Parp7 inhibitors

Abstract

This document provides a compound of formula I: ;, ; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof; a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient; and a method of treating cancer using the pharmaceutical composition.

Description

Prior Technology

[0001] Adenosine diphosphate (ADP)-ribosylation is a highly conserved post-translational modification found in viruses, bacteria, and eukaryotes. It is catalyzed by members of the ART protein superfamily, which transfer ADPr from nicotinamide adenine dinucleotide (NAD+) to the recipient molecule via N-, O-, or S-glycosidic bonds on the target molecule. A subset of ART is poly(adenosine diphosphate-ribose) polymerase (PARP), a member of a family of 17 known enzymes that regulate fundamental cellular processes, including gene F expression, protein degradation, and various cellular stress responses (MCohen, 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 an emerging approach for novel therapeutics.

[0002] Of particular interest is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TIPARP), a protein containing a CCCH-type zinc finger domain (Proc.Nat. Acad. Sci. 114 (10) 2681-2686 (2017)). TIPARP is also known as PARP7 and ARTD14. PARP7 acts as a negative regulator of transcriptional targets of certain aryl hydrocarbon receptors (AHRs). AHRs are subsequently activated by many receptors, including cigarette smoke. PARP7 inhibitors have been shown to restore type I interferon (IFN) signaling responses to nucleic acids and to induce tumor regression in the CT26 tumor-bearing immune-active BALB / c mouse model (Gozgit, et al., Cancer Cell 39, 1214-1226 (2021)).

[0003] There are currently no approved PARP7 inhibitors. Therefore, it would be useful to provide a PARP7 inhibitory compound that has properties suitable for administration as a pharmaceutical agent to mammals (especially humans).

[0004] Therefore, there is a need for modified PARP7 inhibitors for the treatment of cancer. Summary of the Invention

[0005] This document provides compounds and pharmaceutical compositions that can be used as PARP7 inhibitors. Some of the compounds disclosed herein can be used in pharmaceutical compositions with at least one pharmaceutically acceptable excipient for the treatment of patients in need.

[0006] In one embodiment of the present invention, a compound of (I) is provided: (I), Or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, J series ; X 1 is N, C=O, CR 10, or C-(R 10) 2; X2 series N, NR 11, CR 12, or C-(R 12) 2; X3 series N or CR 13; X4 series N or CR 13; X 5 series N or CR 13; or [A] [Selected from:] C, O, N Optionally substituted with one or more R15-substituted 3 to 10-membered cycloalkyl groups; or Optionally substituted with one or more R15-substituted 4 to 11-member heterocyclic groups; When A is 0, n is 0; when A is N, n is 1; and when A is C, n is 1 or 2; When A is N, n is 0 or 1, and L1 is C or NR 17, and L2, L3, and L4 are each C; L1 and L2 are each independently derived from C, C6-10 aryl, 5 to 12 heteroaryl, or NH; L3 and L4 series C; or [L, 1 , ] [and L, 2 , ] [Together with the atoms attached thereto] form a 3- to 12-membered cycloalkyl, C6-10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring, optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5- to 12-membered heteroaryl group is monocyclic or bicyclic; or [L, 1 , ] [and L, 3 , ] [Together with the atoms attached thereto] form a 3- to 12-membered cycloalkyl, C6-10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5- to 12-membered heteroaryl group is monocyclic or bicyclic; or [L, 2 , ] [and L, 3 , ] [Together with the atoms attached thereto] form a 3- to 12-membered cycloalkyl, C6-10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5- to 12-membered heteroaryl group is monocyclic or bicyclic; or [L, 3 , ] [and L, 4 , ] [Together with the atoms attached thereto] form a 3- to 12-membered cycloalkyl, C6-10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5- to 12-membered heteroaryl group is monocyclic or bicyclic; or [L, 2 , ] [and L, 4 , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl, C6-10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5- to 12-membered heteroaryl group is monocyclic or bicyclic, each optionally substituted with one or more R15 groups; [R, 1 , ] [Selected from] H, halo, CH 3, CH 2CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, CN, OR 14, C(O)-R 14, -SF 5; C(O)-N(R 17)(R 18), N(R 17)(R 18), N(R 17)C(O)-R 15, N(R 17)C(O)OR 15, N(R 7)S(O) 2(R 15), N(R 17)C(O)-N(R 17)(R 18), S(O) 2R 15, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18, Optionally substituted with one or more R15-substituted C1-5 alkyl groups; or Optionally substituted with one or more R15-substituted C3-10 cycloalkyl groups; or Optionally, it may be substituted with one or more R15-substituted 5 to 10 heteroaryl groups; or Optionally, it is a C6-10 aryl group substituted with one or more R15 groups; or Optionally, it may be substituted with one or more R15-substituted 4- to 7-membered heterocyclic groups; [R, 2 , ] [Selected from] H, C1-9 alkyl, C2-9 alkenyl, or C2-9 ynyl, wherein any alkyl, alkenyl, and ynyl group may optionally be substituted with one or more R10 groups; [R, 3 , ] [and R, 4 , ] [Each independently selected from] H, C1-9 alkyl, C2-9 alkenyl, C2-9 ynyl, wherein any alkyl, alkenyl, and ynyl group may optionally be substituted with one or more R15 groups, C3-12 cycloalkyl groups optionally substituted with one or more R15 groups, C6-10 aryl groups optionally substituted with one or more R15 groups, 4-11 member heterocyclic groups optionally substituted with one or more R15 groups, or 5-10 member heteroaryl groups optionally substituted with one or more R15 groups; or [R, 2 , ] [and R, 3 , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocycle, which may optionally be substituted with one or more R15s; The 4 to 12-membered cycloalkyl or 4 to 12-membered heterocyclic monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged system is optionally substituted with one or more R15 groups; or [R, 3 , ] [and R, 4 , ] [Together with the atoms to which they are attached] form a 3- to 12-membered cycloalkyl group or a 4- to 12-membered heterocyclic group, each optionally substituted with one or more R15 groups; wherein the 3- to 12-membered cycloalkyl group or the 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each optionally substituted with one or more R15 groups; or [R, 2 , ] [and R, 4 , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 groups; wherein the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic ring is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each optionally substituted with one or more R15 groups; [R, 5a , ] [、R , 5b , R , 6a , ] [、R , 6b , ] [、R , 7a , R , 7b , ] [Each group is independently selected from] H, halogen, NO 2, CN, O-R 14, C(O)-R 16, C(O)-N(R 17)(R 18), N(R 17)(R 18), N(R 17)C(O)-R 16, N(R 17)C(O)O-R 14, N(R 17)S(O) 2(R 16), -N(R 17)C(O)-N(R 18)(R 18), S(O) 2R 16, -SF 5, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18 Optionally substituted with one or more R15-substituted C1-9 alkyl groups; Optionally, C2-9 ynyl groups substituted with one or more R15 groups; Optionally, the C2-9 alkenyl group is substituted with one or more R15 groups; Optionally, it may be a 5 to 12-membered heteroaryl group substituted with one or more R 15; Optionally, the C6-10 aryl group is substituted with one or more R15 groups; Optionally substituted with one or more R15-substituted 4- to 12-member heterocyclic groups; or Optionally substituted with one or more R15-substituted C3-12 cycloalkyl groups; or [R, 5a , ] [and R, 5b , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocycle, each optionally substituted with one or more R15 groups; or [R, 6a , ] [and R, 6b , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocycle, each optionally substituted with one or more R15 groups; or [R7, a , ] [and R, 7b , ] [Together with the atoms to which they are attached] form a 3- to 12-membered cycloalkyl group or a 4- to 12-membered heterocyclic group, each optionally substituted with one or more R15 groups, wherein the 3- to 12-membered cycloalkyl group or the 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each optionally substituted with one or more R15 groups; or [Z] [Selected from:] H, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-8 haloalkyl, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocycloyl), -OC(O) (C1-9 alkyl), -OC(O) (C2-6 alkenyl), -OC(O) (C2-6 alkenyl), -OC(O) (C2-6 ynyl), -OC(O) (C3-15 cycloalkyl), -OC(O) (C1-8 haloalkyl), -OC(O) (C -6-10 aryl), -OC(O) (5 to 12-membered heteroaryl), -OC(O) (4 to 12-membered heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 ynyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 1-8 haloalkyl) 2, -N (C 6-10 aryl) 2, -N (5 to 12-membered heteroaryl) 2. -N(h4 to 12-membered heterocyclic groups) 2. -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 ynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5 to 12-membered heteroaryl), -N(C1-9 alkyl)(4 to 12-membered heterocyclic groups), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 ynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocyclic), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocyclic), -C(O)NH2. -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -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 ynyl) 2. -C(O)N (C 1-8 haloalkyl) 2. -C(O)N (C 6-10 aryl) 2. -C(O)N (5 to 12 member heteroaryl) 2. -C(O)N (4 to 12 member heterocyclic) 2. -NHC(O) (C 1-9 alkyl), -NHC(O) (C 2-6 alkenyl), -NHC(O) (C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl ...1-9 alkyl), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C 6-10 aryl), -S (5 to 12 member heteroaryl), -S (4 to 12 member heterocyclic), -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)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C-1-8 haloalkyl), -S(O) (C 6-10 aryl), -S(O) (5 to 12-membered heteroaryl), -S(O) (4 to 12-membered heterocyclic), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 ynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 6-10 aryl), -S(O) 2 (5 to 12-membered heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic), -S(O) 2NH (C 1-9 alkyl), or -S(O) 2N (C 1-9 alkyl) 2; wherein R 15. Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C6-10 aryl), -NHC(O) (5 to 12-membered heteroaryl), -NHC(O) (4 to 12-membered heterocyclic), -NHC(O)O(C 1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -S(O) 2 (5 to 12 member heteroaryl), -S(O) 2 (4 to 12 member heterocyclic), -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(C 6-10 aryl), -O(5 to 12-membered heteroaryl), -O(4 to 12-membered heterocyclol), or -O(C 1-9 alkyl). 5 to 12 heteroaryl groups substituted by one or more R 13s; C6-10 aryl groups optionally substituted with one or more R15 groups; C3-12 cycloalkyl groups optionally substituted with one or more R15 groups; 4- to 12-membered heterocyclic groups optionally substituted with one or more R15 groups; Any of the following: any 5 to 12-membered heteroaryl, C6-10 aryl, C3-12 cycloalkyl, or 4 to 12-membered heterocyclic monocyclic or bicyclic substituted with one or more R15; and 3 to 12-membered cycloalkyl or 4 to 12-membered heterocyclic monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged heterocyclic monocyclic, bicyclic, or fused bicyclic substituted with one or more R15. [R, 10 , ] [Selected from:] H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R118), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), S(O)2R16, -SF5, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1- 9-alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C6-10 aryl, 5 to 10 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16 groups; [R, 11 , ] [Selected from:] H, C1-9 alkyl, C2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 6 to 12 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16 groups; [R, 12 , ] [Selected from:] H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R118), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), S(O)2R16, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C 2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 5-12 heteroaryl, or 4-12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16 groups; [R, 13 , ] [Independently selected from:] H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R16, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1- 9-alkyl, C2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 5 to 12-membered heteroaryl, or 4 to 12-membered heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16 groups; [R, 15 , ] [Independently selected from:] H, C=O, hydroxyl, halogen, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5 to 12 member heteroaryl, 4 to 12 member heterocyclic, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -OC(O) (C1-9 alkyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkenyl) -2-6 alkynyl), -OC(O) (C 3-15 cycloalkyl), -OC(O) (C 1-8 haloalkyl), -OC(O) (C 6-10 aryl), -OC(O) (5 to 12 member heteroaryl), -OC(O) (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 alkynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12 member heteroaryl), -NH (4 to 12 member heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 alkynyl) 2, -N (C 3-15 cycloalkyl) 2. -N(C 1-8 haloalkyl) 2. -N(C 6-10 aryl) 2. -N(5 to 12-membered heteroaryl) 2. -N(h 4 to 12-membered heterocyclic) 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 ynyl), -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl) (5 to 12-membered heteroaryl), -N(C 1-9 alkyl)(4 to 12-membered heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O) (C 3-15 cycloalkyl), -C(O) (C 1-8 haloalkyl), -C(O) (C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocycloyl), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C-1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12-membered heteroaryl), -C(O)O (4 to 12-membered heterocyclic), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12-membered heteroaryl), -C(O)NH (4 to 12-membered heterocyclic), -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 alkynyl) 2. -C(O)N (C 1-8 haloalkyl) 2. -C(O)N (C 6-10 aryl) 2. -C(O)N (5 to 12 member heteroaryl) 2. -C(O)N (4 to 12 member heterocyclic) 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) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C -1-9 alkyl), -S(C 2-6 alkenyl), -S(C 2-6 ynyl), -S(C 3-15 cycloalkyl), -S(C 1-8 haloalkyl), -S(C 6-10 aryl), -S(5 to 12 heteroaryl), -S(4 to 12 heterocyclic), -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)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C 1-8 haloalkyl), -S(O)(C 6-10 aryl), -S(O)(5 to 12 member heteroaryl), -S(O)(4 to 12 member heterocycloyl), -S(O) 2(C 1-9 alkyl), -S(O) 2(C 2-6 alkenyl), -S(O) 2(C 2-6 ynyl), -S(O) 2(C 3-15 cycloalkyl), -S(O) 2(C 1-8 haloalkyl), -S(O) 2(C 6-10 aryl), -S(O) 2(5 to 12 member heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic group), -S(O)2NH (C1-9 alkyl), or -S(O)2N (C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group of R15 may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic group), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C1-15 cycloalkyl), ... -6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C -6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12-membered heteroaryl), -O (4 to 12-membered heterocyclic), or -O (C1-9 alkyl). [R , 16 , ] [Independently selected from:] H, C=O, halogen, -NO 2, -CN, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 ynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-10 aryl, 5 to 12 member heteroaryl, 4 to 12 member heterocyclic, -OH, -O (C 1-9 alkyl), -O (C 2-6 alkenyl), -O (C 2-6 ynyl), -O (C 3-15 cycloalkyl), -O (C 1-8 haloalkyl), -O (C 6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 2 ... alkyl), -NH (C 2-6 alkyl), -NH (C 2-15 cycloalkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 ynyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 1-8 haloalkyl) 2, -N (C 6-10 aryl) 2, -N (5 to 12-membered heteroaryl) 2, -N (4 to 12-membered heterocyclic) 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 ynyl), -N (C 1-9 alkyl)(C 2-6 ynyl) 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(5 to 12 heteroaryl), -N(C 1-9 alkyl)(4 to 12 heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 6-10 aryl), -C(O)(5 to 12 heteroaryl), -C(O)(4 to 12 heterocyclic), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 ynyl), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)(C 1-8 alkyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)( ...)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocycloyl), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C-6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -C(O)N (C 1-9 alkyl), -C(O)N (C 3-15 cycloalkyl), -C(O)N (C 2-6 alkenyl), -C(O)N (C 2-6 ynyl), -C(O)N (C 3-15 cycloalkyl), -C(O)N (C 1-8 haloalkyl), -C(O)N (C 6-10 aryl), -C(O)N (5 to 12 member heteroaryl), -C(O)N (4 to 12 member heterocyclic), -NHC(O)(C 1-9 alkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -NHC(O)NH (C 1-9 alkyl ... -2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 heteroaryl), -NHC(O)NH (4 to 12 heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C 6-10 aryl), -S (5 to 12 heteroaryl), -S (4 to 12 heterocyclic), -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)(C 6-10 aryl), -S(O)(NH)(5 to 12 heteroaryl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl), -S(O)(C-3-15 cycloalkyl), -S(O) (C 1-8 haloalkyl), -S(O) (C 6-10 aryl), -S(O) (5 to 12-membered heteroaryl), -S(O) (4 to 12-membered heterocyclic), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 ynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 6-10 aryl), -S(O) 2 (5 to 12-membered heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic), -S(O) 2NH (C 1-9 alkyl), or -S(O) 2N (C 1-9 alkyl) 2; Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C6-10 aryl), -NHC(O) (5 to 12-membered heteroaryl), -NHC(O) (4 to 12-membered heterocyclic), -NHC(O)O(C 1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -S(O) 2 (5 to 12 member heteroaryl), -S(O) 2 (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -O (5 to 12-membered heteroaryl), -O (4 to 12-membered heterocyclol), or -O (C 1-9 alkyl); and [R, 17 , ] [and R, 18 , ] [Independently selected from:] H, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C6-10 aryl, 5 to 12 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16.

[0007] In one embodiment of the present invention, a compound represented by formula (Ia) is provided: (Ia), Or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs, J series ; X 1 is N, C=O, CR 10, or C-(R 10) 2; X2 series N, NR 11, CR 12, or C-(R 12) 2; X3 series N or CR 13; X4 series N or CR 13; X 5 series N or CR 13; or [A] [Selected from:] C, O, N Optionally substituted with one or more R15-substituted 3 to 10-membered cycloalkyl groups; or Optionally substituted with one or more R15-substituted 4 to 11-member heterocyclic groups; When A is 0, n is 0; when A is N, n is 1; and when A is C, n is 1 or 2; [R, 1 , ] [Selected from] H, halo, CH 3, CH 2CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, CN, OR 14, C(O)-R 14, -SF 5; C(O)-N(R 17)(R 18), N(R 17)(R 18), N(R 17)C(O)-R 15, N(R 17)C(O)OR 15, N(R 7)S(O) 2(R 15), N(R 17)C(O)-N(R 17)(R 18), S(O) 2R 15, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18 Optionally substituted with one or more R15-substituted C1-5 alkyl groups; or Optionally substituted with one or more R 15-substituted C 3-10 cycloalkyl groups; Optionally, it may be a 5 to 10 heteroaryl group substituted with one or more R 15 groups; Optionally, it is a C6-10 aryl group substituted with one or more R15 groups; or Optionally, it may be substituted with one or more R15-substituted 4 to 7-member heterocyclic groups. [R, 2 , ] [Selected from] H, C1-9 alkyl, C2-9 alkenyl, or C2-9 ynyl, wherein any alkyl, alkenyl, and ynyl group may optionally be substituted with one or more R10 groups; [R, 3 , ] [and R, 4 , ] [Each independently selected from] H, C1-9 alkyl, C2-9 alkenyl, C2-9 ynyl, wherein any alkyl, alkenyl, and ynyl group may optionally be substituted with one or more R15 groups, C3-12 cycloalkyl groups optionally substituted with one or more R15 groups, C6-10 aryl groups optionally substituted with one or more R15 groups, 4-11 member heterocyclic groups optionally substituted with one or more R15 groups, or 5-10 member heteroaryl groups optionally substituted with one or more R15 groups; or [R, 2 , ] [and R, 3 , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocycle, which may optionally be substituted with one or more R15s; The 4 to 12-membered cycloalkyl or 4 to 12-membered heterocyclic monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged system is optionally substituted with one or more R15 groups; or [R, 3 , ] [and R, 4 , ] [Together with the atoms to which they are attached] form a 3- to 12-membered cycloalkyl group or a 4- to 12-membered heterocyclic group, each optionally substituted with one or more R15 groups; wherein the 3- to 12-membered cycloalkyl group or the 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each optionally substituted with one or more R15 groups; or [R, 5a , ] [、R , 5b , R , 6a , ] [、R , 6b , ] [、R , 7a , R , 7b , ] [Each group is independently selected from] H, halogen, NO 2, CN, O-R 14, C(O)-R 16, C(O)-N(R 17)(R 18), N(R 17)(R 18), N(R 17)C(O)-R 16, N(R 17)C(O)O-R 14, N(R 17)S(O) 2(R 16), -N(R 17)C(O)-N(R 18)(R 18), S(O) 2R 16, -SF 5, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18 Optionally substituted with one or more R15-substituted C1-9 alkyl groups; Optionally, C2-9 ynyl groups substituted with one or more R15 groups; Optionally, the C2-9 alkenyl group is substituted with one or more R15 groups; Optionally, it may be a 5 to 12-membered heteroaryl group substituted with one or more R 15; Optionally, the C6-10 aryl group is substituted with one or more R15 groups; Optionally substituted with one or more R15-substituted 4- to 12-member heterocyclic groups; or Optionally substituted with one or more R15-substituted C3-12 cycloalkyl groups; or [R, 5a, ] [and R, 5b , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocycle, each optionally substituted with one or more R15 groups; or [R, 6a , ] [and R, 6b , ] [Together with the atoms to which they are attached] to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocycle, each optionally substituted with one or more R15 groups; or [R7, a , ] [and R, 7b , ] [Together with the atoms to which they are attached] form a 3- to 12-membered cycloalkyl group or a 4- to 12-membered heterocyclic group, each optionally substituted with one or more R15 groups, wherein the 3- to 12-membered cycloalkyl group or the 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each optionally substituted with one or more R15 groups; or [Z] [Selected from:] -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-8 haloalkyl, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocycloyl), -OC(O) (C1-9 alkyl), -OC(O) (C2-6 alkenyl), -OC(O) (C2-6 alkenyl), -OC(O) (C2-6 ynyl), -OC(O) (C3-15 cycloalkyl), -OC(O) (C1-8 haloalkyl), -OC(O) (C -6-10 aryl), -OC(O) (5 to 12-membered heteroaryl), -OC(O) (4 to 12-membered heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 ynyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 1-8 haloalkyl) 2, -N (C 6-10 aryl) 2, -N (5 to 12-membered heteroaryl) 2. -N(h4 to 12-membered heterocyclic groups) 2. -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 ynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5 to 12-membered heteroaryl), -N(C1-9 alkyl)(4 to 12-membered heterocyclic groups), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 ynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocyclic), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocyclic), -C(O)NH2. -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -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 ynyl) 2. -C(O)N (C 1-8 haloalkyl) 2. -C(O)N (C 6-10 aryl) 2. -C(O)N (5 to 12 member heteroaryl) 2. -C(O)N (4 to 12 member heterocyclic) 2. -NHC(O) (C 1-9 alkyl), -NHC(O) (C 2-6 alkenyl), -NHC(O) (C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl ...1-9 alkyl), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 1-9 alkenyl), -6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C 6-10 aryl), -S (5 to 12 member heteroaryl), -S (4 to 12 member heterocyclic), -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)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C-1-8 haloalkyl), -S(O) (C 6-10 aryl), -S(O) (5 to 12-membered heteroaryl), -S(O) (4 to 12-membered heterocyclic), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 ynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 6-10 aryl), -S(O) 2 (5 to 12-membered heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic), -S(O) 2NH (C 1-9 alkyl), or -S(O) 2N (C 1-9 alkyl) 2; wherein R 15. Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C6-10 aryl), -NHC(O) (5 to 12-membered heteroaryl), -NHC(O) (4 to 12-membered heterocyclic), -NHC(O)O(C 1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -S(O) 2 (5 to 12 member heteroaryl), -S(O) 2 (4 to 12 member heterocyclic), -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(C 6-10 aryl), -O(5 to 12-membered heteroaryl), -O(4 to 12-membered heterocyclol), or -O(C 1-9 alkyl). 5 to 12 heteroaryl groups substituted by one or more R 13s; C6-10 aryl groups optionally substituted with one or more R15 groups; C3-12 cycloalkyl groups optionally substituted with one or more R15 groups; 4- to 12-membered heterocyclic groups optionally substituted with one or more R15 groups; Any of the following: any 5 to 12-membered heteroaryl, C6-10 aryl, C3-12 cycloalkyl, or 4 to 12-membered heterocyclic monocyclic or bicyclic substituted with one or more R15; and 3 to 12-membered cycloalkyl or 4 to 12-membered heterocyclic monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged heterocyclic monocyclic, bicyclic, or fused bicyclic substituted with one or more R15. [R, 10 , ] [Selected from:] H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R118), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), S(O)2R16, -SF5, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1- 9-alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C6-10 aryl, 5 to 10 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one or more R16 groups. [R, 11 , ] [Selected from:] H, C1-9 alkyl, C2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 6 to 12 heteroaryl, or 4 to 12 heterocyclic. Any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R 16 groups. [R, 12 , ] [Selected from:] H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R118), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), S(O)2R16, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C 2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 5-12 heteroaryl, or 4-12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16 groups. [R, 13 , ] [Independently selected from:] H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R16, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1- 9-alkyl, C2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic. Any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16 groups; [R, 15 , ] [Independently selected from:] H, C=O, hydroxyl, halogen, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5 to 12 member heteroaryl, 4 to 12 member heterocyclic, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -OC(O) (C1-9 alkyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkenyl) -2-6 alkynyl), -OC(O) (C 3-15 cycloalkyl), -OC(O) (C 1-8 haloalkyl), -OC(O) (C 6-10 aryl), -OC(O) (5 to 12 member heteroaryl), -OC(O) (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 alkynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12 member heteroaryl), -NH (4 to 12 member heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 alkynyl) 2, -N (C 3-15 cycloalkyl) 2. -N(C 1-8 haloalkyl) 2. -N(C 6-10 aryl) 2. -N(5 to 12-membered heteroaryl) 2. -N(h 4 to 12-membered heterocyclic) 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 ynyl), -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl) (5 to 12-membered heteroaryl), -N(C 1-9 alkyl)(4 to 12-membered heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O) (C 3-15 cycloalkyl), -C(O) (C 1-8 haloalkyl), -C(O) (C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocycloyl), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C-1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12-membered heteroaryl), -C(O)O (4 to 12-membered heterocyclic), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12-membered heteroaryl), -C(O)NH (4 to 12-membered heterocyclic), -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 alkynyl) 2. -C(O)N (C 1-8 haloalkyl) 2. -C(O)N (C 6-10 aryl) 2. -C(O)N (5 to 12 member heteroaryl) 2. -C(O)N (4 to 12 member heterocyclic) 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) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C -1-9 alkyl), -S(C 2-6 alkenyl), -S(C 2-6 ynyl), -S(C 3-15 cycloalkyl), -S(C 1-8 haloalkyl), -S(C 6-10 aryl), -S(5 to 12 heteroaryl), -S(4 to 12 heterocyclic), -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)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C 1-8 haloalkyl), -S(O)(C 6-10 aryl), -S(O)(5 to 12 member heteroaryl), -S(O)(4 to 12 member heterocycloyl), -S(O) 2(C 1-9 alkyl), -S(O) 2(C 2-6 alkenyl), -S(O) 2(C 2-6 ynyl), -S(O) 2(C 3-15 cycloalkyl), -S(O) 2(C 1-8 haloalkyl), -S(O) 2(C 6-10 aryl), -S(O) 2(5 to 12 member heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic group), -S(O)2NH (C1-9 alkyl), or -S(O)2N (C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group of R15 may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic group), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C1-15 cycloalkyl), ... -6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C -6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12-membered heteroaryl), -O (4 to 12-membered heterocyclic), or -O (C1-9 alkyl). [R , 16 , ] [Independently selected from:] H, C=O, halogen, -NO 2, -CN, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 ynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-10 aryl, 5 to 12 member heteroaryl, 4 to 12 member heterocyclic, -OH, -O (C 1-9 alkyl), -O (C 2-6 alkenyl), -O (C 2-6 ynyl), -O (C 3-15 cycloalkyl), -O (C 1-8 haloalkyl), -O (C 6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 2 ... alkyl), -NH (C 2-6 alkyl), -NH (C 2-15 cycloalkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 ynyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 1-8 haloalkyl) 2, -N (C 6-10 aryl) 2, -N (5 to 12-membered heteroaryl) 2, -N (4 to 12-membered heterocyclic) 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 ynyl), -N (C 1-9 alkyl)(C 2-6 ynyl) 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(5 to 12 heteroaryl), -N(C 1-9 alkyl)(4 to 12 heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 6-10 aryl), -C(O)(5 to 12 heteroaryl), -C(O)(4 to 12 heterocyclic), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 ynyl), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)(C 1-8 alkyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)( ...)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocycloyl), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -C(O)N (C1-9 alkyl) 2, -C(O)N (C3-15 cycloalkyl) 2, -C(O)N (C2-6 alkenyl) 2, -C(O)N (C2-6 ynyl) 2, -C(O)N (C3-15 cycloalkyl) 2, -C(O)N (C1-8 haloalkyl) 2, -C(O)N (C6-10 aryl) 2, -C(O)N (5 to 12 member heteroaryl) 2, -C(O)N (4 to 12 member heterocyclic) 2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -NHC(O)NH (C 1-9 alkyl ... -2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 heteroaryl), -NHC(O)NH (4 to 12 heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C 6-10 aryl), -S (5 to 12 heteroaryl), -S (4 to 12 heterocyclic), -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)(C 6-10 aryl), -S(O)(NH)(5 to 12 heteroaryl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl), -S(O)(C-3-15 cycloalkyl), -S(O) (C 1-8 haloalkyl), -S(O) (C 6-10 aryl), -S(O) (5 to 12-membered heteroaryl), -S(O) (4 to 12-membered heterocyclic), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 ynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 6-10 aryl), -S(O) 2 (5 to 12-membered heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic), -S(O) 2NH (C 1-9 alkyl), or -S(O) 2N (C 1-9 alkyl) 2; Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C6-10 aryl), -NHC(O) (5 to 12-membered heteroaryl), -NHC(O) (4 to 12-membered heterocyclic), -NHC(O)O(C 1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -S(O) 2 (5 to 12 member heteroaryl), -S(O) 2 (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -O (5 to 12-membered heteroaryl), -O (4 to 12-membered heterocyclol), or -O (C 1-9 alkyl); and [R, 17 , ] [and R, 18 , ] [Independently selected from:] H, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C6-10 aryl, 5 to 12 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more R16.

[0008] Also provided is a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a deuterated analog thereof, and a pharmaceutically acceptable excipient.

[0009] Furthermore, a method for treating cancer in a subject in need is provided, comprising administering to the patient a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Implementation

[0010] [Cross-reference to related applications]

[0011] This application claims priority to U.S. Provisional Patent Application No. 63 / 304,493, filed January 28, 2022; U.S. Provisional Patent Application No. 63 / 378,647, filed October 6, 2022; and U.S. Provisional Patent Application No. 63 / 385,303, filed November 29, 2022, the entire contents of which are incorporated herein by reference for all purposes. [I.] [definition]

[0012] The following description illustrates exemplary methods, parameters, and the like. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as an example of exemplary embodiments.

[0013] The following description illustrates exemplary methods, parameters, and the like. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as an example of exemplary embodiments.

[0014] A dash ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH₂ is attached through a carbon atom. Dashes before or after chemical groups are for convenience; chemical groups may or may not be depicted with one or more dashes without losing their usual meaning. Wavy lines drawn through the structure indicate the attachment point of a group. Unless required by chemical or structural rules, the order in which chemical groups are written or named does not indicate or imply directionality.

[0015] Wavy lines ( Indicates the attachment point.

[0016] The prefix "C uv" indicates that the following group has u to v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0017] The use of the term "about" in this document includes (and describes) embodiments of the value or parameter itself. In some embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In some still embodiments, the term "about" includes an indication of ±1%. Furthermore, the term "about X" includes a description of "X". Additionally, the singular forms "a" and "the" both include plural references unless the context clearly indicates otherwise. Thus, for example, the reference to "the compound" includes a plural of such compounds, and the reference to "the test" includes one or more tests and their equivalents known to those skilled in the art.

[0018] "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl, isobutyl, terbutyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by a chemical name or determined by a molecular formula, it can cover isomers with all positions having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), secondary butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tertiary butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "alkynyl" refers to an alkyl group containing at least one carbon-carbon linkage and having 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes groups having one linkage and one double bond.

[0021] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, secondary-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0023] "alkylthio" refers to the "alkyl-S-" group.

[0024] "Amino" refers to the group -NR yR y, where each R y is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cycloalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0025] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon atoms (i.e., C6-10 aryl), or 6 to 10 carbon atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, tyrosyl, and anthracene. However, aryl does not encompass heteroaryl groups as defined below or overlap with them in any way. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group.

[0026] "Cyano" refers to the -CN group.

[0027] "Keto" refers to the C=O group.

[0028] "Carbamoyl" refers to both "O-carbamoyl" and "N-carbamoyl". O-carbamoyl refers to the group –OC(O)NR yR z, and N-carbamoyl refers to the group -NR yC(O)OR z, where R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each may be optionally substituted.

[0029] "Carboxyl" refers to -C(O)OH.

[0030] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent; each can be optionally substituted, as defined herein.

[0031] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" also includes cycloalkenyl (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0032] "Halogen" or "halo" includes fluorine, chloro, bromine, and iodine groups. "Haloalkyl" refers to a non-branched or branched alkyl group in which one or more hydrogen atoms have been halogenated, as defined above. For example, in the case where residues are substituted with more than one halogen, it can be designated by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be, but are not required to be, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0033] "Heteroalkyl" means an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein the R-series hydrogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic groups may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, wherein the R-series hydrogen, alkyl, aryl, aralkyl, heteroalkyl, or heteroaryl groups may be optionally substituted. As used herein, heteroalkyl groups include 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.

[0034] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls include 1 to 20 cyclic carbon atoms (i.e., C1-20 heteroaryls), 3 to 12 cyclic carbon atoms (i.e., C3-12 heteroaryls), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryls); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryls include pyrimidinyl, purine, pyridinyl, and thiazolyl groups. Benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl, and imidazo[1,5-a]pyridyl, wherein the heteroaryl group can be bonded via any ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass aryl groups as defined above or overlap thereof.

[0035] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated cyclic alkyl group in which one or more heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bicyclic heterocyclic groups, bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be monocyclic or polycyclic, where polycyclic groups can be fused, bridged, or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of its attachment manner (i.e., it can be bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic is intended to encompass any non-aromatic ring containing at least one heteroatom, which can be fused to an aryl or heteroaryl ring, regardless of its attachment to the rest of the molecule. As used herein, heterocyclic groups have 2 to 20 ring atoms (i.e., 4 to 20-membered heterocyclic groups), 2 to 10 ring atoms (i.e., 4 to 12-membered heterocyclic groups), 4 to 10 ring atoms (i.e., 4 to 10-membered heterocyclic groups), 4 to 8 ring atoms (i.e., 4 to 8-membered heterocyclic groups), or 4 to 6 ring carbon atoms (i.e., 4 to 6-membered heterocyclic groups); they may have 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomium independently selected from nitrogen, sulfur, or oxygen. Heterocyclic groups may contain one or more C=O and / or sulfur C=O groups. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, and piperidine. alkyl, oxyalkyl, dioxanepentyl, acrylyl, acrylyl linyl, sulfur PHN, 4- to 7-membered sultam, 4- to 7-membered cyclic carbamates, 4- to 7-membered cyclic carbonates, 4- to 7-membered cyclic sulfides, and Linoyl group. As used herein, the term "bridged heterocyclyl" refers to a four- to ten-membered ring moiety having at least one or more (e.g., one or two) four- to ten-membered ring moieties connected at two non-adjacent atoms of a heterocyclyl group, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclyl groups include bicyclic and tricyclic ring systems. Also used herein, the term "spiroheterocyclyl" refers to a ring system in which a three- to ten-membered heterocyclyl group has one or more additional rings, wherein the one or more additional rings are three- to ten-membered cycloalkyl groups or three- to ten-membered heterocyclyl groups, wherein each atom of the one or more additional rings is also an atom of the three- to ten-membered heterocyclyl group. Examples of spirocyclic heterocyclic rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-C=O-1,2,3,4-tetrahydroisoquinolinyl, 1-C=O-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be linked via any ring of the fused system. As used herein, a bicyclic heterocyclic group is a heterocyclic group attached at two points to another cyclic group, wherein the other cyclic group itself can be a heterocyclic group or a carbocyclic group.

[0036] As used herein, the term "nitrogen or sulfur containing heterocyclyl" refers to a heterocyclyl moiety containing at least one nitrogen atom or at least one sulfur atom, or both nitrogen and sulfur atoms, within a ring structure. It should be understood that, in addition to nitrogen, sulfur, or combinations thereof, other heteroatoms, including oxygen, may be present. Examples of nitrogen or sulfur containing heterocyclyl groups include... linyl, sulfur linyl, thiazolyl, isothiazolyl, 1,2-Dithiolyl, piperidinyl, and piperidine pyridinyl ... Base, and similar.

[0037] "Hydroxy" refers to the group -OH. "Hydroxyalkyl" refers to a non-branched or branched alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group, as defined above.

[0038] "Nitro" refers to the group –NO 2.

[0039] "sulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0040] "alkylsulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0041] "alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or a defined group.

[0042] "Thiocyanate" – SCN.

[0043] "Thiol" refers to the group -SR, where R is a substituent or a defined group.

[0044] "ThiC=O" or "thione" refers to the group (=S) or (S).

[0045] Certain commonly used alternative chemical names may be used. For example, divalent groups such as "alkyl" and "aryl" may also be referred to as "alkylene" and "arylenyl," respectively. Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred to herein as a moiety (e.g., aralkyl), the last group mentioned contains the atoms of that moiety to which it is attached to the rest of the molecule.

[0046] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on the specified atom or group may or may not be substituted with hydrogen atoms other than hydrogen. "Optionally substituted" can be zero to the maximum possible number of substitutions, and each occurrence is independent. When the term "substituted" is used, substitution must be performed on the substituted hydrogen atom of the indicated substituent. The optional substitution may be the same as or different from the (desired) substitution.

[0047] When a part is "optionally substituted" and refers to general terms (such as any "alkyl", "alkenyl", "alkynyl", "haloalkyl", "cycloalkyl", "aryl", or "heteroaryl"), the general term may refer to any of the pre-specifically listed terms, such as (C-1-3 alkyl), (C-4-6 alkyl), -O (C-1-4 alkyl), (C-3-10 cycloalkyl), O- (C-3-10 cycloalkyl), and the like. For example, "any aryl" includes both "aryl" and "-O (aryl)" as well as examples of aryl, such as phenyl or naphthyl, and the like. Furthermore, the term "any heterocyclic" includes both "heterocyclic" and "O- (heterocyclic)" as well as examples of heterocyclic groups, such as oxonyl, tetrahydropiperanyl, N-... Linoyl, piperidinyl, and the like. In the same manner, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteroaryl)" as well as specific heteroaryl groups such as pyridine and the like.

[0048] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, compounds containing acetylamines can exist in equilibrium with imine tautomers. Regardless of the type of tautomers exhibited or the nature of the equilibrium between them, those skilled in the art will understand a compound to include both acetylamine and imine tautomers. Therefore, compounds containing acetylamines should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their acetylamine tautomers.

[0049] Any formula or structure given herein is intended to represent both unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structures shown in the formulas given herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotopically labeled compounds disclosed herein, such as those incorporating radioactive isotopes (such as 3H, 13C, and 14C). These isotopically labeled compounds can be used 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 receptor tissue distribution detection, or for the treatment of patients with radiation.

[0050] This disclosure also includes "deuterated analogues" of Formula I compounds in which one to n hydrogen atoms attached to carbon atoms are replaced with deuterium, where n represents the number of hydrogen atoms in the molecule. Such compounds can exhibit increased resistance to metabolism and can therefore be used to increase the half-life of any Formula I compound 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 using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0051] The deuterium-labeled or substituted therapeutic compounds disclosed herein may possess improved DMPK (drug metabolism and pharmacokinetics) properties regarding distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18F-labeled compounds can be used in PET or SPECT studies. The isotope-labeled compounds and their prodrugs disclosed herein can generally be prepared by performing the procedures disclosed in the following schemes or examples and preparations, and by replacing unlabeled reagents with readily available isotope-labeled reagents. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I.

[0052] The concentration of this heavier isotope (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds disclosed herein, any atom not specifically designated as a particular isotope is intended to represent 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 its naturally abundant isotopic composition. Therefore, in the compounds disclosed herein, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0053] In many cases, the compounds disclosed herein can form acid salts and / or base salts by means of the presence of amine and / or carboxyl groups or similar groups.

[0054] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials suitable for use in animal or human medicine.

[0055] The term "pharmaceutically acceptable salt" as used for 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 with inorganic acids and salts with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (especially a pharmaceutically acceptable addition salt) can be prepared according to known procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include salts of 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, salicylic acid, and the like. Similarly, medically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include (by example only) sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as 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)), dienylamines (i.e., HN(alkenyl)₂), trienylamines (i.e., N(alkenyl)₃), substituted alkenylamines (i.e., NH₂(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)₂), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)₃), mono-, di-, or tricyclic alkylamines (i.e., NH₂(alkyl)), and di- or tricyclic alkylamines (i.e., NH₂(alkyl)). 2-(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include (by way of example only) isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, etc. Piperidine Phosphates, N-ethylpiperidine, and similar compounds.

[0056] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the replacement does not exceed the normal valence of the specified atom. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, acetylated, amino, acetamyl, formamidinyl, aryl, azide, aminomethyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, C=O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar infinite structures obtained by defining substituents by an unlimited number of additional substituents (e.g., a substituted aryl group having a substituted alkyl group itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, a substituted aryl group that is consecutively substituted with two other substituted aryl groups is limited to an aryl group substituted with ((substituted aryl) substituted) aryl group. Similarly, the above definition is not intended to include prohibited substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such prohibited substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substituted element of that group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, one or more substituents may be further substituted with a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is substituted. In other embodiments, substituents may be further substituted with a halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is unsubstituted. Those skilled in the art will recognize that the substituents and other portions of compounds of the general formula herein should be selected to provide sufficiently stable compounds to provide pharmaceutically usable compounds that can be formulated into acceptable stable pharmaceutical compositions. Compounds having such stability are contemplated to fall within the scope of this invention. Those skilled in the art will understand that the foregoing definitions and any combination of substituents should not result in an inoperable species or compound.

[0057] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption delay agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any known media or agent is incompatible with the active ingredient, its use in therapeutic compositions is covered. Additional active ingredients may also be incorporated into the composition.

[0058] A "solvate" is formed through 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.

[0059] Certain commonly used alternative chemical names may be used. For example, divalent groups such as "alkyl" and "aryl" may also be referred to as "alkylene" and "arylenyl," respectively. Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred to herein as a moiety (e.g., aralkyl), the last group mentioned contains the atoms of that moiety to which it is attached to the rest of the molecule.

[0060] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on the specified atom or group may or may not be substituted with hydrogen atoms other than hydrogen. "Optionally substituted" can be zero to the maximum possible number of substitutions, and each occurrence is independent. When the term "substituted" is used, substitution must be performed on the substituted hydrogen atom of the indicated substituent. The optional substitution may be the same as or different from the (desired) substitution.

[0061] When a part is "optionally substituted" and refers to general terms (such as any "alkyl", "alkenyl", "alkynyl", "haloalkyl", "cycloalkyl", "aryl", or "heteroaryl"), the general term may refer to any of the pre-specifically listed terms, such as (C-1-3 alkyl), (C-4-6 alkyl), -O (C-1-4 alkyl), (C-3-10 cycloalkyl), O- (C-3-10 cycloalkyl), and the like. For example, "any aryl" includes both "aryl" and "-O (aryl)" as well as examples of aryl, such as phenyl or naphthyl, and the like. Furthermore, the term "any heterocyclic" includes both "heterocyclic" and "O- (heterocyclic)" as well as examples of heterocyclic groups, such as oxonyl, tetrahydropiperanyl, N-... Linoyl, piperidinyl, and the like. In the same manner, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteroaryl)" as well as specific heteroaryl groups such as pyridine and the like.

[0062] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, compounds containing acetylamines can exist in equilibrium with imine tautomers. Regardless of the type of tautomers exhibited or the nature of the equilibrium between them, those skilled in the art will understand a compound to include both acetylamine and imine tautomers. Therefore, compounds containing acetylamines should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their acetylamine tautomers.

[0063] Any formula or structure given herein is intended to represent both unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structures shown in the formulas given herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotopically labeled compounds disclosed herein, such as those incorporating radioactive isotopes (such as 3H, 13C, and 14C). These isotopically labeled compounds can be used 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 receptor tissue distribution detection, or for the treatment of patients with radiation.

[0064] This disclosure also includes "deuterated analogues" of Formula I compounds in which one to n hydrogen atoms attached to carbon atoms are replaced with deuterium, where n represents the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and can therefore be used to increase the half-life of any Formula I compound 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 using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0065] The deuterium-labeled or substituted therapeutic compounds disclosed herein may possess improved DMPK (drug metabolism and pharmacokinetics) properties regarding distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18F-labeled compounds can be used in PET or SPECT studies. The isotope-labeled compounds and their prodrugs disclosed herein can generally be prepared by performing the procedures disclosed in the following schemes or examples and preparations, and by replacing unlabeled reagents with readily available isotope-labeled reagents. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I.

[0066] The concentration of this heavier isotope (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds disclosed herein, any atom not specifically designated as a particular isotope is intended to represent 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 its naturally abundant isotopic composition. Therefore, in the compounds disclosed herein, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0067] In many cases, the compounds disclosed herein can form acid salts and / or base salts by means of the presence of amine and / or carboxyl groups or similar groups.

[0068] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials suitable for use in animal or human medicine.

[0069] The term "pharmaceutically acceptable salt" as used for 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 with inorganic acids and salts with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (especially a pharmaceutically acceptable addition salt) can be prepared according to known procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include salts of 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, salicylic acid, and the like. Similarly, medically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include (by example only) sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as 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)), dienylamines (i.e., HN(alkenyl)₂), trienylamines (i.e., N(alkenyl)₃), substituted alkenylamines (i.e., NH₂(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)₂), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)₃), mono-, di-, or tricyclic alkylamines (i.e., NH₂(alkyl)), and di- or tricyclic alkylamines (i.e., NH₂(alkyl)). 2-(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include (by way of example only) isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, etc. Piperidine Phosphates, N-ethylpiperidine, and similar compounds.

[0070] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the replacement does not exceed the normal valence of the specified atom. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, acetylated, amino, acetamyl, formamidinyl, aryl, azide, aminomethyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, C=O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar infinite structures obtained by defining substituents by an unlimited number of additional substituents (e.g., a substituted aryl group having a substituted alkyl group itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, a substituted aryl group that is consecutively substituted with two other substituted aryl groups is limited to an aryl group substituted with ((substituted aryl) substituted) aryl group. Similarly, the above definition is not intended to include prohibited substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such prohibited substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substituted element of that group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, one or more substituents may be further substituted with a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is substituted. In other embodiments, substituents may be further substituted with a halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is unsubstituted. Those skilled in the art will recognize that the substituents and other portions of compounds of the general formula herein should be selected to provide sufficiently stable compounds to provide pharmaceutically usable compounds that can be formulated into acceptable stable pharmaceutical compositions. Compounds having such stability are contemplated to fall within the scope of this invention. Those skilled in the art will understand that the foregoing definitions and any combination of substituents should not result in an inoperable species or compound.

[0071] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption delay agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any known media or agent is incompatible with the active ingredient, its use in therapeutic compositions is covered. Additional active ingredients may also be incorporated into the composition.

[0072] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption delay agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any known media or agent is incompatible with the active ingredient, its use in therapeutic compositions is covered. Additional active ingredients may also be incorporated into the composition.

[0073] A "solvate" is formed through 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. II. [combination]

[0074] Patients treated with the PARP7 inhibitors disclosed herein often exhibit diseases or conditions that 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, and the like. Therefore, one aspect of this disclosure is a method for treating cancer comprising administering a compound to a subject of need (particularly human subjects) in combination with one or more compounds that can be used to treat such diseases.

[0075] In some embodiments, the disclosed compounds 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 are administered sequentially and may be administered at different times relative to the disclosed compounds.

[0076] In some embodiments, the compounds or pharmaceutical compositions provided herein are administered together with one or more (e.g., one, two, three, or four) additional therapeutic agents. In some embodiments, additional therapeutic agents include, for example, inhibitory immune checkpoint blockers or inhibitors, stimulating immune checkpoint stimulants, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapy agents, antitumor agents, antiproliferative agents, antiangiogenic agents, anti-inflammatory agents, immunotherapeutic agents, therapeutic antigen-binding molecules (e.g., mono- and multi-specific antibodies or fragments thereof in any form, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives), bispecific antibodies, non-immunoglobulin antibody mimics (e.g., including adnectin, affibody, affilin, affimer, affitin, alphabody, anticarrier, aptamer, armadillo repeat protein (ARM), atrimer, avimer, and designed ankylosing repeat protein (DARPin). (®), fynomer, knottin, Kunitz domain peptide, monobody, and nanoCLAMP), antibody-drug conjugate (ADC), antibody-peptide conjugate, oncolytic virus, gene modifier or editor, cells containing chimeric antigen receptor (CAR) (e.g., including T-cell immunotherapies, NK-cell immunotherapies, or macrophage immunotherapies), cells containing engineered T-cell receptor (TCR-T), or any combination thereof. Descriptive Objectives

[0077] In some embodiments, one or more additional therapeutic agents include, for example, inhibitors, agonists, ligands, modulators, stimulants, blockers, activators, or inhibitors of a target (e.g., a peptide or polynucleotide), such as: 2'-5'-oligoadenylate synthase (OAS1; NCBI gene ID: 4938); 5'-3' exonuclease 1 (XRN1; NCBI gene ID: 54464); extracellular 5'-nucleotidase (NT5E, CD73; NCBI gene ID: 4907); ABL Proto-oncogene 1, non-receptor tyrosine kinases (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI gene ID: 25); absent in melanoma 2 (AIM2; NCBI gene ID: 9447); acetyl-CoA acetylated transferase 2 (ACAA2; NCBI gene ID: 10499); acid phosphatase 3 (ACP3; NCBI gene ID: 55); adenosine deamineases (ADA, ADA1; NCBI gene ID: 100); adenosine receptors (e.g., ADORA1) (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI gene ID: 134, 135, 136, 137); AKT serine / threonine kinase 1 (AKT1, AKT, PKB; NCBI gene ID: 207); alanine aminopeptidase (membrane) (ANPEP, CD13; NCBI gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI gene ID: 238); alpha fetal protein (AFP; NCBI gene ID: 174); copper-containing amine oxidases (e.g., AOC1 (DAO1), AOC2, AOC3) (VAP1); NCBI gene ID: 26, 314, 8639); androgen receptor (AR; NCBI gene ID: 367); angiopoietin (ANGPT1, ANGPT2; NCBI gene ID: 284, 285); angiotensin II receptor type 1 (AGTR1; NCBI gene ID: 185); pro-angiotensin (AGT; NCBI gene ID: 183); apolipoprotein A1 (APOA1; NCBI gene ID: 335); apoptosis-inducing factor Mitochondrial-associated 1 (AIFM1, AIF; NCBI gene ID: 9131); arachidonic acid 5-lipoxygenase (ALOX5; NCBI gene ID: 240); aspartate aminotransferase (ASPG; NCBI gene ID: 374569); astrocyte homolog 1 (ASTE1; NCBI gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI gene ID: 472); ATP-binding cassava family 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-associated proteins (BTLA, CD272; NCBI gene ID: 151888); Baculovirus-containing IAP repeat proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, ...). IAP3), BIRC5 (survivin); NCBI gene ID: 329, 330, 331, 332); basigin (OK blood type) (BSG, CD147; NCBI gene ID: 682); B-cell lymphoma 2 (BCL2; NCBI gene ID: 596); BCL2 binding component 3 (BBC3, PUMA; NCBI gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2) (BIM); Bcl-x; NCBI gene ID: 598, 10018); β3-adrenergic receptor (ADRB3; NCBI gene ID: 155); bone γ-carboxyglutamic acid protein (BGLAP; NCBI gene ID: 632); bone morphogenetic protein 10 ligand (BMP10; NCBI gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI gene ID: 623, 624); B-RAF (BRAF; NCBI gene ID: 273); breakpoint cluster region (BCR; NCBI gene ID: 613); Bromoare region And the outer domain (BET) containing bromo domain proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI gene ID: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI gene ID: 695); cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI gene ID: 1001, 1004); cancer / testicular antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI gene ID: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1). (CB1), CNR2 (CB2); NCBI gene ID: 1268, 1269); carbohydrate sulfonyltransferase 15 (CHST15; NCBI gene ID: 51363); carbonic anhydrases (e.g., CA1, CA2, CA3, CA4, CA5A, CA5B, 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) (CK2); NCBI gene ID: 1452, 1457); apoptotic proteases (e.g., CASP3, CASP7, CASP8; NCBI gene ID: 836, 840, 841, 864); catechol-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: 729230); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8). (CDw198); NCBI gene ID: 1232, 1233, 1234, 1237); CCAAT enhancer-binding protein α (CEBPA, CEBP; NCBI gene ID: 1050); Cell adhesion molecule 1 (CADM1; NCBI gene ID: 23705); Cell cycle 7 (CDC7; NCBI gene ID: 8317); Cell communication network factor 2 (CCN2; NCBI gene ID: 1490); Selenbrom (CRBN; NCBI gene ID: 51185); Checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2) (CHK2); NCBI gene ID: 1111, 11200); Cholecystokinin B receptor (CCKBR; NCBI gene ID: 887); Human chorionic gonadotropin-prolactin 1 (CSH1; NCBI gene ID: 1442); Dendritic proteins (e.g., CLDN6, CLDN18; NCBI gene ID: 9074, 51208);Cluster of differentiation markers (such as CD1A, CD1C, CD1D, CD1E, CD2, CD3α (TRA), CDβ (TRB), CDγ (TRG), CDδ (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 (CSF1R), 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 (IGF2R), 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, 104 3, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 695 5, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941; cluster proteins (CLU; NCBI gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI gene ID: 2155, 2159); type IV collagen α-chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI gene ID: 1282, 1284, 1285, 1286, 1287); collagen subfamily member 10 (COLEC10; NCBI gene ID: 10584); community stimulating factors (e.g., CSF1). (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI gene ID: 1435, 1437, 1440; complement factors (e.g., C3, C5; NCBI gene ID: 718, 727); COP9 signaling subunit 5 (COPS5; NCBI gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371; NCBI gene ID: 160364, 170482, 283420); CXC motif chemotherapeutic ligand 12 (CXCL12; NCBI gene ID: 6387); CXC motif chemotherapeutic receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI gene IDs: 2833, 3577, 3579, 7852; periodic protein D1 (CCND1, BCL1; NCBI gene ID: 595); periodic protein-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. P450 oxidoreductase (POR; NCBI gene ID: 5447); intercytokine-inducible SH2 protein (CISH; NCBI gene ID: 1154); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI gene ID: 1493); death box helicases (e.g., DDX5, DDX6, DDX58; NCBI gene ID: 1655, 1656, 23586); delta-like typical Notch ligands (e.g., DLL3, DLL4; NCBI gene ID: 10683, 54567); diablo IAP-binding mitochondrial proteins (DIABLO, SMAC; NCBI gene ID: 56616); diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI gene ID: 1606, 8525); dickkopf WNT 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); disk-based protein domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167; NCBI gene IDs: 780, 4921); DNA-dependent protein kinase (PRKDC; NCBI gene ID: 5591); DNA topoisomerases (TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI gene IDs: 7150, 7153, 7155, 7156, 8940); Dopachrome tautomerase (DCT; NCBI gene ID: 1638); Dopamine receptor D2 (DRD2; NCBI gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI gene ID: 84444); Exonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI gene ID: 5169); EMAP-like 4 (EML4; NCBI gene ID: 27436); Endothelial glycoprotein (ENG; NCBI gene ID: 2022);Endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI gene ID: 51752, 64167); enhancers of the second unit of the Zeste 2 polycomb inhibitory complex (EZH2; NCBI gene ID: 2146); pterin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI gene ID: 1969, 2041, 2042, 2043, 2044, 2045, 2050); pterin (e.g., EFNA1, EFNA4, EFNB2; NCBI gene ID: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4). (HER4); NCBI gene ID: 1956, 2064, 2065, 2066); Epithelial cell adhesion molecule (EPCAM; NCBI gene ID: 4072); Epithelial cleavage-inducing substance (EPGN; NCBI gene ID: 255324); Eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI gene ID: 1917, 1938); Eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI gene ID: 1973, 1984); Exogenous protein 1 (XP) O1; NCBI gene ID: 7514); Farnesoid X receptor (NR1H4, FXR; NCBI gene ID: 9971); Fas ligands (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); Fc fragments of Ig receptors (e.g., FCER1A, FCGRT, FCGR3A) (CD16); NCBI gene ID: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI gene ID: 83416); Fibroblast activation protein α (FAP; NCBI gene ID: 2191); Fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI gene ID: 2260, 2261, 2263, 2264); Fibroblast growth factors (e.g., FGF1 (FGF α), FGF2 (FGF β), FGF4, FGF5; NCBI gene ID: 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 ID: 2321, 2322, 2324); FMS-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI gene ID: 2323); Local 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: 2348); Forkhead box protein M1 (FOXM1; NCBI gene ID: 2305); Furrin protease (FURIN, PACE; NCBI gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI gene ID: 2534); Galactolectins (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); glutamic acid metabolite receptor 1 (GRM1; NCBI gene ID: 2911); glutamic acid oxidase (GLS; NCBI gene ID: 2744); glutathione S-transferase π (GSTP1; NCBI gene ID: 2950); glycogen synthase kinase 3β (GSK3B; NCBI gene ID: 2932); phosphatidylinositol polysaccharide 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, osteocalcin; 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 maternal imprinted transcripts (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 ID: 3309, 3315, 7184);Blood matrix oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI gene ID: 3162, 3163); heparinase (HPSE; NCBI gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI gene ID: 84868); hepatocyte growth factor (HGF; NCBI gene ID: 3082); HERV-H LTR-associated 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 ID: 3065, 9734, 51564); HRAs proto-oncogenes (GTPases) (HRAS; NCBI gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI gene ID: 2034, 3091); I-κ-B kinase (IKK β; NCBI gene ID: 3551, 3553); IKAROS family zinc fingers (IKZF1) (LYF1), IKZF3; NCBI gene ID: 10320, 22806); Immunoglobulin superfamily member 11 (IGSF11; NCBI gene ID: 152404); Indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2; NCBI gene ID: 3620, 169355); Inducible T cell costimulators (ICOS, CD278; NCBI gene ID: 29851); Inducible T cell costimulator ligands (ICOSLG, B7-H2; NCBI gene ID: 23308); Insulin-like growth factor receptors (e.g., IGF1R, IGF2R; NCBI gene ID: 3480, 3482); Insulin-like growth factors (e.g., IGF1, IGF2; NCBI gene ID: 3479, 3481); Insulin receptors (INSR, CD220; NCBI gene ID: 3643); Integrin subunits (e.g., ITGA5) (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI gene ID: 3678, 3685, 3688, 3695, 3698); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI gene ID: 3383); interleukin-1 receptor-associated 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 IDs: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI gene IDs: 3716, 3717, 3718); bradykinin-related peptidase 3 (KLK3; NCBI gene ID: 354); killer cell immunoglobulin-like receptor, Ig domain, and long cytoplasmic tail (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); kinin family member 11 (KIF11; NCBI gene ID: 3832); KiSS-1 transfer inhibitor (KISS1; NCBI gene ID: 3814);KIT proto-oncogene, receptor tyrosine kinase (KIT, C-KIT, CD117; NCBI gene ID: 3815); KRAS proto-oncogene (GTPase) (KRAS; NCBI gene ID: 3845); lactoferrin (LTF; NCBI gene ID: 4057); LCK proto-oncogene, Src family tyrosine kinase (LCK; NCBI gene ID: 3932); LDL receptor-associated 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); Connector for activated T cells (LAT; NCBI gene ID: 27040); Luteinizing growth hormone / human chorionic gonadotropin 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 ID: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI gene ID: 4067); Lymphocyte cytoplasmic protein 2 (LCP2; NCBI gene ID: 3937); Lysine demethylase 1A (KDM1A; NCBI gene ID: 23028); Lysophosphatidyl receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI gene ID: 1902); Lysine oxygenase (LOX; NCBI gene ID: 4015); Lysine oxygenase-like 2 (LOXL2; NCBI gene ID: 4017); Macrophage migration inhibitory factor (MIF, GIF; NCBI gene ID: 4282); Macrophage stimulation 1 receptor (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 ID: 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, 3133, 3134, 3135); fornix main proteins (MVP, VAULT1; NCBI gene ID: 9961); MALT1 para-apoptotic protease (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 metallopeptides (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP...). 14. MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCB I gene ID: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 43 26, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCBI gene ID: 4170); MDM2 proto-oncogene (MDM2; NCBI gene ID: 4193); p53 MDM4 regulator (MDM4; BMFS6; NCBI gene ID: 4194); Mechanotargets of rapamycin kinase (MTOR, FRAP1; NCBI gene ID: 2475); melan-A (MLANA; NCBI gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI gene ID: 4157, 4148); MER proto-oncogene, tyrosine kinase (MERTK; NCBI gene ID: 10461); mesothelin (MSLN; NCBI gene ID: 10232); MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI gene ID: 4233); methionine aminopeptidase 2 (METAP2, MAP2; NCBI gene ID: 10988); MHC type I polypeptide-related sequences (e.g., MICA, MICB; NCBI gene ID: 4277, 100507436); cleavage-activated protein kinases (e.g., MAPK1) (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 β), MAPK12;NCBI gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 819251; cleavage-activated protein kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI gene IDs: 4217, 1326); cleavage-activated protein kinase kinase 1s (MAP4K1, HPK1; NCBI gene ID: 11184); cleavage-activated protein kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7). (MEK7); NCBI gene ID: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (MPL; NCBI gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., including MUC1 / A, C, D, X, Y, Z, and REP)), MUC5AC, MUC16 (CA125); NCBI gene ID: 4582, 4586, 94025); MYC proto-oncogene, bHLH transcription factor (MYC; NCBI gene ID: 4609); myostatin (MSTN, GDF8; NCBI gene ID: 2660); myristylated alanine protein kinase C receptor (MARCKS; NCBI gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI gene ID: 4883); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI gene ID: 374383); neurotrophic factor, MAGE family member (NDN; NCBI gene ID: 4692); connective cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4) (PVRL4); NCBI gene ID: 5819, 81607); Neural cell adhesion molecule 1 (NCAM1, CD56; NCBI gene ID: 4684); Neurociliary proteins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI gene ID: 8828, 8829); Neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI gene ID: 4914, 4915, 4916); NFKB activator (NKAP; NCBI gene ID: 79576); NIMA-associated kinase 9 (NEK9; NCBI gene ID: 91754); NLR family pyoside domain 3 (NLRP3, NALP3; NCBI gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4);NCBI gene IDs: 4851, 4853, 4854, 4855); NRAS proto-oncogene (GTPase) (NRAS; NCBI gene ID: 4893); Nuclear factor κB (NFKB1, NFKB2; NCBI gene IDs: 4790, 4791); Nuclear factor, erythroblast-like 2 (NFE2L2; NRF2; NCBI gene ID: 4780); Nuclear receptor subfamily 4A member 1 (NR4A1; NCBI gene ID: 3164); Nucleolin (NCL; NCBI gene ID: 4691); Nucleolar phosphoprotein 1 (NPM1; NCBI gene ID: 4869); nucleotide-binding oligomer domain 2 (NOD2; NCBI gene ID: 64127); nudix hydrolase 1 (NUDT1; NCBI gene ID: 4521); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI gene ID: 4255); croton-like δ1 receptor (OPRD1; NCBI gene ID: 4985); ornithine decarboxylase 1 (ODC1; NCBI gene ID: 4953); C=O glutarate dehydrogenase (OGDH; NCBI gene ID: 4967); parathyroxine (PTH; NCBI gene ID: 5741); PD-L1 (CD274; NCBI gene ID: 29126); periostrin (POSTN; NCBI gene ID: 10631); peroxisome proliferation-activating receptor (e.g., PPARα) (PPARα), PPARD (PPARδ), PPARG (PPARγ); NCBI gene IDs: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI gene ID: 5728); phosphatidylinositol-4,5-bisphosphonate 3-kinase (PIK3CA (PI3Kα), PIK3CB (PI3Kβ), PIK3CD (PI3Kδ), PIK3CG (PI3Kα) γ); NCBI gene IDs: 5290, 5291, 5293, 5294; phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; 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);Plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, ...). PDGFR1); NCBI gene ID: 5156, 5159); Neural plexin B1 (PLXNB1; NCBI gene ID: 5364); Poliovirus receptor (PVR) cell adhesion molecules (PVR, CD155; NCBI gene ID: 5817); Polo-like kinase 1 (PLK1; NCBI gene ID: 5347); Poly(ADP-ribose) polymerases (e.g., PARP1, PARP2, PARP3; NCBI gene ID: 142, 10038, 10039); Polycomb protein EED (EED; NCBI gene ID: 8726); Porcupine O-acetylglucosyltransferase (PORCN; NCBI gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI gene ID: 23532); Promelanosome protein (PM EL;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); Convexin 1 (PROM1, CD133;NCBI gene ID:8842); Promyelocytic leukemia (PML;NCBI gene ID:5371); Sphingolipid-activated proteinogen (PSAP;NCBI gene ID:5660); Prostaglandin E receptor 4 (PTGER4;NCBI gene ID:5734); Prostaglandin E synthase (PTGES;NCBI gene ID:9536); Prostaglandin-endoperoxidase (PTGS1) (COX1), PTGS2 (COX2); NCBI gene ID: 5742, 5743); proteasome 20S subunit β9 (PSMB9; NCBI gene ID: 5698); protein arginine methyltransferases (e.g., PRMT1, PRMT5; NCBI gene ID: 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 receptors (PTPRB (PTPB), PTPRC (CD45R); NCBI gene ID: 5787, 5788); prothymosin α (PTMA; NCBI gene ID: 5757);Purine nucleoside phosphorylase (PNP; NCBI gene ID: 4860); purine receptor P2X7 (P2RX7; NCBI gene ID: 5027); PVR-associated immunoglobulin domain (PVRIG, CD112R; NCBI gene ID: 79037); Raf-1 proto-oncogene, serine / threonine kinase (RAF1, c-Raf; NCBI gene ID: 5894); RAR-associated orphan receptor γ (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 transcriptional co-repressor 1 (RB1; NCBI gene ID: 5925); receptor-interacting serine / threonine protein kinase 1 (RIPK1; NCBI gene ID: 8737); ret proto-oncogene (RET; NCBI gene ID: 5979); early retinoic acid transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091; retinoic acid receptor α (e.g., RARA, RARG; NCBI gene IDs: 5914, 5916); visual pigment X receptor (e.g., RXRA, RXRB, RXRG; NCBI gene IDs: 6256, 6257, 6258); Rho-related coiled-coil protein kinases (e.g., ROCK1, ROCK2; NCBI gene IDs: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-β) 1; NCBI gene ID: 6198); Ring finger protein 128 (RNF128, GRAIL; NCBI gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROS1; NCBI gene ID: 6098); Circular guide 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); Secretion coil-associated protein 2 (SFRP2; NCBI gene ID: 6423); Secretion phosphoprotein 1 (SPP1; NCBI gene ID: 6696); Secretion globulin family 1A member 1 (SCGB1A1; NCBI gene ID: 7356); Selectins (e.g., SELE, SELL (CD62L), SELP) (CD62); NCBI gene ID: 6401, 6402, 6403); Semaphorin 4D (SEMA4D; CD100; NCBI gene ID: 10507);Sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI gene ID: 27036, 27180, 89790); signal regulatory protein α (SIRPA, CD172A; NCBI gene ID: 140885); signal transducers and transcriptional activators (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI gene ID: 6772, 6774, 6776, 6777); longevity protein 3 (SIRT3; NCBI gene ID: 23410); members of the SLAM family of signaling lymphocyte activators (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8). (CD353), SLAMF9; NCBI gene ID: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI gene ID: 84189); Smoothed coil type 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), SLC44A4; NCBI gene ID: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI gene ID: 6751, 6752, 6753, 6754, 6755); sonic hedgehog protein communication molecule (SHH; NCBI gene ID: 6469); Sp1 transcription factor (SP1; NCBI gene ID: 6667); neuroamine kinases (e.g., SPHK1, SPHK2; NCBI gene ID: 8877, 568). 48); Neurolamine-1-phosphate receptor 1 (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 proto-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: 26872); Steroid sulfatase (STS; NCBI gene ID: 412);Interferon-responsive cGAMP-interacting protein-stimulating factor 1 (STING1; NCBI gene ID: 340061); superoxide dismutase 1 (SOD1, ALS1; NCBI gene ID: 6647); intercytokine signaling inhibitors (SOCS1 (CISH1), SOCS3 (CISH3); NCBI gene ID: 8651, 9021); synaptic protein 3 (SYN3; NCBI gene ID: 8224); cohesin-glycan 1 (SDC1, CD138, cohesin-glycan; NCBI gene ID: 6382); conuclear protein α (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 receptors (e.g., TACR1, TACR3; NCBI gene ID: 6869, 6870); TANK-binding kinase 1 (TBK1; NCBI gene ID: 29110); end-anchored polymerase (TNKS; NCBI gene ID: 8658); TATA box-binding protein-associated factors, RNA polymerase I subunit B (TAF1B; NCBI gene ID: 9014); T-box transcription factor T (TBXT; NCBI gene ID: 6862); TCDD-induced polymerase (A DP-ribose) polymerase (TIPARP, PAPR7; NCBI gene ID: 25976); tec protein tyrosine kinase (TEC; NCBI gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI gene ID: 7010); telomerase reverse transcriptase (TERT; NCBI gene ID: 7015); tendinin C (TNC; NCBI gene ID: 3371); three major repair exonucleases (e.g., TREX1, TREX2; NCBI gene ID: 1 1277, 11219); thrombin modulators (THBD, CD141; NCBI gene ID: 7056); thymidine kinases (e.g., TK1, TK2; NCBI gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI gene ID: 1890); thymidine nucleotide synthase (TYMS; NCBI gene ID: 7298); thyroxine receptors (THRA, THRB; NCBI gene ID: 7606, 7608); thyroid-stimulating hormone receptor (TSHR; NCBI gene ID: 7253);TNF superfamily 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); TLR 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; transferrin (TF; NCBI gene ID: 7018); transferrin receptors (TFRC, CD71; NCBI gene ID: 7037); transforming growth factors (e.g., TGFA, TGFB1; NCBI gene IDs: 7039, 7040); transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR... 3; NCBI gene ID: 7046, 7048, 7049); Transformin E7 (E7; NCBI gene ID: 1489079); Transglutaminase 5 (TGM5; NCBI gene ID: 9333); 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 for bone marrow cell expression (e.g., TREM1) (CD354), TREM2; NCBI gene ID: 54209, 54210); Nutritional proteins (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 transducers 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); tumor necrosis factor (TNF; NCBI gene ID: 7124); members of the tumor necrosis factor (TNF) receptor superfamily (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, TNFRSF13B, TNFR13C (CD268, BAFFR), TNFRSF14 (CD270, LIG ​​HTR), 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 (T USC2;NCBI gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3;BYK;NCBI gene ID: 7301); tyrosinase (TYR;NCBI gene ID: 7299); tyrosine hydroxylase (TH;NCBI gene ID: 7054); tyrosine kinase 1 with immunoglobulin-like and EGF-like domains (e.g., TIE1, TIE1;NCBI gene ID: 7075); tyrosine protein phosphatase non-receptor type 11 (PTPN11, SHP2;NCBI gene ID: 5781); ubiquitin conjugase E2 I (UBE2I, UBC9; NCBI gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI gene ID: 51377); ubiquitin-specific peptidase 7 (USP7; NCBI gene ID: 7874); ubiquitin-like modifier activator 1 (UBA1; NCBI gene ID: 7317); UL16 binding proteins (e.g., ULBP1, ULBP2, ULBP3);NCBI gene IDs: 79465, 80328, 80328; valine-containing proteins (VCP, CDC48; NCBI gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI gene ID: 7422, 7423); vimentin (VIM; NCBI gene ID: 7431); vitamin D receptor (VDR; NCBI gene ID: 7421); T cell activating inhibitor 1 containing the V-set domain (TCN1, B7-H4; NCBI gene ID: 79679); V-set immunomodulatory receptors (VSIR, VISTA, B7-H5; NCBI gene ID: 64115); WEE1 G2 checkpoint kinase (WEE1; NCBI gene ID: 7465); WRN-like RecQ helicases (WRN; RECQ3; NCBI gene ID: 7486); WT1 transcription factor (WT1; NCBI gene ID: 7490); WW domain-containing transcriptional 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 transcriptional regulator (YAP1; NCBI gene ID: 10413); ζ-chain-associated protein kinase 70 (ZAP70; NCBI gene ID: 7535).

[0078] In some embodiments, one or more additional therapeutic agents include, for example, agents targeting the following: extracellular 5'-nucleotidases (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A receptor (ADORA2A; NCBI gene ID: 135); adenosine A 2B receptor (ADORA2B; NCBI gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); intercytokinin-inducible SH2 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-associated protein (IAP, CD47; NCBI gene ID: 961); interleukin 2 (IL2; NCBI gene ID: 3558); interleukin 2 receptor (IL2RA, IL2RB, IL2RG; NCBI gene ID: 3559, 3560, 3561); Kirsten rat sarcoma virus (KRAS; NCBI gene ID: 3845; including mutations such as KRAS) G12C or G12D); cleavage-activating protein kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor cell kinase 1 (HPK1), NCBI gene ID: 11184); myeloid leukemia sequence 1 apoptosis regulator (MCL1; NCBI gene ID: 4170); phosphatidylinositol-4,5-bisphosphonate 3-kinase, enzyme catalytic subunit δ (PIK3CD; NCBI gene ID: 5293); programmed death ligand 1 (PD-L1, CD274; NCBI gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI gene ID: 3815); signal regulatory protein α (SIRPA, CD172A; NCBI gene ID: 140885) ); TCDD-inducible poly(ADP-ribose) polymerases (TIPARP, PARP7; NCBI gene ID: 25976); T-cell immune receptors with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); Trigger receptor 1 for bone marrow cell expression (TREM1; NCBI gene ID: 54210); Trigger receptor 2 for bone marrow cell expression (TREM2; NCBI gene ID: 54209); Tumor-associated calcium signaling transducers 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); Tumor necrosis factor receptor superfamily members 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); WRN-like RecQ helicases (WRN; NCBI gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI gene ID: 22807). [Illustrative Mechanism of Action] Immune checkpoint modulators

[0079] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent cellular immune escape within the tumor microenvironment. Activation or stimulation of stimulating immune checkpoints can amplify the effects of immune checkpoint inhibitors in cancer therapeutics. In some embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis, et al., Semin Immunol. (2017) 31:64–75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Regulating the suppression of T cells (Tregs) or eliminating Tregs can reduce their suppression of anti-tumor immune responses and have anti-cancer effects (e.g., reviewed in Plitas and Rudensky, Annu.Rev. Cancer Biol.(2020) 4:459-77; Tanaka and Sakaguchi, Eur.J. Immunol.(2019) 49:1140-1146).

[0080] 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), and transmembrane and immunoglobulin domain 2 (TMIGD2, CD28H; N). NCBI gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI gene ID: 8832), CD96 (NCBI gene ID: 10225), CD160 (NCBI 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 activating inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA; NCBI gene ID: 64115); Immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI gene ID: 152404); Natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI gene ID: 374383); HERV-H LTR-associated 2 (HHLA2, B7H7; NCBI gene ID: 11148); inducible T cell costimulators (ICOS, CD278; NCBI gene ID: 29851); inducible T cell costimulator ligands (ICOSLG, B7H2; NCBI gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI gene ID: 7292); TNFRSF8 (CD30; NCBI gene ID: 943), TNFSF8 (CD30L; NCB 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-associated (BTLA); NCBI gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI gene ID: 608), TNFSF13B (BAFF; NCBI gene ID: 10673); TNFRSF18 (GITR; NCBI gene ID: 8784), TNFSF18 (GITRL; NCBI gene ID: 8995); MHC type I polypeptide-associated sequence A (MICA; NCBI gene ID: 100507436); MHC type I polypeptide-associated sequence B (MICB; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 29126); Programmed cell death 1 (PDCD1, PD1, PD-1; N NCBI gene ID: 5133); Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI gene ID: 1493); CD80 (B7-1; NCBI gene ID: 941), CD28 (NCBI gene ID: 940); Connectin 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); Containing PVR-associated immunoglobulin domain (PVRIG, CD112R; NCBI gene ID: 79037); T-cell immune receptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); Containing T-cell immunoglobulin and mucin domain 4 (TIMD4; TIM4; NCBI gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI gene ID: 84868); Galactoglobulin 9 (LGALS9; NCBI gene ID: 3965); Lymphocyte activation 3 (LAG3, CD223; NCBI gene ID: 3902); Messenger lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI gene ID: 6504); Lymphocytes 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); early retinoic acid transcript 1E (RAET1E; ULBP4; NCBI gene ID: 135250); early retinoic acid transcript 1G (RAET1G; ULBP5; NCBI gene ID: 353091); early retinoic acid transcript 1L (RAET1L; ULBP6; NCBI gene ID: 154064); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1; NCBI gene ID: 3811, for example, lireuromab (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 domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI gene ID: 3802); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI gene ID: 3803); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 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); 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).

[0081] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more of one or more T-cell inhibitory immune checkpoint proteins or receptors, or with one or more inhibitors or blockers. Exemplary T-cell suppressor 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-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-associated immunoglobulin domain-containing (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galactoglobulin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three 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 costimulator (ICOS, CD278); inducible T-cell costimulator ligand (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; connexin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0082] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more of the blocking agents 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 receptors (KIRs), with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptors (KIRs), with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptors (KIRs), with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptors (KIRs), with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptors (KIRs), 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); and sialic acid-binding Ig-like lectin 7. (SIGLEC7); and sialic acid-binding 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. Exemplary NK cell-stimulating 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.

[0083] In some embodiments, one or more immune checkpoint inhibitors comprise inhibitors of proteins (e.g., antibodies or fragments thereof, or antibody mimics) of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors comprise small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors comprise inhibitors of proteins (e.g., antibodies or fragments thereof, or antibody mimics) of LAG3.

[0084] Examples of co-administerable CTLA4 inhibitors include ipilimumab, trimemumab, BMS-986218, AGEN1181, zalifrelimab (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, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28) and 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).

[0085] Examples of co-administerable PD-L1 (CD274) or PD-1 (PDCD1) inhibitors include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), and AK-103. (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimzumab (CBT-501), LZM-009, prolgolimab (BCD-100), lodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT-502, dostarlimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), envafolimab (KN-035), sintilimab (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, zimberelimab (AB122), spartalizumab (PDR-001), and compounds disclosed in WO2018195321, WO2020014643, WO2019160882, or WO2018195321, 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), TAK-252 (PD-1 / OX40L), (PD-L1 / 4-1BB), bintrafusp α)(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 lazertinib (GNS-1480; PD-L1 / EGFR).

[0086] Examples of TIGIT inhibitors that can be co-administered include tiragolumab. (RG-6058), vebolimab, dovanalimab, dovanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0087] Examples of LAG3 inhibitors that can be co-administered include leramilimab (LAG525).

[0088] Inhibition of regulatory T cell (Treg) activity or Treg elimination can reduce its suppression of anti-tumor immune responses and has anti-cancer 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 antibodies and / or fusion proteins provided herein are administered co-administered with one or more inhibitors of Treg activity or Treg elimination agents. Treg inhibition or elimination can amplify the effects of immune checkpoint inhibitors in cancer therapeutics.

[0089] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more Treg inhibitors. In some embodiments, the Treg inhibitors can inhibit Treg migration into the tumor microenvironment. In some embodiments, the Treg inhibitors can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitors can modulate cell phenotype and induce the production of pro-inflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI gene ID: 1233) antagonists and the following degraders: 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).

[0090] Examples of co-dispensable Helios degrading agents include, but are not limited to, those that can be added to the table. I-57 (Novartis) and the compounds disclosed in WO2019038717, WO2020012334, WO20200117759 and WO2021101919.

[0091] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more Treg extinction agents. In some embodiments, the Treg extinction agent is an antibody. In some embodiments, the Treg extinction antibody has antibody-dependent cytotoxicity (ADCC) activity. In some embodiments, the Treg extinction antibody system is Fc engineered to enhance ADCC activity. In some embodiments, the Treg extinction antibody system is an antibody-drug conjugate (ADC). Indicative targets of Treg excitators 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).

[0092] In some embodiments, the co-administerable Treg inhibitor or Treg eradicator comprises an antibody or antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of: 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), sialylated Lewis x (CD15s), CD27, extracellular nucleoside triphosphate diphosphate hydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit αE (ITGAE; CD103), interleukin-7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), leucine-rich repeat 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulator (ICOS; CD278), lymphocyte activation 3 (LAG3; CD223), transforming growth factor β1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T cell immune receptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), or combinations thereof.

[0093] Examples of Tregs that can be administered to eliminate anti-CCR8 antibodies 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 WO2021163064, WO2020138489, and WO2021152186.

[0094] Examples of Treg-specific anti-CCR4 antibodies that can be administered include moglicillinumab.

[0095] Suppressing, eliminating, or reprogramming unstimulated myeloid cells in the tumor microenvironment can enhance anticancer immune responses (see, for example, Binnewies et al., Nat. Med. (2018) 24(5): 541-550; WO2016049641). Exemplary targets for eliminating or reprogramming unstimulated myeloid cells include the trigger receptors TREM-1 (CD354, NCBI gene ID: 54210) and TREM-2 (NCBI gene ID: 54209) that trigger myeloid cell expression. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more myeloid cell elimination or reprogramming agents, such as anti-TREM-1 antibodies (e.g., PY159; disclosed in WO2019032624) or anti-TREM-2 antibodies (e.g., PY314; disclosed in WO2019118513). Differentiation cluster promoters or activators

[0096] In some embodiments, the antibodies and / or fusion proteins provided herein are administered co-administered with agents targeting differentiation clusters (CD) markers. Exemplary CD markers that can be co-administered include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, and tagraxofusp. (SL-401), HLA-A2402 / HLA-A0201 restricted epitope peptide vaccine, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranergene Obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivative, AGX-73, rebastinib, NMS-088, lucitinib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverembatinib dimethyl sulfonate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asunercept(APG-101), APO-010, Compounds shown in the lower row: WO2016196388, WO2016033570, WO2015157386, WO199203459, WO199221766, WO 2004080462, WO2005020921, WO2006009755, WO2007078034, WO2007092403, WO2007127317, WO2008005877, WO20121 54480, WO2014100620, WO2014039714, WO2015134536, WO2017167182, WO2018112136, WO2018112140, WO201915506 7, WO2020076105, PCT / US2019 / 063091, WO19173692, WO2016179517, WO2017096179, WO2017096182, WO2017096281, WO2018089628, WO2017096179, WO2018089628, WO2018195321, WO2020014643, WO2019160882, WO2018195321, WO20 0140307, ​​WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO20151386 00, WO2016179399, WO2016205042, WO2017178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, W O2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170, WO2020068752, 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).

[0097] In some embodiments, co-administerable CD-labeled targets include small molecule inhibitors such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, roblitinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), and ripretinib. (DCC-2618), Imatinib Mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229, Telatinib, Vorolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, Motixafortide (BL-8040), LY2510924, Burixafor (TG-0054), X4P-002, Mavorixafor (X4P-001-IO), Plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0098] In some embodiments, co-administerable CD-labeled targeting agents include small molecule agonists such as interleukin-2 receptor subunit γ, eltrombopag, rintatolimod, poly-ICLC (NSC-301463), Riboxxon, Apoxxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, resiquimod, and selgantolimod. (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0099] In some embodiments, co-administerable CD-labeled targets include antibodies such as tafasitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzartamab (MOR-202), TAK-079, TAK573, and daratumumab (DARZALEX). ®), TTX-030, selicrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, mitazalimab (JNJ-64457107), lenziluma, alemtuzuma, emactuzumab, AMG-820, FPA-008 (cabiralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simlukafusp alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatlimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, encelimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20).5) MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, lirilumab (IPH-2102), lacutamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), apamistamab (131I-BC8) (lomab-B), MEDI0562 (tavolixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006, INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, cobolimab (TSR-022), MBG-453, INCAGN-2390, and the compounds disclosed in WO2017096179, WO2017096276, WO2017096189, and WO2018089628.

[0100] In some embodiments, co-administerable CD-labeled targeting agents include cell therapies such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, lisocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), cisagenlecleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), tisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3ζ-EGFRt-expressive T cells, and CD19 / 4-1BBL armed CAR. T-cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζ T-cell, 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's lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silent IL-6 manifested cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (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-CD3ζ-EGFRt expression Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, Tezazaneluse-T, CART-19, Tezazaneluse (CTL-019)), anti-CD20 CAR T-cell therapy (non-Hodgkin's 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 gene knockout T-cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 gene 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 modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, and therapies disclosed in WO2012079000 or WO2017049166. Differentiation cluster 47 (CD47) inhibitor

[0101] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: 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 antibodies or CD47 blockers, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621.Additional illustrative anti-CD47 antibodies include CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), letaplimab (IBI-188), and lemzoparlimab. (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or disclosed in WO199727873, WO199940940, WO2002092784, WO2005044857, WO200904654 1. WO2010070047, WO2011143624, WO2012170250, WO2013109752, WO2013119714, WO2014087248, WO2015191861, WO20160229 71. WO2016023040, WO2016024021, WO2016081423, WO2016109415, WO2016141328, WO2016188449, WO2017027422, WO2017049 251. WO2017053423, WO2017121771, WO2017194634, WO2017196793, WO2017215585, WO2018075857, WO2018075960, WO201808 9508, WO2018095428, WO2018137705, WO2018233575, WO2019027903, WO2019034895, WO2019042119, WO2019042285, WO20190 Compounds in WO22470, WO2019086573, WO2019108733, WO2019138367, WO2019144895, WO2019157843, WO2019179366, WO2019184912, WO2019185717, WO2019201236, WO2019238012, WO2019241732, WO2020019135, WO2020036977, WO2020043188, and WO2020009725.In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is magnumab.

[0102] In some embodiments, CD47 inhibitors are bispecific antibodies targeting CD47, such as 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 / VEGF), 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), and TG-1801. (NI-1701), or NI-1801. SIRPα targeted agent

[0103] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following: a SIRPα target (NCBI gene ID: 140885; UniProt P78324). Examples of SIRPα targets include SIRPα inhibitors (such as AL-008, RRx-001, and CTX-5861) and anti-SIRPα antibodies (such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, and Q-1801 (SIRPα / PD-L1)). Additional SIRPα targeting agents used are described in, for example, WO200140307, ​​WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO2015138600, WO2016179399, WO2016205042, WO20 17178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170, and WO2020068752. FLT3R agonist

[0104] 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 WO2020263830. 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. TNF receptor superfamily (TNFRSF) members, agonists or activators

[0105] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more agonists of the TNF receptor superfamily (TNFRSF) members, such as one or more of the following agonists: 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: 3... 55), 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, ... 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: 8794), ...CD268, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11 D:115650), TNFRSF16 (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).

[0106] Examples of co-administerable anti-TNFRSF4 (OX40) antibodies include MEDI6469, MEDI6383, tavolicimab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0107] Examples of co-administerable anti-TNFRSF5 (CD40) antibodies include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0108] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) can be co-administered.

[0109] Examples of co-administerable anti-TNFRSF9 (4-1BB, CD137) antibodies include: urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0110] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 was co-administered.

[0111] Examples of co-administerable anti-TNFRSF18 (GITR) antibodies include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibody systems are described, for example, in WO2017096179 and WO2018089628.

[0112] Bispecific antibodies targeting members of the TNFRSF family that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), ozogonisab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), plamotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20). Bispecific T cell connector

[0113] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a bispecific T-cell adaptor (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Examples of co-administerable anti-CD3 bispecific antibodies or BiTEs 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), ozonizumab (REGN-1979; CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (blood matrix / CD3), JNJ-7564 (CD3 / blood matrix), AMG-757 (DLL3-CD3), and 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), RG6194 (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;Anti-CD3 binding bispecific molecules may or may not have an Fc, including SSTR2 / CD3, captomoxicillin (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828; CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). Depending on the specific case, anti-CD3 binding bispecific molecules may or may not have an Fc. Descriptive bispecific T-cell connectives that can be co-administered target CD3 and tumor-associated antigens as described herein, including, for example, CD19 (e.g., lantomoxicillin); 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). Bispecific and trispecific natural killer (NK) cell connectors

[0114] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with bispecific NK cell connectives (BiKE) or trispecific NK cell connectives (TriKE) (e.g., without Fc) or bispecific antibodies (e.g., with Fc) targeting: NK cell activation receptors (e.g., CD16A), C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Illustrative anti-CD16 bispecific antibodies, BiKEs, or TriKEs that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Depending on the application, anti-CD16 binding bispecific molecules may or may not have an Fc. Illustrative bispecific NK cell connectors that can be co-administered target CD16 and one or more tumor-associated antigens as described herein, including, for example, CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA type II, and FOLR1. BiKEs and TriKEs are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333–346; Fang, et al., Semin Immunol. (2017) 31:37-54. MCL1 is a regulator of apoptosis and an inhibitor of the BCL2 family member (MCL1).

[0115] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: MCL1 apoptosis regulators (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 tapoclax (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 WO2018183418, WO2016033486, and WO2017147410. SHP2 inhibitors

[0116] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: protein tyrosine phosphatase non-receptor 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 WO2018172984 and WO2017211303. Hematopoietic progenitor cell kinase 1 (HPK1) inhibitors and degrading agents

[0117] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: mitogen-activated protein kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184). Examples of hematopoietic progenitor cell kinase 1 (HPK1) inhibitors include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300. Inhibitors of apoptosis signal-regulated kinase (ASK)

[0118] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an ASK inhibitor, such as mitogen-activated protein kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO 2013112741 (Gilead Sciences). Bruton's tyrosine kinase (BTK) inhibitors

[0119] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, and spebrutinib. (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315. Cyclin-dependent kinase (CDK) inhibitors

[0120] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: 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-J3; NCBI gene ID: 1019); 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 CDK 1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, avocidib (HMR-1275, flovipridol), AT-7519, dinacilib, ibrance, FLX-925, LEE001, palbociclib, samuraciclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, simurosertib hydrate (TAK931), and TG-02. Disk-based protein domain receptor (DDR) inhibitors

[0121] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with the following inhibitors: disk-based receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI gene ID: 780); and / or disk-based receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO2013 / 034933 (Imperial Innovations). Targeting E3 conjugate ligand conjugate

[0122] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with E3-targeting conjugates. Such conjugates have a target protein binding portion and an E3-targeting conjugate (e.g., an inhibitor of apoptosis proteins (IAPs) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and surviving) E3 ubiquitin conjugate, a Von Hippel-Lindau E3 ubiquitin conjugate (VHL) conjugate, a Selenbrom E3 ubiquitin conjugate, a mouse dual microsome 2 homolog (MDM2) E3 ubiquitin conjugate) conjugate, and can be used, for example, via the ubiquitin pathway to promote or increase the degradation of the target protein. In some embodiments, the E3-targeting conjugate comprises a targeting or binding portion that targets or binds the protein described herein and an E3-targeting conjugate or binding portion. In some embodiments, the E3 conjugase ligand conjugate comprises a targeting or binding portion 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 E3 conjugase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of BTK and an E3 conjugase ligand or binding portion). See, for example, WO2018098280. In some embodiments, the E3 conjugase ligand conjugate comprises a binding portion that targets or binds to interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); rapidly accelerating fibrosarcoma (RAF, such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD protein; and an E3 conjugase ligand or binding portion. See, for example, WO2019099926, WO2018226542, WO2018119448, WO2018223909, and WO2019079701. Additional co-deployable targeting E3 conjugate ligand conjugates are described, for example, WO2018237026, WO2019084026, WO2019084030, WO2019067733, WO2019043217, WO2019043208, and WO2018144649. Histone deacetase (HDAC) inhibitors

[0123] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of histone deacetase, such as histone deacetase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include abexistat, ACY-241, AR-42, BEBT-908, belinstat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fenmicstat), entenostat, givenolacta, mosenostat, pabistat, pranostat, quinsinostat (JNJ-26481585), reminolacta, riconolacta, SHP-141, valproic acid (VAL-001), vorinostat, tenostine, remist, and entenostat. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitor

[0124] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, piperanoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Janus kinase (JAK) inhibitors

[0125] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: 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, figotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, molotinib (CYT0387), ilginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019. lysine oxidase-like protein (LOXL) inhibitors

[0126] 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 WO 2009017833 (Arresto Biosciences), WO 2009035791 (Arresto Biosciences), and WO 2011097513 (Gilead Biologics). Matrix metalloproteinase (MMP) inhibitors

[0127] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with inhibitors of matrix metallopeptidases (MMPs), such as the following inhibitors: 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), MM P14 (NCBI gene ID: 4323), MMP15 (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), cipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012027721 (Gilead Biologics). RAS and RAS pathway inhibitors

[0128] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: 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; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI gene ID: 4893) or HRAS proto-oncogene, 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 the polynucleotide (e.g., transcription inhibitors) or peptide (e.g., GTPase inhibitors) level. In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, such as inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that can be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adagrasib (MRTX-849), ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 and KRpep-2d. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 transferin, AZD-4785, siG12D-LODER™, and siG12D extracellular matrix. Exemplary co-administerable MEK inhibitors include binitinib, cobimetinib, PD-0325901, pemate, RG-7304, selmetinib, trametinib, and those described below and herein.Examples of co-administerable Raf dimer inhibitors include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Examples of co-administerable ERK inhibitors include LTT-462, LY-3214996, MK-8353, ravoxertinib, and ulixertinib. Examples of co-administerable Ras GTPase inhibitors include regoratitab. Examples of co-administerable PI3K inhibitors include idelalisib (Zydelig®), alpelisib, buparlisib, pictilisib, inavolisib (RG6114), and ASN-003. Examples of co-administerable AKT inhibitors include cauvatibub and GSK2141795. Examples of co-administerable PI3K / mTOR inhibitors include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, GSK-2126458, invoxib (RG6114), sapanisertib, ME-344, sirolimus (oral nanocrystalline formulation, for cancer), racemetyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) can be suppressed 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. Furthermore, 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. cleavage-inducing protein kinase (MEK) inhibitors

[0129] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the following inhibitors: mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include anquinolone, binitinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), alprazoseptifolia + trametinib, PD-0325901, pemate, LTT462, AS703988, CC-90003, and refatinib. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0130] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with inhibitors of phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunits, such as phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit α (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI gene ID: 5290); phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit β (PIK3CB, p110BETA, ...). PI3K, PI3KBETA, PIK3C1; NCBI gene ID: 5291); phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit γ (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphonate 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, BAY 10824391, BEZ235, bupivacaine (BKM120), BYL719 (edepicyclovir), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, and edepicyclovir (Zydelig). ®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, Regoracitabine, RP5090, RP6530, SRX3177, Taselisib, TG100115, TGR-1202 (Umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Wortmannin, ZSTK474, and described in WO2005113556 (ICOS), WO 2013 / 052699 Compounds listed in (Gilead Calistoga), WO2013116562 (Gilead Calistoga), WO2014100765 (Gilead Calistoga), WO2014100767 (Gilead Calistoga), and WO2014201409 (Gilead Sciences). Spleen tyrosine kinase (SYK) inhibitors

[0131] In some embodiments, the antibodies and / or fusion proteins provided herein are administered co-administered 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-N-yl)- (Linylphenyl)imidazo[1,2-a]pyridine -8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gousatinib (ASN-002), and those described in US8450321 (Gilead Connecticut) and US20150175616. TLR receptor agonists

[0132] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with agonists of TLR receptors (TLRs), such as agonists of 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 co-administerable TLR7 agonists include DS-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, 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 the compounds disclosed below: US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences). Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014056953 (Janssen), WO2014076221 (Janssen), WO2014128189 (Janssen), US20140350031 (Janssen), WO2014023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). The co-administerable TLR7 / TLR8 agonist is NKTR-262.Examples of co-administerable TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, ricilimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed below: US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Examples of co-administerable TLR9 agonists include AST-008, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.. Tyrosine kinase inhibitors (TKIs)

[0133] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with tyrosine kinase inhibitors (TKIs). TKIs can target receptors for epidermal growth factor (EGFR), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, sildenafil, crenolanib, dacomitinib, dasatinib, dovirtinib, E-6201, erdafitinib, erlotinib, gefitinib, giglitinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, and KX2-391. (Src), lapatinib, letatinib, lenvatinib, midotutolin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quinzatinib, ratotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR-targeting agents include neratinib, tucatinib (ONT-380), vantinib, mopotinib (TAK-788), DZD-9008, valitinib, beflutinib (ACEA-0010), EGF816 (nazatinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®), and compounds disclosed in Booth, et al., Cancer Biol Ther. 2018 Feb 1; 19(2):132-137.Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab sarotalocan (RM-1929), seribantumab, nexituzumab, depatuxizumab mafodotin (ABT-414), tomuzotuximab, depatuxizumab (ABT-806), and cetuximab. Chemotherapy

[0134] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with chemotherapy agents or anti-tumor agents.

[0135] As used herein, the term "chemotherapeutic agent / chemotherapeutic" (or "chemotherapy" in the context of treatment with a chemotherapeutic agent) is intended to include any non-protein (e.g., non-peptide) chemical compound that can be used to treat cancer. Examples of chemotherapeutic agents include, but are not limited to: alkylating agents, such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodepa, carboquone, meturedepa, and uredepa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphonamide, triethylenethiophosphonamide, and trimethylolamine; acetogenin, such as blattamethasone. Bullatacin and bullatacinone; camptothecin, including the synthetic analog topotecan; bryophytein and callystatin; CC-1065, including its synthetic analogs adozelesin, carzelesin, and bizelesin; cryptophycin, particularly cryptophycin 1 and cryptophycin 8; dolastatin; bimycin, including the synthetic analog KW-21 89 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil chlorbutyric acid, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estradiol mustard, epoxetine, dichloromethyldiethylamine (mechlorethamine), dichloromethyldiethylamine oxide hydrochloride, mycoflany, novombichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosourea, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calichimycin, especially calichimycin γII and calichimycin phiI1), dynemicin, including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related pigment proteins, enediyne antibiotic chromophores, aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, actinomycin C, carabicin, carrninomycin, carzinophilin, chromomycin, actinomycin D, danomycin, detorubicin, 6-diazo-5-sideoxy-L-leucine, doxorubicin (including N-; linyl-doxorubicin, cyano N- Linoyl-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin, pan-emodin, esorubicin, adamycin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, strepzotocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methylphenidate, etc. Aminepterin, pteropterin, and trimethopterin; purine analogs, such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, doxifluridine, enocitabine, and fluorouridine; androgen, such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergic agents such as amylase, mitotan, and trilostane; folic acid supplements such as frolinic acid; radiotherapy agents such as radium-223; trichothecene, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxoids such as TAXOL®, abraxane, TAXOTERE®, cabazitaxel, BIND-014, and tesetaxel; sabizabulin (Veru-111);Platinum analogues, such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate); Epothilone; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Leucovorin; Lonidamine; Maytansinoids such as Maytansin and Ansifen; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Pheanamet; Pirarubicin; Losoxantrone; Fluoropyrimidine; Folate; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; trabectedin; triaziquone; 2,2',2''-trichlorotriemylamine; carbamate; vindesine; dacarbazin; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiopeta; chlorambucil chlorbutamol; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methylparaben; vincristine; platinum;Etoposide (VP-16); epoxetine; mitroxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); visual pigments such as retinoic acid; capecitabine; NUC-1031; FOLFOX (folate, 5-fluorouracil, oxaliplatin); FOLFIRI (folate, 5-fluorouracil, irinotecan); FOLFOXIRI (folate, 5-fluorouracil, oxaliplatin, irinotecan); FOLFIRINOX (folate, 5-fluorouracil, irinotecan, oxaliplatin); and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated to the antibodies or any targeted agents described herein to produce antibody-drug conjugates (ADCs) or targeted drug conjugates. Antihormones

[0136] Also included in the definition of "chemotherapy agents" are anti-hormonal agents, such as anti-estrogens and selective estrogen receptor modulators (SERMs), aromatase inhibitors, anti-androgens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit the effects of hormones on tumors.

[0137] Examples of anti-estrogens and SERMs include tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene hydrochloride, LY117018, onapristone, and toremifene (FARESTON®).

[0138] Inhibitors of the aromatase enzyme regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, amylglutathione, medroxyprogesterone acetate (MEGACE®), exemestane, formestane, fazodazole, vorcicloazole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0139] Examples of anti-androgens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilumet, bicalutamide, leuprorelin, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antesis).

[0140] Examples of progesterone receptor antagonists include onasone. Additional progesterone-targeting agents include TRI-CYCLEN LO (norethindrone + ethinylestradiol), norgestimate + ethinylestradiol (Tri-Cyclen), and levonorgestrel. Anti-angiogenic agents

[0141] In some embodiments, the antibodies and / or fusion proteins provided herein are administered co-administered with an anti-angiogenic agent. Co-administerable anti-angiogenic agents include retinoids and their derivatives, methoxyestradiol, ANGIOSTATIN®, and ENDOSTATIN. ®, Regorafenib, Niculabuzolium, Suramin, Squalamine, Tissue inhibitor of metalloproteinases 1, Tissue inhibitor of metalloproteinases 2, Plasminogen activator inhibitor-1, Plasminogen activator inhibitor-2, Cartilage-derived inhibitors, Paclitaxel (albumin-bound paclitaxel), Platelet factor 4, Protamine sulfate (herring protamine), Sulfated chitin derivatives (prepared from queen crab shells), Sulfated polysaccharide peptidoglycan complex (sp-pg), Staurosporine, Matrix metabolism regulators including proline analogs such as L-acetyl-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thioproline, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridyl)-2(3h)- Zolpidem, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken inhibitor of metalloproteinases 3 (ChIMP-3), chymostatin, β-cyclodextrin tetradecyl sulfate, epomycin, fumagillin, sodium thiomalate, d-penicillamine, β-1-anticollagenase-serum, α-2-antiplasmin, bifenthrin, lobenzarit disodium, n-2-carboxyphenyl-4-chloro-o-aminebenzoate disodium or "CCA", thalidomide, angiotensin-converting steroids, carboxyamino imidazole, metalloproteinase inhibitors such as BB-94, S100A9 inhibitors such as taquimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies targeting these angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2. Examples of co-administerable anti-VEGFA antibodies include bevacizumab, vanucizumab, faricimab, dilpacimab (ABT-165; DLL4 / VEGF), or navicixizumab (OMP-305B83; DLL4 / VEGF). Anti-fibrotic agent

[0142] In some embodiments, the antibodies and / or fusion proteins provided herein are administered co-administered with an antifibrotic agent. Co-administerable antifibrotic agents include compounds such as β-aminopropionitrile (BAPN), and compounds disclosed in US4965288 relating to inhibitors of lysine oxidase and their use in treating diseases and conditions associated with abnormal collagen deposition, and compounds in US4997854 relating to inhibition of LOX for the treatment of various pathological fibrotic states, which are incorporated herein by reference. Further illustrative inhibitors are those described in US4943593 relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-propenylamine; US5021456, US5059714, US5120764, US5182297, US5252608 relating to 2-(1-naphthyloxymethyl)-3-fluoropropenylamine; and US 20040248871, which are incorporated herein by reference.

[0143] Exemplary antifibrotic agents also include primary amines that react with the carbonyl group at the active site of lysine oxidase, and more specifically those that, upon binding with the carbonyl group, produce products stabilized by resonance, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide 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 selenocysteine ​​lactone.

[0144] Other antifibrotic agents are copper chelators that may or may not penetrate cells. Exemplary compounds include indirect inhibitors, whose blocking originates from aldehyde derivatives resulting from the oxidative deamination of lysine and hydroxylysine residues by lysine oxidase. Examples include thiol amines, particularly D-penicillamine and its analogues, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetaminoethyl)dithio)butyric acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butyric acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetaminoethyl-2-acetaminoethyl thiol sulfonate, and sodium-4-mercaptobutane sulfinate trihydrate. anti-inflammatory agents

[0145] 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, but are not limited to, inhibitors of one or more of the following: argininase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (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), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (N The following are listed: CBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632), prostaglandin-endoperoxidase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin-endoperoxidase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secretory 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 cleavage-promoting protein kinase kinase 8 (MAP3K8, TPL2; NCBI gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, such as a dual inhibitor of COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, or COX-2 / 5-LOX.

[0146] Examples of co-administerable inhibitors of prostaglandin-endoperoxidase 1 (PTGS1, COX-1; NCBI gene ID: 5742) include mofezolac, GLY-230, and TRK-700.

[0147] Examples of co-administerable inhibitors of prostaglandin-endoperoxidase 2 (PTGS2, COX-2; NCBI gene ID: 5743) include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, mesosulide, romecoxib, meloxicam, vardicoxib, zaltoprofen, nimesulide, anizafen, alpracoxib, cimetidine, delacoboxib, fluimidazole, ferocoxib, mavacoxib, NS-398, pamigre, parecoxib, robencoxib, rofecoxib, evodiamine, temacoxib, and zaltoprofen. Examples of co-administerable dual COX1 / COX2 inhibitors include HP-5000, lornoxicam, trimethylamine clotrimazole, bromfenac sodium, ATB-346, and HP-5000. Examples of co-administerable dual COX-2 / carbonic anhydrase (CA) inhibitors include permacoxib and ericyclophosphamide.

[0148] Examples of co-administerable inhibitors of secretory phospholipase A2 and prostaglandin E synthase (PTGES, PGES; gene ID: 9536) include LY3023703 and GRC. 27864, and described in WO2015158204, WO2013024898, WO2006063466, WO2007059610, WO2007124589, WO2010100249, WO2010034796, WO2010034797, WO2012022793, WO2012076673, WO2012076672, WO2010034798, WO2010034799, WO2012022792, WO2009103778, WO2011048004, WO2012087771, WO2012161965, WO20 Compounds in WO2013072825, WO2014167444, WO2009138376, WO2011023812, WO2012110860, WO2013153535, WO2009130242, WO2009146696, WO2013186692, WO2015059618, WO2016069376, WO2016069374, WO2009117985, WO2009064250, WO2009064251, WO2009082347, WO2009117987, and WO2008071173. Further findings revealed that metformin inhibits the COX2 / PGE2 / STAT3 axis and can be co-administered. See, for example, Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0149] Co-administered carbonic anhydrases (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), CA9 (NCBI gene ID: 768), CA10 ( Examples of inhibitors of one or more of the following (NCBI gene IDs: 56934, 770, 771, 377677, 23632): acetazolamide, methazolam, dorzolamide, zonisamide, brinzolamide, and dichlorphenamide. Dual COX-2 / CA1 / CA2 inhibitors that can be co-administered include CG100649.

[0150] Examples of co-administerable inhibitors of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) include meclofenamic acid sodium and zilootenone.

[0151] Dual inhibitors of co-injectable soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) include the compound described in WO2015148954. Dual inhibitors of co-injectable COX-2 / SEH include the compound described in WO2012082647. Dual inhibitors of co-injectable SEH and fatty acid amide hydrolase (FAAH; NCBI gene ID: 2166) include the compound described in WO2017160861.

[0152] Examples of co-administerable inhibitors of cleavage-activated protein kinase kinase 8 (MAP3K8, tumor progression locus-2, TPL2; NCBI gene ID: 1326) include GS-4875, GS-5290, BHM-078, and the following: WO2006124944, WO2006124692, WO2014064215, WO2018005435; 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; and Hu, et al., Bioorg Med Chem Lett.(2011) 21(16):4758-61. Tumor oxygenation

[0153] In some embodiments, the antibodies and / or fusion proteins provided herein are administered co-administered with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Illustrative agents that may be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors, such as PT-2977 and PT-2385; VEGF inhibitors, such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165; and / or oxygen carrier proteins (e.g., serum nitric oxide and / or oxygen-binding protein (HNOX)), such as the OMX-302 and HNOX proteins described in WO2007137767, WO2007139791, WO2014107171, and WO2016149562. Immunotherapy agents

[0154] In some embodiments, the antibodies and / or fusion proteins provided herein are administered co-administered with immunotherapeutic agents. In some embodiments, the immunotherapeutic agent is an antibody. Examples of co-administerable immunotherapeutic agents include: abagovomab, AB308, ABP-980, adecatumumab, afutuzumab, aleemtuzumab, attumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bectumomab, and bevacizumab. mab), bivatuzumab, blinatumomab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutuzumab, cilivatuzumab, conatumumab, dace tuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, dovanizumab, drozitumab, duligotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertomerab Maxomab, Edaracizumab, Farletuzumab, Ficlatuzumab, Figitumumab, Flanvotumab, Futuximab, Ganitumab, Gemtuzumab, Girentuximab, Girentuximab, Ibritumomab, IgovomabImgatuzumab, Indatuximab, Intuzumab, Intetumumab, Ipilimumab (YERVOY) ®, MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, necitumumab, nimotuzumab, nofetumab Nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab Cyramza®, rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumabTacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, cepalimumab, and 3F8 are among the drugs used. Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0155] Exemplary therapeutic antibodies may be further labeled with or in combination with radioactive isotope particles such as indium-111, yttrium-90 (90Y-crivotuzumab), or iodine-131.

[0156] In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Illustrative ADCs that can be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimics targeting the proteins or antigens listed above and herein. Examples of co-administerable ADCs include gemtuzumab, butuximab, belantamab (e.g., belantamab mofostatin), camidanlumab (e.g., camidanlumab tecillin), trastuzumab (e.g., trastuzumab delactin; trastuzumab entacin), intuzumab, grenbutumab, anetumab, and mirvetuximab. (e.g., mivituximab / solavtansin), depertuximab, vadastuximab, labetalizumab, ladiratuzumab (e.g., ladiratuzumab / vedotin), loncastuximab (e.g., loncastuximab / tecillin), sasituzumab (e.g., sasituzumab / gavetcan), dapoxetine (e.g., dapoxetine / drutica; DS-1062);Dato-DXd), Partitusumab (e.g., Partitusumab / druticon), Rivatumumab, Indusatumab, Polatuzumab (e.g., Polatuzumab / Vidodine), Pinatuzumab, Coltuximab, Upifitamab (e.g., Upifitamab / Rilsodotin), Indracemium, Milazumab, Lovatozumab (e.g., Lovatozumab / Texacillin), Enfortumab (e.g., Enfortumab / Vidodine), Tisotumab (e.g., Tisotumab / Vidodine), Figure Tusamitamab (e.g., tuzamitamab lavanten), disitamab (e.g., disitamab vedotin), telisotuzumab, vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMGN529, 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. Co-projectable ADCs are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015–1035 and de Goeij, Current Opinion in Immunology (2016) 40:14–23.

[0157] Illustrated therapeutic agents (e.g., anticancer agents or anticancer drugs) that can bind to drug-conjugating antibodies, fragments thereof, or antibody mimics include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, maytansine or analogues thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyline (e.g., doxorubicin, doxorubicin, pan-epimycin, adamycin), pyrrolobenzodiazepine (PBD), and DNA crosslinking agent SC-DR002. (D6.5), pyruvic acid, microtubule inhibitors (MTIs) (e.g., taxane, vinblastine alkaloids, epothilone), pyrrolobenzodiazepine (PBD) or its dimer, pyruvic acid (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer agents or antitumor drugs described herein. In some embodiments, the therapeutic agent conjugated to the drug-conjugating antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog, such as irinotecan or its active metabolite SN38). In some embodiments, therapeutic agents (e.g., anticancer or antitumor agents) conjugated to the drug-conjugating antibody, its fragments, or antibody mimics include 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 small molecule inhibitors of CD274 or PDCD1 that are conjugated are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitors of CTLA4 that are conjugated include BPI-002.

[0158] In some embodiments, the co-deployable ADC may include antibodies targeting the following: tumor-associated calcium signaling transducer 2 (TROP-2; TACSTD2; EGP-1; NCBI gene ID: 4070). Exemplary anti-TROP-2 antibodies include, but are not limited to, TROP2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), drutecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), gavitecan (Sassinis), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius BioTech), LIV-2008b (LivTech / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), and 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 (Mediterranea)Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and those described in WO2020016662 (Abmart), WO2020249063 (Bio-Thera Solutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech / Chiome), EP20110783675 (Chiome), WO2015098099 (Daiichi Sankyo), WO2017002776 (Daiichi Sankyo), WO2020130125 (Daiichi Sankyo), WO2020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics / Gilead), WO2011068845 (Immunomedics / Gilead), US2016296633 (Immunomedics / Gilead), US2017021017 (Immunomedics / Gilead), US2017209594 (Immunomedics / Gilead), US2017274093 (Immunomedics / Gilead), US2018110772 (Immunomedics / Gilead), US2018185351 (Immunomedics / Gilead), US2018271992 (Immunomedics / Gilead), WO2018217227 (Immunomedics / Gilead), US2019248917 (Immunomedics / Gilead), CN111534585 (Immunomedics / Gilead), US2021093730 (Immunomedics / Gilead), US2021069343 (Immunomedics / Gilead), US8435539 (Immunomedics / Gilead), US8435529 (Immunomedics / Gilead), US9492566The following are listed: (Immunomedics / Gilead), WO2003074566 (Gilead), WO2020257648 (Gilead), US2013039861 (Gilead), WO2014163684 (Gilead), US9427464 (LivTech / Chiome), US10501555 (Abruzzo Theranostic / Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), WO2007095749 (Roche), and WO2020094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody system is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody system is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Patent Nos. 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anticancer agent linked by a linker. In some embodiments, the linker comprises the linker disclosed in USPN 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 doxorubcin (DOX), epirubicin, N- Morphylodoxorubicin (N-) linyl-DOX), cyano N- Linoyl-doxorubicin (cyano N-) The chemotherapeutic agents include linyl-DOX, 2-pyrrolidone-doxime (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lurtotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanamycin, ansamycin, and epothilone. In some embodiments, the chemotherapeutic agent portion is SN-38. In some embodiments, the antibodies and / or fusion proteins provided herein are administered co-administered with sasitrizurumab-gvitacana.

[0159] In some embodiments, the co-administerable ADC includes an antibody targeting carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1; CD66a; NCBI gene ID: 634). In some embodiments, the CEACAM1 anti-hMN-14 system (e.g., described in WO1996011013). In some embodiments, the CEACAM1-ADC is described in WO2010093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein are administered together with the CEACAM1-ADC IMMU-130.

[0160] In some embodiments, the co-administerable ADC includes an antibody targeting the MHC type II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR anti-ADC is hL243 (e.g., described in WO2006094192). In some embodiments, the HLA-DR-ADC is described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein are administered together with the HLA-DR-ADC IMMU-140. Cancer gene therapy and cell therapy

[0161] 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 inserting normal genes into cancer cells to replace mutated or altered genes; gene modification to silence mutated genes; gene methods that directly kill cancer cells; including infusing immune cells designed to replace most of the patient's own immune system to enhance the immune response against cancer cells, or activating the patient's own immune system (T cells or natural killer cells) to kill cancer cells, or finding and killing cancer cells; and gene methods that modify cell activity to further alter endogenous immune reactivity against cancer. Cell therapy

[0162] 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, co-administration of one or more of the following: natural killer (NK) cell populations, NK-T cell populations, T cell populations, intercytokine-induced killer (CIK) cell populations, macrophage (MAC) populations, tumor-infiltrating lymphocyte (TIL) populations, and / or dendritic cell (DC) populations. In some embodiments, the cell therapy involves T cell therapy, such as co-administration of α / β TCR T cell populations, γ / δ TCR T cell populations, regulatory T (Treg) cell populations, and / or TruC™ T cell populations. In some embodiments, the cell therapy involves NK cell therapy, such as co-administration of NK-92 cells. Where appropriate, the cell therapy may involve co-administration of cells intended for autologous, syngeneic, or allogeneic use.

[0163] In some embodiments, cell therapy involves co-deploying cells containing a chimeric antigen receptor (CAR). In such therapies, immune effector cell populations are engineered to express the CAR, wherein the CAR contains a tumor antigen-binding domain. In T-cell therapy, T-cell receptors (TCRs) are engineered to target tumor-derived peptides presented on the surface of tumor cells.

[0164] Regarding the structure of the CAR, in some embodiments, the 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 co-stimulatory domain, or both a primary signaling domain and a co-stimulatory domain. In some embodiments, the primary signaling domain includes a functional signaling 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.

[0165] In some embodiments, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of: CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, 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: 912), 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), PSGL1, 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.

[0166] In some embodiments, the transmembrane domain comprises the transmembrane domain of proteins selected from the group consisting of: α, β, or ζ chains of T cell receptors, 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, C D49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, 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.

[0167] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapeutic agent described herein (e.g., monospecific or multispecific antibodies or their antigen-binding fragments or antibody mimics) binds to tumor-associated antigens (TAAs). In some embodiments, tumor-associated antigens are selected from the following groups: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvll1); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)βDGIcp(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 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor β (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; delta-like 3 (DLL3); folic acid receptor α; receptor tyrosine protein kinase, ERBB2 (Her2 / neu); Mucin 1, cell surface associated (MUC1); Epidermal growth factor receptor (EGFR); Neural cell adhesion molecule (NCAM); Prostate enzyme; Prostatic acid phosphatase (PAP); Elongation factor 2 mutant (ELF2M); Pterin B2; Fibroblast activation protein α (FAP); Insulin-like growth factor 1 receptor (IGF-I receptor), Carbonic anhydrase IX (CAIX); Proteasome (protosome, macropain) subunit β-type 9 (LMP2); Glycoprotein 100 (gp100);Oncogene fusion protein (bcr-abl) composed of breakpoint cluster region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl); tyrosinase; pterin A receptor 2 (EphA2); fucose GM1; sialic acid 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-associated (TEM7R); prostate I six-transmembrane epithelial antigen (STEAP1); dense connexin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor C5 group member D (GPRCSD); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; degenerative lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); globoH glycosylceramide hexasaccharide moiety (GloboH); breast differentiation antigen (NY-BR-1); urolytic protein 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenaline receptor β3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCRγ alternating reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-1a); melanoma-associated antigen 1 (MAGE-A1); ETS translocase gene 6, located on chromosome 12p (ETV6-AML); spermin 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testicular antigen 1 (MADCT-1); melanoma cancer testicular antigen 2 (MAD-CT-2); fos-associated antigen 1; tumor protein p53 (p53); p53 mutant; prostaglandin; survivin; telomerase; prostate cancer tumor antigen 1 (PCTA-1 or galactolectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma cell apoptosis inhibitor (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosamine transferase V (NA17).Paired-box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelodysplastic virus oncogene neuroblastoma-derived homolog (MYCN); ras homolog family member C (RhoC); tyrosinase-associated protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-like binding factor (zinc finger protein) (BORIS or imprinted site regulator brother), squamous cell carcinoma antigen 3 recognized by T cells (SART3); Paired-box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchoring protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ligament 1 (RUI); renal ligament 2 (RU2); aspartate endopeptidase (legumain); human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (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 molecular-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); mucin-like hormone receptor-like 2 containing EGF-like module (EMR2); lymphocyte antigen 75 (LY75); phosphatidylinositol polysaccharide 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin λ-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen presented by the MHC.

[0168] In some embodiments, the tumor antigen is selected from 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, CD46, 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-coupled receptor, alpha-fetoprotein (AFP), angiogenesis factor, exogenous homologous binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D 1) Pterin 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, mesothelin, mouse double microsome 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinogenic fetal antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tendinin, P2-microglobulin, Fc receptor-like 5 (FcRL5).

[0169] In some embodiments, the antigen-binding domain binds to the epitope of a target or tumor-associated antigen (TAA) presented by a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer testicular antigen. In some embodiments, the cancer testicular antigen is selected from the group consisting of: spermatocyte-binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI gene ID: 84519), alpha fetal protein (AFP; AFPD, FETA, HPAFP; NCBI gene ID: 174); and kinase A anchoring protein 4 (AKAP4; AKAP). 82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI gene ID: 8852), ATPase family AAA domain 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI gene ID: 29028), centromere scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI gene ID: 57082), centrosome 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, ESO1, LAGE-2, LAGE2B, NY-ESO-1; NCBI gene ID: 1485), Cancer / Testicular Antigen 2 (CTAG2; CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B; NCBI gene ID: 30848), CCCTC-like binding factors (CTCFL; BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20).2; NCBI gene ID: 140690), catechol α2 (CTNA2; 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), Death Box Helicase 43 (DDX43; CT13, HAGE; NCBI gene ID: 55510), Developmental Pluripotency-Associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI gene ID: 151871), Fetal and Adult Testicular Manifestations 1 (FATE1; CT43, FATE; NCBI gene ID: 89885), FMR1 Neighbors (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI gene ID: 158521), HORMA Domain-Containing 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), large vortex spermatogenic transposon silencing agent (MAEL; CT128, SPATA35; NCBI gene ID: 84944), MAGE family member A1 (MAGEA1; CT 1.1 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: 9 585), NDC80 centromere complex NUF2 components (NUF2; CDCA1, CT106, NUF2R; NCBI gene ID: 83540), nuclear RNA export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI gene ID: 56001), 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), piwiRNA-mediated gene silencing 2 (PIWIL2; CT80, H ILI, 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), X-linked nucleus-associated spermin family member A1 (SPANXA1; CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A; NCB SPANX family members A2 (SPANXA2; CT11.1, CT11.3, SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC; NCBI gene ID: 728712), SPANX family members C (SPANXC; CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE; NCBI gene ID: 64663), and SPANX family members 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), synaptic complex protein 3 (SYCP3;COR1, RPRGL4, SCP3, SPGF4;NCBI gene ID:50511), intercellular bridging factor testis expression 14 (TEX14;CT113, SPGF23;NCB The study included T cell receptors (TCRs) that bind to epitopes of cancer testicular antigens presented by major histocompatibility complex (MHC) molecules, and heterodimers known in the art and applicable to the heterodimers described herein. These heterodimers included: T cell receptors (TCRs) that bind to epitopes of cancer testicular antigens presented by major histocompatibility complex (MHC) molecules, and TCR-like anti-inflammatory systems. (Note: The text also mentions gene IDs for 56155, Dp family members 3 (TFDP3; CT30, DP4, HCA661; NCBI gene ID: 51270), serine protease 50 (PRSS50; CT20, TSP50; NCBI gene ID: 29122), TTK protein kinases (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI gene ID: 7272), and zinc finger protein 165 (ZNF165; CT53, LD65, ZSCAN7; NCBI gene ID: 7718). Cancer testicular antigens associated with tumors are summarized in, for example, Gibbs, et al., Trends Cancer 2018 Oct; 4(10):701-712 and the CT database website cta.lncc.br / index.php. Exemplary TCR and TCR-like antibody systems that bind to the NY-ESO-1 epitope presented by MHC are described in, for example, Stewart-Jones, et al., Proc Natl Acad Sci USA.2009 Apr 7; 106(14):5784-8;WO2005113595, WO2006031221, WO2010106431, WO2016177339, WO2016210365, WO2017044661 , WO2017076308, WO2017109496, WO2018132739, WO2019084538, WO2019162043, WO2020086158, and WO2020086647. Indicative TCR and TCR-like anti-systems of PRAME epitopes associated with MHC are described in, for example, WO2011062634, WO2016142783, WO2016191246, WO2018172533, WO2018234319, and WO2019109821. Exemplary TCR and TCR-like anti-systems binding to epitopes of MHC-presented MAGE variants are described, for example, in WO2007032255, WO2012054825, WO2013039889, WO2013041865, WO2014118236, WO2016055785, WO2017174822, WO2017174823, WO2017174824, WO2017175006, WO2018097951, WO2018170338, WO2018225732, and WO2019204683. Exemplary TCR and TCR-like anti-systems binding to epitopes of MHC-presented alpha fetal protein (AFP) are described, for example, in WO2015011450. Exemplary TCR and TCR-like antibody systems incorporating the SSX2 epitope presented by MHC are described, for example, in WO2020063488. Exemplary TCR and TCR-like antibody systems incorporating the KK-LC-1 (CT83) epitope presented by MHC are described, for example, in WO2017189254.

[0170] Examples of cell therapy include: Algenpantucel-L, Ciprofen-T, and Rivegenlecleucel (BPX-501). US9089520, WO2016100236, 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, Imilecleucel-T, Baltaleucel-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, lentivirus-transferred huCART mesothelial cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL 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.

[0171] In some embodiments, one or more additional co-administered therapeutic agents may be classified according to their mechanism of action into, for example, the following groups: • Medications that target adenosine deaminase, such as pentostatin or cladribine; • Drugs targeting ATM, such as AZD1390; • Targeted MET agents, such as savoritinib, carmatinib, tepotinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; • Agents targeting cleavage-inducing protein kinases, such as anquinolone, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mirdametinib (PD-0325901), pimaertib, refametinib, or compounds disclosed in the following: WO2011008709, WO2013112741, WO2006124944, WO2006124692, WO2014064215, WO2018005435, 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 targeting thymidine kinase, such as aglatimagene besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or Adv-tk); • Drugs targeting the interleukin pathway, such as pegilodecakin (AM-0010) (polyethylene glycolated IL10) and CA-4948 (IRAK4 inhibitor); • Agents targeting members of the cytochrome P450 family, such as letrozole, anastrozole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); • Targeting agents for CD73, such as CD73 inhibitors (e.g., quemliclustat (AB680)) or anti-CD73 antibodies (e.g., olerulimab); • Drugs targeting DKK3, such as MTG-201; • Drugs targeting EEF1A2, such as plitidepsin; • Drugs targeting EIF4A1, such as rohinitib; • Drugs targeting endothelial glycoproteins, such as TRC105 (carotuximab); • Drugs targeting exogenous protein 1, such as eltanexor; • Agents targeting fatty acid amide hydrolases, such as the compound disclosed in WO2017160861; • Drugs targeting members of the heat shock protein 90β family, such as anlotinib; • Medications targeting lactoferrin, such as ruxotemitide (LTX-315); • Agents targeting lysine oxidase, such as compounds disclosed in US4965288, US4997854, US4943593, US5021456, US5059714, US5120764, US5182297, US5252608, or US20040248871; • Drugs targeting members of the MAGE family, such as KITE-718, MAGE-A10C796T, or MAGE-A10 TCR; • Targeted agents for MDM2, such as ALRN-6924, CMG-097, milademetan monotosylate monohydrate (DS-3032b), or AMG-232; • Drugs targeting MDM4, such as ALRN-6924; • Drugs targeting melan-A, such as MART-1 F5 TCR with engineered PBMCs; • Drugs targeting mesothelin, such as CSG-MESO or TC-210; • Drugs targeting METAP2, such as M8891 or APL-1202; • Drugs targeting NLRP3, such as BMS-986299; • Medications that target glutaric acid dehydrogenase, such as devimistat (CPI-613); • Medications that target placental growth factors, such as aflibercept; • Agents targeting SLC10A3, such as compounds disclosed in WO2015148954, WO2012082647, or WO2017160861; • Agents targeting transforming growth factor α (TGFα), such as the compound disclosed in WO2019103203; • Drugs targeting the tumor protein p53, such as kevetrin (a stimulant); • Drugs that target vascular endothelial growth factor A, such as aflibercept; • Drugs that target the vascular endothelial growth factor receptor, such as fruquintinib or MP0250; • Targeted drugs for VISTA, such as CA-170 or HMBD-002; • Targeting agents for WEE1, such as adavosertib (AZD-1775); • Small molecule inhibitors targeting ABL1, such as imatinib, rebastinib, asciminib, or ponatinib (ICLUSIG®); • Small molecule antagonists targeting adenosine receptors, such as CPI-444, AZD-4635, preladenant, etrumadenant (AB928), or PBF-509; • Small molecule inhibitors targeting arachidonic acid 5-lipoxygenase, such as meclofenamate sodium or zileuton; • Small molecule inhibitors targeting ATR serine / threonine kinases, such as BAY-937, ceralasertib (AZD6738), AZD6783, VX-803, or VX-970 (berzosertib); • Small molecule inhibitors targeting AXL receptor tyrosine kinase, such as bemcentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as (S)-6-amino-9-(1-(but-2-ynylpyrrolidone)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, poseltinib (HM71224), ibrutinib (Imbruvica), M-2951 (evobrutinib), tirabrutinib (ONO-4059), and rilzabrutinib. (PRN-1008), spebrutinib (CC-292), vecabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; • Small molecule inhibitors targeting the neurotrophic receptor tyrosine kinase, such as larotrectinib, entrectinib, or selitrectinib (LOXO-195); • Small molecule inhibitors targeting the ROS proto-oncogene 1 receptor tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; • Small molecule inhibitors of non-receptor tyrosine kinases that target the SRC proto-oncogene, such as VAL-201, tirbanibulin (KX2-391), or ilginatinib maleate (NS-018); • Small molecule inhibitors targeting B-cell lymphoma 2, such as navitoclax (ABT-263), venetoclax (ABT-199, RG-7601), or AT-101 (gossypol); • Small molecule inhibitors targeting the bromo domain and its outer domain (BET) containing bromo domain 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), mivebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829; • Small molecule inhibitors targeting carbohydrate sulfonyltransferase 15, such as STNM-01; • Small molecule inhibitors targeting carbonic anhydrase, such as polmacoxib, acetazolamide, or methazolamide; • Small molecule inhibitors targeting catechol-β1, such as CWP-291 or PRI-724; • Small molecule antagonists targeting the CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Vekvir); • Small molecule antagonists targeting CXC motif chemokine receptors (e.g., CXCR4), such as blixafortide; • Small molecule inhibitors targeting cereblon, such as avadomide (CC-122), CC-92480, CC-90009, or iberdomide; • Small molecule inhibitors targeting checkpoint kinase 1, such as SRA737; • Small molecule inhibitors targeting complement components, such as Imprime PGG (Biothera Pharmaceuticals); • Small molecule inhibitors targeting CXC motif chemokine ligands (e.g., CXCL12), such as pegylated pegol (NOX-A12); • Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; • Small molecule inhibitors targeting death box helicase 5, such as supinoxin (RX-5902); • Small molecule inhibitors targeting DGK, such as those described in WO2021130638; • Small molecule inhibitors that target diablo IAP binding to mitochondrial proteins, such as BI-891065; • Small molecule inhibitors targeting dihydrofolate reductase, such as pralatrexate 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-associated coiled-coil protein kinases, such as AT13148 or KD025; • Small molecule inhibitors targeting DNA topoisomerases, such as irinotecan, firtecan pegol, or amrubicin; • Small molecule inhibitors targeting dopamine receptor D2, such as ONC-201; • Small molecule inhibitors targeting DOT1-like histone lysine methyltransferases, such as pinometostat (EPZ-5676); • Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497; • Small molecule inhibitors targeting fatty acid synthases, such as TVB-2640 (Sagimet Biosciences); • Small molecule inhibitors targeting fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144); • Small molecule inhibitors targeting focal adhesion kinase (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098; • Small molecule inhibitors targeting folate receptor 1, such as pralatrexate; • Small molecule inhibitors targeting FOXM1, such as thiomycin; • Small molecule inhibitors targeting galectin 3, such as belapectin (GR-MD-02); • Small molecule antagonists targeting glucocorticoid receptors, such as relacorilant (CORT-125134); • Small molecule inhibitors targeting glutamate, including but not limited to CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); • Small molecule inhibitors targeting GNRHR, such as elagolix, relugolix, or degarelix; • Small molecule inhibitors targeting EPAS1, such as belzutifan (PT-2977 (Merck & Co.)); • Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)), such as the restricted evanib (ivosidenib) (AG-120), vorasidenib (AG-881) (DH1 and IDH2), IDH-305, or enasidenib (AG-221); • Small molecule inhibitors targeting lysine demethylase 1A, such as CC-90011; • Small molecule inhibitors targeting the MAPK interaction serine / threonine kinase, such as tomisartinib (eFT-508); • Small molecule inhibitors targeting the Notch receptor, such as AL-101 (BMS-906024); • Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as volasertib or onvansertib; • Small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), rucaparib, 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-aminobenzoylamine, or CK-102; • Small molecule inhibitors targeting polycomb protein EED, such as MAK683; • Small molecule inhibitors targeting porcupine O-acetylglucosyltransferase, such as WNT-974; Small molecule inhibitors targeting prostaglandin-endoperoxidase synthase, such as HP-5000, lornoxicam, trimethylamine clotrimazole, bromfenac sodium, otenaproxesul (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, reconstituted celecoxib (DRGT-46), AAT-076, mesuoshuli, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, and nimesulide. mesulide, anitrazefine, apricoxib, cimicoxib, deracoxib, flumizole, firocoxib, mavacoxib, pamigrel, parecoxib, robenacoxib, rofecoxib, rutecarpine, tilmacoxib, zaltoprofen, or imrecoxib; • Small molecule inhibitors targeting 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 WO2018172984 or WO2017211303; • Small molecule antagonists targeting retinoic acid receptors, such as tamibarotene (SY-1425); • Small molecule inhibitors targeting ribosomal protein S6 kinase B1, such as MSC2363318A; • Small molecule inhibitors targeting S100 calcium-binding protein A9, such as tasquinimod; • Small molecule inhibitors targeting selectin E, such as uproleselan sodium (GMI-1271); • Small molecule inhibitors targeting SF3B1, such as H3B-8800; • Small molecule inhibitors targeting longevity protein 3, such as YC8-02; • Small molecule inhibitors targeting SMO, such as sonidegib (Odomzo®, formerly LDE-225), vismodegib (GDC-0449), glasdegib (PF-04449913), itraconazole, or patidegib and taladegib; • Small molecule antagonists targeting somatostatin receptors, such as OPS-201; • Small molecule inhibitors targeting neurolamine kinase 2, such as opaganib (Yeliva®, ABC294640); • Small molecule inhibitors targeting STAT3, such as napabucasin (BBI-608); • Small molecule inhibitors targeting end-anchored polymerases, such as G007-LK or stampare (2X-121 (e-7499)); • Small molecule inhibitors targeting TGFBR1, such as galunisertib and PF-06952229; • Small molecule inhibitors targeting thymidine synthase, such as idetrexed (ONX-0801); • Small molecule inhibitors targeting the tumor protein p53, such as CMG-097; • Small molecule inhibitors targeting valine-containing proteins, such as CB-5083; • Small molecule inhibitors targeting WT1, such as ombipepimut-S (DSP-7888); • Small molecule agonists targeting adenosine receptors, such as namodenoson (CF102); • Small molecule agonists targeting asparaginase, such as cristaspase (Erwinase®), GRASPA (ERY-001, ERY-ASP), calaspargase pegol, or pegaspargase; • Small molecule agonists targeting CCAAT enhancer-binding protein α, such as MTL-501; • Targeting small molecule agonists of the cytochrome P450 family, such as mitotane; • Small molecule agonists targeting DexD / H box helicase 58, such as RGT-100; • Small molecule agonists targeting GNRHR, such as leuprorelin acetate, leuprorelin acetate sustained-release stockpile (ATRIGEL), triptorelin pamoate, or goserelin acetate; • Small molecule agonists targeting GRB2, such as prexigebersen (BP1001); • Small molecule agonists targeting NFE2L2, such as omaveloxolone (RTA-408); • Small molecule agonists targeting NOD2, such as mifamurtide (liposomes); • Small molecule agonists targeting the RAR-associated orphan receptor γ, such as cintirorgon (LYC-55716); • Small molecule agonists that target the retinoic acid receptor (RAR), 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 di-AMP; • Small molecule agonists that target thyroid hormone receptor β, such as levothyroxine sodium; • Small molecule agonists targeting tumor necrosis factor, such as tasonermin; • Antisense agents targeting the 5th repeat of baculovirus IAP, such as EZN-3042; • Antisense agents targeting GRB2, such as preceptone; • Antisense agents targeting heat shock protein 27, such as apatorsen; • Antisense agents targeting STAT3, such as danvatirsen (IONIS-STAT3-2.5Rx); • Gene therapy targeting the CC motif chemokine receptor, such as SB-728-T; • Gene therapies targeting interleukins, such as EGENE-001, tavokinogene telseplasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or mDNA-55; • Antibodies targeting cladibin 18, such as claudiximab; • Antibodies targeting cluster proteins, such as AB-16B5; • Antibodies targeting complement components, such as ravulizumab (ALXN-1210); • Antibodies targeting CXC motif chemokine ligands, such as BMS-986253 (HuMax-Inflam); • Antibodies targeting delta-like Notch ligand 4 (DLL4), such as demcizumab and navicixizumab (DLL4 / VEGF); • Antibodies targeting EPH receptor A3, such as non-bazizumab (KB-004); • Antibodies targeting epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845); • Antibodies targeting fibroblast growth factors, such as GAL-F2 and B-701 (vofatamab); • Antibodies targeting hepatocyte growth factor, such as MP-0250; • Antibodies targeting interleukins, such as canakinumab (ACZ885), geovokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), situximab, or tocilizumab; • Antibodies targeting LRRC15, such as ABBV-085 or cusatuzumab (ARGX-110); • Antibodies targeting mesothelin, such as BMS-986148, SEL-403, or anti-MSLN-MMAE; • Antibodies that target myostatin, such as landogrozumab; • Antibodies targeting the Notch receptor, such as tarextumab; • Antibodies targeting TGFB1 (TGFb1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA089, or compounds disclosed in WO2019103203; • Vaccines targeting the fms-related receptor tyrosine kinase, such as HLA-A2402 / HLA-A0201 restriction epitope peptide vaccines; • Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax); • Vaccines targeting PD-L1, such as IO-120 + IO-103 (PD-L1 / PD-L2 vaccines) or IO-103; • Vaccines targeting the tumor protein p53, such as MVA-p53; • Vaccines targeting WT1, such as WT-1 analog peptide vaccines (WT1-CTL); • Cellular therapies targeting baculovirus IAP repeats 5, such as dendritic cell vaccines loaded with tumor lysate / MUC1 / survivin PepTivator; • Cellular therapies targeting carbonic anhydrase, such as DC-Ad-GMCAIX; • Cell therapies targeting CC motif chemokine receptors, such as CCR5-SBC-728-HSPC; • Cellular 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; • Cellular therapies targeting interleukins, such as CST-101; • Cellular therapies targeting KRAS, such as anti-KRAS G12D mTCR PBL; • Cellular therapies targeting MET, such as anti-cMet RNA CAR T; • Cell therapies targeting MUC16, such as JCAR-020; • PD-1-targeted cell therapies, such as PD-1 gene knockout T-cell therapy (esophageal cancer / NSCLC); • Cellular therapies targeting PRAME, such as BPX-701; • Cell therapies targeting transgenic protein E7, such as KITE-439; • Cell therapies targeting WT1, such as WT1-CTL, ASP-7517, or JTCR-016. [Example of Combination Therapy] Combination therapy for lymphoma or leukemia

[0172] Some chemotherapy agents are used to treat lymphoma or leukemia. These agents include interleukin, avodiae, amifostine trihydrate, aminocamptothecin, anti-antineoplaston A10, anti-antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, β-alethine, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), bryozoxin 1, bulsulfan, campath-1H, carboplatin, and carfilzomib (Kyprolis). ®), carmustine, caspofungin acetate, CC-5103, chlorambucil chlorbutate, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, chlorofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, diane-interleukin-toxin conjugate, dexamethasone, docetaxel, sea hare toxin 10, doxorubicin, doxorubicin Hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzatolin, alfa epoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenivel-Amin, filgrastim, frappindole, fludarabine, FR (fludarabine and rituximab), chondroitin (17AAG), hyperCVAD (high-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), epoetinamide, irinotecan hydrochloride, interferon alpha-2b, isaprilone, lenalidomide (REVLIMID®),CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), mycoflann, mesna, methamidophos, mitoxantrone hydrochloride, motexafenone, mycophenolate mofetil, nerabrine, oblimersen (GX15-070), octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), Oxaliplatin, Paclitaxel, Palbociclib (PD0332991), Pefexusine, Pegylated Liposome Doxorubicin Hydrochloride, Perifosin, Prednisolone, Prednisone, Recombinant FLT3 Ligand, Recombinant Human Thrombopoietin, Recombinant Interleukin-11, Recombinant Interleukin-12, Rituximab, R-CHOP (Rituximab and CHOP), R-CVP (Rituximab and CVP), R-FCM (Rituximab and FCM), R-ICE (Rituximab and ICE), and R MCP (rituximab and MCP), R-rocovitine (seliciclib, CYC202), saxaglastine, sildenafil citrate, simvastatin, sirolimus, styrene, tacrolimus, tanespimycin, tamsurolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifranib, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (octanilide, aniline, and oxime), vemurafenib (Zelboraf®), venetoclax (ABT-199).

[0173] One modified approach is radioimmunotherapy, in which a monoclonal antibody system is combined with radioactive isotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tosimomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

[0174] The above-mentioned therapies can complement or combine with stem cell transplantation or treatment. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole-body irradiation, stem cell infusion, bone marrow ablation 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-myeloablative allogeneic hematopoietic stem cell transplantation. Combination therapy for non-Hodgkin's lymphoma

[0175] Treatment for non-Hodgkin's lymphoma (NHL) (especially B-cell origin) includes the use of monoclonal antibodies, standard chemotherapy regimens (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, and prednisolone), all optionally including rituximab (R) and similar), radioimmunotherapy, and combinations thereof, particularly integrative antibody therapy and chemotherapy.

[0176] Examples of unconjugated monoclonal antibodies used to treat NHL / B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epazolizumab, SGN-40, and anti-CD74.

[0177] Examples of experimental antibody agents used to treat NHL / B-cell cancer include oflamumab, ha20, PRO131921, alemtuzumab, galiximumab, SGN-40, CHIR-12.12, epazolizumab, rumizumab, apolizumab, mirtuzumab, and bevacizumab.

[0178] Examples of standard chemotherapy regimens for NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

[0179] Examples of radioimmunotherapy for NHL / B-cell cancer include yttrium-90 tivamumab (ZEVALIN®) and iodine-131 tosimomab (BEXXAR®). Combination therapy for mantle cell lymphoma

[0180] Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0181] Alternative treatments for MCL include immunotherapy. One type of immunotherapy uses monoclonal antibodies such as rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual patient's tumor.

[0182] An improved approach to treating MCL is radioimmunotherapy, which combines monoclonal antibody systems with radioactive isotope particles, such as iodine-131 ticosmomab (BEXXAR®) and yttrium-90 tiemomab (ZEVALIN®). In another instance, BEXXAR® is used in conjunction with CHOP for sequential treatment.

[0183] Other treatments for 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, especially in combination with rituximab.

[0184] Another treatment approach involves administering drugs that cause Bcl-2 protein degradation and increase cancer cells’ sensitivity to chemotherapy, such as Olimerson, in combination with other chemotherapy agents.

[0185] Further treatment options include administration of mTOR inhibitors, which can lead to inhibition of cell growth and even cell death. Non-limiting examples include sirolimus, tamsuloxus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimecoxide), votacoxide, GSK-2126458, and combinations of tamsuloxus with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0186] Other recent therapies for MCL have been revealed. Examples include frappindole, palbociclib (PD0332991), R-rocavitin (selicicilib, CYC202), styrene, omeprazole (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, tamsulosin (TORISEL®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and chondrodysmycin (17 AAG). Waldenstrom's macroglobulinemia combination therapy

[0187] Therapeutic agents used to treat Waldenstrom's macroglobulinemia (WM) include interleukin, alenmab, avocetide, amifostine trihydrate, aminocamptothecin, anti-neoprothiolane A10, anti-neoprothiolane AS2-1, anti-thymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, β-aricin, and bortezomib (VELCADE). ®), bryozoxin 1, busulfan, Campasz-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, diphenhydramine-toxin conjugate, dexamethasone, docetaxel, sea haretoxin 10, doxorubicin hydrochloride, DT-PACE, enzatolin, alfa-edeotinib, epazolizumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenivelamine, filgrastim, fludarabine, ibrutinib, epoxetine, indium-111 monoclonal antibody MN-14, iodine-131 tosimomab, irinotecan hydrochloride, isapril, lymphosteroids Activated killer cells, mycoflavin, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tezagenlelucerase-t, CART-19, CTL-019), monoclonal antibody CD20, motexafenone, mycophenolate mofetil, nerabine, olimol, octreotide acetate, omega-3 fatty acid, oxaliplatin, paclitaxel, pefexine, pegylated liposomal doxorubicin hydrochloride, pentostatin, perifolfen, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, saxaglastine, sildenafil citrate (VIAGRA) ®), simvastatin, sirolimus, tacrolimus, spiramycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tepifenabil, tosimomab, ulocuplumab, vetocilizumab, vincristine sulfate, vinorelbine ditartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 tiemomab, yttrium-90 humanized epazolizumab, and any combination thereof.

[0188] Examples of therapeutic procedures used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biotherapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablation 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-myeloablative allogeneic hematopoietic stem cell transplantation. Diffuse large B-cell lymphoma (DLBCL) combination therapy

[0189] 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 listed agents for WM, and any combinations thereof, such as ICE and RICE. In some embodiments, therapeutic agents for treating DLBCL include rituximab (Rituxan®), cyclophosphamide, doxorubicin hydrochloride (hydroxydanomycin), vincristine sulfate (Oncovin®), prednisone, bendamustine, epoxetine, carboplatin, etoposide, ibrutinib, sennazumab-vitoline (piiq), bendamustine, copanlisib, lenalidomide (Revlimid®), dexamethasone, cytarabine, cisplatin, Yescarta®, Kymriah®, Polivy® (sennazumab-vitoline), BR (bendamustine (Treanda) Rituximab, gemcitabine, oxiplatin, oxaliplatin, tafatizumab, ponazumab, cyclophosphamide, or combinations thereof. In some embodiments, therapeutic agents for treating DLBCL include R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride (hydroxydanomycin) + vincristine sulfate (Oncovin®) + prednisone), rituximab + bendamustine, R-ICE (rituximab + epoxetine + carboplatin + etoposide), rituximab + lenalomide, R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara C) + cisplatin), Polivy® (ponazumab + vitoline) + BR (bendamustine (Treanda®) and rituximab (Rituxan)). R-GemOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafatitamab + lenalidomide), Tafatitamab + Revlimid®, Ponazolizumab + bendamustine, Gemcitabine + oxaliplatin, R-EPOCH (rituximab + etoposide phosphate + prednisone + vincristine sulfate (Oncovin®) + cyclophosphamide + doxorubicin hydrochloride (hydroxydanomycin)), or CHOP (cyclophosphamide + doxorubicin hydrochloride (hydroxydanomycin) + vincristine sulfate (Oncovin®) + prednisone).In some embodiments, therapeutic agents for treating DLBCL include tafatizumab, glofitamab, epcoritamab, Lonca-T (longatuximab / tecillin), debio-1562, sennazumab, Yescarta, JCAR017, ADCT-402, butuximab / vitoltin, MT-3724, odronextamab, Auto-03, Allo-501A, or TAK-007. Combination therapy for chronic lymphocytic leukemia

[0190] Treatment agents used to treat chronic lymphocytic leukemia (CLL) include chlortetracycline, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the listed agents used for WM, and combinations of chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR. High-risk myelodyplasia syndrome (HR MDS) combination therapy

[0191] Therapeutic agents for treating HR MDS include azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, donomycin, and combinations thereof. In some embodiments, combinations include cytarabine + donomycin and cytarabine + idarubicin. In some embodiments, therapeutic agents for treating HR MDS include pevonedistat, venetoclax, sabatolimab, guardactabine, regoracitabine, evanib, enoxab, cillinox, BGB324, DSP-7888, or SNS-301. Low-risk myelodyplastic syndrome (LRMDS) combination therapy

[0192] Therapeutic agents for treating LR MDS include lenalidomide, azacytidine, and combinations thereof. In some embodiments, therapeutic agents for treating LR MDS include roxadustat, luspatercept, emedasta, LB-100, or regoratitab. Combination therapy for acute myeloid leukemia (AML)

[0193] Therapeutic agents used to treat AML include cytarabine, idarubicin, danomycin, midotolin (Rydapt®), venetoclax, azacitidine, ivasidenib, giglitinib, enoxabin, low-dose cytarabine (LoDAC), mitoxantrone, fludarabine, granulocyte colony-stimulating factor, idarubicin, giglitinib (Xospata®), enoxabin (Idhifa®), ivasidenib (Tibsovo®), decitabine (Dacogen®), mitoxantrone, etoposide, gemtuzumab / orzomicin (Mylotarg®), daurismo®, and combinations thereof. In some embodiments, therapeutic agents for treating AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte-colony-stimulating factor (G-CSF), and idarubicin), cytarabine + idarubicin, cytarabine + donomycin + midotolin, venetoclax + azacitidine, cytarabine + donomycin, or MEC (mitoxantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents for treating AML include pervotadine, venetoclax, sabatolimab, eprenetapopt, or ritopramab. Combination therapy for multiple myeloma (MM)

[0194] Treatment agents for MM include lenalidomide, bortezomib, dexamethasone, dabramab (Darzalex®), pomalidomide, cyclophosphamide, carfilzomib (Kyprolis®), elotuzumab (Empliciti), and combinations thereof. In some embodiments, treatment agents for MM include RVS (lenalidomide + bortezomib + dexamethasone), RevDex (lenalidomide plus dexamethasone), CYBORD (cyclophosphamide + bortezomib + dexamethasone), Vel / Dex (bortezomib plus dexamethasone), or PomDex (pomalidomide + low-dose dexamethasone). In some embodiments, treatment agents for MM include JCARH125, TAK-573, belanumab-m, and ide-cel (CAR-T). Breast Cancer Combination Therapy

[0195] Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, atezolizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, isaprilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents for treating 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 for treating 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 for treating breast cancer include trastuzumab derutecan (Enhertu®), datobacillus derutecan (DS-1062), informumab vitolamine (Padcev®), balixafortide, ellastrant, or combinations thereof. In some embodiments, therapeutic agents for treating breast cancer include balixafortide + eribulin. Triple-negative breast cancer (TNBC) combination therapy

[0196] Therapeutic agents for treating TNBC include atezolizumab, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, therapeutic agents for treating TNBC include olaparib (Lynparza®), atezolizumab (Tecentriq®), paclitaxel (Abraxane®), eribulin, bevacizumab (Avastin®), carboplatin, gemcitabine, eribulin mesylate (Halaven®), sasitumumab-gauvitcan (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 for treating TNBC include eryaspase, cavotibub, apexib, rucapare plus nivorumab, atezolizumab plus paclitaxel plus gemcitabine plus capecitabine plus carboplatin, ipataseriti plus paclitaxel, radix lutein plus vedotin plus pembrolimab, durvalumab plus DS-8201a, and triasilib plus gemcitabine plus carboplatin. In some embodiments, therapeutic agents for treating TNBC include trastuzumab derutecan (Enhertu®), datobacillus derutecan (DS-1062), infusorumb vedotin (Padcev®), basafotazone, adagloxad simolenin, lenipramazine-s (NeuVax®), nivolumab (Opdivo®), rucapare, toripalimab (Tuoyi®), camrelizumab, calvatibub, devalumab (Imfinzi®), and combinations thereof. In some embodiments, therapeutic agents for treating TNBC include nivorumab + rucapare, bevacizumab (Avastin®) + chemotherapy, toripalimab + paclitaxel, toripalimab + albumin-bound paclitaxel, camrelizumab + chemotherapy, pembrolizumab + chemotherapy, balsaforme + eribulin, durvalumab + trastuzumab / drutecan, durvalumab + paclitaxel, or cavotibulab + paclitaxel. Bladder cancer combination therapy

[0197] Therapeutic agents for the treatment of bladder cancer include dextribumab (DS-1062), trastuzumab (Enhertu®), erdatinib, eganelisib, lenvatinib, beempegaldesleukin (NKTR-214), or combinations thereof. In some embodiments, therapeutic agents for the treatment of bladder cancer include eganelisib + nivorumab, pembrolizumab (Keytruda®) + infutuzumab + vedotin (Padcev®), nivorumab + ipilimumab, duravalumab + trimelimumab, lenvatinib + pembrolizumab, infutuzumab + vedotin (Padcev®) + pembrolizumab, and beempegaldesleukin + nivorumab. Combination therapy for colorectal cancer (CRC)

[0198] Therapeutic agents for treating CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, folate, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. In some embodiments, therapeutic agents for treating CRC include bevacizumab (Avastin®), folate, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda®), FOLFIRI, regorafenib (Stivarga®), aflibercept (Zaltrap®), cetuximab (Erbitux®), Lonsurf (Orcantas®), XELOX, FOLFOXIRI, or combinations thereof. In some embodiments, therapeutic agents for treating CRC include bevacizumab + folate + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, therapeutic agents for treating CRC include binitinib + encofenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabuxin + FOLFIRI + bevacizumab, and nivorumab + ipilimumab. Combination therapy for esophageal cancer and esophagogastric junction cancer

[0199] Therapeutic agents for the treatment of esophageal cancer and esophagogastric 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 for the treatment of gastroesophageal junction cancer (GEJ) include herceptin, cisplatin, 5-FU, ramicurimab, or paclitaxel. In some embodiments, therapeutic agents for the treatment of GEJ cancer include ALX-148, AO-176, or IBI-188. Combination therapy for gastric cancer

[0200] Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. Head and neck cancer combination therapy

[0201] Therapeutic agents used to treat head and neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivorumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0202] Therapeutic agents for the treatment of head and neck squamous cell carcinoma (HNSCC) include pembrolizumab, carboplatin, 5-FU, docetaxel, cetuximab (Erbitux®), cisplatin, nivorumab (Opdivo®), and combinations thereof. In some embodiments, therapeutic agents for the treatment of 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 for treating HNSCC include durvalumab, durvalumab + trimemumab, nivorumab + ipilimumab, rovaluecel, pembrolizumab, pembrolizumab + epipodil, GSK3359609 + pembrolizumab, lenvatinib + pembrolizumab, refulimab, refulimab + ennobituzumab, ADU-S100 + pembrolizumab, epipodil + nivorumab + ipilimumab / livorumab. Non-small cell lung cancer combination therapy

[0203] Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vincristine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents for the treatment of NSCLC include alectinib (Alecensa®), dabrafenib (Tafinlar®), trametinib (Mekinist®), osimertinib (Tagrisso®), entrectinib (Tarceva®), crizotinib (Xalkori®), pembrolizumab (Keytruda®), carboplatin, pemetrexed (Alimta®), albumin-bound paclitaxel (Abraxane®), ramucirumab (Cyramza®), docetaxel, bevacizumab (Avastin®), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif®), nivorumab (Opdivo®), gefitinib (Iressa®), and combinations thereof. In some embodiments, therapeutic agents for treating NSCLC include dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + albumin-bound paclitaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed + carboplatin, cisplatin + pemetrexed, bevacizumab + carboplatin + albumin-bound paclitaxel, cisplatin + gemcitabine, nivorumab + docetaxel, carboplatin + pemetrexed, carboplatin + albumin-bound paclitaxel, or pemetrexed + cisplatin + carboplatin. In some embodiments, therapeutic agents for NSCLC include dextrose (DS-1062), trastuzumab (Enhertu®), infusorumab (Padcev®), durvalumab, canatumab, semimab, noglucan-alpha, avirumab, tireliumab, dovanilumab, vimbrolizumab, osimertinib, or combinations thereof. In some embodiments, therapeutic agents for treating NSCLC include tatuber / drutecan + pembrolizumab, tatuber / drutecan + durvalumab, durvalumab + trimemumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, noglin-2 (N-803) + pembrolizumab, tislelizumab + atezolizumab, vimbrolizumab + pembrolizumab, or osimertinib + tislelizumab. Small cell lung cancer combination therapy

[0204] Therapeutic agents for the treatment of small cell lung cancer (SCLC) include atezolizumab, bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivorumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents for the treatment of SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivorumab, durvalumab, triasidib, or combinations thereof. In some embodiments, therapeutic agents for the treatment of SCLC include atezolizumab + carboplatin + etoposide, atezolizumab + carboplatin, atezolizumab + etoposide, or carboplatin + paclitaxel. Ovarian cancer combination therapy

[0205] Therapeutic agents used to treat ovarian cancer include 5-fluorouracil, albumin-bound paclitaxel, hexamethylmelamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, epoxetine, irinotecan, letrozole, leuprorelin acetate, liposomal doxorubicin, medroxyprogesterone acetate, mycoflavin, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof. Combination therapy for pancreatic cancer

[0206] Therapeutic agents for the treatment of pancreatic cancer include 5-FU, folate, oxaliplatin, irinotecan, gemcitabine, albumin-bound paclitaxel (Abraxane®), FOLFIRINOX, and combinations thereof. In some embodiments, therapeutic agents for the treatment of pancreatic cancer include 5-FU + folate + oxaliplatin + irinotecan, 5-FU + nano-liposomal irinotecan, folate + nano-liposomal irinotecan, and gemcitabine + albumin-bound paclitaxel. Combination therapy for prostate cancer

[0207] Therapeutic agents used to treat prostate cancer include enzalutamide (Xtandi®), leuprorelin, trifluuridine, tepirimidine (Lonzelv), cabazitaxel, prednisone, abiraterone (Zytiga®), docetaxel, mitoxantrone, bicalutamide, LHRH, flutamide, ADT, sabizabulene (Veru-111), and combinations thereof. In some embodiments, therapeutic agents used to treat prostate cancer include enzalutamide + leuprorelin, trifluuridine + tepirimidine (Lonzelv), cabazitaxel + prednisone, abiraterone + prednisone, docetaxel + prednisone, mitoxantrone + prednisone, bicalutamide + LHRH, flutamide + LHRH, leuprorelin + flutamide, and abiraterone + prednisone + ADT. Additional illustrative combination therapies

[0208] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more of the following therapeutic agents: PI3K inhibitors, Trop-2 binders, CD47 antagonists, SIRPα antagonists, FLT3R agonists, PD-1 antagonists, PD-L1 antagonists, MCL1 inhibitors, CCR8 binders, 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 binders, TREM2 binders, CD137 agonists, GITR binders, OX40 binders, and CAR-T cell therapies.

[0209] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more of the following therapeutic agents: PI3Kd inhibitors (e.g., idealisib), anti-Trop-2 antibody-drug conjugates (e.g., sacituzumab govitecan, datopotamab deruxtecan (DS-1062)), anti-CD47 antibodies, or CD47 blockers (e.g., magnumab, DSP-107, AO-176, ALX-148, letaplimab). (IBI-188), ritopramab, TTI-621, TTI-622), anti-SIRPα antibody (e.g., GS-0189), FLT3L-Fc fusion protein (e.g., GS-3583), anti-PD-1 antibody (pembrolizumab, nivorumab, cepallimab), small molecule PD-L1 inhibitor (e.g., GS-4224), anti-PD-L1 antibody (e.g., atezolizumab, averilumab), small molecule MCL1 inhibitor (e.g., GS-9716), small molecule HPK1 inhibitor (e.g., GS-6451), HPK1 degrader (PROTAC; e.g., ARV-766), small molecule DGKα inhibitor, small molecule CD73 inhibitor (e.g., quinicolasterol (AB680)), anti-CD73 antibody (e.g., olererumab), dual A 2a / A 2b adenosine receptor antagonists (e.g., elumell (AB928)), anti-TIGIT antibodies (e.g., tireliumab, vimbrolizumab, dovanizumab, AB308), anti-TREM1 antibodies (e.g., PY159), anti-TREM2 antibodies (e.g., PY314), CD137 agonists (e.g., AAGEN-2373), GITR / OX40 conjugates (e.g., AAGEN-1223), and CAR-T cell therapies (e.g., axicabtagene ciloleucel, brexucabtagene autoleucel, tisagenlecleucel).

[0210] In some embodiments, the antibodies and / or fusion proteins provided herein are selected from edelixir, sasitrazumab gavetcan, magromumab, GS-0189, GS-3583, cepalimab, GS-4224, GS-9716, GS-6451, quinicolasterol (AB680), elumellide (AB928), dovanalimumab, AB308, PY159, PY314, and AGEN-1223.

[0211] AGEN-2373, Cicasro, and one or more of the following treatments may be administered together. [III.] [Pharmaceutical Compositions]

[0212] While the active ingredient can be administered alone, it is preferable to present it as a pharmaceutical formulation (composition). The formulations of this invention (for both animal and human use) comprise at least one active ingredient (as defined above), together with one or more carriers acceptable to it, and optionally other therapeutic ingredients. The carriers must be "acceptable," meaning they are compatible with the other components of the formulation and harmless to the recipient.

[0213] Formulations include those suitable for the aforementioned routes of administration. Formulations can be conveniently presented in unit dosage forms and can be prepared by any method well known in the field of pharmaceutical technology. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve the step of combining an active ingredient with an inactive ingredient (e.g., a carrier, pharmaceutical excipient, etc.), the inactive ingredient constituting one or more auxiliary components. Typically, formulations are prepared by uniformly and closely combining an active ingredient with a liquid carrier or a finely divided solid carrier, or both, followed by shaping the product as needed.

[0214] In some embodiments, the formulation is suitable for oral administration and is presented in discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.

[0215] In some embodiments, pharmaceutical formulations include one or more compounds of the present invention along with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When intended for oral use, for example, they may be prepared as lozenges, throat lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art of pharmaceutical composition manufacturing, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Lozenges containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing lozenges are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, provitamin, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or coated using known techniques (including microencapsulation) to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate alone or in combination with wax may be used.

[0216] The amount of active ingredient combined with an inactive ingredient to produce a dosage form will vary depending on the host being treated and the specific administration method. For example, in some embodiments, a dosage form for oral administration to humans contains approximately 1 to 1000 mg of the active material, formulated together with an appropriate and convenient amount of a carrier material (e.g., an inactive ingredient or excipient material). In some embodiments, the carrier material varies between approximately 5% and approximately 95% (by weight) of the total composition. In some embodiments, the pharmaceutical composition described herein contains approximately 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 a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition described herein contains no more than approximately 400 mg of a compound of formula I. In some embodiments, the pharmaceutical composition described herein contains approximately 100 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0217] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations disclosed herein may include other pharmaceutical agents known in the art for the type of formulation discussed, such as flavoring agents suitable for oral administration.

[0218] Further, an animal pharmaceutical composition is provided, comprising at least one active ingredient as defined above, together with an animal pharmaceutical carrier.

[0219] Animal pharmaceutical carriers are materials that can be used to administer compositions for specific purposes and can be solid, liquid, or gaseous materials. They are either inert, acceptable in the field of animal pharmaceutical technology, and compatible with the active ingredient. These animal pharmaceutical compositions can be administered orally, parenterally, or by any other desired route of administration.

[0220] The effective dose of an active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is intended for disease prevention (lower dose), the delivery method, and the pharmaceutical formulation, and will be determined by clinicians using known dose increment studies. [IV.] [Investment Methods]

[0221] One or more compounds of formula I (referred to herein as the active ingredient) or a pharmaceutically acceptable salt thereof may be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), and the like. It will be understood that preferred routes may vary depending on, for example, the recipient's condition. The advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally. Thus, in one embodiment, the pharmaceutical composition described herein is an oral dosage form. In some embodiments, the pharmaceutical composition described herein is an oral solid dosage form. [Recipe Example 1]

[0222] Prepare hard gelatin capsules containing the following ingredients: quantity Element (mg / capsule) Active ingredients 30.0 starch 305.0 magnesium stearate 5.0

[0223] Mix the above ingredients and fill them into hard gelatin capsules. [Recipe Example 2]

[0224] The following ingredients are used to prepare the tablet formulation: quantity Element (mg / tablet) Active ingredients 25.0 Cellulose, microcrystals 200.0 colloidal silicon dioxide 10.0 stearic acid 5.0

[0225] The components are blended and compressed to form an ingot. [] [Recipe Example 3]

[0226] Prepare a dry powder inhaler formulation containing the following components: Element weight% Active ingredients 5 lactose 95

[0227] The active ingredient is mixed with lactose, and the mixture is added to a dry powder inhaler. [Recipe Example 4]

[0228] The tablets, each containing 30 mg of the active ingredient, are prepared as follows: quantity Element (mg / tablet) Active ingredients 30.0 mg starch 45.0 mg microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (As a 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg magnesium stearate 0.5 mg talc 1.0 mg total 120 mg

[0229] The active ingredients, starch, and cellulose are passed through a 20-mesh sieve and thoroughly mixed. A solution of polyvinylpyrrolidone is mixed with the resulting powder, which is then passed through a 16-mesh sieve. The resulting granules are dried at 50-60°C and passed through a 16-mesh sieve. Sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a 30-mesh sieve, are then added to the granules. After mixing, the mixture is pressed on a tablet press to produce tablets weighing 120 mg each. [Recipe Example 5]

[0230] The suppositories, each containing 25 mg of the active ingredient, are manufactured as follows: Element quantity Active ingredients 25 mg Saturated fatty acid glycerides to 2,000 mg

[0231] The active ingredient is passed through a 60-mesh US sieve and suspended in saturated fatty acid glycerides, which have previously been melted using the minimum required heat. The mixture is then poured into suppository molds with a nominal capacity of 2.0 g and allowed to cool. [Recipe Example 6]

[0232] Each 5.0 mL dose contains a suspension of 50 mg of the active ingredient, which is manufactured as follows: Element quantity Active ingredients 50.0 mg Three Immortals Glue 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg sucrose 1.75 g Sodium benzoate 10.0 mg Flavorings and colorings qv Purified water to 5.0 mL

[0233] The active ingredients, sucrose, and saccharin are blended and passed through a 10-mesh American sieve, then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavoring agent, and colorant are diluted with some water and added while stirring. Sufficient water is then added to produce the desired volume. [Recipe Example 7]

[0234] The subcutaneous formulation can be prepared as follows: Element quantity Active ingredients 5.0 mg corn oil 1.0 mL [Recipe Example 8]

[0235] Prepare an injectable formulation having the following components: Element quantity Active ingredients 2.0 mg / mL Mannitol, USP 50 mg / mL Gluconic acid, USP qs (pH 5 to 6) Water (distilled, sterile) qs to 1.0 mL Nitrogen, NF qs [Recipe Example 9]

[0236] Prepare a topical formulation having the following components: Element gram Active ingredients 0.2 to 10 Span 60 2.0 Tween 60 2.0 mineral oil 5.0 petrolatum 0.10 Methylparaben 0.15 propylparaben 0.05 BHA (Butyl Hydroxyanisole) 0.01 water qs to 100

[0237] Combine all the above ingredients except water and heat to 60°C with stirring. Then, add a sufficient amount of water at 60°C with vigorous stirring to emulsify the ingredients, followed by adding 100 g of water per 1 qs. [Recipe Example 10]

[0238] Continuous release of components Element Weight range % Active ingredients 50 to 95 Microcrystalline cellulose (filler) 1 to 35 methacrylic acid copolymer 1 to 35 Sodium hydroxide 0.1 to 1.0 Hydroxypropyl methylcellulose 0.5 to 5.0 magnesium stearate 0.5 to 5.0

[0239] The sustained-release formulation disclosed herein can be prepared as follows: the compound and a pH-dependent binder are tightly mixed with any optional excipient (dry blending). The dry-blended mixture is then granulated in the presence of a strong alkaline aqueous solution sprayed onto the blended powder. The granules are dried, sieved, mixed with an optional lubricant (such as talc or magnesium stearate), and pressed into tablets. A preferred strong alkaline aqueous solution is a solution of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in water (optionally containing up to 25% a water-miscible solvent, such as a lower alcohol).

[0240] The resulting tablets can be coated with optional film-forming agents for identification, taste-masking purposes, and to improve ease of swallowing. The film-forming agent will generally be 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, cationic methacrylate copolymers (dimethylaminoethyl methacrylate / methyl methacrylate-butyl ester copolymer - Eudragit® E - Röhm. Pharma), and the like. These film-forming agents may optionally contain colorants, plasticizers, and other supplementary ingredients.

[0241] The compressed tablets preferably have a hardness sufficient to withstand 8 kPa compression. The tablet size will depend primarily on the amount of compound in the tablet. The tablets will contain 300 to 1100 mg of the compound's free base. Preferably, the tablets will contain amounts of the compound's free base in the ranges of 400 to 600 mg, 650 to 850 mg, and 900 to 1100 mg.

[0242] To influence the dissolution rate, the wet mixing time of the compound-containing powder 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, and more preferably 2 to 5 minutes. After granulation, the particles are removed from the granulator and placed in a fluid bed dryer to dry at approximately 60°C. [Recipe Example 11]

[0243] The following ingredients are used to prepare the tablet formulation: quantity Element (mg / tablet) Active ingredients 300.0 Cellulose, microcrystals 100.0 colloidal silicon dioxide 10.0 stearic acid 5.0

[0244] The components are blended and compressed to form an ingot. [V.] [List of abbreviations and initials] [abbreviation] [significance] ℃ Celsius Ac AD-H ADP Acetyl adipic acid dihydrazine Adenosine diphosphate aq. Aqueous solution ATP Adenosine triphosphate D Double Peak DCM dichloromethane dd ddd DIEA Double peak Double peaks N,N-Diisopropylethylamine DIPEA N,N-Diisopropylethylamine (Hünig base) DMA Dimethylacetamide DME 1,2-Dimethoxyethane DMF DMP dimethylformamide Desmartin periodoylane DMSO dimethyl monoxide Dt Double Triple Peak EC 50 EDC Half-maximum effective concentration 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide EDTA EDTA-1,5-diaminetetraacetic acid Eq equivalent ES / MS Electrospray mass spectrometry Et Ethyl EtOAc Ethyl acetate EtOH Ethanol (ethyl alcohol) FBS fetal bovine serum G h gram Hour HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HEPES 2-[4-(2-hydroxyethyl)piperazine] -1-yl]ethanesulfonic acid HCl HOAc hydrochloric acid Acetic acid HPLC High performance liquid chromatography Hrs Hour Hz hertz IC 50 Half-maximum inhibition concentration i-pr Isolute® Isopropyl Polystyrene-divinylbenzene copolymer J Coupling constant (MHz) Li HMDS Lithium bis(trimethylsilyl)acetamide LiOH Lithium hydroxide LiI lithium iodide M Volume Mole M Multiplets M+ Quality Peak M+H+ Mass peak hydrogenation Me methyl MeCN Acetonitrile MeOH Methanol (methyl alcohol) Me 6Sn 2 Hexamethyldistannane (hexamethylditin) Mg mg MgSO4 Magnesium sulfate MHz million Hertz Minimum value minute ml / mL milliliters mM milliliter Mmol Momo NaHCO3 NBS Sodium bicarbonate N-bromosuccinimide n- normal nBu / Bu n-Butyl (normal Butyl) NaH Sodium hydride NaHCO3 Sodium bicarbonate nL Naisheng Nm NMP nanometer 1-Methylpyrrolidone-2-one NMR Nuclear magnetic resonance Ph psi Phenyl pounds per square inch Q Four Peaks qs rac-BINAP Pd G3 A sufficient number to achieve the stated function [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid RP Reverse phase Rt RuPhos® room temperature 2'-Methylamino-1,1'-Biphenyl-2-yl-Palladacycle 4th generation S Single peak T t-BuBrettPhos Pd G3 TEA THF TFA XPhos Pd G4 ® Triple Peak 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate Triethylamine Tetrahydrofuran Trifluoroacetic acid Dicyclohexyl-[2-[2,4,6-tris(propyl-2-yl)phenyl]phenyl]phosphonium; methanesulfonic acid; N-methyl-2-phenylaniline; palladium General Plan [Example]

[0245] The following examples illustrate specific embodiments of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following examples represent techniques fully operational in the practice of this disclosure and can therefore be considered as a particular pattern constituting its practice. However, those skilled in the art will understand, in light of this disclosure, that many changes can be made to the disclosed specific embodiments while still obtaining similar or analogous results without departing from the spirit and scope of this disclosure. i. General Plan A ii. General Plan B iii. General Plan C [Example]

[0246] The following examples illustrate specific embodiments of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following examples represent techniques fully operational in the practice of this disclosure and can therefore be considered as a particular pattern constituting its practice. However, those skilled in the art will understand, in light of this disclosure, that many changes can be made to the disclosed specific embodiments while still obtaining similar or analogous results without departing from the spirit and scope of this disclosure. iv. General Plan A v. General Plan B vi. General Plan C ii. Synthetic Examples Example 1 2-(4-((6-Symoxy-5-(trifluoromethyl)-1,6-dihydro-2-ethylhexylene) Preparation of -4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyridin-2-yl)isoquinoline-1(2H)-one

[0247] [Step 1.] At 0 °C, tributyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate (200 mg, 0.984 mmol) and triethylamine (199 mg, 1.97 mmol) were added dropwise to a stirred solution in dichloromethane (4.50 mL), and the mixture was warmed to room temperature and stirred for 2 h. After completion, the mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give a crude product. The crude residue was purified by column chromatography using 0–100% EtOAc elution in hexane to provide... [4-(] [Tri-butoxycarbonylamine group] [pentyl 4-] [Methylbenzenesulfonate]. ES / MS: m / z 380.4 [M+Na]+.

[0248] [Step 2.] To a mixture of 6-bromo-2H-isoquinoline-1-one (55.0 mg, 0.245 mmol) and 4-(tributoxycarbonylamino)pentyl 4-methylbenzenesulfonate (102 mg, 0.285 mmol) in DMF (0.70 mL), Cs₂CO₃ (160 mg, 0.491 mmol) was added and the reaction was stirred at room temperature for 18 h. After completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give a c...

Claims

1. A compound of formula (I): R1 (I), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, J series; X1 series N, C=O, CR 10, or C-(R 10) 2; X2 series N, NR 11, CR 12, or C-(R 12) 2; X3 series N or CR 13; X4 series N or CR 13; X5 series N or CR 13; or A series selected from: C, O, N, optionally substituted with one or more R 15 3- to 10-membered cycloalkyl; or optionally substituted with one or more R 15 4- to 11-membered heterocyclic group; when A series O, n series 0; when A series N, n series 1; and when A series C, n series 1 or 2; when A series N, n series 0 or 1, and L1 series C or NR 17, and L2, L3, and L4 are each C; L1 and L2 are each independently C, C6-10 aryl, 5 to 12-membered heteroaryl, or NH; L3 and L4 are each C; or L1 and L2 together with the atoms to which they are attached form 3 to 12-membered cycloalkyl, C6-10 aryl, 5 to 12-membered heteroaryl, or 4 to 12-membered heterocyclic, optionally substituted by one or more R15; wherein the 4 to 12-membered cycloalkyl or 4 to 12-membered heterocyclic is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted by one or more R15, and wherein the C6-10 aryl or 5 to 12-membered heteroaryl is monocyclic or bicyclic; or L1 and L3 together with the atoms to which they are attached form 3 to 12-membered cycloalkyl, C6-10 aryl, 5 to 12-membered heterocyclic, or NH. 6-10 aryl, 5-12 heteroaryl, or 4-12 heterocyclic, each optionally substituted with one or more R15 groups; wherein the 4-12 cycloalkyl or 4-12 heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5-12 heteroaryl group is monocyclic or bicyclic; or L2 and L3 together with the atoms to which they are attached form a 3-12 cycloalkyl, C6-10 aryl, 5-12 heteroaryl, or 4-12 heterocyclic, each optionally substituted with one or more R15 groups; wherein the 4-12 cycloalkyl or 4-12 heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5-12 heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5-12 heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5-12 heterocyclic group is monocyclic or bicyclic. 6-10 aryl or 5-12 member heteroaryl groups are monocyclic or bicyclic; or L3 and L4, together with the atoms attached thereto, form 3-12 member cycloalkyl, C6-10 aryl, 5-12 member heteroaryl, or 4-12 member heterocyclic rings, each optionally substituted with one or more R15 groups; wherein the 4-12 member cycloalkyl or 4-12 member heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C...A 6-10 aryl or 5-12 member heteroaryl group is monocyclic or bicyclic; or L2 and L4, together with the atoms attached thereto, form a 3-12 member cycloalkyl, C6-10 aryl, 5-12 member heteroaryl, or 4-12 member heterocyclic ring, each optionally substituted with one or more R15 groups; wherein the 4-12 member cycloalkyl or 4-12 member heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each optionally substituted with one or more R15 groups, and wherein the C6-10 aryl or 5-12 member heteroaryl group is monocyclic or bicyclic, each optionally substituted with one or more R15 groups; R1 is selected from H, halogen, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, OR14, C(O)-R14, -SF 5; C(O)-N(R 17)(R 18), N(R 17)(R 18), N(R 17)C(O)-R 15, N(R 17)C(O)OR 15, N(R 7)S(O) 2(R 15), N(R 17)C(O)-N(R 17)(R 18), S(O) 2R 15, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18, optionally C 1-5 alkyl groups substituted with one or more R 15; or optionally C 3-10 cycloalkyl groups substituted with one or more R 15; or optionally 5 to 10 heteroaryl groups substituted with one or more R 15; or optionally C 3-10 cycloalkyl groups substituted with one or more R 15. 6-10 aryl; or optionally a 4- to 7-membered heterocyclic group substituted with one or more R15; R2 is selected from H, C1-9 alkyl, C2-9 alkenyl, or C2-9 ynyl, wherein any alkyl, alkenyl, or ynyl group is optionally substituted with one or more R10; R3 and R4 are each independently selected from H, C1-9 alkyl, C2-9 alkenyl, or C2-9 ynyl, wherein any alkyl, alkenyl, or ynyl group is optionally substituted with one or more R15, a C3- to 12 cycloalkyl group optionally substituted with one or more R15, a C6- to 10 aryl group optionally substituted with one or more R15, a 4- to 11-membered heterocyclic group optionally substituted with one or more R15, or a 5- to 10-membered heteroaryl group optionally substituted with one or more R15; or R2 and R3 Together with the atoms to which they are attached, they form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and optionally substituted with one or more R15 groups; or R3 and R4 together with the atoms to which they are attached form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 groups.15 substitution; wherein a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, and each is optionally substituted with one or more R 15; or R 2 and R 4 together with the atoms to which they are attached form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic group, each optionally substituted with one or more R 15; wherein a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, and each is optionally substituted with one or more R 15; R 5a, R 5b, R 6a, R 6b, R 7a, R 7b are each independently selected from H, halogen, NO 2, CN, O-R 14, C(O)-R 16, C(O)-N(R 17)(R 18), N(R 17)(R 18) N(R 17)C(O)-R 16, N(R 17)C(O)O-R 14, N(R 17)S(O) 2(R 16), -N(R 17)C(O)-N(R 18)(R 18), S(O) 2R 16, -SF 5, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18, optionally C 1-9 alkyl groups substituted with one or more R 15 groups; optionally C 2-9 alkynyl groups substituted with one or more R 15 groups; optionally C 2-9 alkenyl groups substituted with one or more R 15 groups; optionally 5 to 12 heteroaryl groups substituted with one or more R 15 groups; optionally C 2-9 alkenyl groups substituted with one or more R 15 groups. 6-10 aryl; optionally substituted with one or more R 15 groups of 4 to 12-membered heterocyclic groups; or optionally substituted with one or more R 15 groups of C3-12 cycloalkyl groups; or R 5a and R 5b together with their attached atoms form 3 to 12-membered cycloalkyl groups or 4 to 12-membered heterocyclic groups, each optionally substituted with one or more R 15 groups; or R 6a and R 6b together with their attached atoms form 3 to 12-membered cycloalkyl groups or 4 to 12-membered heterocyclic groups, each optionally substituted with one or more R 15 groups; or R 7a and R 7b together with their attached atoms form 3 to 12-membered cycloalkyl groups or 4 to 12-membered heterocyclic groups, each optionally substituted with one or more R 15 groups. 15-substituted, wherein the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, and each may optionally be substituted with one or more R 15 groups; or the Z group is selected from: H, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-8 haloalkyl, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5- to 12-membered heteroaryl), -O (4- to 12-membered heterocyclic), -OC(O)(C1-9 alkyl), -OC(O) (C 2-6 alkenyl), -OC(O) (C 2-6 alkenyl), -OC(O) (C 2-6 ynyl), -OC(O) (C 3-15 cycloalkyl), -OC(O) (C 1-8 haloalkyl), -OC(O) (C 6-10 aryl), -OC(O) (5 to 12 member heteroaryl), -OC(O) (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12 member heteroaryl), -NH (4 to 12 member heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N(C 2-6 ynyl) 2, -N(C 3-15 cycloalkyl) 2, -N(C 1-8 haloalkyl) 2, -N(C 6-10 aryl) 2, -N(5 to 12 heteroaryl) 2, -N(h4 to 12 heterocyclic) 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 ynyl), -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(5 to 12 heteroaryl), -N(C 1-9 alkyl)(4 to 12 member heterocyclic), -C(O) (C 1-9 alkyl), -C(O) (C 2-6 alkenyl), -C(O) (C 2-6 ynyl), -C(O) (C 3-15 cycloalkyl), -C(O) (C 1-8 haloalkyl), -C(O) (C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocyclic), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C -6-10 aryl), -C(O)O (5 to 12-membered heteroaryl), -C(O)O (4 to 12-membered heterocyclic), -C(O)NH2, -C(O)NH (C1-9 alkyl), -C(O)NH (C2-6 alkenyl), -C(O)NH (C2-6 ynyl), -C(O)NH (C3-15 cycloalkyl), -C(O)NH (C1-8 haloalkyl), -C(O)NH (C6-10 aryl), -C(O)NH (5 to 12-membered heteroaryl), -C(O)NH (4 to 12-membered heterocyclic), -C(O)N (C1-9 alkyl)2. -C(O)N (C 3-15 cycloalkyl) 2. -C(O)N (C 2-6 alkenyl) 2. -C(O)N (C 2-6 ynyl) 2. -C(O)N (C 1-8 haloalkyl) 2. -C(O)N (C 6-10 aryl) 2. -C(O)N (5 to 12 member heteroaryl) 2. -C(O)N (4 to 12 member heterocyclic) 2. -NHC(O) (C 1-9 alkyl), -NHC(O) (C 2-6 alkenyl), -NHC(O) (C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 ...1-9 alkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-12 alkyl), -NHC(O)NH (C 1-12 alkyl), -NHC(O)NH (C 1-12 alkyl), -NHC(O)NH (C 1-12 alkyl), -NHC(O)NH (C 1-12 alkyl), -NHC(O)NH (C 1 1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C 6-10 aryl), -S (5 to 12 member heteroaryl), -S (4 to 12 member heterocyclic), -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)(C -2-6 alkenyl), -S(O) (C 2-6 ynyl), -S(O) (C 3-15 cycloalkyl), -S(O) (C 1-8 haloalkyl), -S(O) (C 6-10 aryl), -S(O) (5 to 12 member heteroaryl), -S(O) (4 to 12 member heterocyclic), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 ynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (CR15 may be substituted with one or more of the following: 6-10 aryl, -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), or -S(O)2N (C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group of R15 may optionally be substituted with one or more of the following: halogen, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C1-8 haloalkyl), -S(O)2 (C6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12-membered heteroaryl), -O (4 to 12-membered heterocyclic), or -O (C1-9 alkyl). 5- to 12-membered heteroaryl groups substituted with one or more R 13 groups; optionally, C 6-10 aryl groups substituted with one or more R 15 groups; optionally, C 3-12 cycloalkyl groups substituted with one or more R 15 groups; optionally, 4- to 12-membered heterocyclic groups substituted with one or more R 15 groups; wherein, Any 5 to 12-membered heteroaryl, C6-10 aryl, C3-12 cycloalkyl, or 4 to 12-membered heterocyclic monocyclic, bicyclic, substituted with one or more R15 groups, and 3 to 12-membered cycloalkyl, or 4 to 12-membered heterocyclic monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged, each substituted with one or more R15 groups, wherein the R10 group is selected from: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R118), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R 14. N(R 17)S(O) 2(R 16), -N(R 17)C(O)-N(R 18)(R 18), S(O) 2R 16, -SF 5, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C6-10 aryl, 5 to 10 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one or more R 16, and the R 11 group is selected from: H, C1-9 alkyl, C2-9 alkenyl, C2-9 ynyl, C 3-12 cycloalkyl, C6-10 aryl, 6 to 12-membered heteroaryl, or 4 to 12-membered heterocyclic, any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group optionally substituted with one or more R16 groups. The R12 group is selected from: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R17) 18)(R 18), S(O) 2R 16, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18, C1-9 alkyl, C2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 5 to 12 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted by one or more R 16 for R 13.The group is independently selected from: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R16, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1- 9-alkyl, C2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 5 to 12-membered heteroaryl, or 4 to 12-membered heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one or more R16 groups; the R15 group is independently selected from: H, C=O, hydroxyl, halogen, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5 to 12-membered heteroaryl, 4 to 12-membered heterocyclic, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C6-10 ... -1-8 haloalkyl), -O (C 6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -OC(O) (C 1-9 alkyl), -OC(O) (C 2-6 alkenyl), -OC(O) (C 2-6 alkenyl), -OC(O) (C 2-6 ynyl), -OC(O) (C 3-15 cycloalkyl), -OC(O) (C 1-8 haloalkyl), -OC(O) (C 6-10 aryl), -OC(O) (5 to 12 member heteroaryl), -OC(O) (4 to 12 member heterocyclic), -NH2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C -6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 ynyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 1-8 haloalkyl) 2, -N (C 6-10 aryl) 2, -N (5 to 12-membered heteroaryl) 2, -N (h4 to 12-membered heterocyclic) 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 ynyl), -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl) (5 to 12 heteroaryl), -N(C 1-9 alkyl)(4 to 12 heterocyclic), -C(O) (C 1-9 alkyl), -C(O) (C 2-6 alkenyl), -C(O) (C 2-6 ynyl), -C(O) (C 3-15 cycloalkyl), -C(O) (C 1-8 haloalkyl), -C(O) (C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocyclic), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocyclic), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -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 ynyl) 2, -C(O)N (C 1-8 haloalkyl) 2, -C(O)N (C 6-10 aryl) 2, -C(O)N (5 to 12 member heteroaryl) 2, -C(O)N (4 to 12 member heterocyclic) 2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C-6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C -6-10 aryl), -S (5 to 12 member heteroaryl), -S (4 to 12 member heterocyclic), -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) (C 2-6 alkenyl), -S(O) (C 2-6 ynyl), -S(O) (C 3-15 cycloalkyl), -S(O) (C 1-8 haloalkyl), -S(O) (C 6-10 aryl), -S(O) (5 to 12 member heteroaryl), -S(O) (4 to 12 member heterocyclic), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 ynyl), -S(O)2 (C 3-15 cycloalkyl), -S(O)2 (C 1-8 haloalkyl), -S(O)2 (C 6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C 1-9 alkyl), or -S(O)2N (C 1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group of R15 may optionally be substituted with one or more of the following: halogroup, 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 (C 1-6 alkyl), -NH (C 1-8 alkyl), -NH (C 1-9 ... -6-10 aryl), -NH (5 to 12 heteroaryl), -NH (4 to 12 heterocyclic), -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)(C 6-10 aryl), -NHC(O)(5 to 12 heteroaryl), -NHC(O)(4 to 12 heterocyclic), -NHC(O)O(C1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -S(O) 2 (5 to 12 member heteroaryl), -S(O) 2 (4 to 12 member heterocyclic), -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(C 6-10 aryl), -O(5 to 12-membered heteroaryl), -O(4 to 12-membered heterocyclol), or -O(C 1-9 alkyl). The R 16 series is independently selected from: H, C=O, halogen, -NO 2, -CN, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 ynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-10 aryl, 5 to 12 member heteroaryl, 4 to 12 member heterocyclic, -OH, -O (C 1-9 alkyl), -O (C 2-6 alkenyl), -O (C 2-6 ynyl), -O (C 3-15 cycloalkyl), -O (C 1-8 haloalkyl), -O (C 6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 2 ...6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 ynyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 1-8 haloalkyl) 2, -N (C 6-10 aryl) 2, -N (5 to 12-membered heteroaryl) 2, -N (4 to 12-membered heterocyclic) 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 ynyl), -N (C 1-9 alkyl)(C 2-6 ynyl) 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C-1-9 alkyl)(5 to 12 heteroaryl), -N(C 1-9 alkyl)(4 to 12 heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 6-10 aryl), -C(O)(5 to 12 heteroaryl), -C(O)(4 to 12 heterocyclic), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 ynyl), -C(O)O(C 3-15 cycloalkyl), -C(O)O(C 1-8 haloalkyl), -C(O)O(C -6-10 aryl), -C(O)O (5 to 12-membered heteroaryl), -C(O)O (4 to 12-membered heterocyclic), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12-membered heteroaryl), -C(O)NH (4 to 12-membered heterocyclic), -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 ynyl) 2. -C(O)N (C 3-15 cycloalkyl) 2. -C(O)N (C 1-8 haloalkyl) 2. -C(O)N (C 6-10 aryl) 2. -C(O)N (5 to 12 member heteroaryl) 2. -C(O)N (4 to 12 member heterocyclic) 2. -NHC(O) (C 1-9 alkyl), -NHC(O) (C 2-6 alkenyl), -NHC(O) (C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocycloyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 2-6 cycloalkyl ...1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C 6-10 aryl), -S (5 to 12 member heteroaryl), -S (4 to 12 member heterocyclic), -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)(C 6-10 aryl), -S(O)(NH)(5 to 12 member heteroaryl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C 1-8 haloalkyl), -S(O)(C 6-10 aryl), -S(O)(5 to 12 member heteroaryl), -S(O)(4 to 12 member heterocyclic), -S(O) 2(C 1-9 alkyl), -S(O) 2(C 2-6 alkenyl), -S(O) 2(C 2-6 ynyl), -S(O) 2(C 3-15 cycloalkyl), -S(O) 2(C 1-8 haloalkyl), -S(O) 2(C -6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), or -S(O)2N (C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12-membered heteroaryl), -NHC(O)O (4 to 12-membered heterocyclic), -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 (C 6-10 aryl), -S(O) 2 (5 to 12-membered heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic), -S(O) 2NH (C 1-9 alkyl), -S(O) 2N (C 1-9 alkyl), -O (C 3-15 cycloalkyl), -O (C The R17 and R18 groups are independently selected from: H, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 heteroaryl, or 4-12 heterocyclic groups, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted by one or more R16 groups.

2. The compound of claim 1, wherein: L1 and L2, together with the atoms to which they are attached, form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and optionally substituted with one or more R15 groups.

3. The compound of claim 1, wherein: L2 and L3 together with the atoms to which they are attached form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, optionally substituted with one or more R15s; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic ring is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and optionally substituted with one or more R15s.

4. The compound of claim 1, wherein: L3 and L4, together with the atoms to which they are attached, form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, optionally substituted with one or more R15; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and optionally substituted with one or more R1.

5. The compound of claim 1, wherein: L2 and L4, together with the atoms to which they are attached, form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, optionally substituted with one or more R15 groups; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic ring is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and optionally substituted with one or more R15 groups.

6. A compound of claim 1, wherein the compound is represented by formula Ia: (Ia), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is a group; X1 is a group of N, C=O, CR10, or C-(R10)2; X2 is a group of N, NR11, CR12, or C-(R12)2; X3 is a group of N or CR13; X4 is a group of N or CR13; X5 is a group of N or CR13; or A is a group selected from: C, O, N, 3 to 10 cycloalkyl groups optionally substituted with one or more R15 groups; or 4 to 11 heterocyclic groups optionally substituted with one or more R15 groups; when A is O, n is 0; when A is N, n is 1; and when A is C, n is 1 or 2; R1 is a group selected from H, halogen, CH 3, CH 2CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, CN, OR 14, C(O)-R 14, -SF 5; C(O)-N(R 17)(R 18), N(R 17)(R 18), N(R 17)C(O)-R 15, N(R 17)C(O)OR 15, N(R 7)S(O) 2(R 15), N(R 17)C(O)-N(R 17)(R 18), S(O) 2R 15, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18 Optionally C 1-5 alkyl groups substituted with one or more R 15; or C 1-5 alkyl groups optionally substituted with one or more R 15. 3-10 cycloalkyl; optionally substituted with one or more R15 groups of 5 to 10 heteroaryl groups; optionally substituted with one or more R15 groups of C6-10 aryl groups; or optionally substituted with one or more R15 groups of 4 to 7 heterocyclic groups. R2 is selected from H, C1-9 alkyl, C2-9 alkenyl, or C2-9 ynyl, wherein any alkyl, alkenyl, or ynyl group is optionally substituted with one or more R10 groups; R3 and R4 are each independently selected from H, C1-9 alkyl, C2-9 alkenyl, or C2-9 ynyl, wherein any alkyl, alkenyl, or ynyl group is optionally substituted with one or more R15 groups, C3-12 cycloalkyl groups optionally substituted with one or more R15 groups, C6-10 aryl groups optionally substituted with one or more R15 groups, or C6-10 aryl groups optionally substituted with one or more R15 groups. A 4- to 11-membered heterocyclic group substituted with 15, or optionally a 5- to 10-membered heteroaryl group substituted with one or more R 15; or R2 and R3 together with the atoms to which they are attached to form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocycle, optionally substituted with one or more R 15; wherein the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and optionally substituted with one or more R 15.15 substitution; or R3 and R4 together with the atoms to which they are attached form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 groups; wherein the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each optionally substituted with one or more R15 groups; or R5a, R5b, R6a, R6b, R7a, R7b are each independently selected from H, halogen, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R 16) -N(R 17)C(O)-N(R 18)(R 18), S(O) 2R 16, -SF 5, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18 Optionally C1-9 alkyl groups substituted with one or more R 15 groups; Optionally C2-9 alkynyl groups substituted with one or more R 15 groups; Optionally C2-9 alkenyl groups substituted with one or more R 15 groups; Optionally 5- to 12-membered heteroaryl groups substituted with one or more R 15 groups; Optionally C6- to 10 aryl groups substituted with one or more R 15 groups; Optionally 4- to 12-membered heterocyclic groups substituted with one or more R 15 groups; or Optionally C3- to 12-cycloalkyl groups substituted with one or more R 15 groups; or R 5a and R 5b, together with the atoms to which they are attached, forms a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 atoms; or R6a and R6b, together with the atoms to which they are attached, form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 atoms; or R7a and R7b, together with the atoms to which they are attached, form a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic ring, each optionally substituted with one or more R15 atoms, wherein the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each optionally substituted with one or more R15 atoms; or the Z group is selected from: -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-8 haloalkyl, -O(C -1-9 alkyl), -O (C 2-6 alkenyl), -O (C 2-6 ynyl), -O (C 3-15 cycloalkyl), -O (C 1-8 haloalkyl), -O (C 6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -OC(O)(C 1-9 alkyl), -OC(O)(C 2-6 alkenyl), -OC(O)(C 2-6 alkenyl), -OC(O)(C-2-6 alkynyl), -OC(O) (C 3-15 cycloalkyl), -OC(O) (C 1-8 haloalkyl), -OC(O) (C 6-10 aryl), -OC(O) (5 to 12 member heteroaryl), -OC(O) (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 alkynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12 member heteroaryl), -NH (4 to 12 member heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 alkynyl) 2, -N (C 3-15 cycloalkyl) 2. -N(C 1-8 haloalkyl) 2. -N(C 6-10 aryl) 2. -N(5 to 12-membered heteroaryl) 2. -N(h 4 to 12-membered heterocyclic) 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 ynyl), -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(5 to 12-membered heteroaryl), -N(C 1-9 alkyl)(4 to 12-membered heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O) (C 3-15 cycloalkyl), -C(O) (C 1-8 haloalkyl), -C(O) (C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocyclic), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocyclic), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -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 (C2-6 alkynyl) 2, -C(O)N(C 1-8 haloalkyl) 2, -C(O)N(C 6-10 aryl) 2, -C(O)N(5 to 12 heteroaryl) 2, -C(O)N(4 to 12 heterocyclic) 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) (C 6-10 aryl), -NHC(O) (5 to 12 heteroaryl), -NHC(O) (4 to 12 heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 6-10 aryl), -NHC(O) (5 to 12 heteroaryl), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 6-10 aryl) 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S(C 2-6 ynyl), -S(C 3-15 cycloalkyl), -S(C 1-8 haloalkyl), -S(C 6-10 aryl), -S(5 to 12 heteroaryl), -S(4 to 12 heterocyclic), -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)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C 1-8 haloalkyl), -S(O)(C -6-10 aryl), -S(O) (5 to 12-membered heteroaryl), -S(O) (4 to 12-membered heterocyclic), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 ynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 6-10 aryl), -S(O) 2 (5 to 12-membered heteroaryl), -S(O) 2 (4 to 12-membered heterocyclic), -S(O) 2NH(C-1-9 alkyl), or -S(O) 2N(C 1-9 alkyl) 2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group of R 15 may optionally be substituted with one or more of the following: halogroup, 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 (C 6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -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)(C 1-9 alkyl) 2, -NHC(O)(C 1-9 cyclo ... -6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C -6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12-membered heteroaryl), -O (4 to 12-membered heterocyclic), or -O (C1-9 alkyl). The following are optional 5- to 12-membered heteroaryl groups substituted with one or more R13 groups; optional C6-10 aryl groups substituted with one or more R15 groups; optional C3-12 cycloalkyl groups substituted with one or more R15 groups; optional 4- to 12-membered heterocyclic groups substituted with one or more R15 groups; wherein any 5- to 12-membered heteroaryl, C6-10 aryl, C3-12 cycloalkyl, or 4- to 12-membered heterocyclic group is monocyclic or bicyclic and substituted with one or more R15 groups, and any 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclic group is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged and each is substituted with one or more R15 groups. The R10 group is selected from: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R 14, C(O)-R16. C(O)-N(R17)(R118), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), S(O)2R16, -SF5, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C 6-10 aryl, 5-10 heteroaryl, or 4-12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one or more R16 groups. The R11 group is selected from: H, C1-9 alkyl, C2-9 alkenyl, C2-9 ynyl, C3-12 cycloalkyl, C6-10 aryl, 6-12 heteroaryl, or 4-12 heterocyclic, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one or more R16 groups. The R12 group is selected from: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R 16. C(O)-N(R17)(R118), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), S(O)2R16, S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C 6-10 aryl, 5-12 heteroaryl, or 4-12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one or more R16 groups. The R13 group is independently selected from: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18)(R17)C(O)-N(R18)(R17)C(O)-N(R18)(R17)C(O)-N(R18)(R17)C(O)-N(R18)(R17)C(O)-N(R18)(R17)C(O)-N(R18)(R17)C(O)-N(R17)C(O)-N(R18)(R17)C(O)-N(R18)C(O)-N( ...18) -SF 5, S(O) 2R 16, S(O) 2N(R 17)(R 18), S(O)(NH)R 17, S(O)(NR 17)NR 18, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 ynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5 to 12 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted by one or more R 16; R 15 is independently selected from: H, C=O, hydroxyl, halogen, -NO 2, -N 3, -CN, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 ynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclic, -O (C 1-9 alkyl), -O (C 2-6 alkenyl), -O (C 2-6 ynyl), -O (C 3-15 cycloalkyl), -O (C 1-8 haloalkyl), -O (C 6-10 aryl), -O (5-12 membered heteroaryl), -O (4-12 membered heterocyclic), -OC(O) (C 1-9 alkyl), -OC(O)(C 2-6 alkenyl), -OC(O)(C 2-6 alkenyl), -OC(O)(C 2-6 ynyl), -OC(O)(C 3-15 cycloalkyl), -OC(O)(C 1-8 haloalkyl), -OC(O)(C 6-10 aryl), -OC(O)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclic), -NH 2. -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12 member heteroaryl), -NH (4 to 12 member heterocyclic), -N (C 1-9 alkyl) 2. -N (C 3-15 cycloalkyl) 2. -N (C 2-6 alkenyl) 2. -N (C 2-6 ynyl) 2. -N (C 3-15 cycloalkyl) 2. -N (C 1-8 haloalkyl) 2. -N (C 6-10 aryl) 2. -N (5 to 12 member heteroaryl) 2. -N (4 to 12 member heterocyclic) 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 ynyl), -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl) (5 to 12 heteroaryl), -N(C 1-9 alkyl)(4 to 12 heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O) (C 2-6 ynyl), -C(O) (C 3-15 cycloalkyl), -C(O) (C 1-8 haloalkyl), -C(O) (C 6-10 aryl), -C(O) (5 to 12 member heteroaryl), -C(O) (4 to 12 member heterocyclic), -C(O)O (C 1-9 alkyl), -C(O)O (C 2-6 alkenyl), -C(O)O (C 2-6 ynyl), -C(O)O (C 3-15 cycloalkyl), -C(O)O (C 1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocyclic), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C -2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -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 ynyl) 2, -C(O)N (C 1-8 haloalkyl) 2, -C(O)N (C 6-10 aryl) 2, -C(O)N (5 to 12 member heteroaryl) 2, -C(O)N (4 to 12 member heterocyclic) 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) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -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 (C 1-9 alkyl), -NHC(O)O (C 1-9 alkenyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 1-9 alkenyl ... -6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -NHC(O)NH (5 to 12 member heteroaryl), -NHC(O)NH (4 to 12 member heterocyclic), -SH, -S (C1-9 alkyl), -S(C 2-6 alkenyl), -S(C 2-6 ynyl), -S(C 3-15 cycloalkyl), -S(C 1-8 haloalkyl), -S(C 6-10 aryl), -S(5 to 12 heteroaryl), -S(4 to 12 heterocyclic), -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)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C 1-8 haloalkyl), -S(O)(C 6-10 aryl), -S(O) (5 to 12-membered heteroaryl), -S(O) (4 to 12-membered heterocyclic), -S(O)2 (C 1-9 alkyl), -S(O)2 (C 2-6 alkenyl), -S(O)2 (C 2-6 ynyl), -S(O)2 (C 3-15 cycloalkyl), -S(O)2 (C 1-8 haloalkyl), -S(O)2 (C 6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C 1-9 alkyl), or -S(O)2N (C 1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group of R15 may optionally be substituted with one or more of the following: halogen, C 1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5 to 12-membered heteroaryl), -NH(4 to 12-membered heterocyclic), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C6-10 aryl), -NHC(O)(5 to 12-membered heteroaryl), -NHC(O)(4 to 12-membered heterocyclic), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C2-6 alkynyl) -3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C-6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (C6-10 aryl), -O (5 to 12-membered heteroaryl), -O (4 to 12-membered heterocyclic), or -O (C1-9 alkyl). The R 16 series is independently selected from: H, C=O, halogen, -NO 2, -CN, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 ynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-10 aryl, 5 to 12 member heteroaryl, 4 to 12 member heterocyclic, -OH, -O (C 1-9 alkyl), -O (C 2-6 alkenyl), -O (C 2-6 ynyl), -O (C 3-15 cycloalkyl), -O (C 1-8 haloalkyl), -O (C 6-10 aryl), -O (5 to 12 member heteroaryl), -O (4 to 12 member heterocyclic), -NH 2, -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 1-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 3-15 cycloalkyl), -NH (C 2-9 alkyl), -NH (C 2-6 alkenyl), -NH (C 2-6 ynyl), -NH (C 2 ...6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2-6 alkyl), -NH (C 2 1-8 haloalkyl), -NH (C 6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C 1-9 alkyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 2-6 alkenyl) 2, -N (C 2-6 ynyl) 2, -N (C 3-15 cycloalkyl) 2, -N (C 1-8 haloalkyl) 2, -N (C 6-10 aryl) 2, -N (5 to 12-membered heteroaryl) 2, -N (4 to 12-membered heterocyclic) 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 ynyl), -N (C 1-9 alkyl)(C 2-6 ynyl) 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(5 to 12 heteroaryl), -N(C 1-9 alkyl)(4 to 12 heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 6-10 aryl), -C(O)(5 to 12 heteroaryl), -C(O)(4 to 12 heterocyclic), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 ynyl), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)(C 1-8 alkyl), -C(O)O(C 1-9 alkyl), -N(C 1-9 alkyl)( ...)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 1-9 alkyl)(C 3-15 cycloalkyl), -C(O)O(C-1-8 haloalkyl), -C(O)O (C 6-10 aryl), -C(O)O (5 to 12 member heteroaryl), -C(O)O (4 to 12 member heterocyclic), -C(O)NH 2, -C(O)NH (C 1-9 alkyl), -C(O)NH (C 2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -C(O)NH (C 3-15 cycloalkyl), -C(O)NH (C 1-8 haloalkyl), -C(O)NH (C 6-10 aryl), -C(O)NH (5 to 12 member heteroaryl), -C(O)NH (4 to 12 member heterocyclic), -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(C2-6 alkynyl) 2. -C(O)N(C3-15 cycloalkyl) 2. -C(O)N(C1-8 haloalkyl) 2. -C(O)N(C6-10 aryl) 2. -C(O)N(5 to 12 heteroaryl) 2. -C(O)N(4 to 12 heterocyclic) 2. -NHC(O) (C1-9 alkyl), -NHC(O) (C2-6 alkenyl), -NHC(O) (C2-6 alkynyl), -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (C6-10 aryl), -NHC(O) (5 to 12 heteroaryl), -NHC(O) (4 to 12 heterocyclic), -NHC(O)O(C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocycloyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 ynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 1-9 alkenyl ... -6-10 aryl), -NHC(O)NH (5 to 12-membered heteroaryl), -NHC(O)NH (4 to 12-membered heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 ynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (C 6-10 aryl), -S (5 to 12-membered heteroaryl), -S (4 to 12-membered heterocyclic), -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) (C 6-10 aryl), -S(O) (NH) (5 to 12 member heteroaryl), -S(O) (C 2-6 alkenyl), -S(O) (C 2-6 ynyl), -S(O) (C 3-15 cycloalkyl), -S(O) (C 1-8 haloalkyl), -S(O) (C 6-10 aryl), -S(O) (5 to 12 member heteroaryl), -S(O) (4 to 12 member heterocyclic), -S(O) 2(C 1-9 alkyl), -S(O) 2(C 2-6 alkenyl), -S(O) 2(C 2-6 ynyl), -S(O) 2(C -3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl), -S(O)2 (C6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C1-9 alkyl), or -S(O)2N (C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more of the following: halogroup, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (C6-10 aryl), -NH (5 to 12-membered heteroaryl), -NH (4 to 12-membered heterocyclic), -N (C1-9 alkyl) 2. -N (C 3-15 cycloalkyl) 2. -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (C 6-10 aryl), -NHC(O) (5 to 12 member heteroaryl), -NHC(O) (4 to 12 member heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (C 6-10 aryl), -NHC(O)O (5 to 12 member heteroaryl), -NHC(O)O (4 to 12 member heterocyclic), -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 (C 6-10 aryl), -S(O)2 (5 to 12-membered heteroaryl), -S(O)2 (4 to 12-membered heterocyclic), -S(O)2NH (C 1-9 alkyl), -S(O)2N (C1-9 alkyl), 2, -O (C 3-15 cycloalkyl), -O (C 1-8 haloalkyl), -O (C 6-10 aryl), -O (5 to 12 heteroaryl), -O (4 to 12 heterocyclic), or -O (C 1-9 alkyl); and R 17 and R 18 are independently selected from: H, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 ynylyl, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 12 heteroaryl, or 4 to 12 heterocyclic, wherein any alkyl, alkenyl, ynylyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted by one or more R 16.

7. The compound of claim 1 or 6 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein J is: .

8. The compound of claim 7 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein the Z group is optionally independently substituted with one or more R 13-substituted 5 to 10 heteroaryl groups.

9. The compound of claim 8 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

10. The compound of claim 1 or 6 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein J is: .

11. The compound of claim 10 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein the Z group is optionally independently substituted by one or more R 13-substituted 5 to 10 heteroaryl groups.

12. The compound of claim 10 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

13. The compound of claim 7 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive).

14. A compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 13 is independently selected from the group consisting of: H, halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, OCF 3, OCHF 2, NO 2, CN, O-R 14, C(O)-R 16, C(O)-N(R 17)(R 18), N(R 17)(R 18), N(R 17)C(O)-R 16, N(R 17)C(O)O-R 14, N(R 17)S(O) 2(R 16), -N(R 17)C(O)-N(R 18)(R 18), -SF 5, S(O) 2R 16. S(O)₂N(R₁₇)(R₁₈), S(O)(NH)R₁₇, S(O)(NR₁₇)NR₁₈, C₁-9 alkyl, C₂-9 alkenyl, and C₂-9 alkynyl. Any of the alkyl, alkenyl, or alkynyl groups may optionally be substituted with one or more R₁₃ groups.

15. The compound of claim 14 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 13 is independently selected from the group consisting of: H, halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, OCHF 2, OCF 3, N(R 17)(R 18), CN, O-R 14, and C(O)-R 16.

16. The compound of claim 15 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R2 is H.

17. A compound of claim 16 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H and R4 is C1-9 alkyl, C3-15 cycloalkyl, 4-12 heterocyclic, C6-10 aryl, or 5-12 heteroaryl. Any alkyl, alkenyl, or alkynyl group may optionally be substituted with one or more R13 groups.

18. The compound of claim 17 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R4 is methyl or ethyl.

19. The compound of claim 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein J is independently selected from the group consisting of:

20. The compound of claim 17 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is NH.

21. The compound of claim 20 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

22. The compound of claim 19 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is CH2.

23. The compound of claim 22 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

24. The compound of claim 19 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is NH and R is methyl or ethyl.

25. The compound of claim 24 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein J is: , .

26. The compound of claim 25 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

27. The compound of claim 26 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is selected from the group consisting of a free halogen group, CH3, CH2F, CHF2, CF3, and C(O)-R14.

28. The compound of claim 27 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is CF3.

29. The compound of claim 28 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

30. A compound of claim 1 or 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein J is: , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

31. The compound of claim 30 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

32. The compound of claim 31 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive), wherein R 13 is attached to any substituted position on Z.

33. The compound of claim 32 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R13 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)₂N(R₁₇)(R₁₈), S(O)(NH)R₁₇, S(O)(NR₁₇)NR₁₈, C₁-9 alkyl, C₂-9 alkenyl, C₂-9 ynyl, and C₃-15 cycloalkyl. Any of the alkyl, alkenyl, or ynyl groups may optionally be substituted with one or more R₁₀ groups.

34. The compound of claim 33 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 13 is selected from the group consisting of: halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, N(R 17)(R 18), CN, O-R 14, and C(O)-R 16.

35. The compound of claim 34 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R2 is H.

36. A compound of claim 35 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R3 is H and R4 is C1-9 alkyl or C3-15 cycloalkyl. Any of the alkyl or cycloalkyl groups may optionally be substituted with one or more R13 groups.

37. The compound of claim 36 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R4 is methyl or ethyl.

38. The compound of claim 37 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein J is independently selected from the group consisting of:

39. The compound of claim 38 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

40. The compound of claim 39, wherein R1 is a halogen group, CH3, CH2F, CHF2, CF3, and C(O)-R14.

41. The compound of claim 40, wherein R1 is CF3.

42. The compound of claim 41 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

43. The compound of claim 1 or 6, wherein J is: , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof.

44. The compound of claim 43, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

45. The compound of claim 44 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive), wherein R 13 is attached to any substituted position on Z.

46. ​​The compound of claim 44 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R13 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, and C3-15 cycloalkyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl may optionally be substituted with one or more R10s.

47. The compound of claim 46 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 13 is independently selected from the group consisting of: halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, N(R 17)(R 18), CN, O-R 14, and C(O)-R 16.

48. The compound of claim 47 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R2 is H.

49. A compound of claim 48 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R3 is H and R4 is C1-9 alkyl or C3-15 cycloalkyl. Any alkyl or cycloalkyl group may optionally be substituted with one or more R13 groups.

50. The compound of claim 49 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R4 is a methyl group.

51. The compound of claim 50 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is NH.

52. The compound of claim 48 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 5a, R 5b, R 6a, R 6b, R 7a, and R 7b are each H.

53. The compound of claim 48 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, and C(O)-R14.

54. The compound of claim 53, wherein R1 is CF3.

55. The compound of claim 54 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

56. The compound of claim 1, wherein J is: , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

57. The compound of claim 56 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein the Z series is selected from: ; wherein the w series is zero to three (inclusive); and the t series is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

58. The compound of claim 57, wherein w is one to two (inclusive); and t is one to three (inclusive), wherein R 13 is attached to any substituted position on Z.

59. A compound of claim 58 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R13 is independently selected from the group consisting of: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl may optionally be substituted with one or more R10.

60. The compound of claim 59 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 13 is selected from the group consisting of: halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, N(R 17)(R 18), CN, O-R 14, and C(O)-R 16.

61. The compound of claim 60 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R2 is H.

62. A compound of claim 60 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R3 is H and R4 is C1-9 alkyl or C3-15 cycloalkyl. Any alkyl or cycloalkyl group may optionally be substituted with one or more R13 groups.

63. The compound of claim 62 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R4 is methyl or ethyl.

64. The compound of claim 63 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is NH.

65. The compound of claim 64 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

66. The compound of claim 65 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, and C(O)-R14.

67. The compound of claim 66, wherein R1 is CF3.

68. The compound of claim 66 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is: .

69. The compound of claim 1 or 6 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein J is: .

70. The compound of claim 69 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein the Z group is optionally substituted with one or more R 13-substituted 5 to 10 heteroaryl groups.

71. The compound of claim 70 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

72. The compound of claim 71 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive), wherein R 13 is attached to any substituted position on Z.

73. The compound of claim 72 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R13 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl may optionally be substituted with one or more R10.

74. The compound of claim 73 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R 13 is selected from the group consisting of: halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, N(R 17)(R 18), CN, O-R 14, and C(O)-R 16.

75. The compound of claim 74 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R2 is H.

76. A compound of claim 74 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R3 is H and R4 is a C1-9 alkyl or C3-15 cycloalkyl. Any alkyl or cycloalkyl group may optionally be substituted with one or more R13 groups.

77. The compound of claim 76 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R4 is methyl or ethyl.

78. The compound of claim 76 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is NH.

79. The compound of claim 76 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is CH2.

80. The compound of claim 79 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

81. The compound of claim 80 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, and C(O)-R14.

82. The compound of claim 81, wherein R1 is CF3.

83. The compound of claim 82 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

84. The compound of claim 1 or 6 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein J is: .

85. The compound of claim 84 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein the Z group is optionally substituted with one or more R 13-substituted 5 to 10 heteroaryl groups.

86. A compound of claim 85 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

87. A compound of claim 86 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive), wherein R 13 is attached to any substituted position on Z.

88. A compound of claim 87 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R13 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl may optionally be substituted with one or more R10.

89. The compound of claim 88 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R 13 is selected from the group consisting of: halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, N(R 17)(R 18), CN, O-R 14, and C(O)-R 16.

90. The compound of claim 89 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R2 is H.

91. The compound of claim 90 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H and R4 is C1-9 alkyl or C3-15 cycloalkyl, wherein any alkyl or cycloalkyl may optionally be substituted with one or more R13.

92. The compound of claim 91 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R4 is methyl or ethyl.

93. The compound of claim 92 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is NH.

94. The compound of claim 92 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is CH2.

95. The compound of claim 94 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

96. The compound of claim 95 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, and C(O)-R14.

97. The compound of claim 96, wherein R1 is CF3.

98. The compound of claim 97 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

99. The compound of claim 1 or 6 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein J is: .

100. The compound of claim 99 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein the Z group is optionally substituted with one or more R 13-substituted 5 to 10 heteroaryl groups.

101. The compound of claim 100 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

102. The compound of claim 101 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive), wherein R 13 is attached to any substituted position on Z.

103. The compound of claim 102 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein R13 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)2N(R17)(R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl may optionally be substituted with one or more R10.

104. The compound of claim 103 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 13 is selected from the group consisting of: halogen, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, N(R 17)(R 18), CN, O-R 14, and C(O)-R 16.

105. The compound of claim 104 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R2 is H.

106. The compound of claim 105 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H and R4 is C1-9 alkyl or C3-15 cycloalkyl, wherein any alkyl or cycloalkyl may optionally be substituted with one or more R13.

107. The compound of claim 106 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R4 is methyl or ethyl.

108. The compound of claim 107 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is NH.

109. The compound of claim 99 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R5a, R5b, R6a, R6b, R7a, and R7b are each H.

110. The compound of claim 109 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is selected from the group consisting of: halogen, CH3, CH2F, CHF2, CF3, and C(O)-R14.

111. The compound of claim 110, wherein R1 is CF3.

112. The compound of claim 111 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

113. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein L1 and L3 together with the atoms to which they are attached form a 6-membered cycloalkyl or 6-membered heterocyclic group, each optionally substituted with one or more R15 groups.

114. The compound of claim 113 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein L1 and L3, together with the atoms to which they are attached, form a structure represented by: , wherein X6, X7, X8, X9, and X10 are independently CH2, CHR15, C=O, NR17, S, SO, SO2, or O, and wherein p is an integer from 0 to 10 (inclusive).

115. The compound of claim 114 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein L1 and L3 together with the atoms to which they are attached form a structure represented by: ; wherein p is an integer from 0 to 10 (inclusive).

116. The compound of claim 114 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein L1 and L3, together with the atoms to which they are attached, form a structure represented by the following:

117. A compound of any one of claims 113 to 116 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein J is selected from the group consisting of:

118. The compound of claim 117 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is an NH4+ group.

119. The compound of claim 118 or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of a free halogen group, CH3, CH2F, CHF2, CF3, and C(O)-R14.

120. The compound of claim 119 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is CF3.

121. The compound of claim 120 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein L4 is C.

122. The compound of claim 121 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 7a and R 7b are each H.

123. The compound of claim 121 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R7a and R7b are each CH3.

124. The compound of claim 121 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 7a is CH 3 and R 7b is H.

125. The compound of claim 122 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

126. The compound of claim 125 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive).

127. The compound of claim 126 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

128. A compound of claim 127 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R13 is independently selected from the group consisting of: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)₂N(R₁₇)(R₁₈), S(O)(NH)R₁₇, S(O)(NR₁₇)NR₁₈, C₁-9 alkyl, C₂-9 alkenyl, and C₂-9 alkynyl. Any of the alkyl, alkenyl, or alkynyl groups may optionally be substituted with one or more R₁₃ groups.

129. The compound of claim 128 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R 13 is independently selected from the group consisting of: H, halogen, NH 2, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, OCHF 2, OCF 3, CN, OR 14, and C(O)-R 16.

130. The compound of claim 129 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: .

131. The compound of claim 117 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is O.

132. The compound of claim 131 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is selected from the group consisting of a free halogen, CH3, CH2F, CHF2, CF3, and C(O)-R14.

133. The compound of claim 132 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is CF3.

134. The compound of claim 133 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein L4 is C.

135. The compound of claim 134 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 7a and R 7b are each H.

136. The compound of claim 134 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R7a and R7b are each CH3.

137. The compound of claim 134 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R 7a is CH 3 and R 7b is H.

138. The compound of claim 134 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is selected from: ; wherein w is zero to three (inclusive); and t is zero to four (inclusive), wherein R 13 is attached to any substituted position on Z.

139. The compound of claim 138 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein w is one to two (inclusive); and t is one to three (inclusive).

140. A compound of claim 139 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R13 is independently selected from the group consisting of: H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O-R14, C(O)-R16, C(O)-N(R17)(R18), N(R17)(R18), N(R17)C(O)-R16, N(R17)C(O)O-R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)(R18), -SF5, S(O)2R 16. S(O)₂N(R₁₇)(R₁₈), S(O)(NH)R₁₇, S(O)(NR₁₇)NR₁₈, C₁-9 alkyl, C₂-9 alkenyl, and C₂-9 alkynyl. Any of the alkyl, alkenyl, or alkynyl groups may optionally be substituted with one or more R₁₃ groups.

141. The compound of claim 140 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 13 is independently selected from the group consisting of: H, halogen, NH 2, CH 3, CH 2F, CHF 2, CF 3, CH 2CF 3, OCH 3, OCHF 2, OCF 3, CN, OR 14, and C(O)-R 16.

142. The compound of claim 141 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein Z is: .

143. A compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a deuterated analog thereof, selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , and.

144. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

145. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

146. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

147. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

148. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

149. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

150. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

151. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

152. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

153. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

154. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

155. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

156. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

157. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

158. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

159. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

160. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

161. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

162. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

163. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

164. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

165. The compound of claim 143 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is:

166. A pharmaceutical composition comprising a compound of any one of claims 1 to 164 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a deuterated analog thereof, and a pharmaceutically acceptable excipient.

167. A method of treating cancer, comprising administering to a patient in need a compound of any one of claims 1 to 164 or a pharmaceutical composition of claim 165, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

168. A pharmaceutical composition comprising a compound of any one of claims 1 to 157 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a deuterated analog thereof, and a pharmaceutically acceptable excipient.

169. A method of treating cancer, comprising administering to a patient in need a compound of any one of claims 1 to 157, or a pharmaceutical composition of claim 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.