, PACE; NCBI gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI gene ID: 2534); Galectin (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI gene ID: 3958, 3964, 3965); Glucocorticoid receptor (NR3C1, GR; NCBI gene ID: 2908); Glucuronidase β (GUSB; NCBI gene ID: 2990); Glu Tamate transfer receptor 1 (GRM1; NCBI gene ID: 2911); glutaminase (GLS; NCBI gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI gene ID: 2950); glycogen synthase kinase 3 beta (GSK3B; NCBI gene ID: 2932); glypican 3 (GPC3; NCBI gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI gene ID: 2796); gonadotropin-releasing hormone receptor (GNRHR; NCBI gene ID: 2798); GPNMB glycoprotein NMB (GPNMB, osteoactivin; NCBI gene ID: 10457); growth differentiation factor 2 (GDF2, BMP9; NCBI gene ID: 2658); growth factor receptor binding protein 2 (GRB2, ASH; NCBI gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL; NCBI gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK;NCBI gene ID: 3055); Heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI gene IDs: 3309, 3315, 7184); Heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI gene IDs: 3162, 3163); Heparanase (HPSE; NCBI gene ID: 10855); Hepatitis A virus cell receptor 2 (HAVCR2, TIM3, CD366; NCBI gene ID: 84868); Liver growth factor (HGF; NCBI gene ID: 3082); HERV-H LTR-related 2 (HHLA2, B7-H7; NCBI gene ID: 11148); histamine receptor H2 (HRH2; NCBI gene ID: 3274); histone deacetylases (e.g., HDAC1, HDAC7, HDAC9; NCBI gene IDs: 3065, 9734, 51564); HRas proto-oncogenes, GTPases (HRAS; NCBI gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI gene IDs: 3551, 3553); IKAROS family zinc fingers (IKZF1 (LYF1), IKZF3; NCBI gene IDs: 10320, 22806); immune Globulin superfamily member 11 (IGSF11; NCBI gene ID: 152404); indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2; NCBI gene ID: 3620, 169355); inducible T cell costimulatory molecule (ICOS, CD278; NCBI gene ID: 29851); inducible T cell costimulatory molecule ligand (ICOSLG, B7-H2; NCBI gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2R; NCBI gene ID: 3480, 3482); insulin-like growth factor (e.g., IGF1, IGF2; NCBI gene ID: 3479, 3481); insulin receptor (INSR, CD220; NCBI gene ID: 3643);Integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI gene IDs: 3678, 3685, 3688, 3695, 3698); cell adhesion molecule 1 (ICAM1, CD54; NCBI gene ID: 3383); interleukin-1 receptor-related kinase 4 (IRAK4; NCBI gene ID: 51135); interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122) ), IL2RG(CD132), IL3RA, IL6R, IL13RA2(CD213A2), IL22RA1; NCBI gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6(HGF), IL7, IL8(CXCL8), IL10(TGIF), IL12A, IL12B, IL15, IL17A(CTLA8), IL18, IL23A, IL24, IL-29(IFNL1)); NCBI gene IDs: 3552, 3553 ,3558,3562,3565,3569,3574,3586,3592,3593,3600,3605,3606,11009,51561,282618); isocitrate dehydrogenase (NADP()1) (e.g., IDH1, IDH2; NCBI gene ID: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI gene ID: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI gene ID: 354); killer cell immunoglobulin-like receptor, Ig domer In and long cytoplasmic tails (e.g., KIR2DL1(CD158A), KIR2DL2(CD158B1), KIR2DL3(CD158B), KIR2DL4(CD158D), KIR2DL5A(CD158F), KIR2DL5B, KIR3DL1(CD158E1), KIR3DL2(CD158K), KIR3DP1(CD158c), KIR2DS2(CD158J); NCBI gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285);Killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insertion domain receptors (KDR, CD309, VEGFR2; NCBI gene ID: 3791); kinesin family member 11 (KIF11; NCBI gene ID: 3832); KiSS-1 transpossession suppressor (KiSS1; NCBI gene I; D:3814); KIT oncogene, receptor tyrosine kinase (KIT, C-KIT, CD117; NCBI gene ID:3815); KRAS oncogene, GTPase (KRAS; NCBI gene ID:3845); lactotransferrin (LTF; NCBI gene ID:4057); LCK oncogene, Src family tyrosine kinase (LCK; NCBI gene ID:3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI gene ID:4035); leucine Rich Repeat 15 (LRRC15; NCBI gene ID: 131578); Leukocyte Immunoglobulin-like Receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI gene ID: 10288, 10859); Leukotriene A4 Hydrolase (LTA4H; NCBI gene ID: 4048); Linker for T Cell Activation (LAT; NCBI gene ID: 27040); Luteinizing Hormone / Cholegonadotropin Receptor (LHCGR; NCBI gene ID: 3973); LY6 / PLAUR domain-containing 3 (LYPD3; NCBI gene ID: 27076); Lymphocyte activation 3 (LAG3; CD223, NCBI gene ID: 3902); Lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI gene IDs: 4063, 17076); LYN oncogene, Src family tyrosine kinase (LYN; NCBI gene ID: 4067); Lypmphocyte cytosolic protein 2 (LCP2; NCBI gene ID: 3937); Ligi Demethylase 1A (KDM1A; NCBI gene ID: 23028); Lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI gene ID: 1902); Lysyl oxidase (LOX; NCBI gene ID: 4015); Lysyl oxidase-like receptor 2 (LOXL2, NCBI gene ID: 4017); Macrophage migration inhibitor (MIF, GIF; NCBI gene ID: 4282); Macrophage-stimulating receptor 1 (MST1R, CD136; NCBI gene ID: 4486);MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); major histocompatibility complexes (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI gene IDs: 3105, 313 3, 3134, 3135); Major vault proteins (MVP, VAULT1, NCBI gene ID: 9961); MALT1 paracaspase (MALT1; NCBI gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI gene IDs: 2872, 8569); Matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP1 1, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NC BI gene ID: 4170); MDM2 oncogene (MDM2; NCBI gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6, NCBI gene ID: 4194); Mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI gene ID: 2475); Melan-A (MLANA; NCBI gene ID: 2315); Melanocortin receptor (MC1R, MC2R; NCBI gene IDs: 4157, 4148); MER proto-oncogene, tyrosine kinase (MERTK; NCBI gene ID: 10461); Mesoserine (MSLN;NCBI gene ID: 10232); MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI gene ID: 4233); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI gene ID: 10988); MHC class I polypeptide-related sequences (e.g., MICA, MICB; NCBI gene IDs: 4277, 100507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI gene IDs: 5594, 5595 , 5599, 5600, 5601, 5602, 819251); Mitogen-activated protein kinase kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2), NCBI gene IDs: 4217, 1326); Mitogen-activated protein kinase kinase kinase kinase 1 (HPK1; NCBI gene ID: 11184); Mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI gene IDs: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (thrombopoietin receptor, MPL; NCBI gene ID: 4352); mucin (e.g., MUC1 (including its splice variants (e.g., MUC1 / A, C, D, X, Y, Z and REP)), MUC5AC, MUC16 (CA125); NCBI gene IDs: 4582, 4586, 94025); MYC oncogene, bHLH transcription factor (MYC; NCBI gene ID: 4609); myostatin (MSTN, GDF8; NCBI gene ID: 2660); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI gene ID: 4883); natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI gene ID: 374383); nexin, MAGE family member (NDN; NCBI gene ID: 4692);Nectin cell adhesion molecules (e.g., nectin2 (CD112, PVRL2), nectin4 (PVRL4); NCBI gene IDs: 5819, 81607); neuronal cell adhesion molecule 1 (NCAM1, CD56; NCBI gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI gene IDs: 8828, 8829); neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI gene ID: 4914) , 4915, 4916); NFKB-activated protein (NKAP; NCBI gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI gene ID: 91754); NLR family pyrin domain-containing 3 (NLRP3, NALP3; NCBI gene ID: 114548); Notch receptor (e.g., notch1, notch2, notch3, notch4; NCBI gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI gene ID: 4893); nuclear factor kappa B (NFK B1, NFKB2; NCBI gene ID: 4790, 4791); Nuclear factor, erythrocyte-like 2 (NFE2L2; NRF2, NCBI gene ID: 4780); Nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI gene ID: 3164); Nucleolin (NCL; NCBI gene ID: 4691); Nucleophosmin 1 (NPM1; NCBI gene ID: 4869); Nucleoside-binding oligomerized domain-containing 2 (NOD2; NCBI gene ID: 64127); Nudix hydrolase 1 (NUDT1; NCBI gene ID: 452 1); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI gene ID: 4255); opioid receptor delta-1 (OPRD1; NCBI gene ID: 4985); ornithine decarboxylase 1 (ODC1; NCBI gene ID: 4953); oxoglutarate dehydrogenase (OGDH; NCBI gene ID: 4967); parathyroid hormone (PTH; NCBI gene ID: 5741); PD-L1 (CD274; NCBI gene ID: 29126); periostin (POSTN; NCBI gene ID: 10631);Peroxisome proliferator-activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI gene IDs: 5465, 5467, 5468); phosphatases and tensin homologs (PTEN; NCBI gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA (PI3KA) PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G2 G15; NCBI gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI gene IDs: 5292, 11040, 415116); placental growth factor (PGF); NCBI gene ID: 5228); plasmin Growth factor activators, urokinases (PLAU, u-PA, ATF; NCBI gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI gene IDs: 5156, 5159); plexin B1 (PLXNB1; NCBI gene ID: 5364); poliovirus receptor (poliovirus Cell adhesion molecule (PVR, CD155; NCBI gene ID: 5817); Pollo-like kinase 1 (PLK1; NCBI gene ID: 5347); Poly(ADP-ribose) polymerase (e.g., PARP1, PARP2, PARP3; NCBI gene ID: 142, 10038, 10039); Polycomb protein EED (EED; NCBI gene ID: 8726); Polcupin O-acyltransferase (PORCN; NCBI gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI gene ID: 23532); Premelanosome protein (PMEL;NCBI gene ID: 6490); progesterone receptor (PGR; NCBI gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI gene ID: 5133); programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2; NCBI gene ID: 80380); prominin 1 (PROM1, CD133; NCBI gene ID: 8842); promyelocytic leukemia (PML; NCBI gene ID: 5371); ;Propiosin (PSAP; NCBI gene ID: 5660);Prostaglandin E receptor 4 (PTGER4; NCBI gene ID: 5734);Prostaglandin E synthase (PTGES; NCBI gene ID: 9536);Prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2); NCBI gene IDs: 5742, 5743);Proteasome 20S subunit beta-9 (PSMB9; NCBI gene ID: 5698);Ta Protein arginine methyltransferase (e.g., PRMT1, PRMT5; NCBI gene IDs: 3276, 10419); protein kinase N3 (PKN3; NCBI gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI gene ID: 5754); protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R)) ;NCBI gene ID: 5787, 5788); Prothymosin α (PTMA;NCBI gene ID: 5757); Purine nucleoside phosphorylase (PNP;NCBI gene ID: 4860); Purinergic receptor P2X7 (P2RX7;NCBI gene ID: 5027); PVR-related immunoglobulin domain-containing (PVRIG, CD112R;NCBI gene ID: 79037); Raf-1 oncogene, serine / threonine kinase (Raf1, c-Raf;NCBI gene I D:5894); RAR-related orphan receptor gamma (RORC; NCBI gene ID: 6097); Ras homolog family member C (RHOC); NCBI gene ID: 389); Ras homolog, mTORC1 binding (RHEB; NCBI gene ID: 6009); RB transcription corepressor 1 (RB1; NCBI gene ID: 5925); receptor interaction serine / threonine protein kinase 1 (RIPK1; NCBI gene ID: 8737); ret proto-oncogene (ret proto-oncogene, RET; NCBI gene ID: 5979); retinoic acid early transcript (e.g., RAET1e, RAET1g, RAET1L; NCBI gene IDs: 135250, 154064, 353091); retinoic acid receptor alpha (e.g., RARA, RARG;NCBI gene IDs: 5914, 5916); Retinoid X receptors (e.g., RXRA, RXRB, RXRG; NCBI gene IDs: 6256, 6257, 6258); Rho-related coiled-coil-containing protein kinases (e.g., ROCK1, ROCK2; NCBI gene IDs: 6093, 9475); Ribosomal protein S6 kinase B1 (RPS6KB1, S6K-beta1; NCBI gene ID: 6198); Ring finger protein 128 (RNF128, GRAIL; NCBI gene ID: 79589); ROS proto-oncogenes Child 1, Receptor tyrosine kinase (ROS1; NCBI gene ID: 6098); Roundabout guidance receptor 4 (ROBO4; NCBI gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI gene ID: 864); S100 calcium-binding protein A9 (S100A9; NCBI gene ID: 6280); Secreted flitre-related protein 2 (SFRP2; NCBI gene ID: 6423); Secreted phosphoprotein 1 (SPP1; NCBI gene ID: 6696); Secretoglobin family 1A Member 1 (SCGB1A1; NCBI gene ID: 7356); Selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI gene IDs: 6401, 6402, 6403); Semaphorin 4D (semaphorin, SEMA4D; CD100, NCBI gene ID: 10507); Sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI gene IDs: 27036, 27180, 89790); Signal regulatory protein alpha (S IRPA, CD172A; NCBI gene ID: 140885); signal transducers and transcription activators (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI gene IDs: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI gene ID: 23410); signal transduction lymphocyte activating molecules (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9;NCBI gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI gene ID: 84189); Smooth, fritzled class receptor (SMO; NCBI gene ID: 6608); Soluble epoxide hydrolase 2 (EPHX2; NCBI gene ID: 2053); Solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC4 4A4; NCBI gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI gene IDs: 6751, 6752, 6753, 6754, 6755); ultrasonic hedgehog signaling molecules (SHH; NCBI gene ID: 6469); WT1 transcription factors (WT1; NCBI gene ID: 6667); sphingosine kinases (e.g., SPHK1, SPHK2; NCBI gene ID: 8877) , 56848); Sphingosine-1-phosphate receptor 1 agonist (S1PR1, CD363; NCBI gene ID: 1901); Spleen-associated tyrosine kinase (SYK; NCBI gene ID: 6850); Splicing factor 3B factor 1 (SF3B1; NCBI gene ID: 23451); SRC oncogene, non-receptor tyrosine kinase (SRC; NCBI gene ID: 6714); Stabilin 1 (STAB1, CLEVER-1; NCBI gene ID: 23166); STEAP family member 1 (STEAP1; NCBI gene ID: 2687 2); Steroid sulfatase (STS; NCBI gene ID: 412); Interferon response cGAMP interactor 1 stimulator 1 (STING1; NCBI gene ID: 340061); Superoxide dismutase 1 (SOD1, ALS1; NCBI gene ID: 6647); Cytokine signaling inhibitors (SOCS1 (CISH1), SOCS3 (CISH3); NCBI gene ID: 8651, 9021); Synapsin 3 (SYN3; NCBI gene ID: 8224); Syndecan 1 (SDC1, CD138, Syndecan;NCBI gene ID: 6382); Synuclein alpha (SNCA, PARK1; NCBI gene ID: 6622); T cell immunoglobulin and mucin domain-containing 4 (TIMD4, SMUCKLER; NCBI gene ID: 91937); T cell immune receptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); Tachykinin receptor (e.g., TACR1, TACR3; NCBI gene IDs: 6869, 6870); Tank binding Kinase 1 (TBK1, NCBI gene ID: 29110); Tankirase (TNKS, NCBI gene ID: 8658); TATA box-binding protein-related factor, RNA polymerase I subunit B (TAF1B; NCBI gene ID: 9014); T-box transcription factor T (TBXT, NCBI gene ID: 6862); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI gene ID: 25976); Lymphocyte-specific Protein tyrosine kinase (TEC); NCBI gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI gene ID: 7010); human telomerase reverse transcriptase (TERT; NCBI gene ID: 7015); tenascin C (TNC; NCBI gene ID: 3371); 3-prime repair exonuclease (e.g., TREX1, TREX2; NCBI gene IDs: 11277, 11219); thrombomodulin ( THBD, CD141; NCBI gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI gene ID: 1890); thymidylate synthase (TYMS; NCBI gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI gene ID: 7606, 7608); thyroid-stimulating hormone receptor (TSHR; NCBI gene ID: 7253);TNF Super Family Members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 ( GITRL); NCBI gene IDs: 944, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995); Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); transf Transferrin (TF; NCBI gene ID: 7018); Transferrin receptor (TFRC, CD71; NCBI gene ID: 7037); Transforming growth factors (e.g., TGFA, TGFB1; NCBI gene ID: 7039, 7040); Transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI gene ID: 7046, 7048, 7049); Transforming protein E7 (E7; NCBI gene ID: 1489079); Transglutaminase 5 (TGM5; NCBI gene ID: 9 333); Transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI gene ID: 7442); Transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H, IGPR1; NCBI gene ID: 126259); Trigger receptors expressed in bone marrow cells (e.g., TREM1 (CD354), TREM2; NCBI gene ID: 54209, 54210); Trophinin (TRO, MAGED3; NCBI gene ID: 7216); Trophoblast glycoprotein (TPBG; NCBI gene ID: 7162);Tryptophan 2,3-dioxygenase (TDO2; NCBI gene ID: 6999); tryptophan hydroxylase (e.g., TPH1, TPH2; NCBI gene ID: 7166, 121278); tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); tumor necrosis factor (TNF; NCBI gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30); ), TNFRSF9(CD137, 4-1BB), TNFRSF10A(CD261), TNFRSF10B(TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B(OPG), TNFRSF12A, T NFRSF13B, TNFR13C (, CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); Tumor protein p53 (TP53; NCBI gene ID: 7157); Tumor suppressor 2, Mitochondrial calcium regulator (TUSC2; NCBI gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCB I gene ID: 7301); tyrosinase (TYR; NCBI gene ID: 7299); tyrosine hydroxylase (TH; NCBI gene ID: 7054); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI gene ID: 7075); tyrosine protein phosphatase, non-receptor type 11 (PTPN11, SHP2; NCBI gene ID: 5781); ubiquitin-conjugating enzyme E2I (UBE2I, UBC9; NCBI gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI gene I D:51377); Ubiquitin-specific peptidase 7 (USP7; NCBI gene ID: 7874); Ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI gene ID: 7317); UL16 binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI gene ID: 79465, 80328, 80328); Balosin-containing proteins (VCP, CDC48; NCBI gene ID: 7415); Vascular cell adhesion molecules 1 (VCAM1, CD106; NCBI gene ID: 7412); Vascular endothelial growth factors (e.g., VEGFA, VEGFB;NCBI gene IDs: 7422, 7423); vimentin (VIM; NCBI gene ID: 7431); vitamin D receptor (VDR; NCBI gene ID: 7421); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7-H4; NCBI gene ID: 79679); V-set immunomodulatory receptor (VSIR, VISTA, B7-H5; NCBI gene ID: 64115); WEE1G2 checkpoint kinase (WEE1; NCBI gene ID: 7465); WRNRecQ-like helicase (WRN; RECQ3, NCBI gene I D:7486); WT1 transcription factor (WT1; NCBI gene ID: 7490); WW domain-containing transcription regulator 1 (WWTR1; TAZ; NCBI gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI gene ID: 6375); XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI gene ID: 2829); Yes1-related transcription regulator (YAP1; NCBI gene ID: 10413); Zeta chain-related protein kinase 70 (ZAP70; NCBI gene ID: 7535).

[0147] In some embodiments, one or more additional therapeutic agents may include, for example, drugs targeting: 5'-nucleotidase ectopropyl alcohol (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Receptor (ADORA2A; NCBI gene ID: 135); adenosine A 2BReceptor (ADORA2B; NCBI gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI gene ID: 1154); diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI gene ID: 1606); Fms-like tyrosine kinase 3 (FLT3, CD135; NCBI gene ID: 2322); integrin-related protein (IAP, CD47; NCBI gene ID: 961); interleukin-2 (IL2; NCBI gene ID: 3558); interleukin-2 receptor (IL2RA, IL2RB, IL2RG; NCBI gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (Kirsten rat sarcoma, KRAS; NCBI gene ID: 3845; including mutations such as KRAS G12C or G12D); mitogen-activated protein kinase kinase kinase 1 (MAP4K1) (also called hematopoietic progenitor kinase 1 (HPK1), NCBI gene ID: 11184); myeloid leukemia sequence 1 apoptosis regulator (MCL1; NCBI gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD; NCBI gene ID: 5293); programmed cell death ligand 1 (PD-L1, CD274; NCBI gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI gene ID: 29126); Gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI gene ID: 3815); signal regulatory protein alpha (SIRPA, CD172A; NCBI gene ID: 140885); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI gene ID: 25976); T cell immune receptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); trigger receptor expressed on bone marrow cell 1 (TREM1; NCBI gene ID: 54210); trigger receptor expressed on bone marrow cell 2 (TREM2; NCBI gene ID: 54209);Tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, CD134, OX40; NCBI gene ID: 7293); Tumor necrosis factor receptor superfamily, member 9 (TNFRSF9, 4-1BB, CD137; NCBI gene ID: 3604); Tumor necrosis factor receptor superfamily, member 18 (TNFRSF18, CD357, GITR; NCBI gene ID: 8784); WRNRecQ-like helicase (WRN; NCBI gene ID: 7486); Zinc finger protein Helios (IKZF2; NCBI gene ID: 22807).

[0148] Exemplary mechanism of action Immune checkpoint modulator In some embodiments, the compounds provided herein are administered together with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulants, activators, or agonists of one or more stimulant immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune evasion of cancer cells in the tumor environment. Activation or stimulation of stimulant immune checkpoints can enhance the effects of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors modulate T cell responses (as outlined, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate the NK cell response (e.g., as outlined in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition of regulatory T cells (Tregs) or Treg depletion can mitigate the suppression of their antitumor immune response and have anticancer effects (e.g., as outlined in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0149] Examples of immune checkpoint proteins or receptors include CD27 (NCBI gene ID: 939), CD70 (NCBI gene ID: 970); CD40 (NCBI gene ID: 958), CD40LG (NCBI gene ID: 959); CD47 (NCBI gene ID: 961), SIRPA (NCBI gene ID: 140885); CD48 (SLAMF2; NCBI gene ID: 962) transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI gene ID: 8832), CD96 (NCBI gene ID: 10225), CD160 (NC BI gene ID: 11126), MS4A1 (CD20; NCBI gene ID: 931), CD244 (SLAMF4; NCBI gene ID: 51744); CD276 (B7H3; NCBI gene ID: 80381); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI gene ID: 152404); natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI gene ID: 374383); HERV-H LTR-related 2 (HHLA2, B7H7; NCBI gene ID: 11148); Inducible T cell costimulator (ICOS, CD278; NCBI gene ID: 29851); Inducible T cell costimulator ligand (ICOSLG, B7H2; NCBI gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; N CBI gene ID: 7292); TNFRSF8 (CD30; NCBI gene ID: 943), TNFSF8 (CD30L; NCBI gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI gene ID: 8797), TNFRSF9 (CD137; NCBI gene ID: 3604), TNFSF9 (CD137L; NCBI gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2;NCBI gene ID: 8795), TNFRSF10 (TRAIL; NCBI gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI gene ID: 8764), TNFSF14 (HVEML; NCBI gene ID: 8740); CD272 (B and T lymphocyte-related (BTLA), NCBI gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI gene ID: 608), TNFSF13B (BAFF; NCBI gene ID: 10673); TNFRSF18 (GITR; NCBI gene ID: 8 784), TNFSF18 (GITRL; NCBI gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI gene ID: 5133); cytotoxic T lymphocyte-related protein 4 (CTLA4, CD152; NCBI gene ID: 1493) );CD80(B7-1;NCBI gene ID:941), CD28(NCBI gene ID:940);Nectin cell adhesion molecule 2(NECTIN2, CD112;NCBI gene ID:5819);CD226(DNAM-1;NCBI gene ID:10666);Poliovirus receptor (PVR) cell adhesion molecule(PVR, CD155;NCBI gene ID:5817);PVR-related immunoglobulin domain-containing(PVRIG, CD112R;NCBI gene ID:79037);T cell immune receptor with Ig and ITIM domains(TIGIT ;NCBI gene ID:201633); T cell immunoglobulin and mucin domain-containing 4 (TIMD4;TIM4, NCBI gene ID:91937); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3;NCBI gene ID:84868); Galectin 9 (LGALS9;NCBI gene ID:3965); Lymphocyte activation 3 (LAG3, CD223;NCBI gene ID:3902); Signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150;NCBI gene ID:6504);Lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI gene ID: 57823); UL16 binding protein 1 (ULBP1; NCBI gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI gene ID: 79465); retinoic acid initial metabolite Copy 1E (RAET1E; ULBP4, NCBI gene ID: 135250); Retinoic acid initial transcript 1G (RAET1G; ULBP5, NCBI gene ID: 353091); Retinoic acid initial transcript 1L (RAET1L; ULBP6, NCBI gene ID: 154064); Killer cell immunoglobulin-like receptor, 3 Ig domains, and long cytoplasmic terminal 1 (KIR, CD158E1; NCBI gene ID: 3811, e.g., lirilumab (IPH-2102, IPH-4102)); Killer cell lectin-like receptor C1( KLRC1, NKG2A, CD159A; NCBI gene ID: 3821); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI gene ID: 22914); Killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI gene ID: 3822); Killer cell lectin-like receptor C3 (KLRC3, NKG2E; NCBI gene ID: 3823); Killer cell lectin-like receptor C4 (KLRC4, NKG2F; NCBI gene ID: 8302); Killer cell immunoglobulin-like receptor, two Ig dormant In, and long cytoplasmic terminal 1 (KIR2DL1; NCBI gene ID: 3802); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic terminal 2 (KIR2DL2; NCBI gene ID: 3803); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic terminal 3 (KIR2DL3; NCBI gene ID: 3804); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1; NCBI gene ID: 3824);Examples include killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI gene ID: 10219); sialic acid-binding Ig-like lectin 7 (SIGLEC7; NCBI gene ID: 27036); and sialic acid-binding Ig-like lectin 9 (SIGLEC9; NCBI gene ID: 27180).

[0150] In some embodiments, the compounds provided herein are administered together with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include: CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-related protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-related (BTLA)); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); Ig and ITIM domain T cell immune receptors with I-1 (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptors 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic terminal 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors.Examples of T cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecules (ICOS, CD278); inducible T cell costimulatory molecule ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). For example, see Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0151] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include: killer cell immunoglobulin-like receptor, 3 Ig domains, and long cytoplasmic end 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, 1 Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 3 Ig domains, and long cytoplasmic tail 2 Examples include (KIR2DL3); killer cell immunoglobulin-like receptor, with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94); killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-bound Ig-like lectin 7 (SIGLEC7); and sialic acid-bound Ig-like lectin 9 (SIGLEC9). In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Examples of NK cell-stimulated immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0152] In some embodiments, one or more immune checkpoint inhibitors include protein-based (e.g., antibody or its fragment, or antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include protein-based (e.g., antibody or its fragment, or antibody mimetic) inhibitors of LAG3.

[0153] Examples of CTLA4 inhibitors that can be administered concurrently include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zarifremab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, and KN-04. Examples include 4. CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0154] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be administered concurrently include pembrolizumab, nivolumab, semiprimab, pizilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosiberimab (CK-301), sasamrimab (PF-06801591), tislerizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX- 10. Retifan Limab (MGA-012), BI-754091, Valstilimab (AGEN-2034), AMG-404, Tripralimab (JS-001), Cetrelimab (JNJ-63723283), Genolimuzumab (CBT-501), LZM-009, Prorugolimab (BCD-100), Rhodapolimab (LY-3300054), SHR-1201, Camrelizumab (SHR-1210), Sym-021, Budigadimab (ABBV-181), PD1-PIK, BAT-1306, Avelumab (MSB0010718C), CX-072, CBT-502, Dostallumab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, Embafolimab (KN-035), Syntilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, Zimbererimab (AB122 ), spartalizumab (PDR-001), and compounds disclosed in International Publication No. 2018195321, International Publication No. 2020014643, International Publication No. 2019160882 or International Publication No. 2018195321, as well as multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 (PD-1 / CTLA4),KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), RG7769(PD-1 / TIM-3), TA K-252 (PD-1 / OX40L), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-15 Examples include 5 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp alfa (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor, such as CA-170, GS-4224, GS-4416, and razertinib (GNS-1480; PD-L1 / EGFR).

[0155] Examples of TIGIT inhibitors that can be administered concurrently include tiragolumab (RG-6058), vivostrimab, donbanalimab, donbanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigirimab.

[0156] An example of a LAG3 inhibitor that can be administered concurrently is relamirimab (LAG525).

[0157] Inhibition of regulatory T cell (Treg) activity or Treg depletion may mitigate their suppression of the antitumor immune response and may have anticancer effects. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, the compounds provided herein are administered together with one or more inhibitors of Treg activity or Treg depletors. Inhibition or depletion of Tregs may enhance the effects of immune checkpoint inhibitors in cancer treatment.

[0158] In some embodiments, the compounds provided herein are administered together with one or more Treg inhibitors. In some embodiments, Treg inhibitors can suppress the migration of Tregs into the tumor microenvironment. In some embodiments, Treg inhibitors can reduce the immunosuppressive function of Tregs. In some embodiments, Treg inhibitors can modulate the cellular phenotype and induce the production of inflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI gene ID: 1233) antagonists, as well as Ikaros zinc finger proteins (e.g., Ikaros (IKZF1; NCBI gene ID: 10320), Helios (IKZF2; NCBI gene ID: 22807), Aiolos (IKZF3; NCBI gene ID: 22806), and Eos (IKZF4; NCBI gene ID: 64375)).

[0159] Examples of Helios-degrading agents that can be administered concurrently include, but are not limited to, I-57 (Novartis), and the compounds disclosed in International Publication Nos. 2019 / 038717, 2020 / 012334, 2020 / 0117759, and 2021 / 101919.

[0160] In some embodiments, the compounds provided herein are administered together with one or more Treg depletion agents. In some embodiments, the Treg depletion agent is an antibody. In some embodiments, the Treg depletion antibody has antibody-dependent cell-mediated cytotoxicity (ADCC) activity. In some embodiments, the Treg depletion antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg depletion antibody is an antibody-drug conjugate (ADC). Examples of Treg depletion agents include, but are not limited to, CD25 (IL2RA; NCBI gene ID: 3559), CTLA4 (CD152; NCBI gene ID: 1493), GITR (TNFRSF18; NCBI gene ID: 8784), 4-1BB (CD137; NCBI gene ID: 3604), OX-40 (CD134; NCBI gene ID: 7293), LAG3 (CD223; NCBI gene ID: 3902), TIGIT (NCBI gene ID: 201633), CCR4 (NCBI gene ID: 1233), and CCR8 (NCBI gene ID: 1237).

[0161] In some embodiments, Treg inhibitors or Treg depletors that may be administered concurrently include CC-motif chemokine receptor 4 (CCR4), CC-motif chemokine receptor 7 (CCR7), CC-motif chemokine receptor 8 (CCR8), CXC-motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neuronal cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), and integrin. The formulation includes antibodies or antigen-binding fragments thereof that selectively bind to cell surface receptors selected from subunit αE (ITGAE; CD103), interleukin-7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), leucine-rich repeat-containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulator (ICOS; CD278), lymphocyte activator 3 (LAG3; CD223), transforming growth factor β1 (TGFB1), hepatitis A virus cell receptor 2 (HAVCR2; CD366, TIM3), T cell immune receptor having Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), and combinations thereof.

[0162] Examples of Treg depletion anti-CCR8 antibodies that may be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor Biomed), IO-1 (Oncurious), and antibodies disclosed in International Publication Nos. 2021 / 163064, 2020 / 138489, and 2021 / 152186.

[0163] An example of a Treg depletion anti-CCR4 antibody that may be administered is mogamulizumab.

[0164] Inhibition, depletion, or reprogramming of non-stimulating myeloid cells in the tumor microenvironment can enhance the anti-cancer response (see, e.g., Binnewies et al., Nat. Med.:2018)24(5):541-550, 2010), International Publication No. 2016 / 049641). Exemplary targets for depleting or reprogramming non-stimulating myeloid cells include the trigger receptors TREM-1 (CD354, NCBI gene ID: 54210) and TREM-2 (NCBI gene ID: 54209), which are expressed on myeloid cells. In some embodiments, the compounds provided herein are administered together with one or more myeloid depletion agents or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; the antibody disclosed in International Publication No. 2019 / 032624) or an anti-TREM-2 antibody (e.g., PY314; the antibody disclosed in International Publication No. 2019 / 118513).

[0165] Differentiation antigen group agonists or activators In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with agents targeting differentiation antigen group (CD) markers. Exemplary CD marker targeters that may be co-administered include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimimer (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), and HLA-A2402 / HLA-A0201 restriction epitope peptide vaccines. Dasatinib, Imatinib, Nilotinib, Sorafenib, Lenvatinib Mesylate, Ofranergene Ovadenovec, Cabozantinib Malate, AL-8326, ZLJ-33, KBP-7018, Sunitinib Malate, Pazopanib Derivative, AGX-73, Levatinib, NMS-088, Lucitanib Hydrochloride, Midostaurin, Cedilanib, Dovitinib, Citravatinib, Tivozanib, Masitinib, Regorafenib, Olberenvatinib Dimesylate (HQP-1351), Cabozan Tinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asnercept (APG-101), APO-010, and International Publication Nos. 2016 / 196388, 2016 / 033570, 2015 / 157386, 1992 / 03459, 1992 / 21766, and 2004 / 080462. International Publication Nos. 2005 / 020921, 2006 / 009755, 2007 / 078034, 2007 / 092403, 2007 / 127317, 2008 / 005877, 2012 / 154480, 2014 / 100620, 2014 / 039714, 2015 / 134536, 2017 / 167182, 2018 / 112136,International Publication No. 2018 / 112140, International Publication No. 2019 / 155067, International Publication No. 2020 / 076105, International Application PCT / US2019 / 063091, International Publication No. 1917 / 3692, International Publication No. 2016 / 179517, International Publication No. 2017 / 096179, International Publication No. 2017 / 096182, International Publication No. 2017 / 096281, International Publication No. 201 International Publication No. 8 / 089628, International Publication No. 2017 / 096179, International Publication No. 2018 / 089628, International Publication No. 2018 / 195321, International Publication No. 2020 / 014643, International Publication No. 2019 / 160882, International Publication No. 2018 / 195321, International Publication No. 2001 / 40307, ​​International Publication No. 2002 / 092784, International Publication No. 2007 / 133811, International Publication No. 2009 / 046541, International Publication No. 2010 / 083253, International Publication No. 2011 / 076781, International Publication No. 2013 / 056352, International Publication No. 2015 / 138600, International Publication No. 2016 / 179399, International Publication No. 2016 / 205042, International Publication No. 2017 / 178653, International Publication No. 2018 / 026600, International Publication No. 2018 / 057 Examples of compounds disclosed include those in Publication No. 669, International Publication Nos. 2018 / 107058, 2018 / 190719, 2018 / 210793, 2019 / 023347, 2019 / 042470, 2019 / 175218, 2019 / 183266, 2020 / 013170, 2020 / 068752, Cancer Discov. 2019 Jan 9(1):8; and Gariepy J., et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).

[0166] In some embodiments, exemplary CD marker targeting agents that may be administered concurrently include PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogalatinib (BAY-1163877), AZD4547, lovritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, and CD11. Examples of small molecule inhibitors include 7-ADC, AZD3229, teratinib, bororanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, mothixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, maborixafor (X4P-001-IO), prelixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0167] In some embodiments, CD marker targeting agents that may be administered concurrently include small molecule agonists, such as interleukin-2 receptor subunit gamma, eltrombopag, lintatrimod, polyICLC (NSC-301463), riboxone, apoxime, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, and mot. Examples of small molecule agonists include Rimod, Reshikimod, Sergantrimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, Covitrimod, Chilsotrimod, Litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, Agatrimod, DIMS-9054, DV-1079, Refitrimod (MGN-1703), CYT-003, and PUL-042.

[0168] In some embodiments, CD marker targeting agents that can be administered concurrently include tafacitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), valrirumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otreltuzumab (TRU-016), isatuximab, ferzaltamab (MOR-202), TAK-079, and TA. K573, Daratumumab (DARZALEX®), TTX-030, Sericrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, Mitazarimab (JNJ-64457107), Drenzyma, Alemtuzumab, Emactuzumab, AMG-820, FPA-008 (Cabilitumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), Verantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), Simurcafusp alfa (RG7461), Urelumab, Utomirumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), F AP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatrimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enserimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20).5) MEDI-9447 (oleculumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, lirirumab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM5 / 6), iodine (131I) apamistamb (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BIO Examples include N-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006, INBRX-109, GEN-1029, pepinemab (VX-15), voplaterimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in International Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628.

[0169] In some embodiments, CD marker targeting agents that may be administered concurrently include cell therapies, such as CD19-ARTEMIS, TBI-1501, CTL-119, huCART-19 T cells, and l iso-cel, lysocabactene maralucel (JCAR-017), axicapbutazine siroleucel (KTE-C19, Yescarta®), axicapbutazine siroleucel (KTE-X19), US7741465, US6319494, UCART-19, tabeleculucel (EBV-CTL), T-tisagenlecroucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt expressing T cells, CD19 / 4-1BBL armored CART cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan, Malaysia; Anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia / non-Hodgkin lymphoma, University Hospital Heidelberg); Anti-CD19 CAR T-cell therapy (silent IL-6 expression, cancer, Shanghai Unicar therapy biopharmaceutical technology); MB-CART2019.1(CD19 / CD20), GC-197(CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 c CAR (CD19 / APRIL), ICG-134, ICG-132 (CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20 CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecroucell-T, CART-19, tisagenlecroucell (CTL-019), anti-CD20 CAR T cell therapy (non-Hodgkin lymphoma), MB-CART2019.1 (CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01(NKG2D LIGAND Examples include MODULATOR, KD-045, PD-L1 t-HANK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, and therapies disclosed in International Publication No. 2012 / 079000 or International Publication No. 2017 / 049166.

[0170] Surface antigen classification 47 (CD47) inhibitorsIn some embodiments, the antibodies and / or fusion proteins provided herein are administered with inhibitors of CD47 (IAP, MER6, OA3; NCBI gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody or CD47-blocking agent, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Further exemplary anti-CD47 antibodies include CC-90002, maglorimab (Hu5F9-G4), AO-176 (Vx-1004), letaplimab (IBI-188), remzopalimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, and 1F8. -GMCSF, SY-102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or International Publication No. 1997 / 27873, International Publication No. 1999 / 40940, International Publication No. 2002 / 092784, International Publication No. 2005 / 044857, International Publication No. 2009 / 046541, International Publication No. 2010 / 070047, International Publication No. 2011 / 143624, International Publication No. 20 International Publication No. 12 / 170250, International Publication No. 2013 / 109752, International Publication No. 2013 / 119714, International Publication No. 2014 / 087248, International Publication No. 2015 / 191861, International Publication No. 2016 / 022971, International Publication No. 2016 / 023040, International Publication No. 2016 / 024021, International Publication No. 2016 / 081423, International Publication No. 2016 / 109415, International Publication No. 2016 / 14 International Publication No. 1328, International Publication No. 2016 / 188449, International Publication No. 2017 / 027422, International Publication No. 2017 / 049251, International Publication No. 2017 / 053423, International Publication No. 2017 / 121771, International Publication No. 2017194634, International Publication No. 2017 / 196793, International Publication No. 2017 / 215585, International Publication No. 2018 / 075857, International Publication No. 2018 / 075960,International Publication Nos. 2018 / 089508, 2018 / 095428, 2018 / 137705, 2018 / 233575, 2019 / 027903, 2019 / 034895, 2019 / 042119, 2019 / 042285, 2019 / 042470, 2019 / 086573, 2019 / 108733, 2019 / 138367, 201 Examples of compounds disclosed in International Publication No. 9 / 144895, International Publication No. 2019 / 157843, International Publication No. 2019 / 179366, International Publication No. 2019 / 184912, International Publication No. 2019 / 185717, International Publication No. 2019 / 201236, International Publication No. 2019 / 238012, International Publication No. 2019 / 241732, International Publication No. 2020 / 019135, International Publication No. 2020 / 036977, International Publication No. 2020 / 043188, and International Publication No. 2020 / 009725. In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPαFc CD40L (SL-172154). In some embodiments, the CD47 inhibitor is maglorimab.

[0171] In some embodiments, the CD47 inhibitors are IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217 (CD47 / DLL3), IMM-26011 (CD47 / FLT3), IMM-0207 (CD47 / V These are bispecific antibodies that target CD47, such as EGF, IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801.

[0172] SIRPα targeting agent In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a SIRPα targeting agent (NCBI gene ID: 140885; UniProt P78324). Examples of SIRPα targeting agents include SIRPα inhibitors (such as AL-008, RRx-001, and CTX-5861), as well as anti-SIRPα antibodies (FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPα / PD-L1)). Additional SIRPα targeting agents that may be used include, for example, International Publication Nos. 2001 / 40307, ​​2002 / 092784, 2007 / 133811, 2009 / 046541, 2010 / 083253, 2011 / 076781, and 2013 / 05. International Publication No. 6352, International Publication No. 2015 / 138600, International Publication No. 2016 / 179399, International Publication No. 2016 / 205042, International Publication No. 2017 / 178653, International Publication No. 2018 / 026600, International Publication No. 2018 / 057669, International Publication No. 2018 / 107058, International Publication No. 2018 / This information is contained in publications 190719, International Publication 2018 / 210793, International Publication 2019 / 023347, International Publication 2019 / 042470, International Publication 2019 / 175218, International Publication 2019 / 183266, International Publication 2020 / 013170, and International Publication 2020 / 068752.

[0173] FLT3R Agonist In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an FLT3R agonist. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an FLT3 ligand. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with, for example, the FLT3L-Fc fusion protein described in International Publication No. 2020 / 263830. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with GS-3583 or CDX-301. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with GS-3583.

[0174] Agonists or activators of members of the TNF receptor superfamily (TNFRSF). In some embodiments, the antibodies and / or fusion proteins provided herein are one or more members of the TNF receptor superfamily (TNFRSF), e.g., TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 355), TNFRSF7 (CD27, NCBI gene ID; 939), TNFRSF8 (CD30, NCBI gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID; 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID; 8 794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 23495), TNFRSF13C (CD268, NCBI gene ID; 115650), TNFRSF1 It is administered with one or more agonists from among 6 (NGFR, CD271, NCBI gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID; 608), TNFRSF18 (GITR, CD357, NCBI gene ID; 8784), TNFRSF19 (NCBI gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI gene ID; 27242), and TNFRSF25 (DR3, NCBI gene ID; 8718).

[0175] Examples of anti-TNFRSF4 (OX40) antibodies that may be administered concurrently include MEDI6469, MEDI6383, tavorixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, as well as those described in International Publication Nos. 2016 / 179517, 2017 / 096179, 2017 / 096182, 2017 / 096281, and 2018 / 089628.

[0176] Exemplary anti-TNFRSF5 (CD40) antibodies that can be administered concurrently include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0177] In some embodiments, the anti-TNFRSF7 (CD27) antibody varylumab (CDX-1127) is co-administered.

[0178] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be administered concurrently include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0179] In some embodiments, the anti-TNFRSF17(BCMA) antibody GSK-2857916 is administered concurrently.

[0180] Examples of anti-TNFRSF18(GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in International Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4(OX40) and TNFRSF18(GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017096179 and 2018089628.

[0181] Examples of bispecific antibodies targeting TNFRSF family members that can be administered concurrently include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronectumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), pramotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20).

[0182] Bispecific T cell engagers In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a bispecific T cell enforcer (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that may be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), and odronectamab (REGN-1979; CD20 / C). D3), ​​MCLA-117 (CD3 / CLEC12A), JNJ-0819 (hem / CD3), JNJ-7564 (CD3 / hem), AMG-757 (DLL3-CD3), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3) ), AMG-427(FLT3 / CD3), AMG-562(CD19 / CD3), AMG-596(EGFRvIII / CD3), AMG-673(CD33 / CD3), AMG-701(BCMA / CD3), AMG-757(DLL3 / CD3 ), AMG-211 (CEA / CD3), blinatumomab (CD19 / CD3), huGD2-BsAb (CD3 / GD2), ERY974 (GPC3 / CD3), GEMoab (CD3 / PSCA), RG6026 (CD20 / CD3), RG6 194(HER2 / CD3), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw123), JNJ-9383(MGD-015), AMG-424(CD38 / CD3), Tidutamab(XmAb-18087 (SSTR2 / CD3), JNJ-63709178 (CD123 / CD3), MGD-007 (CD3 / gpA33), MGD-009 (CD3 / B7H3), IMCgp100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20), Tidutamab (XmAb-18087); SSTR2 / CD3), Katsumakisomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), Mosnetuzumab (RG-7828;Examples include CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). The anti-CD3 binding bispecific molecule may or may not have an Fc, as needed. Exemplary bispecific T-cell engagers that can be co-administered include CD3 and tumor-associated antigens described herein (e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230)).

[0183] Bispecific and tripspecific natural killer (NK) cell engagers In some embodiments, the antibodies and / or fusion proteins provided herein are bi-specific NK-cell engagers (BiKE) or tri-specific NK-cell engagers (TriKE) (e.g., without Fc), or NK cell activation receptors, e.g., CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), innate cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell type C lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (mediating antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), or killer cell immunoglobulin-like receptors. It is administered together with bispecific antibodies (e.g., having Fc) against receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE that may be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). The anti-CD16 binding bispecific molecule may or may not have Fc, as required. Exemplary bispecific NK cell engagers that may be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKE and TriKE are described, for example, Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.

[0184] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with MCL1 apoptosis regulators and BCL2 family members (MCL1, TM;EAT;MCL1L, MCL1S, Mcl-1;BCL2L3, MCL1-ES, bcl2-L-3;mcl1 / EAT;NCBI gene ID:4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in International Publication Nos. 2018 / 183418, 2016 / 033486, and 2017 / 147410.

[0185] SHP2 inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with inhibitors of protein tyrosine phosphatase nonreceptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in International Publication Nos. 2018 / 172984 and International Publication Nos. 2017 / 211303.

[0186] Hematopoietic precursor kinase 1 (HPK1) inhibitors and degrading agents In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of mitogen-activated protein kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184). Examples of hematopoietic precursor kinase 1 (HPK1) inhibitors include, but are not limited to, those described in International Publication Nos. 2020 / 092621, 2018 / 183956, 2018 / 183964, 2018 / 167147, 2018 / 049152, 2020 / 092528, 2016 / 205942, 2016 / 090300, 2018 / 049214, 2018 / 049200, 2018 / 049191, 2018102366, 2018 / 049152, and 2016 / 090300.

[0187] Apoptosis signal-regulated kinase (ASK) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with ASK inhibitors, such as mitogen-activated protein kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors are described in International Publication No. 2011 / 008709 (Gilead Sciences) and International Publication No. 2013 / 112741 (Gilead Sciences).

[0188] Bruton's tyrosine kinase (BTK) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with Bruton's tyrosine kinase inhibitors (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(buta-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebralutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0189] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A, P34CDC2, NCBI gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI gene ID: 1018); cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J31018); NCBI gene ID: 1018 It is administered together with an inhibitor of cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI gene ID: 1021), cyclin-dependent kinase 7 (CDK7, CAK; CAK1, HCAK; MO15, STK1, CDKN7, p39MO15; NCBI gene ID: 1022), or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1, CDC2L4, PITALRE; NCBI gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7 and / or 9 include abemaciclib, arbocidicib (HMR-1275, flavopyridol), AT-7519, dinacyclib, Ibrance, FLX-925, LEE001, palbociclib, samuracyclib, ribociclib, rigosertib, serenexol, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milcilib, trilaciclib, simrosertib hydrate (TAK931), and TG-02.

[0190] Discoidine domain receptor (DDR) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are combined with inhibitors of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI gene ID: 4921). Examples of DDR inhibitors include dasatinib, as well as those disclosed in International Publication No. 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), U.S. Patent Application Publication No. 2011-0287011 (Oncomed Pharmaceuticals), International Publication No. 2013 / 027802 (Chugai Pharmaceutical), and U.S. Patent Application Publication No. 2013 / 034933 (Imperial Innovations).

[0191] Targeted E3 ligase ligand conjugate In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a target E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and Survivor) E3 ubiquitin ligase binding moiety, a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, a Cereblon E3 ubiquitin ligase binding moiety, a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase the degradation of the targeted protein, for example, via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting or binding moiety that targets or binds to the proteins described herein, and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting or binding moiety that targets or binds to a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI gene ID: 868) and hypoxia-inducible factor 1 subunit α (HIF1A; NCBI gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of BTK and the E3 ligase ligand or binding moiety). See, for example, International Publication No. 2018 / 098280. In some embodiments, the targeted E3 ligase ligand conjugate includes interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); rapidly accelerating fibrosarcoma proteins (such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD proteins; and a binding moiety that targets or binds to the E3 ligase ligand or binding moiety.For example, see International Publication Nos. 2019 / 099926, 2018 / 226542, 2018 / 119448, 2018 / 223909, and 2019 / 079701. Additional targeted E3 ligase ligand conjugates that can be administered concurrently are described, for example, in International Publication Nos. 2018 / 237026, 2019 / 084026, 2019 / 084030, 2019 / 067733, 2019 / 043217, 2019 / 043208, and 2018 / 144649.

[0192] Histone deacetylase (HDAC) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with inhibitors of histone deacetylase, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include avexinostat, ACY-241, AR-42, BEBT-908, bellinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mosetinostat, panobinostat, prasinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamstine, remetinostat, and entinostat.

[0193] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrhodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919 vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0194] Janus kinase (JAK) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with inhibitors of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restoltinib, momerotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0195] Lysyl oxidase-like protein (LOXL) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with inhibitors of LOXL proteins, such as LOXL1 (NCBI gene ID: 4016), LOXL2 (NCBI gene ID: 4017), LOXL3 (NCBI gene ID: 84695), LOXL4 (NCBI gene ID: 84171), and / or LOX (NCBI gene ID: 4015). Examples of LOXL2 inhibitors include antibodies described in International Publication No. 2009 / 017833 (Arresto Biosciences), International Publication No. 2009 / 035791 (Arresto Biosciences), and International Publication No. 2011 / 097513 (Gilead Biologics).

[0196] Matrix metalloproteinase (MMP) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are matrix metallopeptidases (MMPs), such as MMP1 (NCBI gene ID: 4312), MMP2 (NCBI gene ID: 4313), MMP3 (NCBI gene ID: 4314), MMP7 (NCBI gene ID: 4316), MMP8 (NCBI gene ID: 4317), MMP9 (NCBI gene ID: 4318); MMP10 (NCBI gene ID: 4319); MMP11 (NCBI gene ID: 4320); MMP12 (NCBI gene ID: 4321), MMP13 (NCBI gene ID: 4322), MMP14 (NCBI gene ID: 4323), MM It is administered together with inhibitors of P15 (NCBI gene ID: 4324), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP19 (NCBI gene ID: 4327), MMP20 (NCBI gene ID: 9313), MMP21 (NCBI gene ID: 118856), MMP24 (NCBI gene ID: 10893), MMP25 (NCBI gene ID: 64386), MMP26 (NCBI gene ID: 56547), MMP27 (NCBI gene ID: 64066), and / or MMP28 (NCBI gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), cipestat (Ro 32-3555), GS-5745 (andecaliximab), and those described in International Publication No. 2012 / 027721 (Gilead Biologics).

[0197] RAS and RAS pathway inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are KRAS proto-oncogene, GTPase (KRAS; also known as NS; NS3, CFC2, RALD; K-Ras; KRAS1, KRAS2, RASK2, KI-RAS; CK-RAS; K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B, c-Ki-ras2; NCBI gene ID: 3845); NRAS proto-oncogene, GTPase (NRAS; also known as NS6 It is administered together with an inhibitor of the ;CMNS;NCMS;ALPS4, N-ras;NRAS1, NCBI gene ID:4893) or the HRAS oncogene, or a GTPase (HRAS; also known as CTLO;KRAS;HAMSV;HRAS1, KRAS2, RASH1, RASK2, Ki-Ras;p21ras, CH-RAS;cK-ras;H-RASIDX;c-Ki-ras;C-BAS / HAS;C-HA-RAS1, NCBI gene ID:3265). Ras inhibitors can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of the following: EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Examples of K-Ras inhibitors that may be administered concurrently include sotrasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1(G12C), adaglasib (MRTX-849), ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602(RasGTP), RT11, MRTX-849(G12C), and K-Ras(G12D) selective inhibitory peptides (including KRpep-2 and KRpep-2d). Examples of KRAS mRNA inhibitors include anti-KRAS U1 adapter, AZD-4785, siG12D-LODER®, and siG12D exosome.Exemplary MEK inhibitors that may be administered concurrently include binimetinib, cobimetinib, PD-0325901, pimacertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that may be administered concurrently include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that may be administered concurrently include LTT-462, LY-3214996, MK-8353, labocertinib, and urixertinib. Exemplary Ras GTPase inhibitors that may be administered concurrently include lyzigocertib. Examples of PI3K inhibitors that may be administered concurrently include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Examples of AKT inhibitors that may be administered concurrently include capivacertib and GSK2141795. Examples of PI3K / mTOR inhibitors that can be administered concurrently include dactricib, omiparisib, boxalisib, gedatricib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanicertib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), racemethyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatacertib (CC-223), SF-1126, and PQR-309 (vimiralisib). In some embodiments, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, for example, Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Additionally, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1 / 2 / 4 inhibitor neratinib. See, for example, Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0198] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with inhibitors of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib + trametinib, PD-0325901, pimacerutib, LTT462, AS703988, CC-90003, and refametinib.

[0199] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB, It is administered together with inhibitors of P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D; NCBI gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, buparisib (BKM120), BYL719 (alperisib), CH5132799, and copanlisib (BAY 80-6946), Duverisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7 604, ligoseltib, RP5090, RP6530, SRX3177, tasericib, TG100115, TGR-1202 (umbralicib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Waltmannin, ZSTK474, and International Publication No. 2005 / 113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Examples include compounds described in International Publication No. 2013 / 116562 (Gilead Calistoga), International Publication No. 2014 / 100765 (Gilead Calistoga), International Publication No. 2014 / 100767 (Gilead Calistoga), and International Publication No. 2014 / 201409 (Gilead Sciences).

[0200] Spleen tyrosine kinase (SYK) inhibitors In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine, BAY-61-3606, celduratinib (PRT-062607), entpretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusatitinib (ASN-002), and those described in U.S. Patent No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 2015 / 0175616.

[0201] Toll-like receptor (TLR) agonist In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with agonists of Toll-like receptors (TLRs), such as TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793). Examples of TLR7 agonists that can be administered concurrently include DS-0509, GS-9620 (vesatolimod), vesatolimod analogues, LHC-165, TMX-101 (imiquimod), GSK-2245035, reciquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509, and U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences). Array Sciences), and U.S. Patent Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent Publication No. 2014 / 0045849 (Janssen), U.S. Patent Publication No. 2014 / 0073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Publication No. 2014 / 0350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx)Examples of compounds disclosed in U.S. Patent Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Publication No. 2013 / 0251673 (Novira Therapeutics). The TLR7 / TLR8 agonist that can be co-administered is NKTR-262. Examples of TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motlimod, reciquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 00736. 42 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), US Patent Application Publication No. 2014 / 0350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), US Patent Application Publication No. 2008 / 0234251 (Array Array Biopharma, U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (VentirxPharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (VentirxExamples include compounds disclosed in U.S. Patent Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Publication No. 2013 / 0251673 (Novira Therapeutics). Examples of TLR9 agonists that can be administered concurrently include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintatrimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0202] Tyrosine kinase inhibitors (TKIs) In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a tyrosine kinase inhibitor (TKI). The TKI may target epidermal growth factor receptor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cejiranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src Examples include, but are not limited to, lapatinib, restaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rosiletinib, sulfatinib (HMPL-012), sunitinib, famitinib, L-malate (MAC-4), tiboanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Examples of EGFR targeting agents include neratinib, tucatinib (ONT-380), tesevatinib, mobocertinib (TAK-788), DZD-9008, baritinib, avivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), rifilafenib (BGB-283), vectibix, razertinib (LECLAZA®), and Booth, et al., Cancer Biol Ther. 2018 Feb. Examples of EGFR-targeting antibodies include, but are not limited to, modotuximab, cetuximab sarotalocan (RM-1929), cerivanthumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab.

[0203] Chemotherapy drugs In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with chemotherapeutic agents or antineoplastic agents.

[0204] As used herein, the terms “chemotherapy agent” or “chemotherapy agent” (or “chemotherapy” when referring to treatment with a chemotherapy agent) mean any non-proteinogenic (e.g., non-peptidogenic) compound useful in the treatment of cancer. Examples of chemotherapy agents include, but are not limited to, alkylating agents, e.g., thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g., benzodepa, carboquan, meturedepa, and uredepa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemiloromelamine; acetogenins, e.g., bratacin and bratacinone; camptothecin, including the synthetic analog topotecan; bryostatin, callistatin; CC-1065, including adzeresin, karzeresin, and bizeresin synthetic analogs; and crypto Ficins, in particular cryptophycin 1 and cryptophycin 8; dorastatin; duocalmycin, including synthetic analogs KW-2189 and CBI-TMI; eryuterobin; 5-azacitidine; pancratistatin; sarcodictiin; spongstatin; nitrogen mustards, e.g., chlorambucil, chlornafadin, cyclophosphamide, gluphosphamide, evophosphamide, bendamustine, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitine, fenestrine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., carmustine, chlorozotosine, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as engine antibiotics (e.g., Calichemycin, especially Calichemycin γII and Calichemycin φI1), dinemycin containing dinemycin A, bisphosphonates such as clodronate, esperamycin, neocardinostatin chromophores and related chromoprotein engine antibiotic chromophores, acrasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kactinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin Detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenime Phosphates, dinostatins, and zolubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folate analogs, e.g., demopterin, methotrexate, pteropterin, and trimethrexate; purine analogs, e.g., cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; an Drogens, e.g., carsterone, dromostanolone propionate, epithiostanol, mepithiostan, and testotractone; anti-adrenal drugs, e.g., aminoglutethimide, mitotane, and trilostane; folic acid supplements, e.g., floric acid; radiotherapy agents such as radium-223; trichothecenes, especially T-2 toxin, beraclin A, loridine A, and anguidin; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Sabizabrin (Veru-111); platinum analogs, e.g., cisplatin and carboplatin, NC-6004 nanoplatin; acegraton; aldofamide glycoside; aminolevulinic acid; enyluracil; amsacrin, hestrabucil; bisanthren; edatrexate; defofamine; demecoltin; diaziquan; elformutin; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea, lentinan; leucovorin; ronidamine; meitansinoids, e.g., meitansin and ansamitosine; mitogwazone; mitoxantrone; mopidamol; nitracrin; pentostatin; fenamet; pirarubicin; losoxantrone; fluoropyrimidine; folic acid; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide K (PSK); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Trabectedin, Triadiquan; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZA) R(registered trademark)); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; bancristine; vinorelbine (NAVELBINE(registered trademark)); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11, topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031, FOLFOX (folic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folic acid, 5-fluorouracil, irinotecan);Examples include FOLFOXIRI (folic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folic acid, 5-fluorouracil, irinotecan, oxaliplatin), and any pharmaceutically acceptable salts, acids, or derivatives of the above. Such agents may be conjugated to an antibody or any targeting agent described herein to create an antibody-drug conjugate (ADC) or a targeted drug conjugate.

[0205] Anti-hormone drugs The definition of "chemotherapeutic agents" includes anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), enzyme aromatase inhibitors, anti-androgens, and any pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to modulate or inhibit the hormonal effects on tumors.

[0206] Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifen, droloxifen, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (FARESTON®).

[0207] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal gland. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestan, fadrozole, borozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0208] Examples of antiandrogen drugs include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enovotherm (GTX-024), darolutamide, and IONIS-AR-2.5 Rx (antisense).

[0209] An example of a progesterone receptor antagonist is onapristone. Further progesterone targeting agents include TRI-CYCLEN LO (norethindrone + ethinylestradiol), norgestimate + ethinylestradiol (Tri-Cyclen), and levonorgestrel.

[0210] Anti-angiogenic agents In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with anti-angiogenic agents. Anti-angiogenic agents that may be administered concurrently include retinoid acids and their derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, nekparanib, suramin, squalamine, tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clepein), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thiapro Examples include phosphorus, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin serum, metalloproteinase-3 chicken inhibitor (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagiline, sodium aurantithiomalate, d-penicillamine, β-1-anticollagenase serum, alpha-2-antiplasmin, bisanthren, lobenzalit disodium, n-2-carboxyphenyl-4-chloroantonylate disodium or "CCA", thalidomide, angiogenesis-inhibiting steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tascinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be administered concurrently include bevacizumab, vanucizumab, falisimab, zilpasimab (ABT-165;DLL4 / VEGF), or nabisixizumab (OMP-305B83);DLL4 / VEGF).

[0211] Antifibrotic agents In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with antifibrotic agents. Antifibrotic agents that may be administered concomitantly include compounds such as beta-aminoproprionitrile (BAPN), as well as compounds disclosed in U.S. Patent No. 4,965,288, relating to lysyl oxidase inhibitors and their use in the treatment of diseases and conditions associated with abnormal collagen deposition, and U.S. Patent No. 4,997,854, relating to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, which are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Patents 4,943,593, 5,021,456, 5,059,714, 5,120,764, and 5,182,297 relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Patent 5,252,608 relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application No. 2004 / 0248871, which are incorporated herein by reference.

[0212] Examples of antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that, after binding to carbonyl, produce a resonance-stabilized product, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazides and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine ​​lactones.

[0213] Other antifibrotic agents are copper chelating agents that either penetrate or do not penetrate cells. Exemplary compounds include indirect inhibitors that inhibit aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamins, particularly D-penicillamine and its analogues, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiol sulfanate, and sodium-4-mercaptobutane sulfinate trihydrate.

[0214] Anti-inflammatory drugs In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an anti-inflammatory agent. Examples of anti-inflammatory agents include arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 This includes, but is not limited to, one or more inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI gene ID: 1326). In some embodiments, the inhibitor is a biinhibitor, such as a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, or COX-2 / 5-LOX biinhibitor.

[0215] Examples of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) inhibitors that can be co-administered include mofezolac, GLY-230, and TRK-700.

[0216] Examples of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743) inhibitors that can be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maesoshri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimeslid, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, lutecarpine, chilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that can be administered concurrently include HP-5000, lornoxicam, ketrolactromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that can be administered concurrently include polmacoxib and imurecoxib.

[0217] Examples of co-administered inhibitors of secretory phospholipase A2 and prostaglandin E synthase (PTGES, PGES; gene ID: 9536) include LY3023703, GRC27864, and international publications 2015 / 158204, 2013 / 024898, 2006 / 063466, 2007 / 059610, 2007 / 124589, and 2010 / 100. International Publication No. 249, International Publication No. 2010 / 034796, International Publication No. 2010 / 034797, International Publication No. 2012 / 022793, International Publication No. 2012 / 076673, International Publication No. 2012 / 076672, International Publication No. 2010 / 034798, International Publication No. 2010 / 034799, International Publication No. 2012 / 022792, International Publication No. 2009 / 103778, International Publication No. 2011 / 048004, International Publication No. 201 International Publication No. 2 / 087771, International Publication No. 2012 / 161965, International Publication No. 2013 / 118071, International Publication No. 2013 / 072825, International Publication No. 2014 / 167444, International Publication No. 2009 / 138376, International Publication No. 2011 / 023812, International Publication No. 2012 / 110860, International Publication No. 2013 / 153535, International Publication No. 2009 / 130242, International Publication No. 2009 / 146696, International Publication Examples of compounds include those described in International Publication No. 2013 / 186692, International Publication No. 2015 / 059618, International Publication No. 2016 / 069376, International Publication No. 2016 / 069374, International Publication No. 2009 / 117985, International Publication No. 2009 / 064250, International Publication No. 2009 / 064251, International Publication No. 2009 / 082347, International Publication No. 2009 / 117987, and International Publication No. 2008 / 071173. Furthermore, metformin has been found to inhibit the COX2 / PGE2 / STAT3 axis and can be administered co-administered. For example, see Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):282 35-46.

[0218] Carbonic anhydrases that can be administered simultaneously (e.g., CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), C Examples of inhibitors for one or more of the following: A9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), and CA14 (NCBI gene ID: 23632) include acetazolamide, metazolamide, dorzolamide, zonisamide, brinzolamide, and diclofenamide. CG100649 is an example of a COX-2 / CA1 / CA2 dual inhibitor that can be co-administered.

[0219] Examples of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) inhibitors that can be co-administered include meclofenamate sodium and dilauton.

[0220] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) that can be co-administered include compounds described in International Publication No. 2015 / 148954. Examples of co-administered COX-2 / SEH dual inhibitors include compounds described in International Publication No. 2012 / 082647. Examples of co-administered SEH and fatty acid amide hydrolase dual inhibitors (FAAH; NCBI gene ID: 2166) include compounds described in International Publication No. 2017 / 160861.

[0221] Examples of mitogen-activated protein kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI gene ID: 1326) that can be co-administered include GS-4875, GS-5290, BHM-078, and, for example, International Publication Nos. 2006 / 124944, 2006 / 124692, 2014 / 064215, 2018 / 005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila, et al. Examples include those described in al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0222] Tumor oxygenation agent In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Exemplary agents that may be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors, e.g., PT-2977, PT-2385; VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding proteins (HNOX)), such as OMX-302 and HNOX proteins described in, for example, International Publication Nos. 2007 / 137767, 2007 / 139791, 2014 / 107171, and 2016 / 149562.

[0223] Immunotherapy agents In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an immunotherapy agent. In some embodiments, the immunotherapy agent is an antibody.Examples of immunotherapeutic agents that can be administered concurrently include avagovomab, AB308, ABP-980, adecatumumab, aftumumab, alemtuzumab, artumomab, amatsuximab, anatumomab, alsitunomab, atezolizumab, bavituximab, vectumomab, bevacizumab, vibatuzumab, blinatumumab, brentuximab, camidanlumab, cantuzumab, catumakisomab, CC49, cetuximab, sitatuzumab, xixtumumab, cribatuzumab, conatumumab, dacetuzumab, darotuzumab, daratumumab, detumomab, and di Nutuximab, dombanarimab, dorodizumab, durigotumab, dusigitumab, eclomeximab, elotuzumab, emibetuzumab, encituximab, erzumakisomab, etalacizumab, falletuzumab, ficratuzumab, figitumumab, frambotuzumab, futuximab, ganituzumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igobomab, imugatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-73) 4016, and MDX-101), iratumumab, rabetuzumab, lexatumumab, lintuzumab, rorbotuzumab, lucatumumab, mapatumumab, matsuzumab, milatuzumab, minretumomab, mitumomab, mogamulitsumab, moxetumomab, naptumomab, narunatumamab, nesitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, okalatuzumab, ofatumumab, oraratumamab, onarutuzumab, oporutuzumab, olegobomab, panitumumab, pulsatuzumab, pasdotox, patrizumab, pemutz Examples include momab, pertuzumab, pintumomab, pritumumab, lacosumomab, radretumumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samarizumab, saturomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, takatuzumab, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotsuzumab, ubirituximab, bertuzumab, borsetuzumab, botumumab, zaltumumab, zimbererimab, and 3F8.Rituximab can be used to treat slow chronic B-cell carcinomas, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0224] The exemplified therapeutic antibodies may be further labeled or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y cribatuzumab), or iodine-131.

[0225] In some embodiments, the immunotherapy agent is an antibody-drug conjugate (ADC). Exemplary ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics targeting proteins or antigens listed above and herein.Examples of ADCs that can be administered concurrently include gemtuzumab, brentuximab, verantamab (e.g., verantamab mahodotin), camidanrumab (e.g., camidanrumab tesirin), tratuzumab (e.g., tratuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuxizumab (e.g., mirvetuxizumab sobatansine), depatuxizumab, vadasotuximab, rabetuzumab, and radilatuzumab (e.g., radilatuzumab vedotin). Roncatuximab (e.g., roncatuximab teslin), sacituzumab (e.g., sacituzumab govitecan), datopotomab (e.g., datopotomab deruxtecan; DS-1062, Dato-DXd), patrituzumab (e.g., patrituzumab deruxtecan), rifastuzumab, indosatuzumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., upifitama brylylsodotin), indituximab, milatuzumab, robalutuzumab (e.g., robalutuzumab) Butesillin), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamablavtansine), disitamab (e.g., disitamab vedotin), terizotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMG Examples include N529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130, and IMMU-140.ADCs that can be co-administered are described, for example, Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0226] Examples of drug-conjugated antibodies, fragments thereof, or exemplary therapeutic agents (e.g., anticancer or antitumor agents) that can be conjugated mimetically include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, mytansine or its analogues (e.g., meltansine / emtansine (DM1), ravtansine / solavtansine (DM4)), anthracyclines (e.g., Examples include doxorubicin, daunorubicin, epirubicin, idarubicin, pyrrolobenzodiazepine (PBD) DNA crosslinking agent SC-DR002 (D6.5), duocalmycin, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epotilone), pyrrolobenzodiazepine (PBD) or its dimers, duocalmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or antineoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to a drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anticancer or antineoplastic agent) that can be conjugated to a drug-conjugated antibody, a fragment thereof, or an antibody mimetic includes immune checkpoint inhibitors. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 includes BPI-002.

[0227] In some embodiments, an ADC that may be administered concurrently is an antibody-targeted tumor-associated calcium signaling molecule 2 (TROP-2; TACSTD2, EGP-1, NCBI gene ID: 4070). Examples of anti-TROP-2 antibodies include TROP-2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Shanghai DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP-2-TRACTr (Janux Therapeutics), and LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius). BioTech), LIV-2008b (Shanghai / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (MediterraneaTheranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and International Publication No. 2020 / 016662 (Abmart), International Publication No. 2020 / 249063 (Bio-Thera Solutions), US Patent Application Publication No. 2019 / 0048095 (Bio-Thera Solutions), US Patent Application Publication No. 2013 / 077458 (LivTech / Chiome), European Patent Application Publication No. 2011 / 0783675 (Chiome), International Publication No. 2015 / 098099 (Daiichi Sankyo), International Publication No. 2017 / 002776 (Daiichi Sankyo), International Publication No. 2020 / 130125 (Daiichi Sankyo), International Publication No. 2020 / 240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021 / 093730 (Daiichi Sankyo), U.S. Patent Application Publication No. 9850312 (DaiichiSankyo), Chinese Patent No. 112321715 (Biosion), US Patent Application Publication No. 2006 / 193865 (Immunomedics / Gilead), US Patent Application Publication No. 2011 / 068845 (Immunomedics / Gilead), US Patent Application Publication No. 2016 / 296633 (Immunomedics / Gilead), US Patent Application Publication No. 2017 / 021017 (Immunomedics / Gilead), US Patent Application Publication No. 2017 / 209 Patent No. 594 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017 / 274093 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 110772 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 185351 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 271992 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 217227 (Imm Immunomedics / Gilead), U.S. Patent Application Publication No. 2019 / 248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021 / 093730 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021 / 069343 (Immunomedics / Gilead), U.S. Patent No. 8435539 (Immunomedics / Gilead), U.S. Patent License No. 8435529 (Immunomedics / Gilead), U.S. Patent No. 9492566 (Immunomedics / Gilead), International Publication No. 2003 / 074566 (Gilead), International Publication No. 2020 / 257648 (Gilead), International Publication No. 2013 / 039861 (Gilead), International Publication No. 2014 / 163684 (Gilead), U.S. Patent No. 9427464 (LivTech / Chiome), U.S. Patent No. 10501555 (Abruzzo Theranostic / Oncoxx), International Publication No. 2018 / 036428 (Sichuan KelunExamples include, but are not limited to, those described in U.S. Patent Publication No. 2013 / 068946 (Pfizer), U.S. Patent Publication No. 2007 / 095749 (Roche), and U.S. Patent Publication No. 2020 / 094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Patents No. 7,238,785, No. 7,517,964, and No. 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody conjugated by a linker and an anticancer agent. In some embodiments, the linker is as disclosed in U.S. Patent No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug portion of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doxorubicin (DOX), epirubicin, morpholino-doxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, ruthecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanmycin, ansamycin, and epotilon. In some embodiments, the chemotherapeutic portion is SN-38. In some embodiments, the antibody and / or fusion protein provided herein is administered together with sacituzumab govitecan.

[0228] In some embodiments, the ADC that may be co-administered is carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1; CD66a, NCBI gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (as described, for example, in International Publication No. 1996011013). In some embodiments, the CEACAM1-ADC is as described in International Publication No. 2010 / 093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein is administered together with CEACAM1-ADC IMMU-130.

[0229] In some embodiments, the ADC that may be co-administered comprises an antibody that targets MHC class II cell surface receptors encoded by human leukocyte antigen complexes (HLA-DRs). In some embodiments, the HLA-DR antibody is hL243 (as described, for example, in International Publication No. 2006 / 094192). In some embodiments, the HLA-DR-ADC is as described in International Publication No. 2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein is administered together with HLA-DR-ADC IMMU-140.

[0230] Cancer gene therapy and cell therapy In some embodiments, the antibodies and / or fusion proteins provided herein are administered in conjunction with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include: insertion of normal genes into cancer cells to replace mutated or altered genes; gene modification to silence mutated genes; genetic approaches to directly kill cancer cells, such as the injection of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response against cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill or detect and kill cancer cells; and genetic approaches to modify cell activity to further alter the intrinsic immune responsiveness to cancer.

[0231] cell therapy In some embodiments, the antibodies and / or fusion proteins provided herein are administered in conjunction with one or more cell therapies. Exemplary cell therapies include, but are not limited to, the co-administration of one or more populations of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor-infiltrating lymphocytes (TILs), and / or dendritic cells (DCs). In some embodiments, the cell therapy involves co-administration of T cell therapy, e.g., populations of α / βTCR T cells, γ / δTCR T cells, regulatory T (Treg) cells, and / or TRuC® T cells. In some embodiments, the cell therapy involves co-administration of NK cell therapy, e.g., NK-92 cells. If necessary, the cell therapy may involve co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0232] In some embodiments, cell therapy involves the co-administration of cells containing a chimeric antigen receptor (CAR). In such therapy, a population of immune effector cells is engineered to express a CAR, which includes a tumor antigen-binding domain. In T cell therapy, the T cell receptor (TCR) is engineered to target tumor-derived peptides presented on the surface of tumor cells.

[0233] Regarding the structure of CAR, in some embodiments, CAR includes an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain includes a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain includes the signaling functional domain of one or more proteins selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0234] In some embodiments, the co-stimulatory domain is a ligand that specifically binds to CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD 4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 9 12), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL 1. It contains one or more functional domains of proteins selected from the group consisting of CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0235] In some embodiments, the transmembrane domain is the α, β, or ζ chain of the T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rβ, IL2Rγ, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E It contains a transmembrane domain of a protein selected from the group consisting of ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0236] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapy agent described herein (e.g., monospecific or multispecific antibodies or their antigen-binding fragments or antibody mimetic) binds to tumor-associated antigens (TAAs). In some embodiments, tumor-associated antigens are selected from the group consisting of: CD19; CD123, CD22, CD30, CD171, CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); type C lectin-like molecule-1 (CLL-1 or CLECLI); CD33, epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38, CD44v6, carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit α-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor α (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testicin or PR SS21); Vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24, platelet-derived growth factor receptor β (PDGFR-β); Stage-specific fetal antigen-4 (SSEA-4); CD20, delta-like 3 (DLL3); Folate receptor α; Receptor tyrosine protein kinase, ERBB2 (Her2 / neu); Mucin 1, cell surface binding (MUC1); Epidermal growth factor receptor (EGFR); Neuronal cell adhesion molecule (NCAM); Prostase; Prostatic acid phosphatase (PAP); Elongation factor 2 variant (ELF2M); Ephrin B2; Fibroblast-activating protein α (FAP);Insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, β-type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of cleavage cluster region (BCR) and Abelson mouse leukemia virus oncogene homolog 1 (abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); prostate I 6 Transmembrane epithelial antigen (STEAP1); Claudin 6 (CLDN6); Thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRCSD); X chromosome open reading frame 61 (CXORF61); CD97, CD179a, anaplastic lymphoma kinase (ALK); Polysialic acid; Placenta-specific antigen 1 (PLAC1); Hexasaccharide moiety of globoH glycoceramide (GloboH); Mammary gland differentiation antigen (NY-BR-1); Uloplakin 2 (UPK2); Hepatitis A virus cell receptor 1 (HAVCR1); Adrenergic receptor β3 (ADRB3); Panexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); Lymphocyte antigen 6 complex, locus K9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCRγ Alternative Reading Frame Protein (TARP); Wilms Tumor Protein (WT1); Cancer / Testicular Antigen 1 (NY-ESO-1); Cancer / Testicular Antigen 2 (LAGE-la); Melanoma-Associated Antigen 1 (MAGE-A1); ETS Translocation Variant Gene 6 (ETV6-AML) located on chromosome 12p; Sperm Protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); Angiopoietin-Binding Cell Surface Receptor 2 (Tie2); Melanoma Carcinoma Testicular Antigen-1 (MADCT-1); Melanoma Carcinoma Testicular Antigen-2 (MADCT-2); Fos-Associated Antigen 1; Tumor Protein p53 (p53); p53 Variant; Prostein; Sulbibin; Telomerase;Prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma apoptosis inhibitor (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myeloma virus oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC binding factor (zinc finger protein)-like (sibling of BORIS or imprint site regulator), squamous cell carcinoma antigen 3 (SART3) recognized by T cells; paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-break point 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous protein 1 (RUI); renal ubiquitous protein 2 (RU2); regmine; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); enteric carboxylesterase; heat shock protein 70-2 variant (mut hsp70-2); CD79a, CD79b, CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin λ-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of tumor-associated antigen presented to the MHC.

[0237] In some embodiments, the tumor antigens are CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD4 6, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1(DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, G protein-binding receptor, α-fetoprotein (AFP), angiogenic factor, exogenous alloconjugate molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA) The following are selected: cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate-binding protein, gp100, hepatitis B surface antigen, κ chain, κ light chain, kdr, λ chain, livin, melanoma-associated antigen, mesoserin, mouse double microchromosome 2 homolog (MDM2), mucin 16 (MUC16), variant p53, variant ras, necrotic antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenacin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0238] In some embodiments, the antigen-binding domain binds to an epitope of a target antigen or tumor-associated antigen (TAA) presented on a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a carcinomatous antigen. In some embodiments, the cancer testicular antigen is acrosin-binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI gene ID: 84519), alpha-fetoprotein (AFP; AFPD, FETA, HPAFP; NCBI gene ID: 174); A kinase anchor protein 4 (AKAP4; AKAP82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI gene ID: 8852), ATPase family AAA domain-containing 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI gene ID: 29028), kinetochore scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI Gene ID: 57082), Centrosole Protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI Gene ID: 55165), Cancer / Testicular Antigen 1A (CTAG1A; ESO1, CT6.1, LAGE-2, LAGE2A, NY-ESO-1, NCBI Gene ID: 246100), Cancer / Testicular Antigen 1B (CTAG1B; CT6.1, CTAG, CTAG1, E SO1, LAGE-2, LAGE2B, NY-ESO-1; NCBI gene ID: 1485), cancer / testis antigen 2 (CTAG2; CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B; NCBI gene ID: 30848), CCCTC-binding factor-like (CTCFL; BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20.2;NCBI gene ID:140690), Cathenin α2 (CTNNA2;CAP-R, CAPR, CDCBM9, CT114, CTNR;NCBI gene ID:1496), Cancer / Testicular Antigen 83 (CT83;CXorf61, KK-LC-1, KKLC1;NCBI gene ID:203413), Cyclin A1 (CCNA1;CT146, NCBI gene ID:8900), Dead-box type helicase 43 (DDX43;CT13, HAGE;NCBI gene ID:55510) Developmental pluripotency-related gene 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI gene ID: 151871), fetal and adult testicular expression 1 (FATE1; CT43, FATE; NCBI gene ID: 89885), FMR1 adjacency (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI gene ID: 158521), HORMA domain-containing gene 1 (HORMAD1; CT46, NOHMA; NCBI gene ID: 84072), insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3; CT98, IMP-3, IMP3, KOC, KOC1, VICKZ3; NCBI gene ID: 10643), leucine zipper protein 4 (LUZP4; CT-28, CT-8, CT28, HOM-TES-85; NCBI gene ID: 51213), lymphocyte antigen 6 family member K (LY6K; CT97, HSJ001348, URLC10, ly-6K; NCBI gene ID: 54742), maelstrom spermatogenesis transposon silencer (MAEL; CT128, SPATA35) ;NCBI gene ID:84944), MAGE family member A1 (MAGEA1;CT1.1, MAGE1;NCBI gene ID:4100); MAGE family member A3 (MAGEA3;CT1.3, HIP8, HYPD, MAGE3, MAGEA6;NCBI gene ID:4102); MAGE family member A4 (MAGEA4;CT1.4, MAGE-41, MAGE-X2, MAGE4, ​​MAGE4A, MAGE4B;NCBI gene ID:4103); MAGE family member A11 (MAGEA11;CT1.11, MAGE-11, MAGE11, MAGEA-11; NCBI gene ID: 4110); MAGE family member C1 (MAGEC1; CT7, CT7.1; NCBI gene ID: 9947); MAGE family member C2 (MAGEC2; CT10, HCA587, MAGEE1; NCBI gene ID: 51438); MAGE family member D1 (MAGED1; DLXIN-1, NRAGE; NCBI gene ID: 9500); MAGE family member D2 (MAGED2; 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2; NCBI gene ID: 10916), Kinesin family member 20B (KIF20B; CT90, KRMP1, MPHOSPH1, MPP-1, MPP1; NCBI gene ID: 9585), NDC80 kinetochore complex NUF2 component (NUF2; CDCA1, CT106, NUF2R; NCBI gene ID: 83540), Nuclear extranucleotide RNA transport factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI gene ID: 5600) 1) PAS domain-containing repressor 1 (PASD1; CT63, CT64, OXTES1; NCBI gene ID: 139135), PDZ-binding kinase (PBK; CT84, HEL164, Nori-3, SPK, TOPK; NCBI gene ID: 55872), piwi-like RNA-mediated gene silencing 2 (PIWIL2; CT80, HILI, PIWIL1L, mili; NCBI gene ID: 55124), melanoma preferential expression antigen (PRAME; CT130, MAPE, OIP-4, OIP4; NCBI Gene ID: 23532), sperm-associated antigen 9 (SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI gene ID: 9043), nuclear X-binding family member A1-associated sperm protein (SPANXA1; CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A; NCBI gene ID: 30014), SPANX family member A2 (SPANXA2; CT11.1, CT11.3. SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC (NCBI gene ID: 728712), SPANX family member C (SPANXC; CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE; NCBI gene ID: 64663), SPANX family member D (SPANXD; CT11.3, CT11.4, SPANX-C, SPANX-D, SPANX-E, SPANXC, SPANXE, dJ171K16.1; NCBI gene ID: 64648), SSX family member 1 (SSX1; CT5.1, SSRC; NCBI gene ID: 6756), SSX family member 2 (SSX2; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI gene ID: 6757) The group is selected from the following: synaptonema structural protein 3 (SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI gene ID: 50511), testicular expression 14 intercellular bridge formation factors (TEX14; CT113, SPGF23; NCBI gene ID: 56155), transcription factor Dp family member 3 (TFDP3; CT30, DP4, HCA661; NCBI gene ID: 51270), serine protease 50 (PRSS50; CT20, TSP50; NCBI gene ID: 29122), TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI gene ID: 7272), and zinc finger protein 165 (ZNF165; CT53, LD65, ZSCAN7; NCBI gene ID: 7718). TCR-like antibodies that bind to the epitopes of cancer-testis antigens presented on T cell receptors (TCRs) and major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer-testis antigens associated with neoplasms are summarized, for example, in Gibbs, et al., Trends Cancer 2018 Oct;4(10):701-712, and in the CT database website at cta.lncc.br / index.php. Exemplary TCRs and TCR-like antibodies that bind to the NY-ESO-1 epitope presented on MHC are, for example, Stewart-Jones, et al.,Proc Natl Acad Sci USA.This is described in International Publications 2009 Apr 7;106(14):5784-8; International Publications 2005 / 113595, 2006 / 031221, 2010 / 106431, 2016 / 177339, 2016 / 210365, 2017 / 044661, 2017 / 076308, 2017 / 109496, 2018 / 132739, 2019 / 084538, 2019 / 162043, 2020 / 086158, and 2020 / 086647. Exemplary TCRs and TCR-like antibodies that bind to the epitopes of PRAME presented on MHC are described, for example, in International Publications 2011 / 062634, 2016 / 142783, 2016 / 191246, 2018 / 172533, 2018 / 234319, and 2019 / 109821. Exemplary TCRs and TCR-like antibodies that bind to the epitopes of MAGE variants presented on MHC are described, for example, in International Publications 2007 / 032255, 2012 / 054825, 2013 / 039889, 2013 / 041865, 2014 / 118236, and 2016 / 055785. These are described in International Publication Nos. 2017 / 174822, 2017 / 174823, 2017 / 174824, 2017 / 175006, 2018 / 097951, 2018 / 170338, 2018 / 225732, and 2019 / 204683. Exemplary TCRs and TCR-like antibodies that bind to the epitope of alpha-fetoprotein (AFP) presented on MHC are described, for example, in International Publication No. 2015 / 011450. Exemplary TCRs and TCR-like antibodies that bind to the epitope of SSX2 presented on MHC are described, for example, in International Publication No. 2020 / 063488. Exemplary TCRs and TCR-like antibodies that bind to the KK-LC-1(CT83) epitope presented on MHC are described, for example, in International Publication No. 2017189254.

[0239] Examples of cell therapies include Algenpantucel-L, Sipuleucel-T, (BPX-501) Ribogen Recurcel (US Patent No. 9089520, International Publication No. 2016 / 100236), AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Imi Recrucel-T, Baltaluce-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral transducer huCART-mesocells, CART-22 cells, EGFRt / 19-28z / 4-1BBL Examples include CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

[0240] In some embodiments, one or more additional concurrently administered therapeutic agents may be classified into the following groups, for example, based on their mechanism of action: • Drugs that target adenosine deaminase, such as pentostatin or cladribine; • Drugs that target ATMs, such as AZD1390; • MET-targeting drugs such as servotinib, capmatinib, tetoponitib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; • Mitogen-activated protein kinase-targeting drugs such as antroquinonol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mildametinib (PD-0325901), pimacertib, and refametinib, or International Publication Nos. 2011 / 008709, 2013 / 112741, 2006 / 124944, 2006 / 124692, 2014 / 064215, 2018 / 005435, Zhou, et al., Cancer Lett. 2017 Nov 1, 408:130-137, Teli, et al., J Enzyme Inhib Med Chem.(2012)27(4):558-70;Gangwall,et al.,Curr Top Med Chem.(2013)13(9):1015-35;Wu,et al.,Bioorg Med Chem Lett.(2009)19(13):3485-8;Kaila,et al.,Bioorg Med Chem.(2007)15(19):6425-42, or Hu, et al., Bioorg Med Chem Lett.(2011)21(16):4758-61; • Drugs that target thymidine kinases, such as agratimazine besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk); Drugs that target the interleukin pathway, such as pegilodecaquin (AM-0010) (PEGylated IL-10) and CA-4948 (IRAK4 inhibitor); Drugs targeting cytochrome P450 family members, such as letrozole, anastrozole, aminoglutethimide, medystrol acetate (MEGACE®), exemestane, formestan, fadrozol, borozol (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); • CD73-targeting drugs such as CD73 inhibitors (e.g., quemliculstat (AB680)) or anti-CD73 antibodies (e.g., oleculumab); • Drugs that target DKK3, such as MTG-201; • Drugs that target EEF1A2, such as platidisin; • Drugs that target EIF4A1, such as rohinitib; • Endoglin-targeting drugs such as TRC105 (inflotuximab); • Drugs that target exopolitin-1, such as eltanexor; • Drugs that target fatty acid amide hydrolases, such as compounds disclosed in International Publication No. 2017 / 160861; • Drugs that target heat shock protein 90-beta family member 1, such as anlotinib; • Drugs that target lactoferrin, such as ruxotemitide (LTX-315); • Lysyl oxidase-targeting agents such as compounds disclosed in U.S. Patent Nos. 4,965,288, 4,997,854, 4,943,593, 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608, or U.S. Patent Publication No. 2004 / 0248871; • Drugs targeting MAGE family members such as KITE-718, MAGE-A10C796T, or MAGE-A10TCR; • MDM2-targeting agents such as ALRN-6924, CMG-097, mirademethane monotosylate monohydrate (DS-3032b), or AMG-232; • Drugs that target MDM4, such as ALRN-6924; • Drugs targeting Melan-A, such as MART-1 F5 TCR-operated PBMCs; • Drugs that target mesothelin, such as CSG-MESO or TC-210; • METAP2-targeting drugs such as M8891 or APL-1202; • Drugs that target NLRP3, such as BMS-986299; • Drugs that target oxoglutarate dehydrogenase, such as devimistat (CPI-613); • Drugs that target placental growth factors, such as aflibercept; • Drugs targeting SLC10A3, such as compounds disclosed in International Publication No. 2015 / 148954, International Publication No. 2012 / 082647, or International Publication No. 2017 / 160861; • Drugs targeting transforming growth factor alpha (TGFα), such as the compounds disclosed in International Publication No. 2019 / 103203; Drugs that target the tumor protein p53, such as kevetrin (a stimulating agent); • Drugs that target vascular endothelial growth factor A, such as aflibercept; • Drugs that target vascular endothelial growth factor receptors, such as fluquinotinib or MP0250; • VISTA-targeting drugs such as CA-170 or HMBD-002; • Drugs targeting WEE1, such as adavosertib (AZD-1775); • Small molecule inhibitors targeting ABL1, such as imatinib, levatinib, aciminib, and ponatinib (ICLUSIG®); • Small molecule antagonists that target adenosine receptors, such as CPI-444, AZD-4635, preradiant, etrumandent (AB928), or PBF-509; • Small molecule inhibitors that target arachidonic acid 5-lipoxygenase, such as sodium meclofenamate or diloton; • Small molecule inhibitors targeting ATR serine / threonine kinases, such as BAY-937, ceraracertib (AZD6738), AZD6783, VX-803, or VX-970 (belzocertib); • Small molecule inhibitors targeting AXL receptor tyrosine kinases, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); · (S)-6-amino-9-(1-(buto-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posertinib (HM71224), ibrutinib (Imbruvica), M Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as -2951 (evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebralutinib (CC-292), becabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; • Small molecule inhibitors that target neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or ceritrectinib (LOXO-195); • Small molecule inhibitors targeting ROS proto-oncogene 1 receptor tyrosine kinases, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; • Small molecule inhibitors targeting SRC proto-oncogene nonreceptor tyrosine kinases, such as VAL-201, tilvanibrin (KX2-391), or irginatinib maleate (NS-018); • Small molecule inhibitors targeting B-cell lymphoma II, such as Navitoclax (ABT-263), Venetoclax (ABT-199, RG-7601), and AT-101 (Gossypol); Small molecule inhibitors targeting bromodomain and extracellular domain (BET) bromodomain-containing proteins such as ABBV-744, INCB-054329, INCB057643, AZD-5153, ABT-767, BMS-986158, CC-90010, NHWD-870, ODM-207, ZBC246, ZEN3694, CC-95775 (FT-1101), mibeblesib, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829; • Small molecule inhibitors targeting carbohydrate sulfotransferase 15, such as STNM-01; • Small molecule inhibitors that target carbonic anhydrase, such as polmacoxib, acetazolamide, or metazolamide; • Small molecule inhibitors targeting catenin beta 1, such as CWP-291 or PRI-724; • Small molecule antagonists that target CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Bicribiroc); • Bilixafortide, a small molecule antagonist that targets CXC-motif chemokine receptors (e.g., CXCR4).

[0241] • Small molecule inhibitors targeting cereblon, such as abbamide (CC-122), CC-92480, CC-90009, or iverdamide; • Small molecule inhibitors that target checkpoint kinase 1, such as SRA737; • Small molecule inhibitors that target complement components, such as Imprime PGG (Biothera Pharmaceuticals); • Small molecule inhibitors that target CXC motif chemokine ligands (such as CXCL12), including olaptesed pegol (NOX-A12); • Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, ceviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; • Small molecule inhibitors that target deadbox helicase 5, such as spinoxin (RX-5902); For example, small molecule inhibitors targeting DGKα, as described in International Publication No. 2021 / 130638; • Small molecule inhibitors that target diablo IAP-binding mitochondrial proteins, such as BI-891065; • Small molecule inhibitors that target dihydrofolate reductase, such as pralatrexed or pemetrexed disodium; • Small molecule inhibitors targeting DNA-dependent protein kinases, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastaurin; • Small molecule inhibitors targeting MARCKS, such as BIO-11006; • Small molecule inhibitors targeting RIPK1, such as GSK-3145094; • Small molecule inhibitors targeting Rho-related coiled-coil protein kinases such as AT13148 or KD025; • Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, filtecan pegol, or amrubicin; • Small molecule inhibitors targeting dopamine receptor D2, such as ONC-201; • Small molecule inhibitors that target DOT1, such as histone lysine methyltransferase (EPZ-5676), pinometostat; • Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497; • Small molecule inhibitors that target fatty acid synthases, such as TVB-2640 (Sagimet Biosciences); • Small molecule inhibitors that target fibroblast growth factor receptor (FGFR2), such as bemarituzumab (FPA144); • Small molecule inhibitors targeting focal adhesion kinases (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098; • Small molecule inhibitors that target folate receptor 1, such as pralatrexate; • Small molecule inhibitors that target FOXM1, such as thiostrepton; • Small molecule inhibitors that target galectin-3, such as belapectin (GR-MD-02); • Small molecule antagonists that target glucocorticoid receptors, such as relacorilant (CORT-125134); • Small molecule inhibitors targeting glutaminase, including but not limited to CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazole-2-yl)ethyl sulfide (BPTES); • Small molecule inhibitors that target GNRHR, such as elagolyx, relugolix, or degarelix; • Small molecule inhibitors targeting EPAS1, such as verzutifan (PT-2977 (Merck & Co.)); • Restricted small molecule inhibitors that target isocitrate dehydrogenase (NADP(+)), such as ivosidenib (AG-120), boracidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221) • Small molecule inhibitors that target lysine demethylase 1A, such as CC-90011; • Small molecule inhibitors that target MAPK-interacting serine / threonine kinases, such as tomibosertib (eFT-508); • Small molecule inhibitors that target Notch receptors, such as AL-101 (BMS-906024); • Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as borasertib or onvancertib; • Small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), lucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazolepali (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121(e-7499)), simmiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP 9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102; • Small molecule inhibitors that target Polycomb protein EEDs such as MAK683; • Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974; • Small molecule inhibitors targeting prostaglandin-endoperoxide synthase, such as HP-5000, lofecoxib, ketrolactromethamine, bromfenac sodium, Otenaproxil (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, re-prescription celecoxib (DRGT-46), AAT-076, Meisoshri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimeslid, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, firocoxib, lofecoxib, lutecarpine, chilmacoxib, zaltoprofen, or imurecoxib; • Small molecule inhibitors that target protein arginine N-methyltransferase, such as MS203, PF-06939999, GSK3368715, or GSK3326595; • Small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720), or compounds disclosed in International Publication No. 2018 / 172984 or International Publication No. 2017 / 211303; • Small molecule antagonists that target retinoic acid receptors, such as tamibarotene (SY-1425); • Small molecule inhibitors that target ribosomal protein S6 kinase B1, such as MSC2363318A; • Small molecule inhibitors that target S100 calcium-binding protein A9, such as tascinimod; • Small molecule inhibitors that target selectin E, such as uproleselan sodium (GMI-1271); • Small molecule inhibitors that target SF3B1, such as H3B-8800; • Small molecule inhibitors that target sirtuin-3, such as YC8-02; • Small molecule inhibitors targeting SMOs, such as soni-degib (Odomzo®, formerly LDE-225), bismodegib (GDC-0449), glass-degib (PF-04449913), itraconazole, or patidegib and taladegib; • Small molecule antagonists that target somatostatin receptors, such as OPS-201; • Small molecule inhibitors that target sphingosine kinase 2, such as opaganib (Yeliva®, ABC294640); • Small molecule inhibitors that target STAT3, such as napabucasin (BBI-608); • Tankirase-targeting small molecule inhibitors such as G007-LK or stenoparib (2X-121(e-7499)); • Small molecule inhibitors targeting TFGBR1, such as garnicertib and PF-06952229; • Small molecule inhibitors that target thymidylate synthase, such as idetrexed (ONX-0801); • Small molecule inhibitors that target the oncoprotein p53, such as CMG-097; • Small molecule inhibitors that target balocin-containing proteins such as CB-5083; • Small molecule inhibitors targeting WT1, such as ombipepimut-S (DSP-7888); • Small molecule agonists that target adenosine receptors such as namodenoson (CF102); • Small molecule agonists that target asparaginases such as chrysanthaspase (Erwinase®), GRASPA (ERY-001, ERY-ASP), GRASPA pegol, or peg asparaginase; • Small molecule agonists that target CCAAT enhancer-binding protein alpha, such as MTL-501; • Small molecule agonists that target the cytochrome P450 family, such as mitotane; • Small molecule agonists that target DExD / H-box helicase 58, such as RGT-100; • Small molecule agonists targeting GNRHR, such as leuprorelin acetate, leuprorelin acetate sustained-release depot (ATRIGEL), triptorelin pamoate, or goserelin acetate; • Small molecule agonists that target GRB2, such as plexijebersen (BP1001); • Small molecule agonists that target NFE2L2, such as omaveloxolone (RTA-408); • Small molecule agonists that target NOD2, such as mifamultide (liposome); • Small molecule agonists that target RAR-related orphan receptor gamma, such as cintirorgon (LYC-55716); • Small molecule agonists that target retinoic acid receptors (RARs), such as tretinoin; • Small molecule agonists targeting STING1, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, cyclic GAMP (cGAMP), or cyclic diAMP; • Small molecule agonists that target thyroid hormone receptor beta, such as levothyroxine sodium; • Small molecule agonists that target tumor necrosis factors such as tasonelmin; • Antisense agents targeting baculovirus IAP repeats, including EZN-3042 and others; • Antisense agents that target GRB2, such as plexijebersen; • Antisense agents that target heat shock protein 27, such as apatorcene; • Antisense agents targeting STAT3, such as danvatirsen (IONIS-STAT3-2.5Rx); • Gene therapy targeting CC motif chemokine receptors such as SB-728-T; Gene therapy targeting interleukins such as EGENE-001, tavokinogene telseplasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55; • Antibodies targeting claudin 18, such as clodiximab; • Antibodies that target clatherin, such as AB-16B5; • Antibodies that target complement components, such as ravulizumab (ALXN-1210); • Antibodies targeting CXC motif chemokine ligands such as BMS-986253 (HuMax-Inflam); • Antibodies targeting delta-like standard notch ligand 4 (DLL4), such as demcizumab and nabixixizumab (DLL4 / VEGF); • Antibodies targeting EPH receptor A3, such as fibatuzumab (KB-004); • Antibodies that target epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845); • Antibodies targeting fibroblast growth factors such as GAL-F2 and B-701 (bofatamab); • Antibodies that target hepatocyte growth factors, such as MP-0250; Antibodies targeting interleukins, such as canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), siltuximab, or tocilizumab; • Antibodies targeting LRRC15, such as ABBV-085 or xatuzumab (ARGX-110); • Antibodies targeting mesoserine, such as BMS-986148, SEL-403, or anti-MSLN-MMAE; • Antibodies that target myostatin, such as landogrozumab; • Antibodies that target the Notch receptor, such as tarectumab; Antibodies targeting TGFB1 (TGFβ1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA089, or compounds disclosed in International Publication No. 2019 / 103203; • Vaccines targeting fms-related receptor tyrosine kinases, such as HLA-A2402 / HLA-A0201 restriction epitope peptide vaccines. • Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax); • IO-120 + IO-103 (PD-L1 / PD-L2 vaccine) or PD-L1 targeting vaccines such as IO-103; • Vaccines that target oncoprotein p53, such as MVA-p53; • Vaccines targeting WT1, such as WT-1 analog peptide vaccines (WT1-CTL); • Cell therapies targeting baculovirus IAP repeats, such as dendritic cell vaccines loaded with tumor lysates / MUC1 / Survivin PepTivator; • Cell therapies targeting carbonic anhydrase, such as DC-Ad-GMCAIX; • Cell therapies targeting CC motif chemokine receptors such as CCR5-SBC-728-HSPC; • Cell therapies targeting folate hydrolase 1, such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN; • Cell therapies targeting GSTP1, such as CPG3-CAR (GLYCAR); • Cell therapies targeting HLA-A, such as FH-MCVA2TCR or NeoTCR-P1; • Cell therapies targeting interleukins such as CST-101; • Cell therapies targeting KRAS, such as anti-KRAS G12D mTCR PBL; • Cell therapies targeting METs, such as anti-cMet RNA CAR T; • Cell therapies targeting MUC16, such as JCAR-020; • Cell therapies targeting PD-1, such as PD-1 knockout T-cell therapy (esophageal cancer / NSCLC); • Cell therapies targeting PRAME, such as BPX-701; • Cell therapy targeting transformed protein E7, such as KITE-439; • Cell therapies targeting WT1, such as WT1-CTL, ASP-7517, or JTCR-016.

[0242] Exemplary combination therapy Lymphoma or leukemia combination therapy Some chemotherapy agents are suitable for treating lymphoma or leukemia. These include aldezleukin, arbocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, β-aretin, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), briostatin 1, brusulfan, campas-1H, carboplatin, and carfilzomib (Kyprol). is(registered trademark)), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cycloporine, cytarabine, denileukin-diffitox, dexamethasone, docetaxel, dorastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone) (Doxanthrone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), Enzastaurin, epoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopyridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (superfractionated cyclophosphamide, vincristi) (doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon α-2b, ixabepyrone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafingadolinium, mycophenolate mofetil,Nelarabine, ovatocrax (GX15-070), oblimersen, octreotide acetate, ω-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab Examples include rituximab and FCM, R-ICE (rituximab and ICE), R-MCP (rituximab and MCP), R-roscovitine (cericiclib, CYC202), salglamostim, sildenafil citrate, simvastatin, sirolimus, styrylsulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, allogeneic lymphocytes for therapeutic use, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine tartrate, SAHA (suberanililohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

[0243] One improved approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies, but not limited to, include iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

[0244] The above treatments may be supplemented with or combined with stem cell transplantation or therapy. Treatment options include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow resection with stem cell support, in vitro processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myelectomy allogeneic hematopoietic stem cell transplantation.

[0245] Combination therapy for non-Hodgkin lymphoma Treatment for non-Hodgkin lymphoma (NHL), particularly B-cell origin lymphoma, includes the use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, and prednisolone)), all of which may include rituximab®, radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy with chemotherapy.

[0246] Examples of non-conjugate monoclonal antibodies for the treatment of NHL / B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-associated apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0247] Examples of experimental antibody drugs used to treat NHL / B-cell cancer include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

[0248] Examples of standard chemotherapy regimens for NHL / B-cell carcinoma include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

[0249] Examples of radioimmunotherapy for NHL / B-cell cancer include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

[0250] Combination therapy for mantle cell lymphoma Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapy regimens, such as CHOP, hyperCVAD, and FCM. These regimens may be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above therapies may be combined with stem cell transplantation or ICE to treat MCL.

[0251] An alternative approach to treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies such as rituximab. Another uses cancer vaccines such as GTOP-99, which are based on the genetic structure of the individual patient's tumor.

[0252] An improved approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential therapy with CHOP.

[0253] Other approaches to treating MCL include autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administration of anti-angiogenic agents such as thalidomide, particularly in combination with rituximab.

[0254] Another treatment approach involves administering drugs that, in combination with other chemotherapy agents, induce the degradation of the Bcl-2 protein, thereby increasing the sensitivity of cancer cells to chemotherapy, such as oblimersen.

[0255] Further therapeutic approaches include the administration of mTOR inhibitors, which can inhibit cell proliferation and even induce cell death. Non-limiting examples include sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (vimiralisib), voxtalisib, GSK-2126458, and temsirolimus in combination with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0256] Other recent therapies for MCL have been disclosed. Examples include flavopyridol, palbociclib (PD0332991), R-roscovitine (celiciclib, CYC202), styrylsulfone, ovatoclax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG).

[0257] Adjunctive therapy for Waldenström-type macroglobulinemia Waldenstrom's type macroglobulinemiaTherapies used to treat macroglobulinemia (WM) include aldesleukin, alemtuzumab, albocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, β-aretin, bortezomib (VELCADE®), briostatin 1, busulfan, campas-1H, carboplatin, and carmustin. Caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin difutitox, dexamethasone, docetaxel, dorastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin α, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 toxin Momab, irinotecan hydrochloride, ixabepirone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (e.g., tisagenlecroicel-T, CART-19, CTL-019), monoclonal antibody CD20, motexafingadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, pento Statins, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, salgramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, allogeneic lymphocytes for therapeutic use, thiotepa, tipifarnib, tositumomab, urocuplumab, vertuzumab, vincristine sulfate, vinorelbine tartrate, vorinostat, WT1Examples include 126-134 peptide vaccines, WT-1 analog peptide vaccines, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0258] Examples of treatments used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole-body radiation therapy, stem cell infusion, bone marrow resection with stem cell support, in vitro processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma-ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myelectomyable allogeneic hematopoietic stem cell transplantation.

[0259] Combination therapy for diffuse large B-cell lymphoma (DLBCL) Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the drugs listed for WM, as well as any combination thereof, such as ICE and RICE. In some embodiments, therapeutic agents used to treat DLBCL include liximab (Rituxan®), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin®), prednisone, bendamustine, ifosfamide, carboplatin, etoposide, ibrutinib, polatuzumab vedotin piiq, bendamustine, copanlisib, lenalidomide (Revlimid®), dexamethasone, cytarabine, cisplatin, Yescarta®, Kymriah®, Polivy® (polatuzumab vedotin), BR (bendamustine (Treanda®)), gemcitabine, oxyplatin, oxaliplatin, tafacitamab, polatuzumab, cyclophosphamide, or combinations thereof.In some embodiments, therapeutic agents used to treat DLBCL include R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone), rituximab + bendamustine, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), rituximab + lenalomide, and R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara). C) + cisplatin), Polivy® (polatuzumab vedotin) + BR (bendamustine (Treanda®) and rituximab (Rituxan®)), R-GeMOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafacitamab + lenalidomide), tafacitamab + Revlimid®, polatuzumab + bendamustine, gemcitabine + oxaliplatin, R-EPOCH (rituximab + etoposide phosphate + prednisone + vincristine sulfate (Oncovin®) + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin)) Examples include CHOP (cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone). In some embodiments, therapeutic agents used to treat DLBCL include tafacitamab, grofitamab, epocolitamab, Lonca-T (loncatuximab tesirin), Debio-1562, polatuzumab, Yescarta, JCAR017, ADCT-402, brentuximab vedotin, MT-3724, odronextamab, Auto-03, Allo-501A, or TAK-007.

[0260] Combination therapy for chronic lymphocytic leukemia Treatments used to treat chronic lymphocytic leukemia (CLL) include a number of drugs listed for chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, and WM, as well as combination chemotherapy and chemoimmunotherapy, which include common combination regimens such as CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0261] Combination therapy for high-risk myelodysplastic syndrome (HR MDS) Therapeutic agents used to treat HR MDS include azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, daunorubicin, and combinations thereof. In some embodiments, combinations include cytarabine + daunorubicin and cytarabine + idarubicin. In some embodiments, therapeutic agents used to treat HR MDS include pevonedistat, venetoclax, sabatrimab, guadecitabine, rigosatib, ivosidenib, enazidenib, selinexol, BGB324, DSP-7888, or SNS-301.

[0262] Low-risk myelodysplastic syndrome (LR MDS) combination therapy Therapeutic agents used to treat LR MDS include lenalidomide, azacitidine, and combinations thereof. In some embodiments, therapeutic agents used to treat LR MDS include roxadustat, raspatercept, imetelstat, LB-100, or ligosatib.

[0263] Combination therapy for acute myeloid leukemia (AML) Therapeutic agents used to treat AML include cytarabine, idarubicin, daunorubicin, midostaurine (Rydapt®), venetoclax, azacitidine, ivasidenib, gilteritinib, enazidenib, low-dose cytarabine (LoDAC), mitozantrone, fludarabine, granulocyte colony-stimulating factor, idarubicin, gilteritinib (Xospata®), enazidenib (Idhifa®), ivosidenib (Tibsovo®), decitabine (Dacogen®), mitozantrone, etoposide, gemtuzumab ozogamicin (Mylotarg®), glass degib (Daurismo®), and combinations thereof. In some embodiments, therapeutic agents used to treat AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte-colony stimulating factor (G-CSF), and idarubicin), cytarabine + idarubicin, cytarabine + daunorubicin + midostaurin, venetoclax + azacitidine, cytarabine + daunorubicin, or MEC (mitozantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents used to treat AML include pevonedistat, venetoclax, sabatrimab, eprenetapopt, or lemzoparlimab.

[0264] Multiple myeloma (MM) combination therapy Therapeutic agents used to treat MM include lenalidomide, bortezomib, dexamethasone, daratumumab (Darzalex®), pomalidomide, cyclophosphamide, carfilzomib (Kyprolis®), elotuzumab (Empliciti), and combinations thereof. In some embodiments, therapeutic agents used to treat MM include RVS (lenalidomide + bortezomib + dexamethasone), RevDex (lenalidomide + dexamethasone), CYBORD (cyclophosphamide + bortezomib + dexamethasone), Vel / Dex (bortezomib + dexamethasone), or PomDex (pomaridomide + low-dose dexamethasone). In some embodiments, therapeutic agents used to treat MM include JCARH125, TAK-573, verantamab-m, and ide-cel(CAR-T).

[0265] Combination therapy for breast cancer Therapies used to treat breast cancer include albumin-bound paclitaxel, anastrozole, atezolizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabépirone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat breast cancer (e.g., HR+ / - / HER2+ / -) include trastuzumab (Herceptin®), pertuzumab (Perjeta®), docetaxel, carboplatin, palbociclib (Ibrance®), letrozole, trastuzumab emtansine (Kadcyla®), fulvestrant (Faslodex®), olaparib (Lynparza®), eribulin, tucatinib, capecitabine, lapatinib, everolimus (Afinitor®), exemestane, eribulin mesylate (Halaven®), and combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab + pertuzumab + docetaxel, trastuzumab + pertuzumab + docetaxel + carboplatin, palbociclib + letrozole, tucatinib + capecitabine, lapatinib + capecitabine, palbociclib + fulvestrant, or everolimus + exemestane. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab deruxtecan Enhertu®, datopotamab deruxtecan, DS-1062, enfortumumab vedotin (Padcev®), valixafortide, elastrant, or combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer include valixafortide + eribulin.

[0266] Triple-negative breast cancer (TNBC) combination therapy Therapeutic agents used to treat TNBC include atezolizumab, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, therapeutic agents used to treat TNBC include olaparib (Lynparza®), atezolizumab (Tecentriq®), paclitaxel (Abraxane®), eribulin, bevacizumab (Avastin®), carboplatin, gemcitabine, eribulin mesylate (Halaven®), sacituzumab govitecan (Trodelvy®), pembrolizumab (Keytruda®), cisplatin, doxorubicin, epirubicin, or combinations thereof. In some embodiments, therapeutic agents for treating TNBC include atezolizumab + paclitaxel, bevacizumab + paclitaxel, carboplatin + paclitaxel, carboplatin + gemcitabine, or paclitaxel + gemcitabine. In some embodiments, therapeutic agents used to treat TNBC include eliaspase, capivacertib, alpelisib, rucaparib + nivolumab, atezolumab + paclitaxel + gemcitabine + capecitabine + carboplatin, ipatasertib + paclitaxel, radilatuzumab vedotin + pembrolimab, durvalumab + DS-8201a, trilaciclib + gemcitabine + carboplatin. In some embodiments, therapeutic agents used to treat TNBC include trastuzumab deruxtecan (Enhertu®), datopotamab deruxtecan (DS-1062), enfortumab vedotin (Padcev®), valixafortide, adagloxad simolenin, neripepimto (NeuVax®), nivolumab (Opdivo®), rucaparib, tripalimab (Tuoyi®), camrelizumab, capivacertib, durvalumab (Imfinzi®), and combinations thereof.In some embodiments, therapeutic agents used to treat TNBC include nivolumab + rucaparib, bevacizumab (Avastin®) + chemotherapy, tripalimab + paclitaxel, tripalimab + albumin-bound paclitaxel, camrelizumab + chemotherapy, pembrolizumab + chemotherapy, valixafortid + eribulin, durvalumab + trastuzumab deruxtecan, durvalumab + paclitaxel, or capivacertib + paclitaxel.

[0267] Combination therapy for bladder cancer Therapeutic agents used to treat bladder cancer include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), erdafitinib, eganerisib, lenvatinib, bempegaldeleukin (NKTR-214), or combinations thereof. In some embodiments, therapeutic agents used to treat bladder cancer include eganerisib + nivolumab, pembrolizumab (Keytruda®) + enfortumumab vedotin (Padcev®), nivolumab + ipilimumab, duravalumab + tremelimumab, lenvatinib + pembrolizumab, enfortumumab vedotin (Padcev®) + pembrolizumab, and bempegaldeleukin + nivolumab.

[0268] Colorectal cancer (CRC) combination therapy Therapeutic agents used to treat CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab (Avastin®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda®), FOLFIRI, regorafenib (Stivarga®), aflibercept (Zaltrap®), cetuximab (Erbitux®), Lonsurf (Orcantas®), XELOX, FOLFOXIRI, or any combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, therapeutic agents used to treat CRC include binimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabucasin + FOLFIRI + bevacizumab, and nivolumab + ipilimumab.

[0269] Combination therapy for esophageal and gastroesophageal junction cancer Therapeutic agents used to treat esophageal cancer and gastroesophageal junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. In some embodiments, therapeutic agents used to treat gastroesophageal junction cancer (GEJ) include Herceptin, cisplatin, 5-FU, ramicurimab, or paclitaxel. In some embodiments, therapeutic agents used to treat GEJ cancer include ALX-148, AO-176, or IBI-188.

[0270] Combination therapy for gastric cancer Therapies used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0271] Combination therapy for head and neck cancer Therapies used to treat head and neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0272] Therapeutic agents used to treat head and neck squamous cell carcinoma (HNSCC) include pembrolizumab, carboplatin, 5-FU, docetaxel, cetuximab (Erbitux®), cisplatin, nivolumab (Opdivo®), and combinations thereof. In some embodiments, therapeutic agents used to treat HNSCC include pembrolizumab + carboplatin + 5-FU, cetuximab + cisplatin + 5-FU, cetuximab + carboplatin + 5-FU, cisplatin + 5-FU, and carboplatin + 5-FU. In some embodiments, therapeutic agents used to treat HNSCC include durvalumab, durvalumab + tremelimumab, nivolumab + ipilimumab, lovaloycel, pembrolizumab, pembrolizumab + epacadostat, GSK3359609 + pembrolizumab, lenvatinib + pembrolizumab, retifanlimab, retifanlimab + enobituzumab, ADU-S100 + pembrolizumab, and epacadostat + nivolumab + ipilimumab / lirirumab.

[0273] Combination therapy for non-small cell lung cancer Therapies used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat NSCLC include alectinib (Alecensa®), dabrafenib (Tafinlar®), trametinib (Mekinist®), osimertinib (Tagrisso®), entrectinib (Tarceva®), crizotinib (Xalkori®), pembrolizumab (Keytruda®), carboplatin, pemetrexed (Alimta®), nab-paclitaxel (Abraxane®), ramucirumab (Cyramza®), docetaxel, bevacizumab (Avastin®), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif®), and nivol. Examples include mab (Opdivo®), gefitinib (Iressa®), and combinations thereof. In some embodiments, therapeutic agents used to treat NSCLC include dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + nab-paclitaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed + carboplatin, cisplatin + pemetrexed, bevacizumab + carboplatin + nab-paclitaxel, cisplatin + gemzar, nivolumab + docetaxel, carboplatin + pemetrexed, carboplatin + nab-paclitaxel, or pemetrexed + cisplatin + carboplatin.In some embodiments, therapeutic agents used for NSCLC include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), enfortumab vedotin (Padcev®), durvalumab, canakinumab, semiprimab, nogapendekin alfa, avelumab, tilagolumab, donbanarimab, vivostrimab, osiperlimab, or combinations thereof. In some embodiments, therapeutic agents used to treat NSCLC include datopotamab deruxtecan + pembrolizumab, datopotamab deruxtecan + durvalumab, durvalumab + tremelimumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, nogapendekin alfa (N-803) + pembrolizumab, tilagolmab + atezolizumab, vivostrimab + pembrolizumab, or osiperlimab + tislerizumab.

[0274] Combination therapy for small cell lung cancer Therapeutic agents used to treat small cell lung cancer (SCLC) include atezolizumab, bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivolumab, durvalumab, trilaciclib, or any combination thereof. In some embodiments, therapeutic agents used to treat SCLC include atezolizumab + carboplatin + etoposide, atezolizumab + carboplatin, atezolizumab + etoposide, or carboplatin + paclitaxel.

[0275] Ovarian cancer combination therapy Therapeutic agents used to treat ovarian cancer include 5-fluorouracil, albumin-conjugated paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[0276] Pancreatic combination therapy Therapeutic agents used to treat pancreatic cancer include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel (Abraxane®), FOLFIRINOX, and combinations thereof. In some embodiments, therapeutic agents used to treat pancreatic cancer include 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, leucovorin + nanoliposomal irinotecan, and gemcitabine + nab-paclitaxel.

[0277] Combination therapy for prostate cancer Therapeutic agents used to treat prostate cancer include enzalutamide (Xtandi®), leuprolide, trifluridine, tipiracil (Lonsurf), cabazitaxel, prednisone, abiraterone (Zytiga®), docetaxel, mitozantrone, bicalutamide, LHRH, flutamide, ADT, sabizabrin (Veru-111), and combinations thereof. In some embodiments, therapeutic agents used to treat prostate cancer include enzalutamide + leuprolide, trifluridine + tipiracil (Lonsurf), cabazitaxel + prednisone, abiraterone + prednisone, docetaxel + prednisone, mitozantrone + prednisone, bicalutamide + LHRH, flutamide + LHRH, leuprolide + flutamide, and abiraterone + prednisone + ADT.

[0278] Additional example combination therapies In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more therapeutic agents selected from PI3K inhibitors, Trop-2 conjugates, CD47 antagonists, SIRPα antagonists, FLT3R agonists, PD-1 antagonists, PD-L1 antagonists, MCL1 inhibitors, CCR8 conjugates, HPK1 antagonists, DGKα inhibitors, CISH inhibitors, PARP-7 inhibitors, Cbl-b inhibitors, KRAS inhibitors (e.g., KRAS G12C or G12D inhibitors), KRAS degraders, β-catenin degraders, Helios degraders, CD73 inhibitors, adenosine receptor antagonists, TIGIT antagonists, TREM1 conjugates, TREM2 conjugates, CD137 agonists, GITR conjugates, OX40 conjugates, and CAR-T cell therapies.

[0279] In some embodiments, the antibodies and / or fusion proteins provided herein include PI3Kδ inhibitors (e.g., idelalisib), anti-Trop-2 antibody drug conjugates (e.g., sacituzumab govitecan, datopotamab deruxtecan (DS-1062)), anti-CD47 antibodies or CD47-blocking agents (e.g., maglorimab, DSP-107, AO-176, ALX-148, retaprimab (IBI-188), remzoparlimab, TTI-621, TTI-622), anti-SIRPα antibodies (e.g., GS-0189), FLT3L-Fc fusion proteins (e.g., GS-3583), and anti-PD-1 antibodies (pembrolizumab, nivolumab, zinberima). Small molecule PD-L1 inhibitors (e.g., GS-4224), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab), small molecule MCL1 inhibitors (e.g., GS-9716), small molecule HPK1 inhibitors (e.g., GS-6451), HPK1 degraders (PROTAC; e.g., ARV-766), small molecule DGKα inhibitors, small molecule CD73 inhibitors (e.g., quemrecrustat (AB680)), anti-CD73 antibodies (e.g., oleculumab), double A 2a / A 2b It is administered with one or more therapeutic agents selected from adenosine receptor antagonists (e.g., etrumadenant (AB928)), anti-TIGIT antibodies (e.g., tilagolumab, vivostrimab, donbanalimab, AB308), anti-TREM1 antibodies (e.g., PY159), anti-TREM2 antibodies (e.g., PY314), CD137 agonists (e.g., AGEN-2373), GITR / OX40 conjugates (e.g., AGEN-1223), and CAR-T cell therapies (e.g., axicaptagen silolucel, brexcaptagen oatlucel, tisagenlecroucel).

[0280] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more therapeutic agents selected from idelalisib, sacituzumab govitecan, maglolimus, GS-0189, GS-3583, zinbererimab, GS-4224, GS-9716, GS-6451, chemriglustat (AB680), etramadenanth (AB928), donbanarimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicaptagen / siloleucel, and brexcabutagen autoleucel.

[0281] Mai. Pharmaceutical composition While it is possible to administer the active ingredients alone, it is sometimes preferable to provide them as pharmaceutical formulations (compositions). Both animal and human formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers and optionally other additional therapeutic components. The carriers must be "acceptable" in the sense that they are compatible with the other components of the formulation and are physiologically harmless to their recipient.

[0282] The formulations include those suitable for the aforementioned routes of administration. The formulations may be presented in unit dosage forms and may be prepared by any of the methods well known in the field of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve associating an active ingredient with one or more inactive components (e.g., carriers, pharmaceutical excipients, etc.) constituting auxiliary components. Generally, formulations are prepared by homogeneously and closely associating an active ingredient with a liquid carrier, a fine solid carrier, or both, and then, if necessary, shaping the product.

[0283] In certain embodiments, formulations suitable for oral administration are presented as individual units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.

[0284] In certain embodiments, a pharmaceutical formulation comprises one or more compounds of the present invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical formulation containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colorings, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a long period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.

[0285] The amount of active ingredient combined with an inactive ingredient to manufacture a dosage form varies depending on the host being treated and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to humans contains about 1 to 1000 mg of active ingredient formulated with an appropriate and convenient amount of carrier material (e.g., an inactive ingredient or excipient). In certain embodiments, the carrier material varies from about 5 to about 95% (by weight) of the total composition. In some embodiments, the pharmaceutical compositions described herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1 to 200 mg, 1 to 100 mg, or 1 to 50 mg of the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain about 400 mg or less of the compound of formula I. In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0286] In particular, please understand that in addition to the components described above, the formulations disclosed herein may also contain other agents commonly used in the art, depending on the type of formulation in question, and for example, those suitable for oral administration may contain flavoring agents.

[0287] A veterinary composition comprising at least one active ingredient as defined above, along with a veterinary carrier, is further provided.

[0288] Veterinary carriers are substances useful for administering compositions, and may be solid, liquid, or gaseous substances that are inert or acceptable in veterinary technology and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0289] The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (at a low dose), the method of delivery, and the pharmaceutical formulation, and is determined by the clinician using conventional dose-escalation studies.

[0290] IV. Route of administration One or more compounds of formula I (referred to herein as active ingredients) or pharmaceutically acceptable salts thereof are administered by any route appropriate to the condition being treated. Preferred routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary, for example, depending on the recipient's condition. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally. Accordingly, in one embodiment, the pharmaceutical composition described herein is an oral dosage form. In certain embodiments, the pharmaceutical composition described herein is an oral solid dosage form.

[0291] Formulation Example 1 Prepare hard gelatin capsules containing the following ingredients.

[0292] [Table 2]

[0293] The above ingredients are mixed and filled into hard gelatin capsules.

[0294] Formulation Example 2 The tablet formulation is prepared using the following ingredients:

[0295] [Table 3]

[0296] The ingredients are blended and compressed to form tablets.

[0297] Formulation Example 3 Prepare a dry powder inhaler formulation containing the following ingredients.

[0298] [Table 4]

[0299] The active ingredient is mixed with lactose, and the mixture is added to a dry powder inhalation device.

[0300] Formulation Example 4 Tablets containing 30 mg of the active ingredient are prepared as follows.

[0301] [Table 5]

[0302] The active ingredients, starch, and cellulose are passed through a 20-mesh US sieve and thoroughly mixed. A solution of polyvinylpyrrolidone is mixed with the resulting powder and then passed through a 16-mesh US sieve. The resulting granules are dried at 50°C to 60°C and passed through a 16-mesh US sieve. Carboxymethyl starch sodium, magnesium stearate, and talc, which have been previously passed through a 30-mesh US sieve, are then added to the granules, mixed, and compressed in a tablet press to obtain tablets weighing 120 mg each.

[0303] Formulation Example 5 Prepare suppositories containing 25 mg of the active ingredient as follows:

[0304] [Table 6]

[0305] The active ingredient is passed through a 60-mesh US sieve and suspended in pre-melted saturated fatty acid glycerides using the minimum necessary heat. The mixture is then poured into suppository forms with a nominal capacity of 2.0 g and allowed to cool.

[0306] Formulation Example 6 A suspension containing 50 mg of the active ingredient per 5.0 mL dose is prepared as follows.

[0307] [Table 7]

[0308] The active ingredients, sucrose, and xanthan gum are blended and passed through a 10-mesh US sieve, then mixed with a pre-prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose. Sodium benzoate, fragrance, and colorant are diluted with some water and added while stirring. Then, sufficient water is added to produce the required volume.

[0309] Formulation example 7 Subcutaneous preparations can be prepared as follows:

[0310] [Table 8]

[0311] Formulation example 8 Prepare an injectable formulation having the following composition.

[0312] [Table 9]

[0313] Formulation example 9 Prepare a topical formulation having the following composition.

[0314] [Table 10]

[0315] Combine all the above ingredients except water and heat to 60°C while stirring. Then, at 60°C, add a sufficient amount of water while stirring vigorously to emulsify the ingredients, and then add an appropriate amount of water. 100g

[0316] Formulation example 10 sustained release composition

[0317] [Table 11]

[0318] The sustained-release formulations of this disclosure can be prepared as follows: The compound, a pH-dependent binder, and an optional excipient are tightly mixed (dry blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base sprayed into the blended powder. The granules are dried, sieved, mixed with an optional lubricant (such as talc or magnesium stearate), and compressed into tablets. The preferred aqueous solution of the strong base is an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in water (optionally containing up to 25% water-miscible solvent, such as a lower alcohol).

[0319] The resulting tablets may be coated with any film-forming agent for identification, taste masking, and to improve swallowability. The film-forming agent is typically present in an amount ranging from 2% to 4% of the tablet weight. Suitable film-forming agents are well known in the art and include hydroxypropyl methylcellulose and cationic methacrylate copolymers (dimethylaminoethyl methacrylate / methyl-butyl methacrylate copolymer - Eudragit® E-RohmPharma). These film-forming agents may optionally contain colorants, plasticizers, and other auxiliary components.

[0320] The compressed tablets preferably have sufficient hardness to withstand compression of 8 kp. The tablet size depends mainly on the amount of compound in the tablet. The tablets contain 300 to 1100 mg of compound free base. Preferably, the tablets contain amounts of compound free base in the ranges of 400 to 600 mg, 650 to 850 mg, and 900 to 1100 mg.

[0321] To influence the dissolution rate, the time during which the compound-containing powder is wet-mixed is controlled. Preferably, the total powder mixing time, i.e., the time the powder is exposed to the sodium hydroxide solution, is in the range of 1 to 10 minutes, preferably 2 to 5 minutes. After granulation, the particles are removed from the granulator and dried in a fluidized bed dryer at approximately 60°C.

[0322] Formulation Example 11 The following ingredients are used to prepare the tablet formulation.

[0323] [Table 12]

[0324] The ingredients are blended and compressed to form tablets.

[0325] IV. List of Abbreviations and Acronyms

[0326] [Table 13-1]

[0327] [Table 13-2]

[0328] V. Examples The following embodiments are included to demonstrate specific embodiments of the Disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that function well in the implementation of the Disclosure and can therefore be considered to constitute a particular form for such implementation. However, those skilled in the art will understand that many modifications can be made in the specific embodiments disclosed, without departing from the spirit and scope of the Disclosure, and still achieving similar or comparable results.

[0329] V. Synthesis example Example 1: Preparation of 6-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazine-1-yl)pentyl)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0330] [ka] Step 1. To a stirred solution of 4-bromo-6-chloropyridazine-3(2H)-one (1.5 g, 7.2 mmol) in DMF (15 mL), NaH (412 mg, 10.7 mmol, 60% in mineral oil) was added at 0°C, followed by SEM-Cl (1.52 mL, 8.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (0-40% ethyl acetate-hexane) to obtain 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one. 1 H NMR(400MHz,Chloroform-d)δ 7.62(s,1H),7.26(s,1H),3.78-3.67(m,2H),1.02-0.89(m,2H),0.00(s,9H). Step 2. To a stirred solution of 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (500 mg, 1.47 mmol) in NMP (5 mL), CuI (56 mg, 0.294 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (848 mg, 4.42 mmol) were added at room temperature. The reaction mixture was sealed with a septum and heated overnight at 80 °C. Completion of the reaction was confirmed by LC-MS. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product was purified by column chromatography (0-30% siRNA) to obtain 6-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one. ES / MS: m / z 351.1[M+Na] + . Step 3. A tightly sealing heavy-walled flask was filled with 6-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (175 mg, 0.532 mmol), CuI (10 mg, 0.053 mmol), Pd(PPh3)4 (49 mg, 0.043 mmol), THF (2.0 mL), ethyl pento-4-isoate (134 mg, 1.06 mmol), and diisopropylamine (0.15 mL, 1.06 mmol). The flask was sealed and the reaction mixture was stirred overnight at 80°C. After cooling, the mixture was filtered. Water was added to the filtrate and subsequently extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product was purified by column chromatography (0-50% ethyl-hexane) to obtain ethyl 5-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)pento-4-inoate. ES / MS: m / z 441.2[M+Na] + . Step 4. A mixture of ethyl 5-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)pentanoate (181 mg, 0.43 mmol) and Pd / C (46 mg of 10% Pd / C, wet) in HCl and MeOH (1.0 mL each) was shaken overnight on a Parr shaker at 30 psi H2. The mixture was filtered through Celite, and the filter pad was rinsed with HCl / MeOH. The filtrate was concentrated to obtain ethyl 5-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)pentanoate. ES / MS: m / z 445.2 [M+Na] + . Step 5. To a suspension of ethyl 5-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)pentanoate (183 mg, 0.43 mmol) in THF (3 mL), 1 N LiOH (1.1 mL) was added. The reaction mixture was stirred at 40 °C for 4 hours. The mixture was diluted with ethyl acetate and quenched with 1 N HCl. After extraction with ethyl acetate, the combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product 5-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)pentanoic acid was used without further purification. ES / MS: m / z 417.2 [M+Na] + . Step 6. The crude product 5-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazine-3-yl)pentanoic acid (approximately 0.43 mmol) from the above was dissolved in DMF (3 mL), and 2-piperazin-1-yl-5-(trifluoromethyl)pyrimidine (hydrochloride, 140 mg, 0.520 mmol) was added, followed by the addition of N,N-diisopropylethylamine (302 μL, 1.73 mmol) and HATU (214 mg, 1.30 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was partitioned into ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (10-100% butyl-hexane) to obtain 6-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)pentyl)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one. ES / MS: m / z 609.2[M+H] + . Step 7.6-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)pentyl)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (168 mg, 0.276 mmol)) was dissolved in DCM (1 mL) and TFA (1 mL). After stirring for 1 hour, the reaction mixture was concentrated. The resulting residue was dissolved in MeOH (1 mL) and treated with ethylenediamine (0.148 mL, 2.21 mmol) at room temperature for 1 hour. After concentration, the residue was directly purified by preparative HPLC (5-100% MeCN in water, 0.1% TFA) to obtain 6-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)pentyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as the -TFA salt. 1H NMR(400MHz,DMSO-d6)δ13.47(s,1H),8.73(d,J=1.0Hz,2H),7.89(s,1H),3.89-3.77(m,4H),3.58-3. 52(m,4H),2.64(t,J=7.4Hz,2H),2.39(t,J=7.3Hz,2H),1.64(p,J=7.4Hz,2H),1.53(p,J=7.3Hz,2H). ES / MS:m / z 501.0[M+H] + .

[0331] Example 2: 6-(6-oxo-6-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazine-1-yl)hexyl)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0332] [ka] The preparation was carried out using the same procedure as in Example 1, but with methylhexa-5-inoate instead of ethylpenta-4-inoate in step 3. ¹H NMR (400 MHz, DMSO-d6) δ 13.45 (s, ¹H), 8.73 (s, ²H), 7.90 (s, ¹H), 3.89-3.77 (m, ²H), 3.59-3.52 (m, ²H), 2.62 (t, J=7.6 Hz, ²H), 2.36 (t, J=7.5 Hz, ²H), 1.67-1.48 (m, ²H), 1.32 (p, J=7.9 Hz, ²H). m / z 493.2 [M+H] + .

[0333] Example 3: 6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)propyl)phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0334] [ka] Step 1.6-Chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (50 mg, 0.152 mmol) was combined with ethyl 3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (56 mg, 0.182 mmol), XPhos Pd G4 (13 mg, 0.015 mmol), cesium fluoride (69 mg, 0.456 mmol), and water (0.1 mL) in dioxane (0.75 mL). The mixture was degassed with N2 and heated to 80°C with stirring for 2 hours. The reaction product was adsorbed onto isolute and purified by column chromatography (3:1 RINKAN / EtOH in heptane) to obtain ethyl 3-[2-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]phenyl]propanoate. ES / MS: m / z 442.8[M-28] + . Step 2. Ethyl 3-[2-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]phenyl]propanoate was saponified according to Step 5 of Example 1 to obtain 3-[2-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]phenyl]propanoic acid. ES / MS: m / z 414.8 [M-28] + . Step 3.3-[2-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]phenyl]propanoic acid was reacted according to Step 6 of Example 1 to obtain 6-[2-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propyl]phenyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one. ES / MS: m / z 679.3[M+Na] + . Step 4.6-[2-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propyl]phenyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one was deprotected according to Step 7 of Example 1 to obtain 6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)propyl)phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one. 1H NMR(400MHz,DMSO-d6)δ13.88(s,1H),8.72(s,2H),8.08(s,1H),7.47-7.37(m,3H),7.38-7.28(m,1H) ),3.78(t,J=5.0Hz,4H),3.50(dt,J=19.3,5.3Hz,4H),2.89(t,J=7.7Hz,2H),2.65(t,J=7.8Hz,2H). ES / MS:m / z 527.1[M+H] + .

[0335] Example 4: 6-(2-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazine-1-yl)ethyl)phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0336] [ka] Step 1: 2-(2-bromophenyl)acetic acid (215 mg, 1.0 mmol) was reacted according to Step 6 of Example 1. Purification by column chromatography (3:1 siRNA / EtOH in heptane) yielded 2-(2-bromophenyl)-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]ethenone. ES / MS: m / z 429.1[M+H] + . Step 2.2-(2-bromophenyl)-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]ethenone (25 mg, 0.058 mmol) was combined with bis(pinacorato)diborone (19 mg, 0.076 mmol), KOAc (17 mg, 0.175 mmol), and dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium(II)dichloromethane (5 mg, 0.006 mmol) in dioxane (0.5 mL). The resulting mixture was degassed with N2 and stirred for 4 hours at 100°C. ℃ The mixture was heated. The reaction product was filtered through Celite, and the filter pad was rinsed with ELISA. The filtrate containing 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]ethenone was used crudely in the next step. Step 3. The crude product 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]ethanone was reacted according to Step 1 of Example 3 to obtain 6-[2-[2-oxo-2-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]ethyl]phenyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one. ES / MS: m / z 642.5[M+H] + . Step 4.6-[2-[2-oxo-2-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]ethyl]phenyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one was deprotected according to Step 7 of Example 1 to obtain 6-(2-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)ethyl)phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one. 1H NMR(400MHz,DMSO-d6)δ13.82(s,1H),8.75(s,2H),7.98(s,1H),7.52(dd,J=7.2,1.7Hz,1H),7.47-7.34(m,2 H),7.32(dd,J=7.2,1.6Hz,1H),3.90(s,2H),3.87-3.75(m,4H),3.58(t,J=5.3Hz,2H),3.51(t,J=5.3Hz,2H). ES / MS:m / z 513.1[M+H] + .

[0337] Example 5: 6-(2-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)butyl)phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0338] [ka] Step 1. 4-(2-bromophenyl)butanoic acid (150 mg, 0.62 mmol) was reacted according to Step 6 of Example 1. Water was added to the reactants, forming a precipitate. This precipitate was collected, washed with water, and dried to obtain 4-(2-bromophenyl)-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]butan-1-one. ES / MS: m / z 457.3[M+H] + . Step 2.4-(2-bromophenyl)-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]butan-1-one was reacted according to Step 2 of Example 4 to obtain 4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]butan-1-one, which was used crudely in the next step. Step 3. The crude product 4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]butan-1-one was reacted according to Step 1 of Example 3. Purification by column chromatography (ELISA in hexane) yielded 6-[2-[4-oxo-4-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]butyl]phenyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one. ES / MS: m / z 670.8[M+H] + . Step 4.6-[2-[4-oxo-4-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]butyl]phenyl]4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one was deprotected according to Step 7 of Example 1 to obtain 6-(2-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)butyl)phenyl)4-(trifluoromethyl)pyridazin-3(2H)-one. 1H NMR(400MHz,DMSO-d6)δ13.86(s,1H),8.73(s,2H),8.02(s,1H),7.47-7.27(m,4H),3.81(dt,J=20.2,5.2Hz, 4H), 3.49(dt,J=15.3,5.3Hz,4H),2.67(dd,J=9.0,6.5Hz,2H),2.30(t,J=7.2Hz,2H),1.71(p,J=7.4Hz,2H). ES / MS:m / z 541.1[M+H] + .

[0339] Example 6: 4-(trifluoromethyl)-6-(3-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazine-1-carbonyl)benzyl)pyridazine-3(2H)-one

[0340] [ka] Step 1.3 - Using [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]benzonitrile (80 mg, 0.328 mmol), 6-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (90 mg, 0.274 mmol) was reacted according to Step 1 of Example 3. Purification by column chromatography (siRNA in hexane) yielded 3-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]methyl]benzonitrile. ES / MS: m / z 432.1[M+Na] + . Step 2.3 - [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]methyl]benzonitrile (53 mg, 0.129 mmol) was combined with Ghaffar-Parkins catalyst (6 mg, 0.013 mmol) in a mixture of EtOH (0.6 mL) and water (0.2 mL), and heated at 80°C for 18 hours. The reaction mixture was filtered through Celite, and the filter pad was rinsed with EtOH. The filtrate was concentrated to obtain 3-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]methyl]benzamide, which was used in the next step without purification. ES / MS: m / z 450.1[M+Na] + . Step 3.3-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-3-yl]methyl]benzamide was dissolved in dioxane and treated with concentrated aqueous HCl. The reaction mixture was heated to 120°C with stirring for 3 hours, then concentrated to obtain 3-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-3-yl]methyl]benzoic acid as a brown residue, which was used crudely in the next step. ES / MS: m / z 299.1[M+H] + . Step 4.3-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-3-yl]methyl]benzoic acid was reacted according to Step 6 of Example 1. After aqueous workup and concentration, the residue was directly purified by preparative HPLC (5-100% MeCN in water, 0.1% TFA) to obtain 4-(trifluoromethyl)-6-(3-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-carbonyl)benzyl)pyridazin-3(2H)-one. 1H NMR(400MHz,DMSO-d6)δ13.57(s,1H),8.74(s,2H),7.92(s,1H),7.47-7.36(m,3H),7.33 (d,J=7.3Hz,1H),4.05(s,2H),3.98-3.79(m,4H),3.77-3.60(m,2H),3.55-3.34(m,2H). ES / MS:m / z 513.1[M+H] + .

[0341] Example 7: 6-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)propyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0342] [ka] Step 1.2-Piperadin-1-yl-5-(trifluoromethyl)pyrimidine hydrochloride (200 mg, 0.744 mmol) and TEA (0.42 mL, 3.0 mmol) were stirred in 5 mL of DCM at 0°C. Propa-2-enoyl chloride (0.08 mL, 1.12 mmol) was added dropwise. After stirring at 0°C for 2 hours, the reaction mixture was quenched with aqueous NaHCO3 solution and extracted three times with DCM. The combined organic layer was concentrated under vacuum and adsorbed onto isolute. Purification by column chromatography (3:1 siRNA / EtOH in heptane) yielded 1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propa-2-en-1-one. ES / MS: m / z 287.1[M+H] + . Step 2.1-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propa-2-en-1-one (66 mg, 0.23 mmol) was combined with 6-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (69 mg, 0.21 mmol), XPhos Pd G4 (18 mg, 0.021 mmol), sodium acetate (21 mg, 0.252 mmol), and tetrabutylammonium iodide (14 mg, 0.038 mmol) in DMA (0.8 mL). The mixture was degassed with N2 and heated to 100°C with stirring for 3 days. The reaction product was poured into water and extracted three times with DCM. The combined organic layer was concentrated under vacuum and adsorbed onto isolute. Purification by column chromatography (toluene in hexane) yielded 6-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propa-1-enyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one. ES / MS: m / z 579.1[M+H] + . Step 3.6-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propa-1-enyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (101 mg, 0.175 mmol) was combined with Pd / C (10% Pd / C of 0.02 mmol, wet) in siRNA and EtOH (1.0 mL each). The mixture was purged with N2, evacuated, and then a balloon containing H2 was attached and stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filter pad was rinsed with DCM. The filtrate was concentrated to obtain 6-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one. ES / MS: m / z 580.9[M+H] + . Step 4.6-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidine-2-yl]piperazin-1-yl]propyl]-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one was deprotected according to Step 7 of Example 1 to obtain 6-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)propyl)-4-(trifluoromethyl)pyridazin-3(2H)-one. 1H NMR(400MHz,DMSO-d6)δ13.46(s,1H),8.74(s,2H),7.95(s,1H),3.88(t,J=5.1Hz,2H),3.81(dd ,J=6.6,4.1Hz,2H),3.58(dt,J=10.6,5.3Hz,4H),2.89(t,J=7.1Hz,2H),2.78(t,J=7.2Hz,2H). ES / MS:m / z 451.0[M+H] + .

[0343] Example 8: 6-(6-oxo-6-(4-(5-(trifluoromethyl)pyrimidine-2-yl)piperazin-1-yl)hexane-2-yl)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0344] [ka] Step 1. DMF (4 mL) was added to a flask containing NaH (60% in mineral oil, 159 mg, 4.16 mmol) under N2 while stirring. A solution of ethyl 2-methyl acetate (500 mg, 3.47 mmol) in DMF (1 mL) was added dropwise, and the resulting mixture was stirred under N2 at ambient temperature. After 1 hour, methyl 4-bromobutanoate (0.66 mL, 5.20 mmol) was added gradually, and the reaction mixture was stirred. After 3 days, the reaction mixture was quenched with water and aqueous NaHCO3 solution, and extracted three times with ethyl. The combined extract w...

Claims

1. Equation (I) 【Chemistry 126】 A compound thereof, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, During the ceremony, n is 1; X is C; R ２ and R ３ These, together with the atoms to which they are bonded, form a 4- to 11-membered cycloalkyl group. Here, the 4- to 11-membered cycloalkyl itself is monocyclic, condensed bicyclic, spirocyclic, or a crosslinking ring, and has one or more R １０ It is optionally replaced by; R １ C １～５ It is an alkylene and has one or more R ５ It is optionally replaced by; L is -C(O)-; R ４ CF ３ And; Q-Z is, 【Chemistry 1】 And; Z is a: They are 5- to 10-membered heteroaryls; Here, the 5- to 10-membered heteroaryl is monocyclic or bicyclic, and may be substituted with one or more R １３ and may be substituted with one or more R ９ ; and may be substituted with one or more R R ５ H, oxo, hydroxy, halo, -NO ２ ,-CN,C １～９ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C) １～９ Alkyl), -O (C ２～６ Alkenyl), -O(C ２～６ Alkinyl), -O(C ３～１５ Cycloalkyl), -O (C １～８ Haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclyl), -NH ２ ,-NH(C １～９ Alkyl), -NH(C ２～６ Alkenyl), -NH(C) ２～６ Alkinyl), -NH(C) ３～１５ Cycloalkyl), -NH(C １～８ Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C) １～９ Alkyl) ２ , -N(C ２～６ Alkenil) ２ , -N(C ２～６ Alkinyl) ２ , -N(C ３～１５ Cycloalkyl) ２ , -N(C １～８ (Haloalkyl) ２ , -N (aryl) ２ , -N (heteroaryl) ２ , -N (heterocycline) ２ , -N(C １～９ (Alkyl) (C ２～６ Alkenyl), -N(C) １～９ (Alkyl) (C ２～６ Alkinyl), -N(C) １～９ (Alkyl) (C ３～１５ Cycloalkyl), -N(C １～９ (Alkyl) (C １～８ Haloalkyl), -N(C) １～９ Alkyl) (aryl), -N (C １～９ Alkyl) (heteroaryl), -N (C １～９ Alkyl) (heterocyclyl), -C(O)(C １～９ Alkyl), -C(O)(C ２～６ Alkenyl), -C(O)(C ２～６ Alkinyl), -C(O)(C ３～１５ Cycloalkyl), -C(O)(C １～８ Haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C) １～９ Alkyl), -C(O)O(C ２～６ Alkenyl), -C(O)O(C ２～６ Alkinyl), -C(O)O(C ３～１５ Cycloalkyl), -C(O)O(C １～８ Haloalkyl), -C(O)O (aryl), -C(O)O (heteroaryl), -C(O)O (heterocyclyl), -C(O)NH ２ , -C(O)NH(C １～９ Alkyl), -C(O)NH(C ２～６ Alkenyl), -C(O)NH(C ２～６ Alkinyl), -C(O)NH(C ３～１５ Cycloalkyl), -C(O)NH(C １～８ Haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C １～９ Alkyl) ２ , -C(O)N(C ３～１５ Cycloalkyl) ２ , -C(O)N(C ２～６ Alkenil) ２ , -C(O)N(C ２～６ Alkinyl) ２ , -C(O)N(C ３～１５ Cycloalkyl) ２ , -C(O)N(C １～８ (Haloalkyl) ２ , -C(O)N(aryl) ２ -C(O)N(heteroaryl) ２ -C(O)N (heterocycline) ２ , -NHC(O)(C １～９ Alkyl), -NHC(O)(C ２～６ alkenyl), -NHC(O)(C ２～６ alkynyl), -NHC(O)(C ３～１５ cycloalkyl), -NHC(O)(C １～８ haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C １～９ alkyl), -NHC(O)O(C ２～６ alkenyl), -NHC(O)O(C ２～６ alkynyl), -NHC(O)O(C ３～１５ cycloalkyl), -NHC(O)O(C １～８ haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C １～９ alkyl), -NHC(O)NH(C ２～６ alkenyl), -NHC(O)NH(C ２～６ alkynyl), -NHC(O)NH(C ３～１５ cycloalkyl), -NHC(O)NH(C １～８ haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C １～９ alkyl), -S(C ２～６ alkenyl), -S(C ２～６ alkynyl), and -S(C ３～１５ cycloalkyl) and is selected from Here, any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more halos, C １～９ Alkyl, C １～８ Haloalkyl, -OH, -NH ２ ,-NH(C １～９ Alkyl), -NH(C ３～１５ Cycloalkyl), -NH(C １～８ Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C) １～９ Alkyl) ２ , -N(C ３～１５ Cycloalkyl) ２ , -NHC(O)(C ３～１５ Cycloalkyl), -NHC(O)(C １～８ Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) １～９ Alkyl), -NHC(O)O(C ２～６ Alkinyl), -NHC(O)O(C) ３～１５ Cycloalkyl), -NHC(O)O(C １～８ Haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclyl), -NHC(O)NH(C) １～９ Alkyl), -S(O)(NH)(C １～９ Alkyl), -S(O)(NH)(C ３～９ Cycloalkyl), -S(O)(NC C １～９ (Alkyl) (C １～９ Alkyl), -S(O)(NH)(aryl), -S(O)(NH)(heteroaryl), S(O) ２ (C １～９ Alkyl), -S(O) ２ (C ３～１５ Cycloalkyl), -S(O) ２ (C １～８ Haloalkyl), -S(O) ２ (Aryl), -S(O) ２ (heteroaryl), -S(O) ２ (Heterocyclyl), -S(O) ２ NH(C) １～９ Alkyl), -S(O) ２ N(C) １～９ Alkyl) ２、 -S(O) ２ NH (aryl), -S (O) ２ NH (heteroaryl), -O (C ３～１５ Cycloalkyl), -O (C １～８ Haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclyl), and -O (C １～９ Optionally substituted with alkyl; R ６ C １～９ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１５ Independently selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl; where any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more R ９ It is optionally replaced by; R ７ and R ８ H, C １～９ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１５ Independently selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl; where any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more R ９ It is optionally replaced by; R ９ H, oxo, hydroxy, halo, -NO ２ ,-CN,C １～９ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C) １～９ Alkyl), -O (C ２～６ Alkenyl), -O(C ２～６ Alkinyl), -O(C ３～１５ Cycloalkyl), -O (C １～８ Haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclyl), -NH ２ ,-NH(C １～９ Alkyl), -NH(C ２～６ Alkenyl), -NH(C) ２～６ Alkinyl), -NH(C) ３～１５ Cycloalkyl), -NH(C １～８ Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C) １～９ Alkyl) ２ , -N(C ２～６ Alkenil) ２ , -N(C ２～６ Alkinyl) ２ , -N(C ３～１５ Cycloalkyl) ２ , -N(C １～８ (Haloalkyl) ２ , -N (aryl) ２ , -N (heteroaryl) ２ , -N (heterocycline) ２ , -N(C １～９ (Alkyl) (C ２～６ Alkenyl), -N(C) １～９ (Alkyl) (C ２～６ Alkinyl), -N(C) １～９ (Alkyl) (C ３～１５ Cycloalkyl), -N(C １～９ (Alkyl) (C １～８ Haloalkyl), -N(C) １～９ Alkyl) (aryl), -N (C １～９ Alkyl) (heteroaryl), -N (C １～９ Alkyl) (heterocyclyl), -C(O)(C １～９ Alkyl), -C(O)(C ２～６ Alkenyl), -C(O)(C ２～６ Alkinyl), -C(O)(C ３～１５ Cycloalkyl), -C(O)(C １～８ Haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C) １～９ Alkyl), -C(O)O(C ２～６ Alkenyl), -C(O)O(C ２～６ Alkinyl), -C(O)O(C ３～１５ Cycloalkyl), -C(O)O(C １～８ Haloalkyl), -C(O)O (aryl), -C(O)O (heteroaryl), -C(O)O (heterocyclyl), -C(O)NH ２ , -C(O)NH(C １～９ Alkyl), -C(O)NH(C ２～６ Alkenyl), -C(O)NH(C ２～６ Alkinyl), -C(O)NH(C ３～１５ Cycloalkyl), -C(O)NH(C １～８ Haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C １～９ Alkyl) ２ , -C(O)N(C ３～１５ Cycloalkyl) ２ , -C(O)N(C ２～６ Alkenil) ２ , -C(O)N(C ２～６ Alkinyl) ２ , -C(O)N(C ３～１５ Cycloalkyl) ２ , -C(O)N(C １～８ (Haloalkyl) ２ , -C(O)N(aryl) ２ -C(O)N(heteroaryl) ２ -C(O)N (heterocycline) ２ , -NHC(O)(C １～９ Alkyl), -NHC(O)(C ２～６ Alkenyl), -NHC(O)(C) ２～６ Alkinyl), -NHC(O)(C) ３～１５ Cycloalkyl), -NHC(O)(C １～８ Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) １～９ Alkyl), -NHC(O)O(C ２～６ Alkenyl), -NHC(O)O(C) ２～６ Alkinyl), -NHC(O)O(C) ３～１５ Cycloalkyl), -NHC(O)O(C １～８ Haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclyl), -NHC(O)NH(C) １～９ Alkyl), -NHC(O)NH(C ２～６ Alkenyl), -NHC(O)NH(C) ２～６ Alkinyl), -NHC(O)NH(C) ３～１５ Cycloalkyl), -NHC(O)NH(C １～８ Haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C) １～９ Alkyl), -S (C ２～６ Alkenyl), -S (C ２～６ Alkinyl), -S (C ３～１５ Cycloalkyl), -S (C １～８ Haloalkyl), -S (aryl), -S (heteroaryl), -S (heterocyclyl), -NHS(O)(C) １～９ Alkyl), -N(C １～９ Alkyl)S(O)(C １～９ Alkyl), -S(O)N(C) １～９ Alkyl) ２ , -S(O)(C １～９ Alkyl), -S(O)(NH)(C １～９ Alkyl), -S(O)(NH)(C ３～９ Cycloalkyl), -S(O)(NC C １～９ (Alkyl) (C １～９ Alkyl), -S(O)(NH)(aryl), -S(O)(NH)(heteroaryl), -S(O)(C ２～６ Alkenyl), -S(O)(C) ２～６ Alkinyl), -S(O)(C) ３～１５ Cycloalkyl), -S(O)(C １～８ Haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O) ２ (C １～９ Alkyl), -S(O) ２ (C ２～６ Alkenyl), -S(O) ２ (C ２～６ Alkinyl), -S(O) ２ (C ３～１５ Cycloalkyl), -S(O) ２ (C １～８ Haloalkyl), -S(O) ２ (Aryl), -S(O) ２ (heteroaryl), -S(O) ２ (Heterocyclyl), -S(O) ２ NH(C) １～９ Alkyl), and -S(O) ２ N(C) １～９ Alkyl) ２ Selected independently of; Here, any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is one or more halos, C １～９ Alkyl, C １～８ Haloalkyl, -OH, -NH ２ ,-NH(C １～９ Alkyl), -NH(C ３～１５ Cycloalkyl), -NH(C １～８ Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C) １～９ Alkyl) ２ , -N(C ３～１５ Cycloalkyl) ２ , -NHC(O)(C ３～１５ Cycloalkyl), -NHC(O)(C １～８ Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) １～９ Alkyl), -NHC(O)O(C ２～６ Alkinyl), -NHC(O)O(C) ３～１５ Cycloalkyl), -NHC(O)O(C １～８ Haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclyl), -NHC(O)NH(C) １～９ Alkyl), -S(O)(NH)(C １～９ Alkyl), S(O) ２ (C １～９ Alkyl), -S(O) ２ (C ３～１５ Cycloalkyl), -S(O) ２ (C １～８ Haloalkyl), -S(O) ２ (Aryl), -S(O) ２ (heteroaryl), -S(O) ２ (Heterocyclyl), -S(O) ２ NH(C) １～９ Alkyl), -S(O) ２ N(C) １～９ Alkyl) ２ , -O(C ３～１５ Cycloalkyl), -O (C １～８ Haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclyl), and -O (C １～９ It is optionally substituted with alkyl; R １０ H, oxo, halo, CH ３ ,CH ２ F, CHF ２ CF ３ ,CH ２ CF ３ , OCH ３ OCF ３ , OCHF ２ NO ２ , CN, O-R ６ , C(O)-R ６ , C(O)-N(R ７ ) (Caution ８ ), N (R ７ ) (Caution ８ ), N (R ７ ) C(O)-R ５ , N(R ７ ) C(O)O-R ５ , N(R ７ ) S(O) ２ (R ５ ), N (R ７ )C(O)-N(R ７ ) (Caution ８ ), S(O) ２ R ９ , S(O) ２ N(R) ７ ) (Caution ８ ), S(O)(NH)R ７ , S(O)(NR ７ ) NR ８ C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Independently selected from alkynyl, 5-11 member alkylspiro rings, and 5-11 member heterospiro rings; R １３ H, oxo, halo, CH ３ ,CH ２ F, CHF ２ CF ３ ,CH ２ CF ３ , OCH ３ OCF ３ , OCHF ２ NO ２ , CN, O-R ６ , C(O)-R ６ , C(O)-N(R ７ ) (Caution ８ ), N (R ７ ) (Caution ８ ), N (R ７ ) C(O)-R ５ , N(R ７ ) C(O)O-R ５ , N(R ７ ) S(O) ２ (R ５ ), N (R ７ )C(O)-N(R ７ ) (Caution ８ ), S(O) ２ R ９ , S(O) ２ N(R) ７ ) (Caution ８ ), S(O)(NH)R ７ , S(O)(NR ７ ) NR ８ C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl and one or more R ９ C is optionally replaced by ２～６ Selected independently of alkinyl, A compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

2. The aforementioned compound, 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

3. The aforementioned compound, 【Transformation 3】 And, In the equation, q is between 0 and 6 (inclusive); and m is between 0 and 5 (inclusive). The compound described in claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

4. Q-Z is, 【Chemistry 145】 is; or Q-Z is 【Chemistry 147】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

5. Z is 【Chemistry 149】 It is; or Z is [Chemical 150] It is; or Z is 【Chemistry 151】 It is; or Z is 【Chemistry 152】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

6. Q-Z is, 【Chemistry 155】 A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. 【Request Item 7】 【Chemistry 7-1】 【Chemistry 7-2】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to claims 1 to 7, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, together with a pharmaceutically acceptable carrier.

9. A composition for use in a method of treating cancer, comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

Images