PARP7 inhibitors

Abstract

Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, a pharmaceutical composition comprising the compound of the invention together with a pharma- ceutically acceptable excipient thereof, and a method of treating cancer therewith. TIFF2025503996000437.tif63128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) 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, each of which is incorporated herein in its entirety for all purposes. [Background technology]

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

[0003] Of particular interest is 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TIPARP), a CCCH-type zinc finger domain-containing protein (Proc. Nat. Acad. Sci. 114(10)2681-2686(2017)). TIPARP is also known as PARP7 and ARTD14. PARP7 acts as a negative regulator of specific aryl hydrocarbon receptor (AHR) transcriptional targets. AHR is then activated by many substrates, including cigarette smoke. PARP7 inhibitors have been shown to restore type I interferon (IFN) signaling responses to nucleic acids and induce tumor regression in an immunocompetent BALB / c mouse model bearing CT26 tumors (Gozgit, et al., Cancer Cell 39, 1214-1226(2021)).

[0004] There are currently no approved PARP7 inhibitory pharmaceuticals. It would therefore be useful to provide PARP7 inhibitor compounds with properties suitable for pharmaceutical administration to mammals, particularly humans. Therefore, there is a need for improved PARP7 inhibitors for cancer treatment. [Prior art documents] [Non-patent literature]

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

[0006] Compounds and pharmaceutical compositions useful as inhibitors of PARP7 are provided herein. Some compounds of the present disclosure can find use in pharmaceutical compositions, together with at least one pharmaceutically acceptable excipient, for treating a subject in need thereof.

[0007] In one embodiment of the present invention, a compound of formula (I) [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: J is [ka] and X 1 are N, C=O, CR 10 , or C-(R 10 )2, X 2 is N, NR 11 , C.R. 12 , or C-(R 12 )2, X 3 is N or CR 13 and X 4 is N or CR 13 and X 5 is N or CR 13 or A is, C, O, N, One or more R 15 3- to 10-membered cycloalkyl optionally substituted with One or more R 15 4-11 membered heterocyclyl optionally substituted with is selected from When A is O, n is 0; when A is N, n is 1; when A is C, n is 1 or 2; When A is N, n is 0 or 1, and L 1 is C or NR 17 and L 2 , L 3 and L 4 are C, respectively, L 1 , L 2 are independently C, C 6~10 aryl, 5- to 12-membered heteroaryl, or NH; L 3 and L 4 are C, respectively, or L 1 and L 2 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 1 and L 3 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 2 and L 3 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 3 and L 4 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 2 and L 4 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 The aryl or 5- to 12-membered heteroaryl may be one or more R 15 and wherein each is a monocyclic or bicyclic ring optionally substituted with ; R 1 H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, OR 14 , C(O)-R 14 , -SF5;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 , One or more R 15 C optionally substituted with 1~5 alkyl; or One or more R 15 C optionally substituted with 3~10 cycloalkyl; or One or more R 15 5-10 membered optionally substituted with heteroaryl; or One or more R 15 C optionally substituted with 6~10 aryl; or One or more R 15 4-7 membered optionally substituted with Heterocyclyl is selected from R 2 is H, C1-9 alkyl, C 2~9 Alkenyl, or C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 10 and optionally substituted with R 3 and R 4 are each independently H, C1-9 alkyl, C 2~9 Alkenyl, C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 15 , one or more R 15C optionally substituted with 3~12 cycloalkyl, one or more R 15 C optionally substituted with 6~10 Aryl, one or more R 15 4- to 11-membered heterocyclyl optionally substituted with, or one or more R 15 optionally substituted with a 5-10 membered heteroaryl optionally substituted with R 2 and R 3 together with the atoms to which they are attached, R 15 forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle optionally substituted with one or more of A 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl may be one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with R 3 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with R 2 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 and wherein the ring structure is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring structure, each optionally substituted with R 5a , R 5b R 6a , R 6b , R 7a R 7b are each independently H, halo, NO2, CN, OR14 , 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 One or more R 15 C optionally substituted with 1~9 alkyl; One or more R 15 C optionally substituted with 2~9 Alkynyl; One or more R 15 C optionally substituted with 2~9 Alkenyl; One or more R 15 5-12 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; One or more R 15 4- to 12-membered heterocyclyl optionally substituted with One or more R 15 C optionally substituted with 3~12 cycloalkyl or R 5a and R 5b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R 6a and R 6b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R7 a and R 7b together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with Z is H, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~8 Haloalkyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -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)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 -N(aryl), -N(5- to 12-membered heteroaryl), -N(4- to 12-membered heterocyclyl), -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 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C2~6 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-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl). , one or more R 13 5-12 membered heteroaryl substituted with; One or more R 15 C optionally substituted with 6~10 Aryl; one or more R 15 C optionally substituted with 3~12 cycloalkyl; one or more R 15 4-12 membered heterocyclyl substituted with and optionally substituted with wherein any 5- to 12-membered heteroaryl, C 6~10 Aryl, C 3~12 Cycloalkyl or 4- to 12-membered heterocyclyl may be one or more R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is substituted with one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each substituted with R 10 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR17 )NR 18 , C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 Aryl, 5-10 membered Heteroaryl or 4-12 membered and heterocyclyl, wherein any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 11 is H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 6- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 12 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 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 alkynyl, C3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 15 are independently H, C=O, hydroxy, halo, -NO2-N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -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)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 -N(aryl), -N(5- to 12-membered heteroaryl), -N(4- to 12-membered heterocyclyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C1~9 Alkyl)(C 2~6 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl) -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl). R 16 are independently H, C=O, halo, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OH, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6alkynyl), -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 heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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(5-12-membered heteroaryl)2-N(4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9alkyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -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 heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(NH)(C 3-9 cycloalkyl), -S(O)(C 1~9 Alkyl)(C 1~9 alkyl), -S(O)(NH)(C 6~10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 6~10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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 6~10aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl), and R 17 and R 18 are independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 is optionally substituted with one or more having In one embodiment of the present invention, a compound represented by formula (Ia) [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: J is [ka] and X 1are N, C=O, CR 10 , or C-(R 10 )2, X 2 is N, NR 11 , C.R. 12 , or C-(R 12 )2, X 3 is N or CR 13 and X 4 is N or CR 13 and X 5 is N or CR 13 or A is, C, O, N, One or more R 15 3 to 10-membered cycloalkyl optionally substituted with One or more R 15 4-11 membered heterocyclyl optionally substituted with is selected from When A is O, n is 0; when A is N, n is 1; when A is C, n is 1 or 2; R 1 H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, OR 14 , C(O)-R 14 , -SF5;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 )NR18 One or more R 15 C optionally substituted with 1~5 alkyl; or One or more R 15 C optionally substituted with 3~10 cycloalkyl; One or more R 15 5-10 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; or One or more R 15 4- to 7-membered heterocyclyl optionally substituted with is selected from R 2 is H, C1-9 alkyl, C 2~9 Alkenyl, or C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 10 and optionally substituted with R 3 and R 4 are each independently H, C1-9 alkyl, C 2~9 Alkenyl, C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 15 , one or more R 15 C optionally substituted with 3~12 cycloalkyl, one or more R 15 C optionally substituted with 6~10 Aryl, one or more R 15 4- to 11-membered heterocyclyl optionally substituted with, or one or more R 15 optionally substituted with a 5-10 membered heteroaryl optionally substituted with R 2 and R 3 together with the atoms to which they are attached, R 15 forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle optionally substituted with one or more of A 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl may be one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with R 3 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with R 5a , R 5b R 6a , R 6b , R 7a R 7b are each independently H, halo, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 One or more R 15 C optionally substituted with 1~9 alkyl; One or more R 15 C optionally substituted with 2~9 Alkynyl; One or more R 15C optionally substituted with 2~9 Alkenyl; One or more R 15 5-12 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; One or more R 15 4- to 12-membered heterocyclyl optionally substituted with One or more R 15 C optionally substituted with 3~12 cycloalkyl or R 5a and R 5b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R 6a and R 6b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R7 a and R 7b together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with Z is -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~8 Haloalkyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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(5-12-membered heteroaryl)2-N(h 4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -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 1~9alkyl)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9alkyl), -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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl). , one or more R 13 5-12 membered heteroaryl substituted with; One or more R 15 C optionally substituted with 6~10 Aryl; one or more R 15 C optionally substituted with 3~12 cycloalkyl; one or more R 15 4-12 membered heterocyclyl substituted with and optionally substituted with wherein any 5- to 12-membered heteroaryl, C 6~10 Aryl, C 3~12 Cycloalkyl or 4- to 12-membered heterocyclyl may be one or more R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is substituted with one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each substituted with R 10H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, 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 alkynyl, C 3~15 Cycloalkyl, C 6~10 Aryl, 5-10 membered Heteroaryl or 4-12 membered and heterocyclyl, wherein any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 11 is H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 6- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl; where any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is R 16 and optionally substituted with one or more of: R 12H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 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 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R18 )(R 18 ), -SF5, 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 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl; where any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is R 16 and optionally substituted with one or more of: R 15 are independently H, C=O, hydroxy, halo, -NO2-N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -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)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-NH(C1~9 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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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(5-12-membered heteroaryl)2-N(h 4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl) -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl). R 16 are independently H, C=O, halo, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OH, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 6~10aryl)2-N(5-12-membered heteroaryl)2-N(4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 6~10aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -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 heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(NH)(C 3-9 cycloalkyl), -S(O)(C 1~9 Alkyl)(C 1~9 alkyl), -S(O)(NH)(C 6~10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2; Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more halo, C 1~9 Alkyl, C1~8 Haloalkyl, -OH, -NH2, -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 heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl), and R 17 and R18 are independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 is optionally substituted with one or more having

[0008] The compounds of the present invention, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogues thereof, can also be used in combination with pharmaceutically acceptable carriers. Add to Also provided are pharmaceutical compositions comprising the agent.

[0009] Further provided is a method of treating cancer in a subject in need thereof, comprising administering to the patient a compound of the invention or a pharmaceutical composition comprising a compound of the invention. In one embodiment, for example, the following items are provided: (Item 1) Compounds of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: J is [ka] and X 1 are N, C=O, CR 10 , or C-(R 10 )2, X 2 is N, NR 11 , C.R. 12 , or C-(R 12 )2, X 3 is N or CR 13 and X 4is N or CR 13 and X 5 is N or CR 13 or A is, C, O, N, One or more R 15 3 to 10-membered cycloalkyl optionally substituted with One or more R 15 4-11 membered heterocyclyl optionally substituted with is selected from When A is O, n is 0; when A is N, n is 1; when A is C, n is 1 or 2; When A is N, n is 0 or 1, and L 1 is C or NR 17 and L 2 , L 3 and L 4 are C, respectively, L 1 , L 2 are independently C, C 6~10 aryl, 5- to 12-membered heteroaryl, or NH; L 3 and L 4 are C, respectively, or L 1 and L 2 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 1 and L 3 together with the atoms to which they are attached, R 153 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 2 and L 3 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 3 and L 4 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 2 and L 4 together with the atoms to which they are attached, R 15 one or more 3 to 12-membered cycloalkyl, each optionally substituted with 6~10The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 The aryl or 5- to 12-membered heteroaryl may be one or more R 15 and wherein each is a monocyclic or bicyclic ring optionally substituted with ; R 1 H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, OR 14 , C(O)-R 14 , -SF5;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 , One or more R 15 C optionally substituted with 1~5 alkyl; or One or more R 15 C optionally substituted with 3~10 cycloalkyl; or One or more R 15 5-10 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; or One or more R 154- to 7-membered heterocyclyl optionally substituted with is selected from R 2 is H, C1-9 alkyl, C 2~9 Alkenyl, or C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 10 and optionally substituted with R 3 and R 4 are each independently H, C1-9 alkyl, C 2~9 Alkenyl, C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 15 , one or more R 15 C optionally substituted with 3~12 cycloalkyl, one or more R 15 C optionally substituted with 6~10 Aryl, one or more R 15 4- to 11-membered heterocyclyl optionally substituted with, or one or more R 15 optionally substituted with a 5-10 membered heteroaryl optionally substituted with R 2 and R 3 together with the atoms to which they are attached, R 15 forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle optionally substituted with one or more of A 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl may be one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with R 3 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with R 2 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 and wherein the ring structure is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring structure, each optionally substituted with R 5a , R 5b R 6a , R 6b , R 7a R 7b are each independently H, halo, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , One or more R 15 C optionally substituted with 1~9 alkyl; One or more R 15 C optionally substituted with 2~9 Alkynyl; One or more R 15 C optionally substituted with 2~9 Alkenyl; One or more R 15 5-12 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; One or more R 15 4-12 membered optionally substituted with heterocyclyl; or One or more R 15 C optionally substituted with 3~12 cycloalkyl or R 5a and R 5b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R 6a and R 6b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R7 a and R 7b together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with Z is H, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~8 Haloalkyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 -N(aryl), -N(5- to 12-membered heteroaryl), -N(4- to 12-membered heterocyclyl), -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 alkynyl), -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)(5-12 membered heteroaryl), -N(C1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N (C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6alkenyl), -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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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 1~8haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5 -O(4- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl). One or more R 13 5-12 membered heteroaryl substituted with; One or more R 15 C optionally substituted with 6~10 Aryl; one or more R 15 C optionally substituted with 3~12 cycloalkyl; one or more R 15 4-12 membered heterocyclyl substituted with and optionally substituted with wherein any 5- to 12-membered heteroaryl, C 6~10 Aryl, C 3~12 Cycloalkyl or 4- to 12-membered heterocyclyl may be one or more R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is substituted with one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each substituted with R 10H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, 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 alkynyl, C 3~15 Cycloalkyl, C 6~10 Aryl, 5-10 membered Heteroaryl or 4-12 membered and heterocyclyl, wherein any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 11 is H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 6- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl; where any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is R 16 and optionally substituted with one or more of: R 12H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 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 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R18 )(R 18 ), -SF5, 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 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 15 are independently H, C=O, hydroxy, halo, -NO2-N3, -CN, C1 ~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -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 6~10aryl), -OC(O)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 -N(aryl), -N(5- to 12-membered heteroaryl), -N(4- to 12-membered heterocyclyl), -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 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C2~6 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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl) -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 Ants -NHC(O)NH(5-12 membered heteroaryl), -NHC(O)NH(4-12 membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl). R 16 are independently H, C=O, halo, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OH, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 3~15cycloalkyl)2-N(C 1~8 haloalkyl)2-N(C 6~10 aryl)2-N(5-12-membered heteroaryl)2-N(4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 Al -N(C 1~9 Alkyl)(C 2~6 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C1~8 haloalkyl), -C(O)NH(C 6~10 aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -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 heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(NH)(C 3-9 cycloalkyl), -S(O)(C 1~9 Alkyl)(C 1~9 alkyl), -S(O)(NH)(C 6~10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl), and R 17 and R 18 are independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of The compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 2) L 1 and L 2 together with the atoms to which they are attached, R 15 and the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl optionally substituted with one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with The compound according to item 1. (Item 3) L 2 and L 3 together with the atoms to which they are attached, R 15 and the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more of R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with The compound according to item 1. (Item 4) L 3 and L 4 together with the atoms to which they are attached, R 15and the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl optionally substituted with one or more R 1 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with The compound according to item 1. (Item 5) L 2 and L 4 together with the atoms to which they are attached, R 15 and the 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more of R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with The compound according to item 1. (Item 6) The compound has the formula Ia [ka] wherein J is [ka] and X 1 are N, C=O, CR 10 , or C-(R 10 )2, X 2 is N, NR 11 , C.R. 12 , or C-(R 12 )2, X 3 is N or CR 13 and X 4 is N or CR 13 and X 5 is N or CR 13 or A is, C, O, N, One or more R15 3 to 10-membered cycloalkyl optionally substituted with One or more R 15 4-11 membered heterocyclyl optionally substituted with is selected from When A is O, n is 0; when A is N, n is 1; when A is C, n is 1 or 2; R 1 H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, OR 14 , C(O)-R 14 , -SF5;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 One or more R 15 C optionally substituted with 1~5 alkyl; or One or more R 15 C optionally substituted with 3~10 cycloalkyl; One or more R 15 5-10 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; or One or more R 15 4- to 7-membered heterocyclyl optionally substituted with is selected from R2 is H, C1-9 alkyl, C 2~9 Alkenyl, or C 2~9 Selected from alkynyl The alkyl, alkenyl, and alkynyl groups each may be selected from one or more R 10 and optionally substituted with R 3 and R 4 are each independently H, C1-9 alkyl, C 2~9 Alkenyl, C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 15 , one or more R 15 C optionally substituted with 3~12 cycloalkyl, one or more R 15 C optionally substituted with 6~10 Aryl, one or more R 15 4- to 11-membered heterocyclyl optionally substituted with, or one or more R 15 optionally substituted with a 5-10 membered heteroaryl optionally substituted with R 2 and R 3 together with the atoms to which they are attached, R 15 forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle optionally substituted with one or more of A 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl may be one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with R 3 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with R 5a , R5b R 6a , R 6b , R 7a R 7b are each independently H, halo, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 One or more R 15 C optionally substituted with 1~9 alkyl; One or more R 15 C optionally substituted with 2~9 Alkynyl; One or more R 15 C optionally substituted with 2~9 Alkenyl; One or more R 15 5-12 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; One or more R 15 4- to 12-membered heterocyclyl optionally substituted with One or more R 15 C optionally substituted with 3~12 cycloalkyl or R 5a and R 5btogether with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R 6a and R 6b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R7 a and R 7b together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with Z is -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~8 Haloalkyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -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)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-NH(C1~9 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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 -N(aryl), -N(5- to 12-membered heteroaryl), -N(4- to 12-membered heterocyclyl), -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 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S( O)(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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2-NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2-N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl). One or more R 13 5-12 membered heteroaryl substituted with; One or more R 15 C optionally substituted with 6~10 Aryl; one or more R 15 C optionally substituted with 3~12 cycloalkyl; one or more R 15 4-12 membered heterocyclyl substituted with and optionally substituted with wherein any 5- to 12-membered heteroaryl, C 6~10 Aryl, C 3~12 Cycloalkyl or 4- to 12-membered heterocyclyl may be one or more R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is substituted with one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each substituted with R 10 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, 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 alkynyl, C 3~15 Cycloalkyl, C 6~10 Aryl, 5-10 membered Heteroaryl or 4-12 membered and heterocyclyl, wherein any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 11 is H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 6- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl; where any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is R 16 and optionally substituted with one or more of: R 12 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R18 )(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 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R16 and optionally substituted with one or more of: R 15 are independently H, C=O, hydroxy, halo, -NO2-N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -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)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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 1~8haloalkyl)2-N(C 6~10 aryl)2-N(5-12-membered heteroaryl)2-N(h 4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -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)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl) , -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -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)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2-NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2-N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 Alkini -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl), R 16 are independently H, C=O, halo, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OH, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -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 heterocyclyl), -NH2-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-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -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(5-12-membered heteroaryl)2-N(4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -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)(5-12 membered heteroaryl), -N(C1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -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 heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -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 heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(NH)(C 3-9 cycloalkyl), -S(O)(C1~9 Alkyl)(C 1~9 alkyl), -S(O)(NH)(C 6~10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -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)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9alkyl), -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(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(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 heterocyclyl), or -O(C 1~9 alkyl), and R 17 and R 18 are independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of Item 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 7) J is a group having the formula: [ka] 7. The compound according to claim 1 or 6, wherein: (Item 8) Z independently represents one or more R 13 8. The compound of claim 7, wherein R is 5-10 membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 9) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached to any substitutable position on Z, 9. A compound according to item 8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 10) 7. The compound according to claim 1 or 6, wherein J is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 11) Z independently represents one or more R 13 11. The compound of item 10, wherein R is 5-10 membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 12) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached to any substitutable position on Z, Item 10. The compound according to item 10, or a pharmaceutically acceptable salt, stereoisomer, or stereoisomeric form thereof. A mixture of these compounds, or deuterated analogs. (Item 13) 8. The compound according to item 7, wherein w is 1 to 2, inclusive, and t is 1 to 3, inclusive, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 14) R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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, and C2-9 alkynyl, wherein any alkyl, alkenyl, or alkynyl is selected from the group consisting of R 13 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 15) R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH 3、 OCHF2, OCF3, N(R 17 )(R 18 ), CN, OR 14 , and C(O)-R16 15. The compound according to item 14, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 16) R 2 is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 17) R 3 is H and R 4 is C1-9 alkyl, C 3~15 Cycloalkyl, 4-12 membered heterocyclyl, C 6~10 17. The compound of claim 16, wherein R is aryl, or 5- to 12-membered heteroaryl, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein any alkyl, alkenyl, or alkynyl is R 13 is optionally substituted with one or more having (Item 18) R 4 18. The compound according to item 17, wherein is methyl or ethyl, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 19) J is independent, The following formula: [ka] 19. The compound according to item 18, selected from the group consisting of: (Item 20) 18. The compound according to item 17, wherein A is NH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 21) R 5a , R 5b , R 6a , R 6b R 7a , and R 7band each are H, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. , or deuterated analogs. (Item 22) 20. The compound according to item 19, wherein A is CH2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 23) R 5a , R 5b , R 6a , R 6b R 7a , and R 7b 23. The compound according to item 22, wherein each of R, R, and R is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 24) A is NH and R 4 20. The compound according to item 19, wherein is methyl or ethyl, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 25) J is a group having the formula: [ka] 25. The compound according to item 24, wherein: (Item 26) R 5a , R 5b , R 6a , R 6b R 7a , and R 7b 26. The compound according to item 25, wherein each is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 27) R 1 Halo, CH3, CH2F, CHF2, CF3, and C(O)-R 14 27. The compound according to item 26, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 28) R 1 28. The compound according to item 27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein is CF3. (Item 29) 29. The compound according to item 28, wherein Z is selected from the following formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 30) J, [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof; A compound according to item 1 or item 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 31) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached to any substitutable position on Z, 31. The compound according to item 30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 32) w is 1 to 2 inclusive, t is 1 to 3 inclusive, and R 13 But the assignment on Z 32. The compound according to claim 31, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: (Item 33) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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 alkynyl, and C 3~15 cycloalkyl, wherein any alkyl, alkenyl, or alkynyl is selected from the group consisting of R 10 33. The compound of claim 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 34) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH 3、 N(R 17 )(R 18 ), CN, OR 14 , and C(O)-R 16 34. The compound according to item 33, selected from the group consisting of: (Item 35) R 2 35. The compound according to item 34, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 36) R 3 is H and R 4is C1-9 alkyl or C 3~15 cycloalkyl, where any alkyl or cycloalkyl is R 13 36. The compound of claim 35, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, optionally substituted with one or more of: (Item 37) R 4 37. The compound according to item 36, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein is methyl or ethyl. (Item 38) J is independent, The following formula: [ka] 38. The compound according to item 37, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 39) R 5a , R 5b , R 6a , R 6b R 7a , and R 7b 39. The compound according to item 38, wherein each of (Item 40) R 1 Halo, CH3, CH2F, CHF2, CF3, and C(O)-R 14 Item 39. The compound according to item 39, wherein (Item 41) R 1 41. The compound according to item 40, wherein is CF3. (Item 42) 42. The compound according to item 41, wherein Z is selected from the following formula: a salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 43) J, [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof; The compound according to item 1 or 6. (Item 44) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached to any substitutable position on Z. (Item 45) w is 1 to 2 inclusive, t is 1 to 3 inclusive, and R 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 46) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, S(O)2R 16 , S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR18 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, and C3- 15 cycloalkyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is selected from the group consisting of R 10 45. The compound of claim 44, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 47) R 13 but independently halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH 3、 N(R 17 )(R 18 ), CN, OR 14 , and C(O)-R 16 47. The compound according to item 46, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 48) R 2 48. The compound according to item 47, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 49) R 3 is H and R 4 is C1-9 alkyl or C3- 15 cycloalkyl, where any alkyl or cycloalkyl is R 13 49. The compound of claim 48, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 50) R 4 50. The compound according to item 49, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein is methyl. (Item 51) 51. The compound according to item 50, wherein A is NH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 52) R 5a , R 5b , R 6a , R 6b R 7a , and R 7b 49. The compound according to item 48, wherein each is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 53) R 1 Halo, CH3, CH2F, CHF2, CF3, and C(O)-R 14 49. The compound according to item 48, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 54) R 1 54. The compound according to item 53, wherein is CF3. (Item 55) 55. The compound according to item 54, wherein Z is selected from the following formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 56) J, [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. (Item 57) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. (Item 58) w is 1 to 2 inclusive, t is 1 to 3 inclusive, and R13 is attached to any substitutable position on Z. (Item 59) R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3 ,OCH3,OCF3,OCHF2,NO2,CN,OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is selected from the group consisting of R 10 59. The compound of claim 58, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 60) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH 3、 N(R 17 )(R 18 ), CN, OR 14 , and C(O)-R 16 60. The compound according to item 59, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 61) R 2 61. The compound according to item 60, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 62) R 3 is H and R 4 is C1-9 alkyl or C3- 15 61. The compound according to item 60, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein any alkyl or cycloalkyl is R 13 is optionally substituted with one or more having (Item 63) R 4 63. The compound according to item 62, wherein is methyl or ethyl, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 64) 64. The compound according to item 63, wherein A is NH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 65) R 5a , R 5b , R 6a , R 6b R 7a , and R 7b 65. The compound according to item 64, wherein each is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 66) R 1 Halo, CH3, CH2F, CHF2, CF3, and C(O)-R 14 66. The compound according to item 65, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 67) R 1 67. The compound according to item 66, wherein is CF3. (Item 68) 67. The compound according to item 66, wherein Z is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 69) 7. The compound according to claim 1 or 6, wherein J is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 70) Z is one or more R 13 70. The compound of item 69, wherein R is 5-10 membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 71) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 72) w is 1 to 2 inclusive, t is 1 to 3 inclusive, and R 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 73) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is selected from the group consisting of R 10 73. The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, optionally substituted with one or more of: (Item 74) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH 3、 N(R 17 )(R 18 ), CN, OR 14 , and C(O)-R 16 74. The compound according to item 73, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 75) R 2 75. The compound according to item 74, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 76) R 3 is H and R 4 is C1-9 alkyl or C3- 15 cycloalkyl, where any alkyl or cycloalkyl is R 1375. The compound of item 74, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 77) R 4 77. The compound according to item 76, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein is methyl or ethyl. (Item 78) 77. The compound according to item 76, wherein A is NH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 79) 77. The compound according to item 76, wherein A is CH2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 80) R 5a , R 5b , R 6a , R 6b R 7a , and R 7b 79. The compound according to item 79, wherein each is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 81) R 1 Halo, CH3CH2F, CHF2, CF3, and C(O)-R 14 81. The compound according to item 80, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 82) R 1 82. The compound according to item 81, wherein is CF3. (Item 83) 83. The compound according to item 82, wherein Z is selected from the following formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 84) 7. The compound according to claim 1 or 6, wherein J is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 85) Z is one or more R 13 85. The compound of item 84, wherein R is 5-10 membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 86) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 87) w is 1 to 2 inclusive, t is 1 to 3 inclusive, and R 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 88) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R18 )(R 18 ), -SF5, 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, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is selected from the group consisting of R 10 88. The compound of item 87, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 89) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH 3、 N(R 17 )(R 18 ), CN, OR 14 , and C(O)-R 16 89. The compound according to item 88, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 90) R 2 89. The compound according to item 89, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 91) R 3 is H and R 4 is C1-9 alkyl or C3- 15 cycloalkyl, and any alkyl or cycloalkyl is R 13 91. The compound of claim 90, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, optionally substituted with one or more of: (Item 92) R 4 92. The compound according to item 91, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein is methyl or ethyl. (Item 93) 93. The compound according to item 92, wherein A is NH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 94) 93. The compound according to item 92, wherein A is CH2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 95) R 5a , R 5b , R 6a , R 6b R 7a , and R 7b 95. The compound according to item 94, wherein each is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 96) R 1 Halo, CH3CH2F, CHF2, CF3, and C(O)-R 14 96. The compound according to item 95, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 97) R 1 97. The compound according to item 96, wherein is CF3. (Item 98) 98. The compound according to item 97, wherein Z is selected from the following formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 99) 7. The compound according to claim 1 or 6, wherein J is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 100) Z is one or more R 1399. The compound of claim 99, wherein R is 5-10 membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 101) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 102) w is 1 to 2 inclusive, t is 1 to 3 inclusive, and R 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 103) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is selected from the group consisting of R 10 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 104) R 13 Halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH 3、 N(R 17 )(R 18 ), CN, OR 14 , and C(O)-R 16 104. The compound according to item 103, selected from the group consisting of: (Item 105) R 2 is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 106) R 3 is H and R 4 is C1-9 alkyl or C3- 15 cycloalkyl, and any alkyl or cycloalkyl is R 13 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 107) R 4 is methyl or ethyl, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 108) 108. The compound according to item 107, wherein A is NH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 109) R 5a , R5b , R 6a , R 6b R 7a , and R 7b 99. The compound according to item 99, wherein each is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 110) R 1 Halo, CH3CH2F, CHF2, CF3, and C(O)-R 14 109. The compound according to item 109, selected from the group consisting of: (Item 111) R 1 111. The compound according to item 110, wherein is CF3. (Item 112) 112. The compound according to item 111, wherein Z is selected from the following formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 113) L 1 and L 3 together with the atoms to which they are attached, R 15 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 114) L 1 and L 3 together with the atoms to which they are bonded, [ka] wherein X 6 , X 7 , X 8 , X 9 and X 10 are independently CH2, CHR 15, C=O, NR 17 , S, SO, SO2, or O, and p is an integer from 0 to 10, inclusive, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 115) L 1 and L 3 together with the atoms to which they are bonded, [ka] wherein p is an integer from 0 to 10 inclusive, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 116) L 1 and L 3 together with the atoms to which they are attached form the following formula: [ka] 115. The compound according to item 114, which forms a structure represented by: (Item 117) 117. The compound according to any one of items 113 to 116, wherein J is selected from the group consisting of: [ka] (Item 118) 118. The compound according to item 117, wherein A is NH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 119) R 1 Halo, CH3, CH2F, CHF2, CF3, and C(O)-R 14119. The compound according to item 118, selected from the group consisting of: (Item 120) R 1 119. The compound according to item 119, wherein is CF3, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 121) L 4 121. The compound according to item 120, wherein is C, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 122) R 7a and R 7b and R are each H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 123) R 7a and R 7b and each is CH3, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 124) R 7a is CH3 and R 7b 122. The compound according to item 121, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 125) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 126) 126. The compound of item 125, wherein w is 1 to 2, inclusive, and t is 1 to 3, inclusive, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 127) 127. The compound according to item 126, wherein Z is selected from the following formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 128) R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, 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, and C2-9 alkynyl where any alkyl, alkenyl, or alkynyl is R 13 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 129) R 13are independently H, halo, NH2, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCHF2, OCF3, CN, OR 14 , and C(O)-R 16 129. The compound according to item 128, selected from the group consisting of: (Item 130) 129. The compound according to item 129, wherein Z is selected from the following formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 131) 118. The compound according to item 117, wherein A is O, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 132) R 1 Halo, CH3, CH2F, CHF2, CF3, and C(O)-R 14 132. The compound according to item 131, selected from the group consisting of: (Item 133) R 1 133. The compound according to item 132, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein is CF3. (Item 134) L 4 134. The compound according to item 133, wherein is C, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 135) R 7a and R 7b and R are each H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 136) R 7a and R 7band each is CH3, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 137) R 7a is CH3 and R 7b is H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 138) Z, [ka] wherein w is 0 to 3, inclusive, and t is 0 to 4, inclusive; 13 is attached at any substitutable position on Z, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 139) 139. The compound according to item 138, wherein w is 1 to 2, inclusive, and t is 1 to 3, inclusive, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. (Item 140) R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 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)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, S(O)2R 16 , S(O)2N(R 17 )(R18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, or alkynyl is selected from the group consisting of R 13 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, optionally substituted with one or more of: (Item 141) R 13 are independently H, halo, NH2, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCHF2, OCF3, CN, OR 14 , and C(O)-R 16 141. The compound according to item 140, selected from the group consisting of: (Item 142) Z is a group having the formula: [ka] 142. The compound according to item 141, wherein: (Item 143) [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Item 144) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 145) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 146) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 147) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 148) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 149) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 150) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 151) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 152) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 153) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 154) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 155) The following formula: [ka] 144. The compound according to item 143, wherein: , a mixture of stereoisomers, or a deuterated analogue. (Item 156) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 157) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 158) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 159) 144. The compound according to item 143, which is of the formula: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. [ka] (Item 160) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 161) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 162) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 163) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 164) The following formula: [ka] 144. The compound according to item 143, wherein: (Item 165) [ka] 144. The compound according to item 143, wherein: (Item 166) A compound according to any one of items 1 to 164, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a pharmaceutically acceptable Add to and a pharmaceutical composition comprising: (Item 167) A method for treating cancer, comprising administering to a patient in need thereof a compound according to any one of items 1 to 164 or a pharmaceutical composition according to item 165, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. (Item 168) A compound according to any one of items 1 to 157, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a pharmaceutically acceptable Add to and a pharmaceutical composition comprising: (Item 169) A method for treating cancer, comprising administering to a patient in need thereof a compound according to any one of items 1 to 157 or a pharmaceutical composition according to item 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. DETAILED DESCRIPTION OF THE INVENTION

[0010] I. Definition The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0011] The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0012] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes before or after chemical groups are for convenience; chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0013] Wavy line [ka] indicates the point of attachment. "C u~v The prefix "" indicates that the following group has carbon atoms u through v. For example, "C 1~6 "Alkyl group" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0014] Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, for that term, "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0015] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2)).

[0016] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or having 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0017] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or having 2 to 4 carbon atoms (i.e., C 2~4 "alkynyl" refers to an alkyl group. The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0018] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0019] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms have been replaced by a halogen.

[0020] "Alkylthio" refers to the group "alkyl-S-".

[0021] "Amino" is the group -NR y R y where each R yis independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0022] "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 refers to a group having 6 to 20 carbon ring atoms (i.e., C 6~20 aryl), having 6 to 12 carbon ring atoms (i.e., C 6~10 aryl), or having 6 to 10 carbon ring atoms (i.e., C 6~10 (aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0023] "Cyano" refers to the group --CN.

[0024] "Keto" refers to the group C=O.

[0025] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group refers to the group, and -NR y C(O)OR z "N-carbamoyl group" refers to both the "N-carbamoyl group" and the "N-carbamoyl group" y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which can be optionally substituted.

[0026] "Carboxyl" refers to -C(O)OH.

[0027] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent, each of which can be optionally substituted as defined herein.

[0028] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms have been replaced by a halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0030] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl contains 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.

[0031] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having 1 to 20 ring carbon atoms (i.e., C 1~20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3~8Heteroaryl) and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached via any ring of the fused system. Any aromatic ring having single or multiple fused rings containing at least one heteroatom is considered heteroaryl regardless of attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0032] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bicyclic heterocyclyl groups, bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, and polycyclic rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of attachment (i.e., it can be attached via a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass rings in which any non-aromatic ring containing at least one heteroatom may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl has 2 to 20 ring atoms (i.e., 4-20-membered heterocyclyl), 2 to 12-membered heterocyclyl, 4 to 10 ring atoms (i.e., 4-10-membered heterocyclyl), 4 to 8 ring atoms (i.e., 4-8-membered heterocyclyl), or 4 to 6 ring carbon atoms (i.e., 4-6-membered heterocyclyl), and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. The heterocyclyl may contain one or more C=O and / or thioC=O groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, diC=Oranyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 4- to 7-membered sultam, 4- to 7-membered cyclic carbamate, 4- to 7-membered cyclic carbonate, 4- to 7-membered cyclic sulfide, and morpholinyl.As used herein, the term "bridged heterocyclyl" refers to a 4- to 10-membered ring moiety in which two non-adjacent atoms of a heterocyclyl having one or more (e.g., one or two) 4- to 10-membered ring moieties are connected, each heteroatom independently, to at least one heteroatom selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also, as used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, wherein the one or more additional rings are 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, and wherein a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl 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]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group attached at two points to another cyclic group, which may itself be a heterocyclic group or a carbocyclic group.

[0033] 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 the ring structure. It is understood that other heteroatoms, including oxygen, may be present in addition to nitrogen, sulfur, or a combination thereof. Examples of nitrogen- or sulfur-containing heterocyclyls include morpholinyl, thiomorpholinyl, thiazolyl, isothiazolyl, oxazolidinone 1,2-dithiolyl, piperidinyl, piperazinyl, and the like.

[0034] "Hydroxy" or "hydroxyl" refers to the group -OH. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms has been replaced by hydroxyl.

[0035] "Nitro" refers to the -NO2 group.

[0036] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or defined group.

[0037] "Alkylsulfonyl" refers to the group -S(O)2R, where R is a substituent or defined group.

[0038] "Alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or defined group.

[0039] "Thiocyanate" -SCN.

[0040] "Thiol" refers to the group -SR, where R is a substituent or defined group.

[0041] "ThiC=O" or "thione" refers to the (=S) or (S) group.

[0042] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as one moiety, e.g., arylalkyl, the last-mentioned group contains the atom by which the moiety is attached to the remainder of the molecule.

[0043] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a non-hydrogen moiety. "Optionally substituted" may be from 0 to the maximum number of possible substitutions, and each occurrence is independent. When the term "substituted" is used, the substitution must be on a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from the (required) substitution.

[0044] When a moiety is "optionally substituted" and reference is made to any general term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," this general term includes (C- 1~3 alkyl), (C 4~6 alkyl), -O(C 1~4 alkyl), (C 3~10 cycloalkyl), O-(C 3~10

[0033] The term "any heterocyclyl" can refer to any preceding specifically recited term, such as aryl, cycloalkyl, or aryl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryl such as phenyl or naphthyl. Also, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyl such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl, and the like. Similarly, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heterolyl)," as well as specific heteroaryls such as pyridine.

[0045] Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0046] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, 3 H, 13 C and 14 and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients.

[0047] The present disclosure also includes "deuterated analogs" of compounds of Formula I in which one to n hydrogens bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0048] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0049] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0050] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0051] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0052] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts containing inorganic acids and salts containing organic acids. In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines

[0033] Suitable amines include, but are not limited to, primary, secondary, and tertiary amines such as (substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0053] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, C=O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining the substituents with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. Unless otherwise specified, if a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted, and those skilled in the art will recognize that the substituents and other moieties of the compounds of the general formula herein should be selected to provide a compound that is sufficiently stable to provide a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds with such stability are considered to be within the scope of the present invention. Those skilled in the art should understand that any combination of the above definitions and substituents should not result in an inoperable species or compound.

[0054] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable Add to "Agents" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0055] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0056] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as one moiety, e.g., arylalkyl, the last-mentioned group contains the atom by which the moiety is attached to the remainder of the molecule.

[0057] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a non-hydrogen moiety. "Optionally substituted" may be from 0 to the maximum number of possible substitutions, and each occurrence is independent. When the term "substituted" is used, the substitution must be on a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from the (required) substitution.

[0058] When a moiety is "optionally substituted" and reference is made to any general term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," this general term includes (C- 1~3 alkyl), (C 4~6 alkyl), -O(C 1~4 alkyl), (C 3~10 cycloalkyl), O-(C 3~10

[0033] The term "any heterocyclyl" can refer to any preceding specifically recited term, such as aryl, cycloalkyl, or aryl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryl such as phenyl or naphthyl. Also, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyl such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl, and the like. Similarly, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heterolyl)," as well as specific heteroaryls such as pyridine.

[0059] Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0060] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, 3 H, 13 C and 14 and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients.

[0061] The present disclosure also includes "deuterated analogs" of compounds of Formula I in which one to n hydrogens bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0062] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0063] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0064] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0065] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0066] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts containing inorganic acids and salts containing organic acids. In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines

[0033] Suitable amines include, but are not limited to, primary, secondary, and tertiary amines such as (substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0067] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, C=O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining the substituents with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. Unless otherwise specified, if a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted, and those skilled in the art will recognize that the substituents and other moieties of the compounds of the general formula herein should be selected to provide a compound that is sufficiently stable to provide a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds with such stability are considered to be within the scope of the present invention. Those skilled in the art should understand that any combination of the above definitions and substituents should not result in an inoperable species or compound.

[0068] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable Add to "Agents" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0069] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable Add to "Agents" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0070] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided. II. Combination

[0071] Patients treated by administering the PARP7 inhibitors of the present disclosure often exhibit diseases or conditions that would benefit from treatment with other therapeutic agents. These diseases or conditions may be of an oncological nature or may be associated with inflammation, metabolic disorders, gastrointestinal disorders, etc. Accordingly, one aspect of the present disclosure is a method for treating cancer, comprising administering to a subject, particularly a human subject, a compound in combination with one or more compounds useful for treating such diseases.

[0072] In some embodiments, the compounds of the present disclosure are co-formulated with one or more additional active ingredients. In some embodiments, the other active ingredients are administered approximately simultaneously in separate dosage forms. In some embodiments, the other active ingredients are administered sequentially and may be administered at different times relative to the compounds of the present disclosure.

[0073] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more (e.g., 1, 2, 3, or 4) additional therapeutic agents. In some embodiments, the additional therapeutic agent is selected from the group consisting of, for example, an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist, or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferative agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (e.g., monospecific and multispecific antibodies in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimic (e.g., adnectin, affibody molecule, affilin, affimer, afftin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein, and the like). protein, DARPin®), finomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifying or editing agents, cells comprising a chimeric antigen receptor (CAR), engineered T cell receptors (TCR-T), including, for example, T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics, or any combination thereof. Exemplary Targets

[0074] In some embodiments, the one or more additional therapeutic agents include, for example, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator, or suppressor of a target (e.g., a polypeptide or polynucleotide), such as: 2'-5'-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5'-nucleotidase ecto (NT5E, CD73; NCBI Gene ID: 4907); ABL gene Oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); Absent-in-melanoma 2 (AIM2; NCBI Gene ID: 9447); Acetyl-CoA acyltransferase 2 (ACAA2; NCBI Gene ID: 10499); Acid phosphatase 3 (ACP3; NCBI Gene ID: 55); Adenosine deaminase (ADA, ADA1; NCBI Gene ID: 100); Adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA 2B (A2b, A2BR), ADORA3 (A3); NCBI Gene ID: 134, 135, 136, 137); AKT serine / threonine kinase 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase, membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha-fetoprotein (AFP; NCBI Gene ID: 174); amine oxidase copper-containing (e.g., AOC1 (DAO1), AOC2, AOC 3 (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); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); apoptosis-inducing factor mitochondrial-associated 1 (AIFM1, AIF; NCBI Gene ID: 9131);Arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); asteraid homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI Gene ID: 472); ATP-binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI Gene ID: 5243); ATP-dependent Clp-protease (CLPP; NCBI Gene ID: 8192); ATR serine / threonine kinase (ATR; NCBI Gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI Gene ID: 558); B and T lymphocyte-associated (BTLA, CD272; NCBI Gene ID: 151888); baculovirus IAP repeat-containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene IDs: 329, 330, 331, 332); basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 68 2); B-cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2-binding protein 3 (BBC3, PUMA; NCBI Gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene ID: 598, 10018); beta 3-adrenergic receptor (ADRB3; NCBI Gene ID: 155); bone gamma-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 IDs: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain and ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695);Cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004); cancer / testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363); carbonic anhydrases (CA1, CA2, CA3, CA4, CA5A, CA5 B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI Gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677); carcinoembryonic antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI Gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK 2); NCBI Gene ID: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene ID: 836, 840, 841, 864); catenin β1 (CTNNB1; NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); CC motif chemokine ligand 21 (CCL21; NCBI Gene ID: 6366); CC motif chemokine receptor 2 (CCR2; NCBI Gene ID: 72923 0); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI Gene ID: 1232, 1233, 1234, 1237); CCAAT enhancer-binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NCBI Gene ID: 8317); cell communication network factor 2 (CCN2; NCBI Gene ID: 1490);Cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatomammotropic hormone 1 (CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI Gene IDs: 9074, 51208); markers of cluster of differentiation - (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD3 beta (TRB), CD3 gamma (TRG), CD3 delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 ( BLAST1), CD52, CD55(DAF), CD58(LFA3), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CS F1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 (IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), CD194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2) R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902 , 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI Gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI Gene IDs: 2155, 2159); collagen type IV alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI Gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily members colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI Gene IDs: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI Gene IDs: 718, 727); COP9 signalosome subunit 5 (COPS5; NCBI Gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD3 71); CD371; NCBI Gene ID: 160364, 170482, 283420; C-X-C motif chemokine ligand 12 (CXCL12; NCBI Gene ID: 6387); C-X-C motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI Gene ID: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI Gene ID: 595);cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI Gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (CCNG1; NCBI Gene ID: 900); cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidations; reductase (POR; NCBI Gene ID: 5447); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD-box helicases (e.g., DDX5, DDX6, DDX58; NCBI Gene IDs: 1655, 1656, 23586); delta-like canonical Notch ligands (e.g., DLL3, DLL4; NCBI Gene IDs: 10683, 54567); diablo IAP-binding mitochondria Chondriac proteins (DIABLO, SMAC; NCBI Gene ID: 56616); diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI Gene IDs: 1606, 8525); Dickkopf WNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI Gene IDs: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); discoidin 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 (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI Gene IDs: 7150, 7153, 7155, 7156, 8940); dopachrome tautomer (DCT; NCBI Gene ID: 1638); dopamine receptor D2 (DRD2; NCBI Gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI Gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI Gene ID: 5169); EMAP-like 4 (EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene IDs: 51752, 64167);enhancer of zeste2 polycomb repressive complex 2 subunit (EZH2; NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI Gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variants) 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); epidermal mitogen-activating factor (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: 197 3, 1984); exopolitin-1 (XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fa ligand (FASLG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragment of Ig receptor (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene ID: NCBI Gene ID: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI Gene ID: 83416); fibroblast activation protein alpha (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 alpha), FGF2 (FGF beta), 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); focal adhesion kinase 2 (PTK2, FAK1; NCBI Gene ID: 5747); folate hydrolase 1 (FO LH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); flurin (flurin, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI Gene ID: 2534); galectins (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene IDs: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; N NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glutamate transfer receptor 1 (GRM1; NCBI Gene ID: 2911); glutaminase (GLS; NCBI Gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 2950); glycogen synthase kinase 3 beta (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI Gene ID: 2719); ID: 2796); gonadotropin-releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI Gene ID: 10457); growth differentiation factor 2 (GDF2, BMP9; NCBI Gene ID: 2658); growth factor receptor-bound protein 2 (GRB2, ASH; NCBI Gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL; NCBI Gene ID: 2984); H19 imprinted maternally expressed transcript (H19;NCBI Gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK; NCBI Gene ID: 3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI Gene IDs: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene IDs: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatic 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 IDs: 3065, 9734, 51564); HRas proto-oncogene, GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI Gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI Gene IDs: 3551, 3553); IKAROS family zinc finger (IKZF1 (LYF1), IKZF3; NCBI Gene IDs: 10320, 22806); immune Indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2, NCBI Gene IDs: 3620, 169355); inducible T cell costimulatory molecule (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulatory molecule ligand (ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2R; NCBI Gene IDs: 3480, 3482); insulin-like growth factor (e.g., IGF1, IGF2; NCBI Gene IDs: 3479, 3481); insulin receptor (INSR, CD220; NCBI Gene ID: 3643);Integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene 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 ID: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI Gene ID: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI Gene ID: 354); killer cell immunoglobulin-like receptor, Ig domain and long cytoplasmic tails (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI Gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285);Killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene ID: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (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); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene, Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 4 035); leucine-rich repeat-containing 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NCBI Gene ID: 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 cytosolic protein 2 (LCP2; NCBI Gene ID: 3937); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase-like 2 (LOXL2; NCBI Gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 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 IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); major histocompatibility complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene IDs: 3105, 313 3, 3134, 3135); major vault protein (MVP, VAULT1; NCBI Gene ID: 9961); MALT1 paracaspase (MALT1; NCBI Gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene ID: 2872, 8569); matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP1 1, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI Gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCBI NCBI Gene ID: 4170); MDM2 oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI Gene ID: 2475); melan-A (MLANA; NCBI Gene ID: 2315); melanocortin 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); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI Gene ID: 10988); MHC class I polypeptide-related sequence (e.g., MICA, MICB; NCBI Gene IDs: 4277, 100507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI Gene IDs: 5594, 5595, 5596) 9, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI Gene IDs: 4217, 1326); mitogen-activated protein kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene IDs: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (thrombopoietin receptor, MPL; NCBI Gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., 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); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4883); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, MAGE family member (NDN; NCBI Gene ID: 4692);Nectin 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); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene ID: 8828, 8829); neurotrophin receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene ID: 4914 , 4915, 4916); NFKB-activating protein (NKAP; NCBI Gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain-containing 3 (NLRP3, NALP3; NCBI Gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI Gene ID: 4893); Nuclear factor kappa B (NFK B1, NFKB2; NCBI Gene ID: 4790, 4791); nuclear factor, erythroid 2-like 2 (NFE2L2; NRF2; NCBI Gene ID: 4780); nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI Gene ID: 3164); nucleolin (NCL; NCBI Gene ID: 4691); nucleophosmin 1 (NPM1; NCBI Gene ID: 4869); nucleotide-binding oligomerization domain-containing 2 (NOD2; NCBI Gene ID: 64127); nudix hydrolase 1 (NUDT1; NCBI Gene ID: 452 1); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI Gene ID: 4255); Opioid receptor delta 1 (OPRD1; NCBI Gene ID: 4985); Ornithine decarboxylase 1 (ODC1; NCBI Gene ID: 4953); C=O glutarate dehydrogenase (OGDH; NCBI Gene ID: 4967); Parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); Periostin (POSTN; NCBI Gene ID: 10631);Peroxisome proliferator-activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene ID: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA; PI3K a PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3CG (PI3K gamma); NCBI Gene ID: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2 G15; NCBI Gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI Gene IDs: 5292, 11040, 415116); placental growth factor (PGF); NCBI Gene ID: 5228); plasminogen activator gen 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); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus receptor (poliovirus receptor, PVR) cell adhesion molecule (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 IDs: 142, 10038, 10039); polycomb protein EED (EED; NCBI Gene ID: 8726); porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI Gene ID: 23532); premelanosome protein (PMEL;NCBI Gene ID: 6490); progesterone receptor (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); Prominin1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (P; ML; NCBI Gene ID: 5371); propiosin (PSAP; NCBI Gene ID: 5660); prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); prostaglandin E synthase (PTGES; NCBI Gene ID: 9536); prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2); NCBI Gene IDs: 5742, 5743); proteasome 20S subunit beta 9 (PSMB9; NCBI gene ID: 5698); protein arginine methyltransferases (e.g., PRMT1, PRMT5; NCBI gene IDs: 3276, 10419); protein kinase N3 (PKN3; NCBI gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI gene ID: 5754); protein tyrosine phosphatase receptor (PTPRB (PTPB), PTP RC (CD45R); NCBI Gene ID: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X7 (P2RX7; NCBI Gene ID: 5027); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene, serine / threonine kinase (RAF1, c-Raf; NCBI Gene ID: 79037) I Gene ID: 5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); Ras homolog family member C (RHOC; NCBI Gene ID: 389); Ras homolog, mTORC1-binding (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 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); retinoic acid early transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091);Retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene ID: 5914, 5916); retinoid X receptor (e.g., RXRA, RXRB, RXRG; NCBI Gene ID: 6256, 6257, 6258); Rho-associated coiled-coil-containing protein kinase (e.g., ROCK1, ROCK2; NCBI Gene ID: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-beta1; NCBI Gene ID: 6198); ring finger protein 128 (RNF128, GRAIL; NCBI Gene ID: 6198) NCBI Gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROS1; NCBI Gene ID: 6098); roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium-binding protein A9 (S100A9; NCBI Gene ID: 6280); secreted flutrient-related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID: 6696); Cretoglobin family 1A member 1 (SCGB1A1; NCBI Gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene IDs: 6401, 6402, 6403); semaphorin 4D (semaphorin, SEMA4D; CD100; NCBI Gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI Gene IDs: 27036, 27180, 89790); signal-regulatory proteins signal transducer and activator of transcription (SIRPA, CD172A; NCBI Gene ID: 140885); signal transducer and activator of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene ID: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI Gene ID: 23410); signaling lymphocyte activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9);NCBI Gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI Gene ID: 84189); smooth, frizzled class receptor (SMO; NCBI Gene ID: 6608); soluble epoxide hydrolase 2 (EPHX2; NCBI Gene ID: 2053); solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC4 4A4; NCBI Gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI Gene IDs: 6751, 6752, 6753, 6754, 6755); sonic hedgehog signaling molecule (SHH; NCBI Gene ID: 6469); Sp1 transcription factor (SP1; NCBI Gene ID: 6667); sphingosine kinase (e.g., SPHK1, SPHK2; NCBI Gene ID: 8877 , 56848); sphingosine-1-phosphate receptor 1 agonist (S1PR1, CD363; NCBI Gene ID: 1901); spleen-related 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: 2687 2); steroid sulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interactor 1 (STING1; NCBI Gene ID: 340061); superoxide dismutase 1 (SOD1, ALS1; NCBI Gene ID: 6647); suppressor of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI Gene ID: 8651, 9021); synapsin 3 (SYN3; NCBI Gene ID: 8224); syndecan 1 (SDC1, CD138, syndecan;NCBI Gene ID: 6382); synuclein alpha (SNCA, PARK1; NCBI Gene ID: 6622); T-cell immunoglobulin and mucin domain-containing 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene IDs: 6869, 6870); TANK binding kinase 1 (TBK1, NCBI Gene ID: 29110); tankyrase (TNKS, NCBI Gene ID: 8658); TATA box-binding protein-associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25976); lymphocyte-specific Protein tyrosine kinase (TEC); NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010); human telomerase reverse transcriptase (TERT; NCBI Gene ID: 7015); tenascin C (TNC; NCBI Gene ID: 3371); 3 prime repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); thrombomodulin ( THBD, CD141; NCBI Gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI Gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene ID: 7606, 7608); thyrotropin receptor (TSHR; NCBI Gene ID: 7253);TNFSF 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; Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); Transfection Transferrin (TF; NCBI Gene ID: 7018); Transferrin Receptor (TFRC, CD71; NCBI Gene ID: 7037); Transforming Growth Factor (e.g., TGFA, TGFB1; NCBI Gene ID: 7039, 7040); Transforming Growth Factor Receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI Gene ID: 7046, 7048, 7049); Transforming Protein E7 (E7; NCBI Gene ID: 1489079); Transglutaminase 5 (TGM5; NCBI Gene ID: 9 333); transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI Gene ID: 7442); transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptors expressed in myeloid cells (e.g., TREM1 (CD354), TREM2; NCBI Gene IDs: 54209, 54210); trophinin (TRO, MAGED3; NCBI Gene ID: 7216); trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162);tryptophan 2,3-dioxygenase (TDO2; NCBI Gene ID: 6999); tryptophan hydroxylase (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor (TNF; NCBI Gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (C; D27), TNFRSF8(CD30), TNFRSF9(CD137, 4-1BB), TNFRSF10A(CD261), TNFRSF10B(TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11 B(OPG), TNFRSF12A, TNFRSF13B, TNFR13C(, CD268, BAFFR), TNFRSF14(CD270, LIGHTR), TNFRSF16, TNFRSF17(CD269, BCMA), TNFRSF18(GITR, CD357) , TNFRSF19, TNFRSF21, TNFRSF25; NCBI Gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); tumor protein p53 (TP53; NCBI Gene ID: 7157); tumor suppressor 2, mitochondrial calcium regulator (TUSC2; NCBI Gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI Gene ID: 7301); tyrosinase (TYR; NCBI Gene ID: 7299); tyrosine hydroxylase (TH; NCBI Gene ID: 7054); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine protein phosphatase, non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin-conjugating enzyme E2I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminus hydrolase L5 (UCHL5; NCBI Gene ID: 51377); ubiquitin-specific peptidase 7 (USP7; NCBI Gene ID: 7874); ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI Gene ID: 7317); UL16-binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene IDs: 79465, 80328, 80328); valosin-containing protein (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); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunoregulatory receptor (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRNRecQ-like helicase (WRN; RE CQ3; NCBI Gene ID: 7486); WT1 transcription factor (WT1; NCBI Gene ID: 7490); WW domain-containing transcription factor 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-associated transcription factor (YAP1; NCBI Gene ID: 10413); Zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535);

[0075] In some embodiments, the one or more additional therapeutic agents include, for example, 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Adenosine A receptor (ADORA2A; NCBI gene ID: 135) 2Breceptor (ADORA2B; NCBI Gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI Gene ID: 1606); Fms-like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); integrin-associated protein (IAP, CD47; NCBI Gene ID: 961); interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin-2 receptor (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (Kirsten rat sarcoma, KRAS; NCBI Gene ID: 3845; including mutations such as KRAS G12C or G12D; mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator (MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293); programmed death-ligand 1 (PD-L1, CD274; NCBI Gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 29126) Gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI Gene ID: 3815); signal-regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210); triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209);Tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, CD134, OX40; NCBI Gene ID: 7293); tumor necrosis factor receptor superfamily, member 9 (TNFRSF9, 4-1BB, CD137; NCBI Gene ID: 3604); tumor necrosis factor receptor superfamily, member 18 (TNFRSF18, CD357, GITR; NCBI Gene ID: 8784); WRNRecQ-like helicase (WRN; NCBI Gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807); Exemplary Mechanisms of Action Immune Checkpoint Modulators

[0076] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor environment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, 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). Inhibition of regulatory T cells (Tregs) or Treg depletion can relieve 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).

[0077] Examples of immune checkpoint proteins or receptors include CD27 (NCBI Gene ID: 939), CD70 (NCBI Gene ID: 970); CD40 (NCBI Gene ID: 958), CD40LG (NCBI Gene ID: 959); CD47 (NCBI Gene ID: 961), SIRPA (NCBI Gene ID: 140885); CD48 (SLAMF2; NCBI Gene ID: 962), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI Gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI Gene ID: 8832), CD96 (NCBI Gene ID: 10225), CD160 (NCBI Gene ID: 10226), and the like. 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 activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-associated 2 (HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; N NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797), TNFRSF9 (CD137; NCBI Gene ID: 3604), TNFSF9 (CD137L; NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2;NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA), NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8 784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI Gene ID: 5133); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493 CD80 (B7-1; NCBI Gene ID: 941), CD28 (NCBI Gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI Gene ID: 5819); CD226 (DNAM-1; NCBI Gene ID: 10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); T cell immunoreceptor with Ig and ITIM domains (TIGIT ;NCBI Gene ID: 201633); T-cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4; NCBI Gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); Galectin 9 (LGALS9; NCBI Gene ID: 3965); Lymphocyte activation 3 (LAG3, CD223; NCBI Gene ID: 3902); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI Gene ID: 6504);Lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI gene ID: 57823); UL16 binding protein 1 (ULBP1; NCBI gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI gene ID: 79465); retinoic acid early translocation Retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early 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, e.g., lirilumab (IPH-2102, IPH-4102)); killer cell lectin-like receptor C1 ( 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 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).

[0078] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PV RIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (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 with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule 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; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0079] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and a long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 2 (KIR2DL3); (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94), killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-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 with one or more agonists or activators of one or more NK cell-stimulatory immune checkpoint proteins or receptors. Exemplary NK cell-stimulatory immune checkpoint proteins or receptors include: CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., 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.

[0080] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., an antibody or fragment thereof, or an antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of LAG3.

[0081] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, 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, and KN-04. 4, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0082] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered 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), 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), genolimuzumab (CBT-501), LZM-009, prorugolimab (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, dostallimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), embafolimab (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, zimbelelimab (AB122), spartalizumab (P DR-001), and compounds disclosed in WO 2018195321, WO 2020014643, WO 2019160882, or WO 2018195321, and 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 / OX4) 0L), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1), FS-118(LAG-3 / PD-L1), FPT-155(CTLA4 / P PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp alfa (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, PD-L1 inhibitors include CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0083] Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vivostarob, domvanalimab, domvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0084] An example of an inhibitor of LAG3 that can be co-administered is leramirimab (LAG525).

[0085] Inhibition of regulatory T cell (Treg) activity or Treg depletion can alleviate the suppression of anti-tumor immune responses and may have 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 with one or more inhibitors of Treg activity or Treg depletion agents. Treg inhibition or depletion can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment.

[0086] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can suppress migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor can modulate cell phenotype and induce the production of proinflammatory cytokines. Exemplary Treg inhibitors include CCR4 (NCBI Gene ID: 1233) antagonists and degraders of 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).

[0087] Examples of heliolytic agents that may be co-administered include, but are not limited to: I-57 (Novartis), and compounds disclosed in WO 2019038717, WO 2020012334, WO 20200117759, and WO 2021101919.

[0088] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more Treg-depleting agents. In some embodiments, the Treg-depleting agent is an antibody. In some embodiments, the Treg-depleting antibody has antibody-dependent cellular cytotoxicity (ADCC) activity. In some embodiments, the Treg-depleting antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg-depleting antibody is an antibody-drug conjugate (ADC). Exemplary targets of Treg depleting agents include, but are not limited to, CD25 (IL2RA; NCBI Gene ID: 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18; NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID: 3604), OX-40 (CD134; NCBI Gene ID: 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).

[0089] In some embodiments, Treg inhibitors or Treg depletors that may be co-administered include C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic Treg receptor 4 (CCR4; CD184), TNFRSF18 (GITR, CD357), TNFRSF18 ...TNFRSF18 (4-1BB, CD137), Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit and combinations thereof.

[0090] Examples of Treg-depleting anti-CCR8 antibodies that may be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and antibodies disclosed in WO2021163064, WO2020138489, and WO2021152186.

[0091] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0092] Inhibition, depletion, or reprogramming of unstimulated myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5):541-550; WO 2016049641). Exemplary targets for depleting or reprogramming unstimulated myeloid cells include triggering receptors expressed on myeloid cells, TREM-1 (CD354, NCBI Gene ID: 54210) and TREM-2 (NCBI Gene ID: 54209). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more myeloid cell-depleting or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; an antibody disclosed in WO 2019032624) or an anti-TREM-2 antibody (e.g., PY314; an antibody disclosed in WO 2019118513). Cluster of differentiation agonists or activators

[0093] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agent that targets a cluster of differentiation (CD) marker. Exemplary CD marker-targeting agents that can be co-administered include: 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, tagraxofusp (SL-401), and HLA-A2402 / HLA-A0201-restricted epitope peptide vaccine. , dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranelgene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, revastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverenvatinib dimesylate (HQP-1351), cabozantinib and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asnercept (APG-101), APO-010, and International Publication Nos. 2016196388, 2016033570, 2015157386, 199203459, 199221766, 2004080462, and 2004080462. 2005020921, International Publication No. 2006009755, International Publication No. 2007078034, International Publication No. 2007092403, International Publication No. 2007127317, International Publication No. 2008005877, International Publication No. 2012154480, International Publication No. 2014100620, International Publication No. 2014039714, International Publication No. 2015134536, International Publication No. 2017167182, International Publication No. 2018112136, International Publication No. 2018112140,International Publication No. 2019155067, International Publication No. 2020076105, International Application PCT No. US2019063091, International Publication No. 19173692, International Publication No. 2016179517, International Publication No. 2017096179, International Publication No. 2017096182, International Publication No. 2017096281, International Publication No. 2018089628, International Publication International Publication No. 2017096179, International Publication No. 2018089628, International Publication No. 2018195321, International Publication No. 2020014643, International Publication No. 2019160882, International Publication No. 2018195321, International Publication No. 200140307, ​​International Publication No. 2002092784, International Publication No. 2007133811, International Publication No. 20090 46541, International Publication No. 2010083253, International Publication No. 2011076781, International Publication No. 2013056352, International Publication No. 2015138600, International Publication No. 2016179399, International Publication No. 2016205042, International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 2018057669 , WO 2018107058, WO 2018190719, WO 2018210793, WO 2019023347, WO 2019042470, WO 2019175218, WO 2019183266, WO 2020013170, WO 2020068752, 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).

[0094] In some embodiments, agents targeting CD markers that may be co-administered include the following: PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, lobritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, CD117 - small molecule inhibitors such as ADC, AZD3229, telatinib, borolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), Plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0095] In some embodiments, agents targeting CD markers that may be co-administered include the following: interleukin-2 receptor subunit gamma, eltrombopag, lintatolimod, poly ICLC (NSC-301463), reboxone, apoxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, levothyroxine ... Small molecule agonists such as siquimod, sergantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, ritenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0096] In some embodiments, agents targeting CD markers that may be co-administered include the following: 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, felzalutamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX®), TTX-030, cericlerumab ( RG7876), APX-005M, ABBV-428, ABBV-927, mitazarimab (JNJ-64457107), lenzilumab, alemtuzumab, emactuzumab, AMG-820, FPA-008 (caviralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulukafusp alfa 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, leratolimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enselimab (TSR-033), atipotuzumab, BrevaRex (MAB-AR-20).5), MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, rituximab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), 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, covolimab (TSR-022), MBG-453, INCAGN-2390, and antibodies such as the compounds disclosed in WO 2017 / 096179, WO 2017096276, WO 2017096189, and WO 2018089628.

[0097] In some embodiments, agents targeting CD markers that may be co-administered include the following: CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, iso-cel, lysocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), Ttisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL-armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), Anti-CD19 CAR T-cell therapy (Acute lymphoblastic leukemia / Non-Hodgkin's lymphoma, University Hospital Heidelberg), Anti-CD19 CAR T-cell therapy (Silent IL-6 expression, Cancer, Shanghai Unicar Therapeutic Biopharmaceutical Therapeutic 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-CD20CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecleucel-T, CART-19, tisagenlecleucel (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 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01(NKG2D LIGAND Modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, or cell therapies such as those disclosed in WO 2012079000 or WO 2017049166. Cluster of differentiation 47 (CD47) inhibitors

[0098] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (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 exemplary anti-CD47 antibodies include the following: CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), retaplimab (IBI-188), lemzoparimab (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 International Publication No. 199727873, International Publication No. 199940940, International Publication No. 2002092784, International Publication No. 2005044857, International Publication No. 2009046541, International Publication No. 2010070047, International Publication No. 2011143624, International Publication No. 2012170250, International Publication No. 2013109752, International Publication No. 2013119714, International Publication No. 2014087248, International Publication No. 2015191861, International Publication No. 2016022971, International Publication No. 2016023040, International Publication No. 2016024021, International Publication No. 2016081423, International Publication No. 2016109415, International Publication No. 2016141328, International Publication No. 2016188449, International Publication No. 2017027422, International Publication No. 2017049251, International Publication No. 2017053423, International Publication No. 2017121771, International Publication No. 2017194634, International Publication No. 2017196793, International Publication No. 2017215585, International Publication No. 2018075857, International Publication No. 2018075960, International Publication No. 2018089508, International Publication No. 2018095428,International Publication No. 2018137705, International Publication No. 2018233575, International Publication No. 2019027903, International Publication No. 2019034895, International Publication No. 2019042119, International Publication No. 2019042285, International Publication No. 2019042470, International Publication No. 2019086573, International Publication No. 2019108733, International Publication No. 2019138367, International Publication No. 2019144895, International Publication No. 201 and WO 2020009725. 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 magrolimab.

[0099] In some embodiments, the CD47 inhibitor is 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), or any combination thereof. GF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801. SIRPα targeting agent

[0100] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with a SIRPα targeting agent (NCBI Gene ID: 140885; UniProt P78324). Examples of SIRPα targeting agents include SIRPα inhibitors (such as AL-008, RRx-001, and CTX-5861) and anti-SIRPα antibodies (such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPα / PD-L1). Additional SIRPα targeting agents of use are described in, for example, WO 200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO 2011076781, WO 201206627, WO 201306627, WO 20140307, ​​WO 20140307, ​​WO 20140308, WO 20140309 ... 13056352, International Publication No. 2015138600, International Publication No. 2016179399, International Publication No. 2016205042, International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 2018057669, International Publication No. 2018107058, International Publication No. 2018190719, International Publication No. 2018210793, International Publication No. 2019023347, International Publication No. 2019042470, International Publication No. 2019175218, International Publication No. 2019183266, International Publication No. 2020013170 and International Publication No. 2020068752. FLT3R agonists

[0101] 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 a FLT3 ligand. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an FLT3L-Fc fusion protein, for example, as 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.

[0102] Agonists or activators of TNF Receptor Superfamily (TNFRSF) members. In some embodiments, the antibodies and / or fusion proteins provided herein inhibit one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI gene ID; 355), TNFRSF7 (CD27, NCBI gene ID; 939), TNFRSF8 (CD30, NCBI gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID; 8795), TNFRSF10C (CD263, TR AILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650) , and further combined with one or more agonists of 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).

[0103] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tabolixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0104] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0105] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0106] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0107] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0108] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication Nos. WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO 2017096179 and WO 2018089628.

[0109] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronectumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), pramotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20). Bispecific T cell engager

[0110] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a bispecific T cell engager (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), odronextamab (REGN-1979; CD20 / CD3). 3), MCLA-117(CD3 / CLEC12A), JNJ-0819(heme / CD3), JNJ-7564(CD3 / heme), AMG-757(DLL3-CD3), AMG-330(CD33 / CD3), AMG-420(BCMA / CD 3),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), RG61 94(HER2 / CD3), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw123), JNJ-9383(MGD-015), AMG-424(CD38 / CD3), tidutamab(XmAb-18087 (SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20), tidutamab (XmAb-18087; SSTR2 / CD3), catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828;Examples of suitable anti-CD3 binding bispecific molecules include CD20 / CD3, CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc. Exemplary bispecific T cell engagers that can be co-administered target CD3 and tumor-associated antigens described herein, including, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230). Bispecific and trispecific natural killer (NK) cell engagers

[0111] In some embodiments, the antibodies and / or fusion proteins provided herein are directed against a bi-specific NK-cell engager (BiKE) or tri-specific NK-cell engager (TriKE) (e.g., Fc-less), or NK cell activating receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KCRs), and the like. and bispecific antibodies (e.g., with Fc) against KIR (K1 receptors, KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE, that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., including CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKE and TriKE 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 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0112] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of the MCL1 apoptosis regulator, a BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO2018183418, WO2016033486, and WO2017147410. SHP2 inhibitors

[0113] In some embodiments, antibodies and / or fusion proteins provided herein are administered with an inhibitor of 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 kinase 1 (HPK1) inhibitors and degraders

[0114] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184).

[0013] Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300. Apoptosis signal-regulating kinase (ASK) inhibitors

[0115] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an ASK inhibitor, such as mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO2013112741 (Gilead Sciences). Bruton's tyrosine kinase (BTK) inhibitors

[0116] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of Bruton's tyrosine kinase (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-ynoyl)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, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315. Cyclin-dependent kinase (CDK) inhibitors

[0117] In some embodiments, the antibodies and / or fusion proteins provided herein are directed to 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); 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 CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, simulosertib hydrate (TAK931), and TG-02. Discoidin domain receptor (DDR) inhibitors

[0118] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with an inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication Nos. 2009-0142345 (Takeda Pharmaceutical), 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations). Targeted E3 ligase ligand conjugates

[0119] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a target E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and Survival) E3 ubiquitin ligase binding moiety, a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, a cereblon E3 ubiquitin ligase binding moiety, or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase degradation of the targeted protein, e.g., via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein described herein and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of, e.g., BTK and an E3 ligase ligand or binding moiety). See, e.g., WO2018098280. In some embodiments, the targeted E3 ligase ligand conjugate comprises a binding moiety that targets or binds to interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); a rapidly accelerated fibrosarcoma (RAF, such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD protein; and an E3 ligase ligand or binding moiety.See, e.g., WO 2019099926, WO 2018226542, WO 2018119448, WO 2018223909, WO 2019079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, e.g., in WO 2018237026, WO 2019084026, WO 2019084030, WO 2019067733, WO 2019043217, WO 2019043208, and WO 2018144649. Histone deacetylase (HDAC) inhibitors

[0120] In some embodiments, the antibodies and / or fusion proteins provided herein are further combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, and entinostat. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0121] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with an inhibitor of 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, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Janus kinase (JAK) inhibitors

[0122] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restortinib, momelotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019. Lysyl oxidase-like protein (LOXL) inhibitors

[0123] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of a LOXL protein, e.g., 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 the antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences), and WO 2011 / 097513 (Gilead Biologics). Matrix metalloproteinase (MMP) inhibitors

[0124] In some embodiments, the antibodies and / or fusion proteins provided herein are directed against a matrix metallopeptidase (MMP), such as MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP18 (NCBI Gene ID: 4327), MMP19 (NCBI Gene ID: 4330), MMP20 (NCBI Gene ID: 4331), MMP21 (NCBI Gene ID: 4332), MMP22 (NCBI Gene ID: 4333), MMP23 (NCBI Gene ID: 4334), MMP24 (NCBI Gene ID: 4335), MMP25 (NCBI Gene ID: 4336), MMP26 (NCBI Gene ID: 4337), MMP27 (NCBI Gene ID: 4338), MMP28 (NCBI Gene ID: 4339), MMP29 (NCBI Gene ID: 4340), MMP29 (NCBI Gene ID: 4341), MMP29 (NCBI Gene ID: 4342), MMP29 (NCBI Gene ID: 4343), MMP29 (NCBI Gene ID: 4344), MMP29 (NCBI Gene and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012 / 027721 (Gilead Biologics). RAS and RAS pathway inhibitors

[0125] In some embodiments, the antibodies and / or fusion proteins provided herein are directed against the 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); the NRAS proto-oncogene, GTPase (NRAS; also known as NS6 ;CMNS;NCMS;ALPS4;N-ras;NRAS1;NCBI Gene ID:4893) or HRAS proto-oncogene, an inhibitor of a GTPase (HRAS; also known as CTLO;KRAS;HAMSV;HRAS1;KRAS2;RASH1;RASK2;Ki-Ras;p21ras;CH-RAS;cK-ras;H-RASIDX;c-Ki-ras;C-BAS / HAS;C-HA-RAS1;NCBI Gene ID:3265). Ras inhibitors can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that may 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 adaptor-, AZD-4785, siG12D-LODER™, and siG12D-exosomes.Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, rabocertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that can be co-administered include lidigosertib. Exemplary PI3K inhibitors that may be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Exemplary AKT inhibitors that may be co-administered include capivasertib and GSK2141795. Exemplary PI3K / mTOR inhibitors that may be co-administered include daptolisib, omipalisib, voxalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nano-amorphous formulation, 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 (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Also, K-RAS and mutant N-RAS can be reduced by neratinib, an irreversible inhibitor of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137. Mitogen-activated protein kinase (MEK) inhibitors

[0126] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0127] In some embodiments, the antibodies and / or fusion proteins provided herein are directed to phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, and / or an inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, bupallisib (BKM120), BYL719 (alpelisib), CH5132799, and copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7 604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication No. 2005 / 113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Sciences, Inc., New York, NY, USA) Calistoga), WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga), and WO 2014 / 201409 (Gilead Sciences). Spleen Tyrosine Kinase (SYK) inhibitor

[0128] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, celdulatinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut), and U.S. Patent Application Publication No. 20150175616. Toll-like receptor (TLR) agonists

[0129] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an agonist of a toll-like receptor (TLR), e.g., an agonist 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 TLR7 agonists that may be co-administered 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 those disclosed in U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014056953 (Janssen), WO 2014076221 (Janssen), WO 2014128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Examples include compounds disclosed in Therapeutics.An example of a TLR7 / TLR8 agonist that can be co-administered is NKTR-262. Examples of TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 201400736 42 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira and compounds disclosed in U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics).Exemplary TLR9 agonists that may be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, 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 lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Tyrosine kinase inhibitors (TKIs)

[0130] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with a tyrosine kinase inhibitor (TKI), which can target the epidermal growth factor receptor (EGFR) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, and KX2-391 (Src ), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib, L-malic acid, (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR-targeted agents include neratinib, tucatinib (ONT-380), tecevatinib, mobocertinib (TAK-788), DZD-9008, valitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®, and Booth, et al., Cancer Biol Ther. 2018 Feb. 1;19(2):132-137. Antibodies that target EGFR include, but are not limited to, modotuximab, cetuximab sarotarocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab. chemotherapy drugs

[0131] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with a chemotherapeutic or anti-neoplastic agent.

[0132] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) are meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of 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; ethyleneimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including the synthetic analogs adozelesin, carzelesin, and bizelesin; cryptoxanthin; ficins, especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi I1), dynemycins, including dynemycin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin , detorubicin, 6-diazo-5-C=OL-norleucine, doC=O rubicin (including morpholino-C=O rubicin, cyanomorpholino-C=O rubicin, 2-pyrrolino-C=O rubicin, and deoxy-C=O rubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodolubicin, streptonigrin, streptozocin, tubercidin, ube antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as furoic acid; radiotherapeutic agents such as radium-223; trichothecenes, particularly T-2 toxin, veracrine A, roridin A, and anguidine; taxoids, such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel;Sabizablin (Veru-111); platinum analogues such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; hestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformutine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidines; folinic acid; podophyllic acid, 2-ethylhydrazide; procarbazine; polysaccharide K (PSK); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Trabectedin, Triaziquone; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZA R®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin, aminopterin, xeloda; ibandronate; CPT-11; topoisomerase inhibitors RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan);Examples include FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated to antibodies or any of the targeting agents described herein to create antibody drug conjugates (ADCs) or targeted drug conjugates. Antihormonal drugs

[0133] Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

[0134] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0135] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0136] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (apatorsen).

[0137] Examples of progesterone receptor antagonists include onapristone. Additional progesterone targeting agents include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri-Cyclen), and levonorgestrel. Antiangiogenic agents

[0138] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an anti-angiogenic agent. Anti-angiogenic agents that may be co-administered include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necapranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shell), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,l-3,4-dehydroproline, thiaproline, and the like. benzodiazepine, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-2 serum, chicken inhibitor of metalloproteinases-3 (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, β-1 anticollagenase serum, alpha-2 antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthonylate disodium or "CCA", thalidomide, angiogenesis-suppressing steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be co-administered include bevacizumab, vanucizumab, faricimab, zilpacimab (ABT-165; DLL4 / VEGF), or nabicikizumab (OMP-305B83; DLL4 / VEGF). antifibrotic agents

[0139] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an anti-fibrotic agent. Anti-fibrotic agents that may be co-administered include compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Patent No. 4,965,288, which relates to inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal collagen deposition, and U.S. Patent No. 4,997,854, which relates to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, each of which is incorporated herein by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, U.S. Pat. No. 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application No. 20040248871, which are incorporated herein by reference.

[0140] Exemplary antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that generate resonance-stabilized products after binding to the carbonyl, such as the following primary amines: ethylenamine, 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 selenohomocysteine ​​lactone.

[0141] Other antifibrotic agents are copper chelators, which may or may not be cell-permeable. Exemplary compounds include indirect inhibitors that inhibit the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate. anti-inflammatory agents

[0142] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an anti-inflammatory agent. Exemplary anti-inflammatory agents include arginase (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 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 377678), and the like. NCBI Gene ID: 23632), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX dual inhibitor.

[0143] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) that can be co-administered include mofezolac, GLY-230, and TRK-700.

[0144] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maceoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that may be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that may be co-administered include pormacoxib and imrecoxib.

[0145] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include LY3023703, GRC27864, and the compounds disclosed in WO 2015 / 158204, WO 2013 / 024898, WO 2006 / 063466, WO 2007 / 059610, WO 2007 / 124589, WO 2010 / 100 249, WO 2010 / 034796, WO 2010 / 034797, WO 2012 / 022793, WO 2012 / 076673, WO 2012 / 076672, WO 2010 / 034798, WO 2010 / 034799, WO 2012 / 022792, WO 2009 / 103778, WO 2011 / 048004, WO 201 2 / 087771, WO 2012 / 161965, WO 2013 / 118071, WO 2013 / 072825, WO 2014 / 167444, WO 2009 / 138376, WO 2011 / 023812, WO 2012 / 110860, WO 2013 / 153535, WO 2009 / 130242, WO 2009 / 146696, WO Examples of compounds that can be co-administered include those described in International Publication Nos. 2013 / 186692, 2015 / 059618, 2016 / 069376, 2016 / 069374, 2009 / 117985, 2009 / 064250, 2009 / 064251, 2009 / 082347, 2009 / 117987, and 2008 / 071173. Additionally, metformin has been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. See, e.g., Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0146] Carbonic anhydrases that may be co-administered (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), CA Examples of inhibitors of one or more of CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632) include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and diclophenamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0147] Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) that may be co-administered include meclofenamate sodium and zileuton.

[0148] Soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that may be co-administered include compounds described in WO 2015 / 148954. Dual COX-2 / SEH inhibitors that may be co-administered include compounds described in WO 2012 / 082647. Dual SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) inhibitors that may be co-administered include compounds described in WO 2017 / 160861.

[0149] Examples of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) genes that can be co-administered include GS-4875, GS-5290, BHM-078, and the compounds described in WO 2006 / 124944, WO 2006 / 124692, WO 2014 / 064215, WO 2018 / 005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila, et al. al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61. Tumor oxygenators

[0150] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Exemplary agents that can 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., heme nitric oxide and / or oxygen-binding protein (HNOX)), such as OMX-302 and HNOX proteins, as described in International Publication Nos. 2007137767, 2007139791, 2014107171, and 2016149562. immunotherapy agents

[0151] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody.Examples of immunotherapeutic agents that may be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutumumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumumab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, diazepam, and azidotazumab. Nutuximab, dombanalimab, drozitumab, durigotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, framvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-73) 4016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minletumomab, mitumomab, mogamulitumab, moxetumomab, naptumomab, narutuzumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatuzumab, pasudotox, patritumab, pemtu These include momab, pertuzumab, pintumomab, pritumumab, racotumomab, radletuzumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubirituximab, veltuzumab, borsetuzumab, votumumab, zalutumumab, zimvelerimab, and 3F8.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.

[0152] The exemplified therapeutic antibodies may be further labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0153] In some embodiments, the immunotherapeutic agent is an antibody drug conjugate (ADC). Exemplary ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein.Examples of ADCs that may be co-administered include gemtuzumab, brentuximab, belantamab (e.g., belantamab mafodotin), camidanlumab (e.g., camidanlumab tesirin), trastuzumab (e.g., trastuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuximab (e.g., mirvetuximab sovatansine), depatuximab, vadasotuximab, labetuzumab, lazilatuzumab (e.g., lazilatuzumab vedotin), Roncatuximab (e.g., roncatuximab tesulin), sacituzumab (e.g., sacituzumab govitecan), datopotomab (e.g., datopotomab deruxtecan; DS-1062; Dato-DXd), patrituzumab (e.g., patrituzumab deruxtecan), rifastuzumab, indosatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., upifitamab rilsodotin), indituximab, milatuzumab, robalbutuzumab (e.g., robalbutuzumab mabutesillin), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamavutansine), dicitamab (e.g., dicitamab vedotin), terizotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMG Examples include N529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130, and IMMU-140.ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0154] Exemplary therapeutic agents (e.g., anti-cancer or anti-tumor agents) that can be conjugated to a drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, maytansine or analogs thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyclines (e.g., Examples of suitable anti-cancer or anti-neoplastic agents include doC=O rubicin, daunorubicin, epirubicin, idarubicin, pyrrolobenzodiazepine (PBD) DNA crosslinker SC-DR002 (D6.5), duocarmycins, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or dimers thereof, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), and other anti-cancer or anti-neoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to the drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anti-cancer or anti-neoplastic agent) that can be conjugated to the drug-conjugated antibody, fragment thereof, or antibody mimetic includes an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 comprises BPI-002.

[0155] In some embodiments, an ADC that can be co-administered comprises an antibody targeting tumor-associated calcium signaling factor 2 (TROP-2; TACSTD2; EGP-1; NCBI gene ID: 4070). Exemplary anti-TROP-2 antibodies include TROP-2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Shanghai DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP-2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius) BioTech), LIV-2008b (Shanghai / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (MediterraneaTheranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), as well as International Publication No. 2020016662 (Abmart), International Publication No. 2020249063 (Bio-Thera Solutions), U.S. Patent Application Publication No. 20190048095 (Bio-Thera Solutions), U.S. Patent Application Publication No. 2013077458 (LivTech / Chiome), European Patent Application Publication No. 20110783675 (Chiome), International Publication No. 2015098099 (Daiichi Sankyo), International Publication No. 2017002776 (Daiichi Sankyo), International Publication No. 2020130125 (Daiichi Sankyo), International Publication No. 2020240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021093730 (Daiichi Sankyo), U.S. Patent Application Publication No. 9850312 (DaiichiSankyo), Chinese Patent No. 112321715 (Biosion), U.S. Patent Application Publication No. 2006193865 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2011068845 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2016296633 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017021017 (Immunomedics / Gilead), U.S. Patent Application Publication No. 20172095 94 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017274093 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018110772 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018185351 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018271992 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018217227 (Immunomedics / Gilead) nomedics / Gilead), U.S. Patent Application Publication No. 2019248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021093730 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021069343 (Immunomedics / Gilead), U.S. Patent No. 8435539 (Immunomedics / Gilead), U.S. Patent Xu No. 8435529 (Immunomedics / Gilead), U.S. Patent No. 9492566 (Immunomedics / Gilead), WO 2003074566 (Gilead), WO 2020257648 (Gilead), WO 2013039861 (Gilead), WO 2014163684 (Gilead), U.S. Patent No. 9427464 (LivTech / Chiome), U.S. Patent No. 10501555 (Abruzzo Theranostic / Oncoxx), WO 2018036428 (Sichuan KelunExamples of antibodies include, but are not limited to, those described in Pharma, WO 2013068946 (Pfizer), WO 2007095749 (Roche), and WO 2020094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Pat. 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 anti-cancer agent joined by a linker. In some embodiments, the linker includes a linker disclosed in U.S. Pat. No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug moiety of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doC=O rubicin (dC=Orubicin, DOX), epirubicin, morpholino doC=O rubicin (morpholino-DOX), cyanomorpholino doC=O rubicin (cyanomorpholino-DOX), 2-pyrrolino-dC=O rubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lutotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanmycin, ansamycin, and epothilone. In some embodiments, the chemotherapeutic moiety is SN-38. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with sacituzumab govitecan.

[0156] In some embodiments, ADCs that may be co-administered include antibodies targeting carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a; NCBI gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (e.g., as described in WO 1996011013). In some embodiments, the CEACAM1-ADC is as described in WO 2010093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, antibodies and / or fusion proteins provided herein are administered with CEACAM1-ADC IMMU-130.

[0157] In some embodiments, an ADC that may be co-administered comprises an antibody that targets an MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO 2006094192). In some embodiments, the HLA-DR-ADC is as described in WO 2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, antibodies and / or fusion proteins provided herein are administered with HLA-DR-ADC IMMU-140. Cancer Gene Therapy and Cell Therapy

[0158] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include inserting normal genes in...

Claims

【Request Item 1】 【Chemistry 340】 【Chemistry 341】 【Chemistry 342】 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. 【Request Item 2】 【Chemistry 343】 2. The compound of claim 1, wherein: 【Request Item 3】 【Chemistry 344】 2. The compound of claim 1, wherein: 【Request Item 4】 【Chemistry 345】 2. The compound of claim 1, wherein: 【Request Item 5】 【Chemistry 346】 2. The compound of claim 1, wherein: 【Request Item 6】 【Chemistry 347】 2. The compound of claim 1, wherein: 【Request Item 7】 【Chemistry 348】 2. The compound of claim 1, wherein: 【Request Item 8】 【Chemistry 349】 2. The compound of claim 1, wherein: 【Request Item 9】 【Chemicals 350】 2. The compound of claim 1, wherein: 【Request Item 10】 【Chemistry 351】 2. The compound of claim 1, wherein: 【Request Item 11】 【Chemistry 352】 2. The compound of claim 1, wherein: 【Request Item 12】 【Chemistry 353】 2. The compound of claim 1, wherein: 【Request Item 13】 【Chemistry 354】 2. The compound of claim 1, wherein: 【Request Item 14】 【Chemistry 355】 2. The compound of claim 1, wherein: 【Request Item 15】 【Chemistry 356】 2. The compound of claim 1, wherein: 【Request Item 16】 【Chemistry 357】 2. The compound of claim 1, wherein: 【Request Item 17】 【Chemistry 358】 2. The compound of claim 1, wherein: 【Request Item 18】 【Chemistry 359】 2. The compound of claim 1, wherein: 【Request Item 19】 【Hua360】 2. The compound of claim 1, wherein: 【Request Item 20】 【Chemistry 361】 2. The compound of claim 1, wherein: 【Request Item 21】 【Chemistry 362】 2. The compound of claim 1, wherein: 【Request Item 22】 【Chem363】 2. The compound of claim 1, wherein: 【Request Item 23】 【Chemistry 364】 2. The compound of claim 1, wherein: 【Request Item 24】 【Chemistry 365-1】 【Chemistry 365-2】 【Chemical 365-3】 【Chemistry 365-4】 【Chemistry 365-5A】 6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-7-[5-(trifluoromethyl)pyrimidin-2-yl]-1H-quinazoline-2,4-dione, 【Chemistry 365-5B】 【Chemical 365-6】 【Chemistry 365-7】 【Chemical 365-8】 【Chemical 365-9】 【Chemical 365-10】 【Chemistry 365-11】 【Chemistry 365-12】 【Chemistry 365-13】 【Chemistry 365-14】 【Chemistry 365-15】 【Chemistry 365-16】 【Chemistry 365-17】 【Chemical 365-18】 【Chemistry 365-19】 【Chemistry 365-20】 【Chemistry 365-21】 【Chemistry 365-22】 【Chemical 365-23】 【365-24】 【Chemistry 365-25】 【Chemistry 365-26】 【Chemistry 365-27】 【Chemistry 365-28】 【Chemistry 365-29】 【365-30】 【Chemistry 365-31】 【Chemistry 365-32】 【Chemistry 365-33】 【Chemistry 365-34】 【365-35】 【Chemistry 365-36】 【Chemistry 365-37】 【Chemistry 365-38】 【Chemistry 365-39】 [Chemistry 365-40] 【Chemistry 365-41】 【Chemistry 365-42】 【Chemistry 365-43】 【Chemistry 365-44】 7-fluoro-6-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl)methyl)isoquinolin-1(2H)-one, 【Chemistry 365-45】 【Chemistry 365-46】 【Chemistry 365-47】 【Chemistry 365-48】 【Chemistry 365-49】 【365-50】 【Chemistry 365-51】 【Chemistry 365-52】 【Chemistry 365-53】 【Chemistry 365-54】 【Chemistry 365-55】 【Chemistry 365-56】 【Chemistry 365-57】 【Chemistry 365-58】 【Chemistry 365-59】 【Chemical 365-60】 【Chemistry 365-61】 【Chemistry 365-62】 【Chemistry 365-63】 【Chemistry 365-64】 【Chemistry 365-65】 【Chemical 365-66】 【Chemistry 365-67】 [Chemical 365-68] 【Chemistry 365-69】 [Chemistry 365-70] 【Chemistry 365-71】 【Chemistry 365-72】 【Chemistry 365-73】 【Chemistry 365-74】 6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl)methyl)isoquinolin-1(2H)-one, 【Chemistry 365-75】 【Chemistry 365-76】 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof,

25. 25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, and a pharmaceutically acceptable excipient.

26. 25. A composition for use in a method of treating cancer, comprising a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof.

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