PARP7 inhibitors

Abstract

This specification provides compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof, pharmaceutical compositions comprising the compounds of this disclosure together with pharmaceutically acceptable excipients, and methods for treating cancer using the same. Compounds and pharmaceutical compositions useful as PARP7 inhibitors are provided herein. Some of the compounds of this disclosure can be used in pharmaceutical compositions together with at least one pharmaceutically acceptable excipient to treat subjects requiring treatment. TIFF2026527805000210.tif55170

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Application No. 63 / 515,755, filed on 26 July 2023 under Section 119(e) of the U.S. Patent Act, the contents of which are incorporated herein by reference in their entirety. [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 and transfers ADPr from nicotinamide adenine dinucleotide (NAD+) to a substrate via N-glycosidic, O-glycosidic, or S-glycosidic bonds on the target molecule. A subset of ART is poly(adenosine diphosphate-ribose) polymerase (PARP), a family of 17 known enzymes that regulate fundamental cellular processes including gene expression, proteolysis, and multiple cellular stress responses (MS. Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. (Nat. Chem Biol 14, 236-243 (2018))). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and presents a new 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 certain aryl hydrocarbon receptor (AHR) transcriptional targets. AHRs are then activated by many substrates, including tobacco smoke. PARP7 inhibitors have been shown to restore type I interferon (IFN) signaling responses to nucleic acids and induce tumor regression in an immunocompetent BALB / c mouse model harboring CT26 tumors (Gozgit, et al., Cancer Cell 39, 1214-1226(2021)).

[0004] Currently, there are no approved PARP7 inhibitor drugs. Therefore, it is useful to provide PARP7 inhibitor compounds that have properties suitable for administration as pharmaceuticals to mammals, particularly humans. Therefore, improved PARP7 inhibitors are needed 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) [Overview of the project]

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

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

Chemical formula

Chemical formula

[0008] Provided herein are compounds of formula (I'), [ka] or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, During the ceremony, J is [ka] And, X 1 N, CR 4 , or CR 4 R 4 And, X 2 CR 5 And, X 3 CR 5 And, X 4 is N or CR 5 And, X 5 CR 5 And, X 6 CR 5 And, A is either O or NH, R 1 These are H, C1-6 alkyl, and C 3-12 Selected from cycloalkyl groups, where C1-6 alkyl is one or more R groups. 6 Replaced by optional selection, R 2 H, halo, C1-6 alkyl, -OH, -O(C 1-6 Selected from alkyl and cyclopropyl, R 3a and R 3b These are independently H, halo, -OH, C1-6 alkyl, and -O(C 1-6 Selected from alkyl groups, where each C1-6 alkyl group is independently one or more R groups. 6 Replaced by optional selection, Z is one or more R 7A 5- to 12-membered heteroaryl optionally substituted with one or more Rs 7 A C optionally substituted with one or more Rs 6-10 An aryl optionally substituted with one or more Rs 7 A C optionally substituted with one or more Rs 3-12 A cycloalkyl, and one or more Rs 7 Selected from a 4- to 12-membered heterocyclyl optionally substituted with one or more Rs, wherein the 5- to 12-membered heteroaryl or C 6-10 Aryl is monocyclic or bicyclic, and C 3-12 Cycloalkyl or 4- to 12-membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged Each R 4 Is independently H, halo, C 1-6 Alkyl, C 3-12 Cycloalkyl, and -O(C 1-6 Alkyl), and is selected from Each R 5 Is independently H, halo, C 1-6 Alkyl, C 4-10 Cycloalkyl, -OH, and -O(C 1-6 Alkyl), and is selected from Each R 6 Is independently H, halo, -OH, -O(C 1-6 Haloalkyl), and -O(C 1-6 Alkyl), and is selected from Each R 7 Is independently halo, C 1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl), and C 3-12 Cycloalkyl, and is selected from, where each C 1-6 Alkyl is optionally substituted with one or more halos or -OH

[0009] Also provided is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, together with a pharmaceutically acceptable excipient

[0010] Furthermore, there is provided a method of treating cancer in a subject that requires cancer treatment, the method comprising administering to the patient a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure.

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] I. DEFINITIONS The following description sets forth exemplary methods, parameters, and the like. However, such description is not intended to limit the scope of the present disclosure, but rather should be recognized as being provided as an illustration of exemplary embodiments.

[0012] A dash ("-") not between two letters or symbols is used to indicate the point of attachment for a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dashes before or after a chemical group are for convenience, and the chemical groups may be shown with or without one or more dashes without losing their normal meaning. A wavy line drawn across a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0013] Wavy line

Chemical formula

[0014] "C u-v " as a prefix indicates that the following group has u - v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has 1 - 6 carbon atoms.

[0015] In this specification, references to values ​​or parameters "about" include (and are described) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. Furthermore, for that term, "about X" includes a description of "X". Also, the singular forms "a" and "the" include plural references unless specifically indicated in the context. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0016] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 Alkyl compounds include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is designated by its chemical name or identified by its molecular formula, all positional isomers having that number of carbon atoms may be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0017] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2-20 Alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 This refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0018] "Alkynyl" contains at least one carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2-6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 This refers to an alkyl group having an alkynyl bond. The term "alkynyl" also includes an alkynyl group having one triple bond and one double bond.

[0019] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0020] A "haloalkoxy" refers to an alkoxy group defined above in which one or more hydrogen atoms are replaced by halogens.

[0021] "Alkylthio" refers to the "alkyl-S-" group.

[0022] "Ashiru" is -C(O)R y It refers to the base, and in the formula, R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0023] "Amide" is -C(O)NR y R z The "C-amide" group and -NR refer to the group. y C(O)R z It refers to both the "N-amide group" and the group, and in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z These together form cycloalkyl or heterocyclines, each of which may be optionally substituted as defined herein.

[0024] "Amino" is the base -NR y R y This refers to, and in the formula, each R y Each of these is 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.

[0025] "Amidino" is -C(NR y )(NR z 2) refers to, in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0026] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) structure including a condensed system. As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6~20 Aryl), 6-12 ring carbon atoms (i.e., C 6~10 Aryl), or 6 to 10 ring carbon atoms (i.e., C 6~10 They contain an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryls do not include, or overlap in any way with, heteroaryls 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.

[0027] "Cyano" refers to the -CN group.

[0028] "Keto" refers to the C=O group.

[0029] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group and -NR refer to the group. y C(O)OR z It refers to both the "N-carbamoyl group" and the group, and in the formula, R y and R z These are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be optionally substituted.

[0030] "Carboxyl" refers to -C(O)OH.

[0031] "Ester" (i.e., carboxyl ester) refers to both -OC(O)R and -C(O)OR, where R is a substituent, each of which may be optionally substituted as defined herein.

[0032] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures, including condensed ring systems, bridged ring systems, and spirocyclic systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl refers to a ring with 3 to 20 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 a ring of 3-6 carbon atoms (i.e., C 3-6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] "Guanidino" is -NR y C(=NR z )(NR y R z ) refers to, and in the formula, each R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0034] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodine. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogens. For example, if a residue is substituted with two or more halogens, it may be referred to by using a prefix corresponding to the number of halogenated moieties. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may but are not necessarily the same halogen. Examples of haloalkyls include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0035] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Examples of heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, and -S(O)2-, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, a heteroalkyl group comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0036] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 Heteroaryls), or 3 to 8 ring carbon atoms (i.e., C 3~8A heteroaryl group comprises a heteroaryl group and, independently, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridadinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bonded via any of the rings in the fused system. Any aromatic ring having one or more fused rings containing at least one heteroatom is considered a heteroaryl regardless of its bond to the rest of the molecule (i.e., via any one of the fused rings). A heteroaryl is defined as one that does not contain an aryl or does not overlap with an aryl, as defined above.

[0037] A “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, bridging heterocyclyl groups, condensed heterocyclyl groups, and spiro-heterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, and polycyclics may be condensed, bridging, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl regardless of bonding (i.e., it can be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, whose ring may be condensed with an aryl ring or heteroaryl ring regardless of bonding to the rest of the molecule. As used herein, a heterocyclyl has 2 to 20 ring atoms (i.e., a 4 to 20-membered heterocyclyl), 2 to 10 ring atoms (i.e., a 4 to 12-membered heterocyclyl), 4 to 10 ring atoms (i.e., a 4 to 10-membered heterocyclyl), 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclyl), or 4 to 6 ring carbon atoms (i.e., a 4 to 6-membered heterocyclyl), and independently has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, sulfur, or oxygen. A heterocyclyl may contain one or more C=O groups and / or 1 C=O groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, diC=Olanyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 4-7 membered sultams, 4-7 membered cyclic carbamates, 4-7 membered cyclic carbonates, 4-7 membered cyclic sulfides, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4-10 membered cyclic moiety connected to two non-adjacent atoms of a heterocyclyl, where one or more (e.g., one or two) 4-10 membered cyclic moieties have at least one heteroatom, each heteroatom independently selected from nitrogen, oxygen, and sulfur.As used herein, crosslinked heterocyclyls include bicyclic and tricyclic ring systems. Furthermore, as used herein, the term “spiroheterocyclyl” refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, where the one or more additional rings are 3- to 10-membered cycloalkyls or 3- to 10-membered heterocyclyls, and where a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-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, and heterocyclyls can be bonded via any of the rings in the condensation system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group bonded at two points to another cyclic group, and the other cyclic group may itself be a heterocyclic or carbocyclic group.

[0038] As used herein, the term “nitrogen- or sulfur-containing heterocyclil” means a heterocyclil moiety containing at least one nitrogen atom or at least one sulfur atom, or both nitrogen and sulfur atoms, within its ring structure. It should be understood that other heteroatoms, including oxygen, may be present in addition to nitrogen, sulfur, or any combination thereof. Examples of nitrogen- or sulfur-containing heterocyclils include morpholinyl, thiomorpholinyl, thiazolyl, isothiazolyl, oxazolidinone 1,2-dithiolyl, piperidinyl, and piperazinyl.

[0039] "Hydroxy" or "hydroxyl" refers to an -OH group. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0040] "Imino" is -C(NR y )R z It refers to the base, and in the formula, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0041] "Nitro" refers to the -NO2 group.

[0042] "Sulfonyl" refers to the -S(O)2R group, where R is a substituent or a defined group.

[0043] "Alkylsulfonyl" refers to the -S(O)2R group, where R is a substituent or a defined group.

[0044] "Alkylsulfinyl" refers to the -S(O)R group, where R is a substituent or a defined group.

[0045] "Thiocyanate" refers to the -SCN group.

[0046] "Thiol" refers to the -SR group, where R is a substituent or a defined group.

[0047] "C=O" or "thione" refers to a C(=S) group or a C(S) group.

[0048] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" or "alkylenyl" groups, or "arylene" or "aryrenyl" groups, respectively. Also, unless otherwise expressly indicated, a combination of groups is referred to herein as a part, and for example, the arylalkyl group mentioned last contains an atom, by which the part is bonded to the rest of the molecule.

[0049] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both instances in which the event or situation occurs and instances in which it does not. The term “optionally substituted” means that one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen part. “Optionally substituted” can range from zero to the maximum number of possible substitutions, and each substitution occurs independently. Where the term “substituted” is used, the substitution must occur on a substitutable hydrogen atom of the indicated substituent. Optional substitutions may or may not be the same as (mandatory) substitutions.

[0050] If a part is "optionally substituted" and any general term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl" is mentioned, then this general term is (C- 1-3 (Alkyl), (C 4-6 Alkyl), -O(C 1-4 (Alkyl), (C 3-10 Cycloalkyl), O-(C 3-10 This can refer to any preceding specifically enumerated term such as cycloalkyl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryls such as phenyl or naphthyl. Similarly, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyls such as oxetanyl, tetrahydropyranil, morpholino, and piperidinyl. Likewise, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteroaryl)," as well as certain heteroaryls such as pyridine.

[0051] Some compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imido acid tautomers. Regardless of which tautomers are shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound contains both amide and imido acid tautomers. Therefore, amide-containing compounds are understood to contain their imido acid tautomers. Similarly, imido acid-containing compounds are understood to contain their amide tautomers.

[0052] A "stereoisomer" refers to a compound that has the same atoms bonded together by the same bonds but has different three-dimensional structures that are not interchangeable. This disclosure intends various stereoisomers or mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed.

[0053] Furthermore, any formulas or structures provided herein are intended to represent both the unlabeled and isotope-labeled forms of the compounds. Isotope-labeled compounds have the structure represented by the formulas provided herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Examples of isotope-labeled compounds in this disclosure include, but are not limited to, I. 3 H and 14These compounds incorporate radioactive isotopes such as [specific radioactive isotopes]. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation therapy for patients.

[0054] This disclosure also includes “deuterated analogues” or “deuterated analogs” of the compound of formula (I), in which 1 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, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens are replaced by deuterium.

[0055] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to greater metabolic stability, such as extended half-life in vivo, reduced dose requirements, and / or improved therapeutic index. 18Fluorine-labeled compounds may be useful in PET or SPECT testing. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting readily available isotope-labeled reagents with non-isotope-labeled reagents, by performing the procedures disclosed in the scheme or the examples and preparations described below. In this context, deuterium is understood to be a substituent in the compound of formula (I).

[0056] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, where a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in the isotopic composition of the natural abundance of hydrogen. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0057] In many cases, the compounds of this disclosure can form acidic salts and / or basic salts in the presence of an amino group and / or a carboxyl group or a similar group.

[0058] pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human medicinal use.

[0059] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts containing inorganic acids and salts containing organic acids. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acidic salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating this solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl Examples of preferred amines include, but are not limited to, salts of primary, secondary, and tertiary amines such as 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 preferred amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0060] The term "substituted" means that one or more hydrogen atoms (e.g., 1 to 5, 1 to 4, 1 to 3, etc.) on a specified atom or group are replaced by one or more other substituents (e.g., 1 to 5, 1 to 3, etc.), provided that the normal valence of the specified atom is not exceeded. Examples of one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, C=O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar non-tertiary structures obtained by defining substituents with an infinitely increasing number of substituents (e.g., substituted aryls having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., methyl substituted with five fluorine or heteroaryl groups having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as defined herein. Unless otherwise specified, where a group is described as being optionally substituted, any substituent of the group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to alkyl groups having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted. Those skilled in the art will recognize that substituents and other parts of the compounds of the general formula herein should be selected to provide compounds that are stable enough to provide pharmaceutically useful compounds that can be formulated into acceptablely stable pharmaceutical compositions. Compounds having such stability are intended to be within the scope of this disclosure. Those skilled in the art should understand that the above definitions and any combination of substituents should not result in unmanipulable species or compounds.

[0061] As used herein, “pharmaceutically acceptable carriers” or “pharmaceutically acceptable excipients” include all kinds of solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in therapeutic compositions, provided that it is not incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the composition.

[0062] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0063] In this context, the terms “therapeutably effective” or “effective dose” indicate that a material or amount of material is effective in preventing, alleviating, or improving one or more symptoms of a disease or condition, and / or extending the survival of the subject being treated. The therapeutically effective dose varies depending on the compound, the disorder or condition and its severity, and the age and weight of the mammal being treated. For example, the effective dose is the amount sufficient to achieve a beneficial or desired clinical outcome. The effective dose may be provided in a single dose or in divided doses that provide the effective dose over multiple doses. Determining the amount considered effective may be based on individual factors for each subject, including the size, age, injury, and / or the disease or injury being treated, and the time elapsed since the injury occurred or the onset of the disease. A person skilled in the art will be able to determine the effective dose for a given subject based on these considerations, which are routinely practiced in the art.

[0064] II. Compounds Provided herein are compounds of formula (I), [ka] or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, During the ceremony, J is [ka] And, X 1 N, CR 4 , or CR 4 R 4 And, X 2 CR 5 And, X 3 CR 5 And, X 4 is N or CR 5 And, X 5 CR 5 And, X6 is CR 5 and A is O or NH R 1 is selected from H, C1-6 alkyl, and C 3-12 cycloalkyl, where C1-6 alkyl is optionally substituted with one or more R 6 s R 2 is selected from H, halo, C1-6 alkyl, -OH, -O(C 1-6 alkyl), and cyclopropyl R 3a and R 3b are each independently selected from H, halo, -OH, C1-6 alkyl, and -O(C 1-6 alkyl), where each C1-6 alkyl is independently optionally substituted with one or more R 6 s Z is a 5- to 12-member heteroaryl optionally substituted with one or more R 7 s, a C 7 aryl optionally substituted with one or more R 6-10 s, a C 7 cycloalkyl optionally substituted with one or more R 3-12 s, and a 4- to 12-member heterocyclyl optionally substituted with one or more R 7 s, where the 5- to 12-member heteroaryl or C 6-10 aryl is monocyclic or bicyclic, and the C 3-12 cycloalkyl or 4- to 12-member heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic, or bridged Each R 4 is independently selected from H, halo, C 1-6 alkyl, C 3-12 cycloalkyl, and -O(C 1-6 alkyl) Each R 5 is independently selected from H, halo, C 1-6 alkyl, C 4-10 cycloalkyl, -OH, and -O(C 1-6 alkyl) C Each R 6These are independently H, halo, -OH, -O(C) 1-6 Haloalkyl), and -O(C 1-6 Selected from alkyl, Each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl, where each C 1-6 Alkyl is optionally substituted with one or more halo, -OH, or CN groups. The compound is 2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 5-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 5-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 6-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-2-[5-(trifluoromethyl)pyridine-2-yl]-1,6-naphthyridine-5-one, 6-[5-(difluoromethoxy)pyridin-2-yl]-8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 8-Fluoro-6-(5-Fluoropyridine-2-yl)-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrazine-2-yl]isoquinoline-1-one, 7-Fluoro-6-(5-methoxypyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1-benzofuran-7-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1,4-benzodioxin-5-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 7-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-pyridine-2-ylisoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethoxy)pyridine-2-yl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-6-(5-fluoropyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-6-(5-fluoropyridine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(2,2,2-trifluoroethyl)pyridin-2-yl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Chloro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 4-methyl-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyridin-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-6-(5-fluoropyridine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-6-(5-fluoropyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyridin-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-[5-(trifluoromethyl)pyridine-2-yl]quinazolin-4-one, 6-Fluoro-7-(5-fluoropyridine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-(5-Fluoropyrimidine-2-yl)-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-(7H-pyrrolo[2,3-d]pyrimidine-2-yl)quinazolin-4-one, 6-Fluoro-7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-cyclopropylpyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-methoxypyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-fluoropyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-hydroxy-5-methyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-6-[5-(2-hydroxypropan-2-yl)pyrimidine-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(1,1-difluoro-2-hydroxyethyl)pyridine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-methylpyrimidine-2-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-(4-Amino-5-methylpyrimidin-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one, 7-(2-Amino-5-methylpyrimidin-4-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one, 6-(2-Amino-5-methylpyrimidin-4-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one, 6-[4-Amino-5-(trifluoromethyl)pyrimidin-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one, 7-[5-(Difluoromethyl)pyrimidin-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one, 7-(5-Cyclopropylpyrimidin-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one, 7-Fluoro-6-(5-methylsulfonylpyrimidin-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one, 7,8-Difluoro-2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one, 2-[(4R)-4-Duterio-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7,8-difluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4S)-4-Duterio-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7,8-difluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, (S)-2-(2,2-difluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 6-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-7-(5-methylpyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(5-amino-4-fluoropyridine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-amino-4-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5-chloropyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-fluoropyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[2-amino-5-(difluoromethyl)pyrimidine-4-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-cyclopropylpyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5,5-dimethyl-6,7-dihydropyrrolo[2,3-d]pyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[2-amino-5-(difluoromethyl)pyrimidine-4-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-7-(5-methylsulfonylpyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-[5-(2-hydroxyethoxy)pyrimidine-2-yl]-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-Fluoro-6-[5-(2-hydroxyethoxy)pyrimidine-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-Methoxy-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]oxy]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]quinazolin-4-one, 7-(5-chloropyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]quinazolin-4-one, 7,8-difluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-Fluoro-3-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5-chloropyrimidine-2-yl)-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[6-amino-5-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 2-[(4R)-5-(difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[4-(trifluoromethyl)pyrazole-1-yl]isoquinoline-1-one, 2-[(4R)-5-ethoxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, (S)-6-(4-amino-5-ethoxypyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-ethoxypyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-methoxypyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, 6-[4-amino-5-(triduteriomethoxy)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, (S)-6-(4-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(5-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-fluoro-7-(4-morpholino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(6-amino-5-(difluoromethyl)pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(thieno[2,3-d]pyrimidine-2-yl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-chloropyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-chloropyridine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(1H-pyrazolo[3,4-d]pyrimidine-6-yl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-(difluoromethyl)thiazole-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(pyrazolo[1,5-a]pyridine-2-yl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(benzo[d]oxazol-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(benzo[d]thiazole-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)thiazole-2-yl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloro-6-methylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-fluoro-6-(6-fluoroquinazolin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(4-(trifluoromethyl)oxazole-2-yl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(difluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-isopropylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methyl-5-(trifluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(5-(difluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-(difluoromethyl)-5-fluoropyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(8-aminoimidazo[1,2-a]pyrazine-6-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(thiazolo[5,4-b]pyridine-5-yl)isoquinoline-1(2H)-one, (S)-6-([1,2,4]triazolo[1,5-a]pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-7-(5-(difluoromethyl)pyridin-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-(5-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-methoxypyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-(5-(difluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-methoxypyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-chloropyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-chloropyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (S)-4-amino-6'-fluoro-3'-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-[2,7'-biquinazoline]-4'(3'H)-one, (S)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5,7-dihydrofl[3,4-d]pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-7,7-dimethyl-5,7-dihydrofluoro[3,4-d]pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-aminoquinazolin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-1,3,5-triazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methyl-1,3,5-triazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (R)-6-(6-amino-5-(difluoromethyl)pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-methoxypyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethoxy)pyrazine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyrazine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-(5-(difluoromethoxy)pyrazine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoro-7-(5-(trifluoromethyl)pyrimidine-2-yl)quinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyrimidine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-2-(5-(trifluoromethyl)pyridine-2-yl)-1,6-naphthyridine-5(6H)-one, (R)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(4-amino-5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-6-(5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(4-amino-5-methoxypyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(5-chloropyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(6-amino-5-(difluoromethyl)pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)thiazole-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(3,4-dihydro-2H-pyran-6-yl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyridine-2-yl)isoquinoline-1(2H)-one, (R)-6-(5-amino-6-(trifluoromethyl)pyridine-3-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethyl)pyridine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyridine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoro-7-(5-(trifluoromethyl)pyridine-2-yl)quinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-(5-(trifluoromethyl)pyridine-2-yl)pyrido[2,3-d]pyrimidine-4(3H)-one, (R)-2-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-1,6-naphthyridine-5(6H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyridine-2-yl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoro-6-(5-(trifluoromethyl)pyridine-2-yl)isoquinoline-1(2H)-one, (R)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-2-(5-(difluoromethyl)pyridine-2-yl)-1,6-naphthyridine-5(6H)-one, (R)-6-(6-amino-5-fluoropyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-chloropyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-methylpyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-7-(5-cyclopropylpyrazine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloro-6-cyclopropylpyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(6-amino-5-methoxypyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrazine-2-yl)isoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoro-7-(5-(trifluoromethyl)pyrazine-2-yl)quinazoline-4(3H)-one, (R)-6-(5-amino-1H-1,2,4-triazol-3-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethyl)pyrazine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloropyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4R)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-Fluoro-2-[(4R)-4-[[6-Oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]-6-[5-(trifluoromethyl)-2-pyridyl]isoquinoline-1-one, (R)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)-5-(trifluoromethoxy)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((3S,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((3R,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-7-fluoro-2-(6,6,6-trifluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloropyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(6-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(6-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-7-(5-(difluoromethyl)pyrimidine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(5-chloropyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoro-7-(5-(trifluoromethyl)pyrimidine-2-yl)quinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, 7-Fluoro-2-((4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((2S,4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((2R,4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-([1,2,4]triazolo[1,5-a]pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-7-([1,2,4]triazolo[1,5-a]pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-fluoroquinazoline-4(3H)-one, 6-Fluoro-7-(5-methoxypyrimidine-2-yl)-3-[[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]cyclohexyl]methyl]quinazolin-4-one, or (S)-7-fluoro-6-(5-methyl-6-(trifluoromethyl)pyridine-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one.

[0065] Provided herein are compounds of formula (I'), [ka] or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, During the ceremony, J is [ka] And, X 1 N, CR 4 , or CR 4 R 4 And, X 2 CR 5 And, X 3 CR 5 And, X 4 is N or CR 5 And, X 5 CR 5 And, X 6 CR 5 And, A is either O or NH, R 1 These are H, C1-6 alkyl, and C 3-12 Selected from cycloalkyl groups, where C1-6 alkyl is one or more R groups. 6 Replaced by optional selection, R 2 H, halo, C1-6 alkyl, -OH, -O(C 1-6 Selected from alkyl and cyclopropyl, R 3a and R 3b These are independently H, halo, -OH, C1-6 alkyl, and -O(C 1-6 Selected from alkyl groups, where each C1-6 alkyl group is independently one or more R groups. 6 Replaced by optional selection, Z is one or more R 7 5-12 member heteroaryls that are optionally substituted, one or more R 7 C is replaced by optional selection. 6-10 Aryl, one or more R 7 C is replaced by optional selection. 3-12 Cycloalkyl, and one or more R 7 A selection is made from 4- to 12-membered heterocyclines that are optionally substituted, where a 5- to 12-membered heteroaryl or C 6-10 Aryls are monocyclic or bicyclic, C 3-12 Cycloalkyl or 4-12 membered heterocyclils are monocyclic, bicyclic, condensed bicyclic, spirocyclic, or cross-linked. Each R 4 These are H, Halo, and C, independently. 1-6 Alkyl, C 3-12 Cycloalkyl, and -O(C 1-6 Selected from alkyl, Each R 5 These are H, Halo, and C, independently. 1-6 Alkyl, C 4-10 Cycloalkyl, -OH, and -O(C 1-6 Selected from alkyl, Each R 6 These are independently H, halo, -OH, -O(C) 1-6 Haloalkyl), and -O(C1-6 Selected from alkyl, Each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl, where each C 1-6 Alkyl is optionally substituted with one or more halos or -OH groups. The compound is 2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 5-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 5-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 6-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-2-[5-(trifluoromethyl)pyridine-2-yl]-1,6-naphthyridine-5-one, 6-[5-(difluoromethoxy)pyridin-2-yl]-8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 8-Fluoro-6-(5-Fluoropyridine-2-yl)-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrazine-2-yl]isoquinoline-1-one, 7-Fluoro-6-(5-methoxypyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1-benzofuran-7-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1,4-benzodioxin-5-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 7-Fluoro-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-pyridine-2-ylisoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethoxy)pyridine-2-yl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-6-(5-fluoropyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-6-(5-fluoropyridine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(2,2,2-trifluoroethyl)pyridin-2-yl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Chloro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 4-methyl-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyridin-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-6-(5-fluoropyridine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-6-(5-fluoropyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyridin-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-[5-(trifluoromethyl)pyridine-2-yl]quinazolin-4-one, 6-Fluoro-7-(5-fluoropyridine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-(5-Fluoropyrimidine-2-yl)-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-(7H-pyrrolo[2,3-d]pyrimidine-2-yl)quinazolin-4-one, 6-Fluoro-7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-cyclopropylpyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-methoxypyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-fluoropyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-hydroxy-5-methyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-6-[5-(2-hydroxypropan-2-yl)pyrimidine-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(1,1-difluoro-2-hydroxyethyl)pyridine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-methylpyrimidine-2-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-(4-amino-5-methylpyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(2-amino-5-methylpyrimidine-4-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(2-amino-5-methylpyrimidine-4-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(5-cyclopropylpyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-Fluoro-6-(5-methylsulfonylpyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4R)-4-Duterio-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7,8-difluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4S)-4-Duterio-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7,8-difluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, (S)-2-(2,2-difluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 6-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-7-(5-methylpyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(5-amino-4-fluoropyridine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-amino-4-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5-chloropyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-fluoropyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[2-amino-5-(difluoromethyl)pyrimidine-4-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-cyclopropylpyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5,5-dimethyl-6,7-dihydropyrrolo[2,3-d]pyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[2-amino-5-(difluoromethyl)pyrimidine-4-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-7-(5-methylsulfonylpyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-[5-(2-hydroxyethoxy)pyrimidine-2-yl]-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-Fluoro-6-[5-(2-hydroxyethoxy)pyrimidine-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-Methoxy-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]oxy]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]quinazolin-4-one, 7-(5-chloropyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]quinazolin-4-one, 7,8-difluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-Fluoro-3-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5-chloropyrimidine-2-yl)-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[6-amino-5-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 2-[(4R)-5-(difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[4-(trifluoromethyl)pyrazole-1-yl]isoquinoline-1-one, 2-[(4R)-5-ethoxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, (S)-6-(4-amino-5-ethoxypyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-ethoxypyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-methoxypyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, 6-[4-amino-5-(triduteriomethoxy)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, (S)-6-(4-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(5-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-fluoro-7-(4-morpholino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(6-amino-5-(difluoromethyl)pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(thieno[2,3-d]pyrimidine-2-yl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-chloropyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-chloropyridine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(1H-pyrazolo[3,4-d]pyrimidine-6-yl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-(difluoromethyl)thiazole-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(pyrazolo[1,5-a]pyridine-2-yl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(benzo[d]oxazol-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(benzo[d]thiazole-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)thiazole-2-yl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloro-6-methylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-fluoro-6-(6-fluoroquinazolin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(4-(trifluoromethyl)oxazole-2-yl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(difluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-isopropylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methyl-5-(trifluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(5-(difluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-(difluoromethyl)-5-fluoropyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(8-aminoimidazo[1,2-a]pyrazine-6-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(thiazolo[5,4-b]pyridine-5-yl)isoquinoline-1(2H)-one, (S)-6-([1,2,4]triazolo[1,5-a]pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-7-(5-(difluoromethyl)pyridin-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-(5-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-methoxypyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-(5-(difluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-methoxypyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-chloropyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-chloropyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (S)-4-amino-6'-fluoro-3'-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-[2,7'-biquinazoline]-4'(3'H)-one, (S)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5,7-dihydrofl[3,4-d]pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-7,7-dimethyl-5,7-dihydrofluoro[3,4-d]pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-aminoquinazolin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-1,3,5-triazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methyl-1,3,5-triazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (R)-6-(6-amino-5-(difluoromethyl)pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-methoxypyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethoxy)pyrazine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyrazine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-(5-(difluoromethoxy)pyrazine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoro-7-(5-(trifluoromethyl)pyrimidine-2-yl)quinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyrimidine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-2-(5-(trifluoromethyl)pyridine-2-yl)-1,6-naphthyridine-5(6H)-one, (R)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(4-amino-5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-6-(5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(4-amino-5-methoxypyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(5-chloropyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(6-amino-5-(difluoromethyl)pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)thiazole-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(3,4-dihydro-2H-pyran-6-yl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyridine-2-yl)isoquinoline-1(2H)-one, (R)-6-(5-amino-6-(trifluoromethyl)pyridine-3-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethyl)pyridine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyridine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoro-7-(5-(trifluoromethyl)pyridine-2-yl)quinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-(5-(trifluoromethyl)pyridine-2-yl)pyrido[2,3-d]pyrimidine-4(3H)-one, (R)-2-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-1,6-naphthyridine-5(6H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyridine-2-yl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7,8-difluoro-6-(5-(trifluoromethyl)pyridine-2-yl)isoquinoline-1(2H)-one, (R)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-2-(5-(difluoromethyl)pyridine-2-yl)-1,6-naphthyridine-5(6H)-one, (R)-6-(6-amino-5-fluoropyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-chloropyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-methylpyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-7-(5-cyclopropylpyrazine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloro-6-cyclopropylpyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(6-amino-5-methoxypyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrazine-2-yl)isoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoro-7-(5-(trifluoromethyl)pyrazine-2-yl)quinazoline-4(3H)-one, (R)-6-(5-amino-1H-1,2,4-triazol-3-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(difluoromethyl)pyrazine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloropyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4R)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4-one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-Fluoro-2-[(4R)-4-[[6-Oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]-6-[5-(trifluoromethyl)-2-pyridyl]isoquinoline-1-one, (R)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)-5-(trifluoromethoxy)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((3S,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((3R,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-7-fluoro-2-(6,6,6-trifluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloropyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(6-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(6-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-7-(5-(difluoromethyl)pyrimidine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(5-chloropyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoro-7-(5-(trifluoromethyl)pyrimidine-2-yl)quinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, 7-Fluoro-2-((4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((2S,4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((2R,4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-([1,2,4]triazolo[1,5-a]pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-7-([1,2,4]triazolo[1,5-a]pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-fluoroquinazoline-4(3H)-one, It is not 6-fluoro-7-(5-methoxypyrimidine-2-yl)-3-[[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]cyclohexyl]methyl]quinazolin-4-one.

[0066] In some embodiments, R 3a and R 3b Each of these is independently H, F, -OH, or -OCH3, or methyl.

[0067] In some embodiments, R 3a and R 3b These are, independently, H, F, -OH, or -OCH3.

[0068] In some embodiments, R 3a and R 3b H is H.

[0069] In some embodiments, R 3a H is R 3b These are halo, -OH, C1-6alkyl, and -O(C 1-6 Selected from alkyl groups, where each C1-6 alkyl group is independently one or more R groups. 6 It is optionally replaced by R. In some embodiments, 3a H is R 3b These are halo, -OH, C1-6alkyl, and -O(C 1-6 Selected from alkyl groups, where each C1-6 alkyl group independently has 1-5 R groups. 6 It is optionally replaced by R. In some embodiments, 3a H is R 3b R is selected from halo, -OH, and -OMe. In some embodiments, R 3a H is R 3b is F. In some embodiments, R 3a H is R 3b is -OH or methyl. In some embodiments, R 3a H is R 3b It is -OH.

[0070] In some embodiments, the compound of formula (IA) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, wherein A, J, R 1 , and R 2 This is as described in this specification.

[0071] In some embodiments, the compound of formula (IB) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, wherein A, J, R 1 , and R 2 This is as described in this specification.

[0072] In some embodiments, the compound is 7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-fluoro-2-[(2S,4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H It is not -pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, or 7-fluoro-2-[(2R,4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one.

[0073] In some embodiments, the compound of formula (IC) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, wherein A, J, R 1 , and R 2 This is as described in this specification.

[0074] In some embodiments, the compound of formula (ID), [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, wherein A, J, R 1 , and R 2 This is as described in this specification.

[0075] In some embodiments, A is NH. In some embodiments, A is O.

[0076] In some embodiments, the compound of formula (II-A) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0077] In some embodiments, the compound of formula (II-B) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0078] In some embodiments, the compound is 7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-fluoro-2-[(2S,4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H It is not -pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, or 7-fluoro-2-[(2R,4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one.

[0079] In some embodiments, the compound of formula (II-C) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0080] In some embodiments, the compound of formula (II-D) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0081] In some embodiments, the compound of formula (III-A) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0082] In some embodiments, the compound of formula (III-B) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0083] In some embodiments, the compound of formula (III-C) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0084] In some embodiments, the compound of formula (III-D) [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, where J, R 1 , and R 2 This is as described in this specification.

[0085] In some embodiments, the compound of formula (IV-A) [ka] Alternatively, a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a deuterated analog thereof is provided, where J is as described herein.

[0086] In some embodiments, R 1 R is methyl, ethyl, -CH2OCF2H, -CH2OCH3, -CF3, or -CH2OH. In some embodiments, R 1 is methyl, ethyl, -CH2OCF2H, -CH2OCH3, or -CF3. In some embodiments, R 1 It is methyl, ethyl, or -CH2(OCHF2).

[0087] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl or -CH2(OCHF2). In some embodiments, R 1 is ethyl. In some embodiments, R 1 This is -CH2(OCHF2).

[0088] In some embodiments, R 2 H, Halo, C 1-6 Alkyl, -OH, or -O(C 1-6 It is alkyl.

[0089] In some embodiments, R 2 is H. In some embodiments, R 2 It is -OH.

[0090] In some embodiments, R 1 R is methyl, ethyl, -CH2OCF2H, -CH2OCH3, -CF3, or -CH2OH, 2 H is H.

[0091] In some embodiments, R 1 R is methyl, ethyl, -CH2OCF2H, -CH2OCH3, -CF3, or -CH2OH, 2 H is R 3a and R 3b These are, independently, H, F, -OH, -OCH3, or methyl.

[0092] The dashed lines in ring J indicate single or double bonds (i.e., X 1 is =N-, =C(R 4 )-, or -C(R 4 )2-)

[0093] In some embodiments, J is [ka] That is the case.

[0094] In some embodiments, J is [ka] In some embodiments, J is [ka] That is the case.

[0095] In some embodiments, J is [ka] That is the case.

[0096] In some embodiments, R 4 is F. In some embodiments, R 4 H is H.

[0097] Several embodiments, each R 5 These are independently selected from H and halo. In some embodiments, each R 5 is F. In some embodiments, each R 5 is H. In some embodiments, R 5 It is either F or H.

[0098] In some embodiments, R 4 F is F, and each R 5 is H. In some embodiments, R 4 F is F, and each R5 is F. In some embodiments, R 4 H is R 5 One or two of them are F, and the remaining R 5 is H. In some embodiments, R 4 H is R 5 It is either F or H.

[0099] In some embodiments, J is [ka] It is selected from the group consisting of the following.

[0100] In some embodiments, J is [ka] That is the case.

[0101] In some embodiments, J is given by the following equation [ka] That is the case.

[0102] In some embodiments, J is given by the following equation [ka] That is the case.

[0103] In some embodiments, J is given by the following equation [ka] That is the case.

[0104] In some embodiments, J is [ka] That is the case.

[0105] In some embodiments, J is given by the following equation [ka] That is the case.

[0106] In some embodiments, J is given by the following equation [ka] That is the case.

[0107] In some embodiments, Z is 1 to 3 R 7 A 4-12 member heterocycline or 1-3 R is optionally replaced. 7 A 5-12 member heteroaryl that is optionally substituted, and each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-3 Alkyl), -O(C 1-3 Alkyl, and C 3-6 Selected from cycloalkyl, where each C 1-6 Alkyl groups are optionally substituted with 1 to 4 halos, -OH groups, or CN groups.

[0108] In some embodiments, Z is one or more R 7 It is a 4- to 12-membered heterocycline that is optionally substituted. In some embodiments, Z is 1 to 5 R 7 It is a 4- to 12-membered heterocycline that is optionally substituted. In some embodiments, Z is 1 to 3 R 7 It is a 4- to 12-membered heterocycline that is optionally substituted. In some embodiments, Z is 1 to 2 R 7 These are 4- to 12-membered heterocyclines that are optionally substituted.

[0109] In some embodiments, Z is one or more R 7 It is a 5- to 12-membered heteroaryl that is optionally substituted. In some embodiments, Z is 1 to 5 R 7 It is a 5- to 12-membered heteroaryl that is optionally substituted. In some embodiments, Z is 1 to 3 R 7It is a 5- to 12-membered heteroaryl that is optionally substituted. In some embodiments, Z is 1-2 R 7 These are 5- to 12-member heteroaryls that are optionally substituted.

[0110] In some embodiments, Z is one or more R 7 It is a 6-membered heteroaryl that is optionally substituted. In some embodiments, Z is 1 to 3 R 7 It is a 6-membered heteroaryl that is optionally substituted. In some embodiments, Z is an unsubstituted 6-membered heteroaryl. In some embodiments, Z is one R 7 It is a 6-membered heteroaryl substituted with . In some embodiments, Z is two R 7 It is a six-membered heteroaryl substituted with R. In some embodiments, Z is one or more R 7 It is a 9-membered heteroaryl that is optionally substituted. In some embodiments, Z is an unsubstituted 9-membered heteroaryl.

[0111] In some embodiments, Z is [ka] And, In the formula, w is 0 to 3 including both ends, t is 0 to 4 including both ends, and R 7 It is bonded to any substitutable position on Z.

[0112] In some embodiments, w is zero. In some embodiments, w is 1. In some embodiments, w is 3.

[0113] In some embodiments, t is zero. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0114] Several embodiments, each R 7 It is independently, Halo, C1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl groups, in the formula, each C 1-6 The alkyl group is optionally substituted with one or more halo, -OH, or CN groups. In some embodiments, each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl groups, in the formula, each C 1-6 The alkyl group is optionally substituted with 1 to 5 halos, -OH groups, or CN groups. In some embodiments, each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl groups, in the formula, each C 1-6 The alkyl group is optionally substituted with 1 to 4 halos, -OH groups, or CN groups. In some embodiments, each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-3 Alkyl), -O(C 1-3 Alkyl, and C 3-6 Selected from cycloalkyl groups, in the formula, each C 1-6 Alkyl groups are optionally substituted with 1 to 4 halos, -OH groups, or CN groups.

[0115] Several embodiments, each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl groups, in the formula, each C 1-6 The alkyl group is optionally substituted with one or more halo or -OH groups. In some embodiments, each R 7 It is independently, Halo, C 1-6Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl groups, in the formula, each C 1-6 The alkyl group is optionally substituted with 1 to 5 halos or -OH groups. In some embodiments, each R 7 It is independently, Halo, C 1-6 Alkyl, -NH2, -SO2(C 1-6 Alkyl), -O(C 1-6 Alkyl, and C 3-12 Selected from cycloalkyl groups, in the formula, each C 1-6 Alkyl groups are optionally substituted with 1 to 4 halos or -OH groups.

[0116] In some embodiments, R 7 C 1-6 Alkyl compounds are deuterated.

[0117] In some embodiments, R 7 is a halo. In some embodiments, R 7 F is F. In some embodiments, R 7 It is Cl.

[0118] In some embodiments, R 7 is unsubstituted C 1-6 It is alkyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 It is ethyl.

[0119] In some embodiments, R 7 C is optionally replaced with 1, 2, or 3 halos. 1-6 It is alkyl. In some embodiments, R 7 C is optionally replaced by 1, 2, or 3 Fs. 1-6 It is alkyl. In some embodiments, R 7 C is optionally replaced by 1, 2, or 3 -OH groups. 1-6 It is alkyl. In some embodiments, R 7C is optionally replaced with 1, 2, 3, or 4 halos or -OH groups. 1-6 It is alkyl. In some embodiments, R 7 C is optionally replaced by 1, 2, or 3 halos or -OH groups. 1-6 It is alkyl. In some embodiments, R 7 C is optionally replaced by 1, 2, or 3 F or -OH groups. 1-6 It is alkyl.

[0120] In some embodiments, R 7 is trifluoromethyl. In some embodiments, R 7 R is difluoromethyl. In some embodiments, 7 R is 1,1-difluoroethyl. In some embodiments, R 7 R is 2-hydroxypropan-2-yl. In some embodiments, R 7 R is 1-hydroxyethyl. In some embodiments, R 7 is 1,1-difluoro-2-hydroxyethyl. In some embodiments, R 7 is 1-hydroxy-2,2,2-trifluoroethyl. In some embodiments, R 7 is 1-hydroxy-2,2-difluoroethyl. In some embodiments, R 7 It is -CH2C(H)(OH)-CF3. In some embodiments, R 7 is -C(CH3)(OH)(CF3). In some embodiments, R 7 is -C(CH3)(OH)(CHF2). In some embodiments, R 7 is tert-butyl. In some embodiments, R 7 is 1,2-difluoroethyl. In some embodiments, R 7 This is -C(CH-3)2F.

[0121] In some embodiments, R 7 is -O(C 1-6 It is alkyl, and in the formula, C 1-6The alkyl group is unsubstituted. In some embodiments, R 7 is -O(C 1-6 It is alkyl, and in the formula, C 1-6 The alkyl group is optionally substituted with one, two, or three halos. In some embodiments, R 7 is -O(C 1-6 It is alkyl, and in the formula, C 1-6 The alkyl group is optionally substituted with 1, 2, or 3 -OH groups. In some embodiments, R 7 is -O(C 1-6 It is alkyl, and in the formula, C 1-6 The alkyl group is optionally substituted with one, two, or three CNs.

[0122] In some embodiments, R 7 is methoxy. In some embodiments, R 7 is trijuteromethoxy. In some embodiments, R 7 R is difluoromethoxy. In some embodiments, R 7 is trifluoromethoxy. In some embodiments, R 7 is 2-hydroxyethoxy. In some embodiments, R 7 is -OCH2CN. In some embodiments, R 7 It is -OCF2CH2OH.

[0123] In some embodiments, R 7 It is -NH2.

[0124] In some embodiments, R 7 is -SO2(C 1-6 It is alkyl. In some embodiments, R 7 It is -SO2CH3.

[0125] In some embodiments, R 7 C 3-12 It is cycloalkyl. In some embodiments, R 7 It is cyclopropyl.

[0126] In some embodiments, Z is [ka] That is the case.

[0127] In some embodiments, Z is given by the following equation [ka] That is the case.

[0128] In some embodiments, compounds, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof are provided, selected from the following: [Table 3-1] [Table 3-2] [Table 3-3]

[0129] Some embodiments provide compounds selected from Table 1 or Table 2, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof.

[0130] In some embodiments, compounds selected from Table 1, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof are provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27]

[0131] In some embodiments, compounds selected from Table 2, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof are provided. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 [Table 2-44] [Table 2-45] [Table 2-46]

[0132] III. Treatment method Methods for treating diseases in which inhibition of PARP is beneficial are disclosed herein, and the methods include administering the compounds disclosed herein. Also disclosed herein are methods for treating diseases in which inhibition of PARP7 is beneficial, and the methods include administering the compounds disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer such as stomach cancer and colorectal cancer, or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, triple-negative breast cancer, urothelial carcinoma, or cervical cancer.

[0133] In some embodiments, the cancer includes BRCA1 and / or BRCA2 mutations.

[0134] In some embodiments, cancers comprising BRCA1 and / or BRCA2 mutations include bladder cancer, brain and CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, triple-negative breast cancer, urothelial carcinoma, or uterine cancer.

[0135] A method for treating cancer is provided herein, comprising administering to a patient in need of treatment for cancer a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, or a pharmaceutical composition comprising a compound disclosed herein.

[0136] Some embodiments provide methods for treating cancer, the methods comprising administering to a patient in need of treatment for cancer an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, or a pharmaceutical composition comprising a compound disclosed herein.

[0137] IV. Combinations Patients treated with the PARP7 inhibitors of this disclosure often have diseases or conditions that would benefit from treatment with other therapeutic agents. These diseases or conditions may be of an oncological nature or may be associated with inflammation, metabolic disorders, gastrointestinal disorders, etc. Accordingly, one aspect of this disclosure is a method for treating cancer, the method comprising administering the compounds of this disclosure, in combination with one or more compounds useful for treating such diseases, to subjects in need of treatment for cancer, in particular human subjects.

[0138] In some embodiments, the compounds of the Disclosure are co-formulated with one or more additional active ingredients. In some embodiments, the other active ingredients are administered in separate dosage forms at approximately the same time. In some embodiments, the other active ingredients may be administered sequentially and at different times with respect to the compounds of the Disclosure.

[0139] In some embodiments, the compounds or pharmaceutical compositions provided herein are administered together with one or more (e.g., one, two, three, or four) additional therapeutic agents. In some embodiments, additional therapeutic agents include, for example, inhibitory immune checkpoint blockers or inhibitors, stimulative immune checkpoint stimulants, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapy agents, antineoplastic agents, antiproliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapy agents, therapeutic antigen-binding molecules (e.g., monospecific and multispecific antibodies of any form, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and their fragments), bispecific antibodies, non-immunoglobulin antibody mimics (e.g., adonectin, afibody, affin, affimer, afitin, alphabody, antikalin, peptide aptamers, armadillo repeat protein (ARM), atrimers, avimers, designed ankyrin repeat protein) Examples include proteins (including DARPin®), finomers, Nottin, Knitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editing agents, cells containing chimeric antigen receptors (CARs) (e.g., T-cell immunotherapy agents, NK-cell immunotherapy agents, or macrophage immunotherapy agents), cells containing genetically modified T-cell receptors (TCR-T), or any combination thereof.

[0140] Exemplary target In some embodiments, one or more additional therapeutic agents include, for example, inhibitors, agonists, antagonists, ligands, modifiers, stimulants, blockers, activators, or inhibitors of a target (e.g., polypeptides or polynucleotides), such as: 2'-5'-oligoadenylate synthetase (OAS1, NCBI gene ID: 4938), 5'-3' exoribonuclease 1 (XRN1, NCBI gene ID: 54464), 5'-nucleotidase ecto (NT5E, CD73, NCBI gene ID: 4907), ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL, NCBI gene ID: 25), and Absent-in melanoma 2 (AIM2, NCBI gene ID: 9447). ), acetyl-CoA acyltransferase 2 (ACAA2, NCBI gene ID: 10499), acid phosphatase 3 (ACP3, NCBI gene ID: 55), adenosine deaminase (ADA, ADA1, NCBI gene ID: 100), adenosine receptor (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3), NCBI gene ID: 134, 135, 136, 137), AKT serine / Threonine kinase 1 (AKT1, AKT, PKB, NCBI gene ID: 207), alanylaminopeptidase, membrane (ANPEP, CD13, NCBI gene ID: 290), ALK receptor tyrosine kinase (ALK, CD242, NCBI gene ID: 238), α-fetoprotein (AFP, NCBI gene ID: 174), copper-containing amine oxidase (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1), NCBI gene IDs: 26, 314, 8639), Androgen receptor (AR, NCBI gene ID: 367), angiopoietin (ANGPT1, ANGPT2, NCBI gene IDs: 284, 285), angiotensin II receptor type 1 (AGTR1, NCBI gene ID: 185), angiotensinogen (AGT, NCBI gene ID: 183), apolipoprotein A1 (APOA1, NCBI gene ID: 335), apoptosis-inducing factor mitochondrial-related 1 (AIFM1, AIF, NCBI gene ID: 9131),Arachidonic acid 5-lipoxygenase (ALOX5, NCBI gene ID: 240), asparaginase (ASPG, NCBI gene ID: 374569), asteroid homolog 1 (ASTE1, NCBI gene ID: 28990), ATM serine / threonine kinase (ATM, NCBI gene ID: 472), ATP-binding cassette subfamily B member 1 (ABCB1, CD243, GP170, NCBI gene ID: 5243), ATP-dependent Clp-protease (CLPP, NCBI gene ID: 8192), ATR serine / threonine Kinase (ATR, NCBI gene ID: 545), AXL receptor tyrosine kinase (AXL, NCBI gene ID: 558), B and T lymphocyte-related (BTLA, CD272, NCBI gene ID: 151888), baculovirus IAP repeat-containing protein (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (Survivin), NCBI gene IDs: 329, 330, 331, 332), basidine (Ok blood group) (BSG, CD147, NCBI gene ID: 682), B cell lymphoma 2 (B CL2 (NCBI gene ID: 596), BCL2 binding component 3 (BBC3, PUMA, NCBI gene ID: 27113), BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM), Bcl-x, NCBI gene IDs: 598, 10018), β3-adrenergic receptor (ADRB3, NCBI gene ID: 155), bone gamma-carboxyglutamate protein (BGLAP, NCBI gene ID: 632), bone morphogenetic protein-10 ligand (BMP10, NCBI gene ID: 27302), bradykinin receptor (e.g., ,BDKRB1, BDKRB2, NCBI gene ID: 623, 624), B-RAF (BRAF, NCBI gene ID: 273), cleavage cluster region (BCR, NCBI gene ID: 613), bromodomain and external domain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT, NCBI gene ID: 6046, 8019, 23476, 676), Bruton's tyrosine kinase (BTK, NCBI gene ID: 695), cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin),NCBI gene IDs: 1001, 1004), cancer / testicular antigens (e.g., CTAG1A, CTAG1B, CTAG2, NCBI gene IDs: 1485, 30848, 246100), cannabinoid receptors (e.g., CNR1(CB1), CNR2(CB2), NCBI gene IDs: 1268, 1269), carbohydrate sulfotransferase 15 (CHST15, NCBI gene ID: 51363), carbonic anhydrase (e.g., CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA 12, CA13, CA14, NCBI gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677), carcinoembryonic antigen-associated cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c), NCBI gene IDs: 1048, 1084, 4680), casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2), NCBI gene IDs: 1452, 1457), Caspa -ase (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: 729230), CC motif chemokine receptor (e.g., CC R3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198), NCBI gene IDs: 1232, 1233, 1234, 1237), CCAAT enhancer-binding protein α (CEBPA, CEBP, NCBI gene ID: 1050), cell adhesion molecule 1 (CADM1, NCBI gene ID: 23705), cell 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 somatomammotropin hormone 1 (CSH1, NCBI gene ID: 1442), claudins (e.g., CLDN6, CLDN18, NCBI gene IDs: 9074, 51208), differentiation cluster markers (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3α (TRA), CDβ (TRB), CDγ (TR) G), CDδ(TRD), CD4, CD8A, CD8B, CD19, CD20(MS4A1), CD22, CD24, CD25(IL2RA, TCGFR), CD28, CD33(SIGLEC3), CD37, CD38, CD39(ENTPD1), CD40(TNFRSF5) ), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLAST1), CD52, CD55 (DAF), CD58 (LFA3), CD74, CD79a, CD79b, CD80 (B7-1), CD84, CD86 (B7-2), CD96 (TACTILE), CD99(MIC2), CD115(CSF1R), CD116(GMCSFR, CSF2RA), CD122(IL2RB), CD123(IL3RA), CD128(IL8R1), CD132(IL2RG), CD135(FLT3), CD137(TNFRSF9, 4 -1BB), CD142(TF, TFA), CD152(CTLA4), CD160, CD182(IL8R2), CD193(CCR3), CD194(CCR4), CD195(CCR5), CD207, CD221(IGF1R), CD222(IGF2R), CD223 (LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4), NCBI gene ID:909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 95 2, 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 ID: 2155, 2159), collagen-type IVα chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 (NCBI gene IDs: 1282, 1284, 1285, 1286, 1287), collectin subfamily member 10 (COLEC10, NCBI gene ID: 10584), colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF), NCBI gene IDs: 1435, 1437, 1440), complement factors (e.g., C3, C5, NCBI gene IDs: 718, 727), COP9 signalosome subunit 5 (COPS5) ,NCBI gene ID:10987), C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371), CD371, NCBI gene IDs:160364, 170482, 283420), CXC-motif chemokine ligand 12 (CXCL12, NCBI gene ID:6387), CXC-motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), C XCR4 (CD184), NCBI gene IDs: 2833, 3577, 3579, 7852), cyclin D1 (CCND1, BCL1, NCBI gene ID: 595), cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12, NCBI gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755), cyclin G1 (CCNG1, NCBI gene ID: 900),Cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1, NCBI gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595), cytochrome P450 oxidoreductase (POR, NCBI gene ID: 5447), etc. Itokine-inducible SH2-containing protein (CISH, NCBI gene ID: 1154), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152, NCBI gene ID: 1493), DEAD-box helicase (e.g., DDX5, DDX6, DDX58, NCBI gene IDs: 1655, 1656, 23586), delta-like canonical Notch ligand (e.g., DLL3, DLL4, NCBI gene IDs: 10683, 54567), Diablo IAP-binding mitochondrial protein (DIABLO, SMAC, NCBI gene ID: 56616), diacylglycerol kinase (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 kinases (PRKDC, NCBI gene ID: 5591), DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B, NCBI gene IDs: 7150, 7153, 7155, 7156, 8) 940), 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 (endoglin, ENG, NCBI gene ID: 2022), endoplasmic reticulum aminopeptidase (e.g., ERAP1, ERAP2, NCBI gene IDs: 51752, 64167), zeste2 polycomb repression complex 2 subunit enhancer (EZH2, NCBI gene ID: 2146),Ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4, NCBI gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050), ephrin (e.g., EFNA1, EFNA4, EFNB2, NCBI gene IDs: 1942, 1945, 1948), epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB 4 (HER4), NCBI gene IDs: 1956, 2064, 2065, 2066), epithelial cell adhesion molecule (EPCAM, NCBI gene ID: 4072), epithelial mitotic factor (EPGN, NCBI gene ID: 255324), eukaryotic translation elongation factors (e.g., EEF1A2, EEF2, NCBI gene IDs: 1917, 1938), eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A, NCBI gene IDs: 1973, 1984), exportin-1 (XPO1, NCBI gene ID: 7514), farnesoid X receptor (NR1H 4. FXR (NCBI gene ID: 9971), Fas ligands (FASLG, FASL, CD95L, CD178, TNFSF6, NCBI gene ID: 356), fatty acid amide hydrolase (FAAH, NCBI gene ID: 2166), fatty acid synthase (FASN, FAS, NCBI gene ID: 2194), Ig receptor Fc fragments (e.g., FCER1A, FCGRT, FCGR3A (CD16), NCBI gene IDs: 2205, 2214, 2217), Fc receptor-like 5 (FCRL5, CD307, NCBI gene ID: 83416), Fibroblast-activating protein α (FAP, NCBI gene ID: 2191), fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334), NCBI gene IDs: 2260, 2261, 2263, 2264), fibroblast growth factors (e.g., FGF1 (FGFα), FGF2 (FGFβ), FGF4, FGF5, NCBI gene IDs: 2246, 2247, 2249, 2250), fibronectin 1 (FN1, MSF, NCBI gene ID: 2335),FMS-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2), NCBI gene IDs: 2321, 2322, 2324), FMS-related receptor tyrosine kinase 3 ligand (FLT3LG, NCBI gene ID: 2323), adhesion plaque kinase 2 (PTK2, FAK1, NCBI gene ID: 5747), folate hydrolase 1 (FOLH1, PSMA, NCBI gene ID: 2346), folate receptor 1 (FOLR1, NCBI gene ID: 2348), forkhead box ta Protein M1 (FOXM1, NCBI gene ID: 2305), FURIN (FURIN, PACE, NCBI gene ID: 5045), FYN tyrosine kinase (FYN, SYN, NCBI gene ID: 2534), galectin (e.g., LGALS3, LGALS8 (PCTA1), LGALS9, NCBI gene IDs: 3958, 3964, 3965), glucocorticoid receptor (NR3C1, GR, NCBI gene ID: 2908), glucuronidase β (GUSB, NCBI gene ID: 2990), glutamate metabolite 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 3β (GSK3B, NCBI gene ID: 2932), glypican 3 (GPC3, NCBI gene ID: 2719), gonadotropin-releasing hormone 1 (GNRH1, NCBI gene ID: 2796), gonadotropin-releasing hormone receptor (GNRHR, NCBI gene ID: 2798), GPNMB glycoprotein nmb (GPN MB (osteoactivin, NCBI gene ID: 10457), growth and differentiation factor 2 (GDF2, BMP9, NCBI gene ID: 2658), growth factor receptor binding protein 2 (GRB2, ASH, NCBI gene ID: 2885), guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL, NCBI gene ID: 2984), H19 with maternally derived transcript imprinted (H19, NCBI gene ID: 283120), HCK proto-oncogene, Src family tyrosine kinase (HCK, NCBI gene ID: 3055),Heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96), NCBI gene IDs: 3309, 3315, 7184), heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1), NCBI gene IDs: 3162, 3163), heparanase (HPSE, NCBI gene ID: 10855), hepatitis A virus cell receptor 2 (HAVCR2, TIM3, CD366, NCBI gene ID: 84868), hepatic growth factor (HGF, NCBI gene ID: 3082), HERV-H LTR-related genes 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 oncogenes, GTPases (HRAS, NCBI gene ID: 3265), hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1), NCBI gene IDs: 2034, 3091), I-Kappa-B kinase (IKKβ, NCBI gene IDs: 3551, 3553), IKAROS family zinc fingers (IKZF1 (LYF1), IKZF3, NCBI gene ID: 10320) , 22806), immunoglobulin superfamily member 11 (IGSF11, NCBI gene ID: 152404), indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2, NCBI gene ID: 3620, 169355), inducible T cell costimulator (ICOS, CD278, NCBI gene ID: 29851), inducible T cell costimulator ligand (ICOSLG, B7-H2, NCBI gene ID: 23308), insulin-like growth factor receptor (e.g., IGF1R, IGF2R, NCBI gene ID: 3480, 3482), insulin-like growth factor (e.g., IGF1, IGF2, NCBI gene ID: 3479, 3481), insulin receptor (insulin receptor, INSR, CD220, NCBI gene ID: 3643), integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1),ITGB7 (NCBI gene IDs: 3678, 3685, 3688, 3695, 3698), cell adhesion molecule 1 (ICAM1, CD54, NCBI gene ID: 3383), interleukin-1 receptor-related kinase 4 (IRAK4, NCBI gene ID: 51135), interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1, NCBI gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985), interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6(HGF), IL7, IL8(CXCL8), IL10(TGIF), IL12A, IL12B, IL15, IL17A(CTLA8), IL18, IL23A, IL24, IL-29(IFNL1), NCBI gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618), isocitrate dehydrogenase (NADP(+)1) (e.g., IDH1, IDH2, NCBI gene IDs: 3417, 3418), Janus kinase (e.g., JAK1, JAK2, JAK3, NCBI gene IDs: 3716, 3717, 3718), kallikrein-related peptidase 3 (KLK3, NCBI gene ID: 354), killer cell immunoglobulin-like receptor, Ig domain and long cytoplasmic tail (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (C D158F), KIR2DL5B, KIR3DL1(CD158E1), KIR3DL2(CD158K), KIR3DP1(CD158c), KIR2DS2(CD158J), NCBI gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285), killer cell lectin-like receptors (e.g., KLRC1(CD159A), KLRC2(CD159c), KLRC3, KLRRC4, KLRD1(CD94), KLRG1, KLRK1(NKG2D, CD314),NCBI gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914), kinase insertion domain receptors (KDR, CD309, VEGFR2, NCBI gene ID: 3791), kinesin family member 11 (KIF11, NCBI gene ID: 3832), KiSS-1 transpossession suppressor (KISS1, NC, BI gene ID:3814), KIT oncogene, receptor tyrosine kinase (KIT, C-KIT, CD117, NCBI gene ID:3815), KRAS oncogene, GTPase (KRAS, NCBI gene ID:3845), lactotransferrin (LTF, NCBI gene ID:4057), LCK oncogene, Src family tyrosine kinase (LCK, NCBI gene ID:3932), LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R, NCBI gene ID:4035), leucine-rich repeat-containing 15 (LRRC15, NCBI gene ID: 131578), leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D), NCBI gene IDs: 10288, 10859), leukotriene A4 hydrolase (LTA4H, NCBI gene ID: 4048), linker for T cell activation (LAT, NCBI gene ID: 27040), luteinizing hormone / chorionic gonadotropin receptor (LHCGR, NCBI gene ID: 3973), LY6 / PLAUR domain-containing 3 (LYPD3, N CBI gene ID: 27076), lymphocyte activation 3 (LAG3, CD223, NCBI gene ID: 3902), lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205), NCBI gene IDs: 4063, 17076), LYN oncogene, Src family tyrosine kinase (LYN, NCBI gene ID: 4067), lymphocyte cytoplasmic protein 2 (LCP2, NCBI gene ID: 3937), lysine demethylase 1A (KDM1A, NCBI gene ID: 23028), lysophosphatidic acid receptor 1 (LPAR1, EDG 2, LPA1, GPR26, NCBI gene ID: 1902), lysyl oxidase (LOX, NCBI gene ID: 4015), lysyl oxidase-like 2 (LOXL2, NCBI gene ID: 4017), macrophage migration inhibitor (MIF, GIF, NCBI gene ID: 4282), macrophage-stimulating receptor 1 (MST1R, CD136, NCBI gene ID: 4486), MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10,MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2, NCBI gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740), major histocompatibility complexes (e.g., HLA-A, HLA-E, HLA-F, HLA-G, NCBI gene IDs: 3105, 3133, 3134, 3135), major vault proteins (MVP, VAULT1, NCBI gene ID: 9961), MALT1 paracaspase (MALT1, NCBI gene ID: 9961), Gene ID: 10892), MAPK-activated protein kinase 2 (MAPKAPK2, NCBI gene ID: 9261), MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2, NCBI gene IDs: 2872, 8569), matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, M MP27, 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 gene ID: 4170), MDM2 proto-oncogene (MDM2, NCBI gene ID: 4193), p53 MDM4 regulator (MDM4, BMFS6, NCBI Gene ID: 4194), Mechanistic targets of rapamycin kinase (MTOR, FRAP1, NCBI gene ID: 2475), Melan-A (MLANA, NCBI gene ID: 2315), Melanocortin receptor (MC1R, MC2R, NCBI gene ID: 4157, 4148), MER proto-oncogene, tyrosine kinase (MERTK, NCBI gene ID: 10461), Mesoserine (MSLN, NCBI gene ID: 10232), MET proto-oncogene, Receptor tyrosine kinase (MET, c-Met, HGFR, NCBI gene ID: 4233),Methionyl aminopeptidase 2 (METAP2, MAP2, NCBI gene ID: 10988), MHC class I polypeptide-related sequences (e.g., MICA, MICB, NCBI gene IDs: 4277, 100507436), mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38β), MAPK12, NCBI gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 81) 9251), mitogen-activated protein kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2), NCBI gene IDs: 4217, 1326), mitogen-activated protein kinase 1 (MAP4K1, HPK1, NCBI gene ID: 11184), mitogen-activated protein kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7), NCBI gene IDs: 5604, 5605, 5609), MPL oncogenes, thrombopoietin receptor (MPL, NCBI gene ID: 4352), mucin (e.g., MUC1 (including its splice variants (e.g., MUC1 / A, C, D, X, Y, Z and REP)), MUC5AC, MUC16 (CA125), NCBI gene 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), sodium Diuretic peptide receptor 3 (NPR3, NCBI gene ID: 4883), natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7-H6, NCBI gene ID: 374383), Nectin, MAGE family member (NDN, NCBI gene ID: 4692), Nectin cell adhesion molecule (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4), NCBI gene ID: 5819, 81607), Neuronal cell adhesion molecule 1 (NCAM1, CD56, NCBI gene ID: 4684), Neuropilin (e.g.,NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2), NCBI gene IDs: 8828, 8829), neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC), NCBI gene IDs: 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: 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: 8828, 8829), neurotrophic receptor tyrosine kinases ( Child ID: 114548), Notch receptor (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4, NCBI gene IDs: 4851, 4853, 4854, 4855), NRAS proto-oncogene, GTPase (NRAS, NCBI gene ID: 4893), nuclear factor kappa B (NFKB1, NFKB2, NCBI gene IDs: 4790, 4791), nuclear factor, erythrocyte-like 2 (NFE2L2, NRF2, NCBI gene ID: 4780), nuclear receptor subfamily 4 group A member 1 (NR4A1, NCBI gene ID: 3164), Nu Creolin (NCL, NCBI gene ID: 4691), Nucleophosmin 1 (NPM1, NCBI gene ID: 4869), Nucleoside-binding oligomerized domain-containing 2 (NOD2, NCBI gene ID: 64127), Nudix hydrolase 1 (NUDT1, NCBI gene ID: 4521), 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: 4691) 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 (PPARα), PPARD (PPARδ), PPARG (PPARγ), NCBI gene IDs: 5465, 5467, 5468), phosphatases and tensin homologs (PTEN,NCBI gene ID: 5728), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA (PI3Kα), PIK3CB (PI3Kβ), PIK3CD (PI3Kδ), PIK3CG (PI3Kγ), NCBI gene IDs: 5290, 5291, 5293, 5294), phospholipase (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15, NCBI gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 8 1579, 84647), Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3, NCBI gene IDs: 5292, 11040, 415116), placental growth factor (PGF, NCBI gene ID: 5228), plasminogen activator, urokinase (PLAU, u-PA, ATF, NCBI gene ID: 5328), platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1), NCBI gene IDs: 5156, 5159), plexin B1 (PLXNB1, NCBI gene ID: 5364), poliovirus receptor (poliovirus Cell adhesion molecule (PVR, CD155, NCBI gene ID: 5817), Polo-like kinase 1 (PLK1, NCBI gene ID: 5347), poly(ADP-ribose) polymerase (e.g., PARP1, PARP2, PARP3, NCBI gene IDs: 142, 10038, 10039), Polycomb protein EED (EED, NCBI gene ID: 8726), porcupine O-acyltransferase (PORC N (NCBI gene ID: 64840), PRAME nuclear receptor transcription regulator (PRAME, NCBI gene ID: 23532), premelanosome protein (PMEL, NCBI gene ID: 6490), progesterone receptor (PGR, NCBI gene ID: 5241), programmed cell death 1 (PDCD1, PD-1, CD279, NCBI gene ID: 5133), programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2,NCBI gene ID: 80380), prominin 1 (PROM1, CD133, NCBI gene ID: 8842), promyelocytic leukemia (PML, NCBI gene ID: 5371), propiocin (PSAP, NCBI gene ID: 5660), prostaglandin E receptor 4 (PTGER4, NCBI gene ID: 5734), pro, Staglandin E synthase (PTGES, NCBI gene ID: 9536), prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2), NCBI gene IDs: 5742, 5743), proteasome 20S subunit β9 (PSMB9, NCBI gene ID: 5698), protein arginine methyltransferase (e.g., PRMT1, PRMT5, NCBI gene IDs: 3276, 10419), protein kinase N3 (PKN3, NCBI gene ID: 29941), protein Phosphatase 2A (PPP2CA, NCBI gene ID: 5515), protein tyrosine kinase 7 (inactive) (PTK7, NCBI gene ID: 5754), protein tyrosine phosphatase receptor (PTPRB, PTPRC (CD45R), NCBI gene ID: 5787, 5788), prothymosin α (PTMA, NCBI gene ID: 5757), purine nucleoside phosphorylase (PNP, NCBI gene ID: 4860), purinergic receptor P2X7 (P2RX7, NCBI gene ID: 5027), PVR-related immunoglobulins Contains brin domain (PVRIG, CD112R, NCBI gene ID: 79037), Raf-1 proto-oncogene, serine / threonine kinase (RAF1, c-Raf, NCBI 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 transcription corepressor 1 (RB1, NCBI gene ID: 5925), receptor phase Interactions with serine / threonine protein kinase 1 (RIPK1, NCBI gene ID: 8737), retinoic acid 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 α (e.g., RARA, RARG, NCBI gene IDs: 5914, 5916), retinoid X receptors (e.g., RXRA, RXRB, RXRG, NCBI gene IDs: 6256, 6257, 6258),Rho-related coiled-coil-containing protein kinases (e.g., ROCK1, ROCK2, NCBI gene IDs: 6093, 9475), ribosomal protein S6 kinase B1 (RPS6KB1, S6K-β1, NCBI gene ID: 6198), ring finger protein 128 (RNF128, GRAIL, NCBI gene ID: 79589), ROS oncogene 1, receptor tyrosine kinase (ROS1, NCBI gene ID: 6098), roundabout guidance receptor 4 (ROBO4, NCBI gene ID: 54538), RUNX funnel Millie transcription factor 3 (RUNX3, NCBI gene ID: 864), S100 calcium-binding protein A9 (S100A9, NCBI gene ID: 6280), secreted frizzled-related protein 2 (SFRP2, NCBI gene ID: 6423), secreted phosphoprotein 1 (SPP1, NCBI gene ID: 6696), secretoglobin family 1A member 1 (SCGB1A1, NCBI gene ID: 7356), selectins (e.g., SELE, SELL (CD62L), SELP (CD62), NCBI gene IDs: 6401, 6402, 6) 403), semaphorin 4D (SEMA4D, CD100, NCBI gene ID: 10507), sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10, NCBI gene IDs: 27036, 27180, 89790), signal regulatory protein α (SIRPA, CD172A, NCBI gene ID: 140885), signaling factors and transcriptional activators (e.g., STAT1, STAT3, STAT5A, STAT5B, NCBI gene IDs: 6772, 6774, 6776, 6777), Sirtuin-3 (SIRT3, NCBI gene ID: 23410), signaling lymphocyte-activating molecules (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9, NCBI gene IDs: 56833, 57823, 89886, 114836), SLIT and NTRK-like family member 6 (SLITRK6, NCBI gene ID: 84189), smooth, 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), SLC44A4, NCBI gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935), somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5, NCBI gene ID: 675) 1, 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-associated tyrosine kinase (SYK, NCBI gene ID: 6850), Splicing factor 3B factor 1 (SF3B1, NCBI gene ID: 23451), SRC oncogene, non-receptor tyrosine kinase (SRC, NCBI gene ID: 6714), Stabilin 1 (STAB1, CLEVER-1, NCBI gene ID: 23166), STEAP family member 1 (STEAP1, NCBI gene ID: 26872), steroid sulfatase (STS, NCBI gene ID: 412), interferon response cGAMP interactor 1 stimulator (STING1, NCBI gene ID: 340061), superoxide dismutase 1 (SOD1 ALS1 (NCBI gene ID: 6647), cytokine signaling inhibitors (SOCS1 (CISH1), SOCS3 (CISH3), NCBI gene IDs: 8651, 9021), synapsin 3 (SYN3, NCBI gene ID: 8224), syndecan 1 (SDC1, CD138, syndecan, NCBI gene ID: 6382), synuclein α (SNCA, PARK1, NCBI gene ID: 6622), T cell immunoglobulin and mucin domain-containing 4 (TIMD4, SMUCKLER, NCBI gene ID: 91937),T cell immune receptors 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), tankylase (TNKS, NCBI gene ID: 8658), TATA box-binding protein-related factors, 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), tec protein tyrosine kinase (TEC, NCBI gene ID: 7006), TEK receptor tyrosine kinase (TEK, CD202B, TIE2, NCBI gene ID: 7010), telomerase reverse transcriptase (TERT, NCBI gene ID: 7015), tenascin C (TNC, NCBI gene ID: 3371), 3-prime repair exonuclease (e.g., TREX1, TREX2, NCBI gene ID: 11277, 11 219), thrombomodulin (THBD, CD141, NCBI gene ID: 7056), thymidine kinase (e.g., TK1, TK2, NCBI gene ID: 7083, 7084), thymidine phosphorylase (TYMP, NCBI gene ID: 1890), thymidylate synthase (TYMS, NCBI gene ID: 7298), thyroid hormone receptor (THRA, THRB, NCBI gene ID: 7606, 7608), thyroid-stimulating hormone receptor (TSHR, NCBI gene ID: 7253), TNF superfamily members (e.g., TNFS) F4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD25) 4, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL), NCBI gene ID: 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), transferrin (TF, NCBI gene ID: 7018), Lansferrin receptor (TFRC, CD71, NCBI gene ID: 7037), transforming growth factors (e.g., TGFA, TGFB1, NCBI gene IDs: 7039, 7040), transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3, NCBI gene IDs: 7046, 7048, 7049), transforming protein E7 (E7, NCBI gene ID: 1489079), transglutaminase 5 (TGM5, NCBI gene ID: 9333), transient receptor latent cation channel subfamily V member 1 (TRPV1, VR1 (NCBI gene ID: 7442), transmembrane and immunoglobulin domain-containing proteins (TMIGD2, CD28H, IGPR1, NCBI gene ID: 126259), trigger receptors expressed in bone marrow cells (e.g., TREM1 (CD354), TREM2, NCBI gene IDs: 54209, 54210), trophin (TRO, MAGED3, NCBI gene ID: 7216), trophoblast glycoprotein (TPBG, NCBI gene ID: 7162), tryptophan 2,3-dioxygenase (TDO2, NCBI gene ID: 6999) , tryptophan hydroxylase (e.g., TPH1, TPH2, NCBI gene ID: 7166, 121278), tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1, NCBI gene ID: 4070), tumor necrosis factor (TNF, NCBI gene ID: 7124), tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor),TNFRSF7(CD27)、TNFRSF8(CD30)、TNFRSF9(CD137、4-1BB)、TNFRSF10A(CD261)、TNFRSF10B(TRAIL、DR5、CD262)、TNFRSF10C、TNFRSF10D、TNFRSF11A、TNFRSF11B(OPG)、TNFRSF12A、TNFRSF13B、TNFR13C(、CD、 268, 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 Factor 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), tyrosine kinases with immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1, NCBI gene ID: 7075), tyrosine protein phosphatase nonreceptor type 11 (PTPN11, SHP2, NCBI gene ID: 5781), ubiquitin-conjugating enzyme E2I (UBE2I, UBC9, NCBI gene ID: 7329), ubiquitin C-terminal hydrolase L5 (UCHL5, NCBI gene ID: 51377), ubiquitin-specific peptidase 7 (USP7, NCBI gene ID: 7874), ubiquitin-like modifier activator enzyme 1 (UBA1, NCBI gene ID: 7317), UL16-binding proteins (e.g., ULBP1, ULBP2, ULBP3, NCBI gene IDs: 79465, 80328, 80328), balocin-containing proteins (VCP, CDC48, NCBI gene ID: 741) 5) Vascular cell adhesion molecule 1 (VCAM1, CD106, NCBI gene ID: 7412), vascular endothelial growth factor (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 immunomodulatory receptor (VSIR, VISTA, B7-H5, NCBI gene ID: 64115), WEE1 G2 checkpoint kinase (WEE1, NCBI gene ID: 7465), WRN RecQ-like helicase (WRN, RECQ3, NCBI gene ID: 7486), WT1 transcription factor (WT1, NCBI gene ID: 7490), WW domain-containing transcription regulator 1 (WWTR1, TAZ, NCBI gene ID: 25937), XC motif chemokine ligand 1 (XCL1, ATAC, NCBI gene ID: 6375), XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1, NCBI gene ID: 2829), Yes1-related transcription regulator (YAP1, NCBI gene ID: 10413), zeta chain-related protein kinase 70 (ZAP70, NCBI gene ID: 7535).

[0141] In some embodiments, one or more additional therapeutic agents include, for example, 5'-nucleotidase ectopropyl alcohol (NT5E or CD73, NCBI gene ID: 4907), adenosine A 2A Receptor (ADORA2A, NCBI gene ID: 135), adenosine A 2BReceptor (ADORA2B, NCBI gene ID: 136), CC motif chemokine receptor 8 (CCR8, CDw198, NCBI gene ID: 1237), cytokine-inducible SH2-containing protein (CISH, NCBI gene ID: 1154), diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α, NCBI gene ID: 1606), fms-like tyrosine kinase 3 (FLT3, CD135, NCBI gene ID: 2322), integrin-related protein (IAP, CD47, NCBI gene ID: 961), interleukin-2 (IL2, NCBI gene ID: 3558), interleukin-2 receptor (IL2RA, IL2RB, IL2RG, NCBI gene IDs: 3559, 3560, 3561), Kirsten rat sarcoma virus (KRAS, NCBI gene ID: 3845, KRAS (including mutations such as G12C or G12D), mitogen-activated protein kinase kinase kinase 1 (MAP4K1) (also called hematopoietic progenitor kinase 1 (HPK1), NCBI gene ID: 11184), myelocyte leukemia sequence 1 apoptosis regulator (MCL1, NCBI gene ID: 4170), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD, NCBI gene ID: 5293), programmed cell death ligand 1 (PD-L1, CD274, NCBI gene ID: 29126), programmed cell death protein 1 (PD-1, CD279, NCBI gene ID: 5133), proto-oncogene c-KIT (KIT, CD117, NCBI gene ID: 3815), signal regulatory protein α (SIRPA, CD172A, NCBI gene ID: 140885), TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7, NCBI gene ID: 25976), T cell immune receptor with Ig and ITIM domains (TIGIT, NCBI gene ID: 201633), bone Trigger receptor 1 (TREM1, NCBI gene ID: 54210) expressed on myelocytes, trigger receptor 2 (TREM2, NCBI gene ID: 54209) expressed on bone marrow cells, 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), WRN RecQ-like helicase (WRN, NCBI gene ID: 7486), zinc finger protein Helios (IKZF2, NCBI gene ID: 22807).

[0142] Illustrative mechanism of action Immune checkpoint modulator In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulants, activators, or agonists of one or more stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor microenvironment. Activation or stimulation of stimulating immune checkpoints can enhance the effects of immune checkpoint inhibitors in cancer treatment. In some embodiments, immune checkpoint proteins or receptors modulate T cell responses (as outlined, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate the NK cell response (see, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition or depletion of regulatory T cells (Tregs) may mitigate the suppression of their antitumor immune response and have anticancer effects (see, e.g., Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77 and Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0143] 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 (N CBI gene ID: 11126), MS4A1 (CD20, NCBI gene ID: 931), CD244 (SLAMF4, NCBI gene ID: 51744), CD276 (B7H3, NCBI gene ID: 80381), V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4), V-set immunomodulatory receptor (VSIR, B7H5, VISTA, NCBI gene ID: 64115), immunoglobulin superfamily member 11 (IGSF11, VSIG3, NCBI gene ID: 152404), natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6, NCBI gene ID: 374383), HERV-H LTR-related 2 (HHLA2, B7H7, NCBI gene ID: 11148), Inducible T cell costimulator (ICOS, CD278, NCBI gene ID: 29851), Inducible T cell costimulator ligand (ICOSLG, B7H2, NCBI gene ID: 23308), TNF receptor superfamily member 4 (TNFRSF4, OX40, NCBI gene ID: 7293), TNF superfamily member 4 (TNFSF4, OX40L, N CBI gene ID: 7292), TNFRSF8 (CD30, NCBI gene ID: 943), TNFSF8 (CD30L, NCBI gene ID: 944), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF9 (CD137, NCBI gene ID: 3604), TNFSF9 (CD137L, NCBI gene ID: 8744), TNFRSF10B (CD262, DR5, TRAILR2,NCBI gene ID: 8795), TNFRSF10 (TRAIL, NCBI gene ID: 8743), TNFRSF14 (HVEM, CD270, NCBI gene ID: 8764), TNFSF14 (HVEML, NCBI gene ID: 8740), CD272 (B and T lymphocyte-related (BTLA), NCBI gene ID: 151888), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFSF13B (BAFF, NCBI gene ID: 10673), TNFRSF18 (GITR, NCBI gene ID: 8784), TNFSF18 (GITRL, NCBI gene ID: 8995), MHC class I polypeptide-related sequence A (MICA, NCBI gene ID: 100507436), MHC class I polypeptide-related sequence B (MICB, NCBI gene ID: 4277), CD274 (CD274, PDL1, PD-L1, NCBI gene ID: 29126), programmed cell death 1 (PDCD1, PD1, PD-1, NCBI gene ID: 5133), cytotoxic T lymphocyte-related protein 4 (CTLA4, CD152, NCBI gene ID: 1493), CD80 (B7 -1, NCBI gene ID: 941), CD28 (NCBI gene ID: 940), Nectin cell adhesion molecule 2 (NECTIN2, CD112, NCBI gene ID: 5819), CD226 (DNAM-1, NCBI gene ID: 10666), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155, NCBI gene ID: 5817), PVR-related immunoglobulin domain-containing (PVRIG, CD112R, NCBI gene ID: 79037), T cell immune receptor with Ig and ITIM domains (TIGIT, NCBI gene ID: 20 1633), T cell immunoglobulin and mucin domain-containing 4 (TIMD4, TIM4, NCBI gene ID: 91937), hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3, NCBI gene ID: 84868), galectin 9 (LGALS9, NCBI gene ID: 3965), lymphocyte activation 3 (LAG3, CD223, NCBI gene ID: 3902), signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150, NCBI gene ID: 6504), lymphocyte antigen 9 (LY9, CD229,SLAMF3 (NCBI gene ID: 4063), SLAM family member 6 (SLAMF6, CD352, NCBI gene ID: 114836), SLAM family member 7 (SLAMF7, CD319, NCBI gene ID: 57823), UL16 binding protein 1 (ULBP1, NCBI gene ID: 80329), UL16 binding protein 2 (ULBP2, NCBI gene ID: 80328), UL16 binding protein 3 (ULBP3, NCBI gene ID: 79465), retinoic acid 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, 3 Ig domains and long cytoplasmic tail 1 (KIR, CD158E1, NCBI gene ID: 3811, e.g., lirirumab (IPH-2102, IPH-4102)), killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A, NCBI gene ID: 38 21) Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314, NCBI gene ID: 22914), killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C, NCBI gene ID: 3822), killer cell lectin-like receptor C3 (KLRC3, NKG2E, NCBI gene ID: 3823), killer cell lectin-like receptor C4 (KLRC4, NKG2F, NCBI gene ID: 8302), killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1, NCBI gene ID: 3802), killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2, NCBI gene ID: 3803), killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3, NCBI gene ID: 3804), killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1), killer cell lectin-like receptor D1 (KLRD1, NCBI gene ID: 3824), killer cell lectin-like receptor G1 (KLRG1, CLEC15A, MAFA,Examples include 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).

[0144] In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more T-cell inhibitory immune checkpoint proteins or receptor blockers or inhibitors. Examples of T cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1), programmed cell death ligand 1 (PDCD1LG2, PD-L2, CD273), programmed cell death 1 (PDCD1, PD1, PD-1), cytotoxic T lymphocyte-related protein 4 (CTLA4, CD152), CD276 (B7H3), V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4), V-set immunomodulatory receptor (VSIR, B7H5, VISTA), immunoglobulin superfamily member 11 (IGSF11, VSIG3), TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML), CD272 (B and T lymphocyte-related (BTLA)), and PVR-related immunoglobulin domain-containing (PVRIG, CD1 Examples include 12R), T cell immune receptors having 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, 3 Ig domains and long cytoplasmic tail 1 (KIR, CD158E1), killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 1 (KIR2DL1), killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2), killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 3 (KIR2DL3), and killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors.Examples of T cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70, CD40, CD40LG, inducible T cell costimulators (ICOS, CD278), inducible T cell costimulator ligands (ICOSLG, B7H2), TNF receptor superfamily member 4 (TNFRSF4, OX40), TNF superfamily member 4 (TNFSF4, OX40L), TNFRSF9 (CD137), TNFSF9 (CD137L), TNFRSF18 (GITR), TNFSF18 (GITRL), CD80 (B7-1), CD28, nectin cell adhesion molecule 2 (NECTIN2, CD112), CD226 (DNAM-1), CD244 (2B4, SLAMF4), and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). For example, see Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0145] In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more NK cell inhibitory immune checkpoint proteins or receptors or blockers or inhibitors. Illustrative NK cell inhibitory immune checkpoint proteins or receptors include: Killer cell immunoglobulin-like receptor, 3 Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); Killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 1 (KIR2DL1); Killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 3 Examples include (KIR2DL3), a killer cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1), killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A), killer cell lectin-like receptor D1 (KLRD1, CD94), killer cell lectin-like receptor G1 (KLRG1, CLEC15A, MAFA, 2F1), sialic acid-bound Ig-like lectin 7 (SIGLEC7), and sialic acid-bound Ig-like lectin 9 (SIGLEC9). In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Examples of NK cell-stimulated immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1), CD244 (2B4, SLAMF4), killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314), and SLAM family member 7 (SLAMF7). See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75, Fang, et al., Semin Immunol. (2017) 31:37-54, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0146] In some embodiments, one or more immune checkpoint inhibitors include protein-based inhibitors (e.g., antibodies or fragments thereof, or antibody mimics) of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include protein-based inhibitors (e.g., antibodies or fragments thereof, or antibody mimics) of LAG3.

[0147] Examples of CTLA4 inhibitors that can be administered concurrently include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zarifremab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, and KN-04. 4. Examples include 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).

[0148] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be administered concurrently include pembrolizumab, nivolumab, semiprimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosiberimab (CK-301), sasamrimab (PF-06801591), tislerizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, and HLX-1. 0, Retifan Limab (MGA-012), BI-754091, Valstilimab (AGEN-2034), AMG-404, Tripalimab (JS-001), Cetrelimab (JNJ-63723283), Genolimuzumab (CBT-501), LZM-009, Prorugolimab (BCD-100), Rhodapolimab (LY-3300054), SHR-1201, Camrelizumab (SHR-1210), Sym-021, Buzigalimab (ABBV-181), PD1-PIK, BAT-1306, Avelumab (MSB0010718C), CX-072, CBT-502, Dostallumab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), Embafolimab (KN-035), Syntilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, Zimbererimab (AB122), Spartali Zumab (PDR-001), and compounds disclosed in International Publication Nos. 2018195321, 2020014643, 2019160882, or 2018195321, as well as the 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 / Examples include PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp α (M7824, PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor such as CA-170, GS-4224, GS-4416, and razertinib (GNS-1480, PD-L1 / EGFR).

[0149] Examples of TIGIT inhibitors that can be administered concurrently include tiragolumab (RG-6058), vivostrimab, domvanarimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigirimab.

[0150] An example of a LAG3 inhibitor that can be administered concurrently is relamirimab (LAG525).

[0151] Inhibition of regulatory T cell (Treg) activity or Treg depletion may mitigate the suppression of the antitumor immune response and have anticancer effects. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77 and Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more inhibitors of Treg activity or Treg depletors. Inhibition or depletion of Tregs can enhance the effects of immune checkpoint inhibitors in cancer treatment.

[0152] In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more Treg inhibitors. In some embodiments, Treg inhibitors can suppress the migration of Tregs into the tumor microenvironment. In some embodiments, Treg inhibitors can reduce the immunosuppressive function of Tregs. In some embodiments, Treg inhibitors can modulate the cellular phenotype and induce the production of inflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI gene ID: 1233) antagonists and degradants 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).

[0153] Examples of Helios-degrading agents that may be administered concurrently include, but are not limited to, I-57 (Novartis) and the compounds disclosed in International Publication Nos. 2019038717, 2020012334, 20200117759, and 2021101919.

[0154] In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more Treg depletion agents. In some embodiments, the Treg depletion agent is an antibody. In some embodiments, the Treg depletion antibody has antibody-dependent cytotoxic (ADCC) activity. In some embodiments, the Treg depletion antibody is Fc gene-engineered to have enhanced ADCC activity. In some embodiments, the Treg depletion antibody is an antibody-drug conjugate (ADC). Examples of typical targets for Treg depletion agents include, but are not limited to, CD25 (IL2RA, NCBI gene ID: 3559), CTLA4 (CD152, NCBI gene ID: 1493), GITR (TNFRSF18, NCBI gene ID: 8784), 4-1BB (CD137, NCBI gene ID: 3604), OX-40 (CD134, NCBI gene ID: 7293), LAG3 (CD223, NCBI gene ID: 3902), TIGIT (NCBI gene ID: 201633), CCR4 (NCBI gene ID: 1233), and CCR8 (NCBI gene ID: 1237).

[0155] In some embodiments, Treg inhibitors or Treg depletors that may be administered concurrently include CC-motif chemokine receptor 4 (CCR4), CC-motif chemokine receptor 7 (CCR7), CC-motif chemokine receptor 8 (CCR8), CXC-motif chemokine receptor 4 (CXCR4, CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), and cells. T-lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​CD39), protein tyrosine phosphatase receptor type C (PTPRC, CD45), neuronal cell adhesion molecule 1 (NCAM1, CD56), selectin L (SELL; CD62L), integrin The product contains antibodies or antigen-binding fragments thereof that selectively bind to cell surface receptors selected from the group consisting of β-unit αE (CD103), interleukin-7 receptor (IL7R, CD127), CD40 ligand (CD40LG, CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), leucine-rich repeat-containing 32 (LRRC32, GARP), IKAROS family zinc finger 2 (IKZF2, HELIOS), inducible T cell costimulator (ICOS, CD278), lymphocyte activator 3 (LAG3, CD223), transforming growth factor β1 (TGFB1), hepatitis A virus cell receptor 2 (HAVCR2, CD366, TIM3), T cell immune receptor having Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b, TNFR2), IL2RA (CD25), or combinations thereof.

[0156] Examples of Treg depletion anti-CCR8 antibodies that may be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and antibodies disclosed in International Publication Nos. 2021163064, 2020138489, and 2021152186.

[0157] An example of a Treg depletion anti-CCR4 antibody that may be administered is mogamulizumab.

[0158] Inhibition, depletion, or reprogramming of non-stimulated myeloid cells in the tumor microenvironment can enhance the anti-cancer immune response (see, for example, Binnewies et al., Nat. Med. (2018) 24(5):541-550, International Publication No. 2016049641). Exemplary targets for depleting or reprogramming non-stimulated myeloid cells include the trigger receptors TREM-1 (CD354, NCBI gene ID: 54210) and TREM-2 (NCBI gene ID: 54209), which are expressed on myeloid cells. In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with one or more myeloid depletion agents or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159, the antibody disclosed in International Publication No. 2019032624) or an anti-TREM-2 antibody (e.g., PY314, the antibody disclosed in International Publication No. 2019118513).

[0159] Agonists or activators of differentiation clusters In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with agents targeting cluster of differentiation (CD) markers. Exemplary CD marker-targeting agents that may be co-administered include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimimer (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), and HLA-A2402 / HLA-A0201 restriction epitope peptide. Dovitinib, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranergene ovadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, levatinib, NMS-088, lucitanib hydrochloride, midostaurin, cedilanib, dovitinib, citravatinib, tivozanib, masitinib, regorafenib, olberenvatinib dimesile Famitinib (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, Asnercept (APG-101), APO-010, and International Publication Nos. 2016196388, 2016033570, 2015157386, 199203459, 199221766, and 200 No. 4080462, No. 2005020921, No. 2006009755, No. 2007078034, No. 2007092403, No. 2007127317, No. 2008005877, No. 2012154 No. 480, No. 2014100620, No. 2014039714, No. 2015134536, No. 2017167182, No. 2018112136, No. 2018112140, No. 2019155067,Same No. 2020076105, International Application PCT / US2019 / 063091, International Publication No. 19173692, Same No. 2016179517, Same No. 2017096179, Same No. 2017096182, Same No. 2017096281, Same No. 2018089628, Same No. 20170 No. 96179, No. 2018089628, No. 2018195321, No. 2020014643, No. 2019160882, No. 2018195321, 200140307, ​​2002092784, 2007133811, 2009046541 No. 2010083253, No. 2011076781, No. 2013056352, No. 2015138600, No. 20161 No. 79399, No. 2016205042, No. 2017178653, No. 2018026600, No. 2018057669, No. Examples of compounds disclosed include those listed in Nos. 2018107058, 2018190719, 2018210793, 2019023347, 2019042470, 2019175218, 2019183266, 2020013170, 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).

[0160] In some embodiments, the CD marker-targeting drugs that may be administered concurrently include small molecule inhibitors, such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), logalatinib (BAY-1163877), AZD4547, robritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BL Examples include U-263, CD117-ADC, AZD3229, teratinib, bororanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, tinxafor (TG-0054), X4P-002, mavolixafor (X4P-001-IO), prelixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0161] In some embodiments, the drugs targeting the CD marker that may be administered concurrently include small molecule agonists, such as interleukin-2 receptor subunit gamma, eltrombopag, lintatrimod, polyICLC (NSC-301463), riboxone, apoxime, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin α (ABBV-621), and E-6. Examples include 887, Motrimod, Reshikimod, Sergantrimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, Kobitrimod, Chilsotrimod, Litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, Agatrimod, DIMS-9054, DV-1079, Refitrimod (MGN-1703), CYT-003, and PUL-042.

[0162] In some embodiments, the CD marker-targeting agents that can be administered concurrently include antibodies such as tafacitamab (MOR208, MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), valrirumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otreltuzumab (TRU-016), isatuximab, ferzaltamab (MOR-202), TAK-079, and T AK573, Daratumumab (DARZALEX®), TTX-030, Sericrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, Mitazarimab (JNJ-64457107), Renzrumab, Alemtuzumab, Emactuzumab, AMG-820, FPA-008 (Cabilizumab), PRS-343 (CD-13 7 / HER2), AFM-13 (CD16 / CD30), verantamab mahodotin (GSK-2857916), AFM26 (BCMA / CD16A), Simulcaphusp α (RG7461), urerumab, utomirumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FA P-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatrimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enserimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20).5) MEDI-9447 (Olecumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, Lirirumab (IPH-2102), Lactamab (IPH-4102), Monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), Iodine (131I) apamistamab (131I-BC8 (iomab-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, C Examples include TB-006, INBRX-109, GEN-1029, pepinemab (VX-15), voplaterimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in International Publication Nos. 2017096179, 2017096276, 2017096189, and 2018089628.

[0163] In some embodiments, CD marker-targeting agents that may be administered concurrently include cell therapies such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, iso-cel, lysocabactene maralucel (JCAR-017), axicapbutazine siroleucel (KTE-C19, Yescarta®), axicapbutazine siroleucel (KTE-X19), US7741465, US6319494, UCART-19, taberecureucel (EBV-CTL), T tisagenlecroucel-T (CTL019), CD19CAR-CD28-CD3ζ-EGFRt-expressing T cells, and CD19 / 4-1BBL armored CAR. T-cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28ζT cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia / non-Hodgkin lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silent IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1(CD19 / CD20), GC-197(CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR(CD19 / APRIL), ICG-134, ICG-132(CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20 CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3ζ-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecroucell-T, CART-19, tisagenlecroucell (CTL-019), anti-CD20 CAR T cell therapy (non-Hodgkin lymphoma), MB-CART2019.1 (CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 Examples include cCAR, CYAD-01 (NKG2D ligand modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, or therapies disclosed in International Publication No. 2012079000 or 2017049166.

[0164] Differentiation cluster 47 (CD47) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of CD47 (IAP, MER6, OA3, NCBI gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody or CD47 blocker, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621.Additional exemplary anti-CD47 antibodies include CC-90002, maglorimab (Hu5F9-G4), AO-176 (Vx-1004), retaprimab (IBI-188), remzopalimab (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. 19972. No. 7873, No. 199940940, No. 2002092784, No. 2005044857, No. 2009046541, Same No. 2010070047, Same No. 2011143624, Same No. 2012170250, Same No. 2013109752, Same No. 2013 119714, 2014087248, 2015191861, 2016022971, 201602304 No. 0, No. 2016024021, No. 2016081423, No. 2016109415, No. 2016141328, No. 2 No. 016188449, No. 2017027422, No. 2017049251, No. 2017053423, No. 201712 No. 1771, No. 2017194634, No. 2017196793, No. 2017215585, No. 2018075857, Same No. 2018075960, No. 2018089508, No. 2018095428, No. 2018137705, No. 201 No. 8233575, No. 2019027903, No. 2019034895, No. 2019042119, No. 201904228 Examples of compounds disclosed in No. 5, No. 2019042470, No. 2019086573, No. 2019108733, No. 2019138367, No. 2019144895, No. 2019157843, No. 2019179366, No. 2019184912, No. 2019185717, No. 2019201236, No. 2019238012, No. 2019241732, No. 2020019135, No. 2020036977, No. 2020043188, and No. 2020009725 include those disclosed in No. 5, No. 2019042470, No. 2019086573, No. 2019108733, No. 2019138367, No. 2019144895, No. 2019157843, No. 2019179366, No. 2019184912, No. 2019185717, No. 2019201236, No. 2019238012, No. 2019241732, No. 2020019135, No. 2020036977, No. 2020043188, and No. 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 maglorimab.

[0165] In some embodiments, the CD47 inhibitor is a bispecific antibody targeting CD47, such as IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217 (CD47 / DLL3), IMM-26011 (CD47 / These include FLT3), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801.

[0166] Drugs targeting SIRPa In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with a SIRPa-targeting agent (NCBI gene ID: 140885, UniProt P78324). Examples of SIRPa-targeting agents include SIRPa inhibitors such as AL-008, RRx-001, and CTX-5861, as well as anti-SIRPa antibodies such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, and Q-1801 (SIRPa / PD-L1). The additional SIRPα-targeting drugs used include, for example, International Publication Nos. 200140307, ​​2002092784, 2007133811, 2009046541, 2010083253, 2011076781, 2013056352, 2015138600, 2016179399, 2016205042, and 20 It is listed in documents No. 17178653, No. 2018026600, No. 2018057669, No. 2018107058, No. 2018190719, No. 2018210793, No. 2019023347, No. 2019042470, No. 2019175218, No. 2019183266, No. 2020013170, and No. 2020068752.

[0167] FLT3R Agonist In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an FLT3R agonist. In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an FLT3 ligand. In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with, for example, the FLT3L-Fc fusion protein described in International Publication No. 2020263830. In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with GS-3583 or CDX-301. In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with GS-3583.

[0168] Agonists or activators of members of the TNF receptor superfamily (TNFRSF). In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are agonists of one or more members of the TNF receptor superfamily (TNFRSF), for example, TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134, NCBI gene ID: 7293), TNFRSF5 (CD40, NCBI gene ID: 958), TNFRSF6 (F AS (NCBI gene ID: 355), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3 , NCBI gene ID: 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), T It is administered with one or more agonists from among NFRSF16 (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).

[0169] Examples of anti-TNFRSF4 (OX40) antibodies that can be administered concurrently include MEDI6469, MEDI6383, tavorixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in International Publication Nos. 2016179517, 2017096179, 2017096182, 2017096281, and 2018089628.

[0170] Exemplary anti-TNFRSF5 (CD40) antibodies that can be administered concurrently include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0171] In some embodiments, the anti-TNFRSF7 (CD27) antibody varylumab (CDX-1127) is administered concurrently.

[0172] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be administered concurrently include urelumab, utomirumab (PF-05082566), AGEN-2373, and ADG-106.

[0173] In some embodiments, the anti-TNFRSF17(BCMA) antibody GSK-2857916 is administered concurrently.

[0174] Examples of anti-TNFRSF18(GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in International Publication Nos. 2017096179, 2017096276, 2017096189, and 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4(OX40) and TNFRSF18(GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017096179 and 2018089628.

[0175] Examples of bispecific antibodies targeting TNFRSF family members that can be administered concurrently include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronexutamab (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).

[0176] Bispecific T cell engagers In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with a bispecific T cell engager (e.g., one without Fc) or an anti-CD3 bispecific antibody (e.g., one with Fc). Examples of exemplary anti-CD3 bispecific antibodies or BiTEs that can be administered concurrently 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), odronexutamab (REGN-1979, CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (heme / CD3), JNJ-7564 (CD3 / heme), and AMG-757.(DLL3-CD3), AMG-330(CD33 / CD3), AMG-420(BCMA / CD3), AMG-427(FLT3 / CD3), AMG-562(CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-673(CD33 / CD3), AMG-701(BCMA / CD3), AMG-757(DLL3 / CD3), AMG-211(CEA / CD3), Blinatsumo Mab(CD19 / CD3), huGD2-BsAb(CD3 / GD2), ERY974(GPC3 / CD3), GEMoab(CD3 / PSCA), RG6026(CD20 / CD3), RG6194 (HER2 / CD3), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw123), JNJ-9383(MGD-015), AMG-424(CD38 / CD3), Tidutamab (XmAb-18087(SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-00 9(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20), Tidutamab(XmAb-1808 Examples include 7. SSTR2 / CD3), catumakisomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosnetuzumab (RG-7828, CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). The anti-CD3 binding bispecific molecule may or may not have an Fc, as needed. Exemplary bispecific T cell engagers that can be administered concurrently target CD3 and tumor-associated antigens described herein, such as 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); and PD-L1 (Horn, et al., Oncotarget. 2017 Aug).Examples include 3;8(35): 57964-57980) and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10;403:224-230).

[0177] Bispecific and tripspecific natural killer (NK) cell engagers In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with bispecific antibodies (e.g., with Fc) against bispecific NK cell engagers (BiKE) or trispecific NK cell engagers (TriKE) (e.g., without Fc), or NK cell activating receptors, such as CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), innate cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell type C lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (mediating antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKEs, or TriKEs that may be administered concurrently include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). The anti-CD16 binding bispecific molecule may or may not have an Fc, as required. Exemplary bispecific NK cell engagers that may be administered concurrently target CD16 and one or more tumor-associated antigens described herein, such as CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1. BiKEs and TriKEs are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346 and Fang, et al., Semin Immunol. (2017) 31:37-54.

[0178] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with MCL1 apoptosis regulators and inhibitors of BCL2 family members (MCL1, TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1 / EAT, NCBI gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in International Publications 2018183418, 2016033486, and 2017147410.

[0179] SHP2 inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with inhibitors of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2, NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in International Publication Nos. 2018172984 and 2017211303.

[0180] Hematopoietic progenitor cell kinase 1 (HPK1) inhibitors and degrading agents In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of mitogen-activated protein kinase kinase kinase 1 (MAP4K1, HPK1, NCBI gene ID: 11184). Examples of hematopoietic progenitor cell kinase 1 (HPK1) inhibitors include, but are not limited to, those described in International Publication Nos. 2020092621, 2018183956, 2018183964, 2018167147, 2018049152, 2020092528, 2016205942, 2016090300, 2018049214, 2018049200, 2018049191, 2018102366, 2018049152, and 2016090300.

[0181] Apoptosis signal-regulating kinase (ASK) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with ASK inhibitors, such as mitogen-activated protein kinase kinase 5 (MAP3K5, ASK1, MAPKKK5, MEKK5, NCBI gene ID: 4217). Examples of ASK1 inhibitors are described in International Publication No. 2011008709 (Gilead Sciences) and No. 2013112741 (Gilead Sciences).

[0182] Bruton's tyrosine kinase (BTK) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with inhibitors of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(buta-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebralutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0183] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein include 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), and cyclin-dependent kinase 4 (CDK4, CMM3, PS It is administered together with an inhibitor of K-J3 (NCBI gene ID: 1019), cyclin-dependent kinase 6 (CDK6, MCPH12, PLSTIRE, NCBI gene ID: 1021), cyclin-dependent kinase 7 (CDK7, CAK, CAK1, HCAK, MO15, STK1, CDKN7, p39MO15, NCBI gene ID: 1022), or cyclin-dependent kinase 9 (CDK9, TAK, C-2k, CTK1, CDC2L4, PITALRE, NCBI gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, arbocidicib (HMR-1275, flavopyridol), AT-7519, dinacilib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexol, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milcilib, trilaciclib, simrosertib hydrate (TAK931), and TG-02.

[0184] Discoidine domain receptor (DDR) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are combined with inhibitors of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE, NCBI gene ID: 780) and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN, NCBI gene ID: 4921). Examples of DDR inhibitors include dasatinib, as well as those disclosed in International Publication No. 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), U.S. Patent Application Publication No. 2011-0287011 (Oncomed Pharmaceuticals), International Publication No. 2013 / 027802 (Chugai Pharmaceutical), and U.S. Patent Application Publication No. 2013 / 034933 (Imperial Innovations).

[0185] Targeted E3 ligase ligand conjugate In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with a targeted E3 ligase ligand conjugate. Such a conjugate has a target protein binding moiety and an E3 ligase binding moiety (e.g., an apoptotic protein inhibitor (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, a mouse double micro2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase the degradation of the targeted protein, for example, via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugate comprises a target moiety or binding moiety that targets or binds to the proteins described herein, and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate includes a target or binding site that targets or binds to a protein selected from the Cbl proto-oncogene B (CBLB, Cbl-b, Nbla00127, RNF56, NCBI gene ID: 868) and hypoxia-inducible factor 1 subunit α (HIF1A, NCBI gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate includes a kinase inhibitor (e.g., a small molecule kinase inhibitor of BTK and the E3 ligase ligand or binding site). See, for example, International Publication No. 2018098280. In some embodiments, the targeted E3 ligase ligand conjugate comprises a binding site that targets or binds to interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4), rapidly accelerating fibrosarcoma proteins (such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD proteins, and an E3 ligase ligand or binding site. See, for example, International Publication Nos. 2019099926, 2018226542, 2018119448, 2018223909, and 2019079701.Additional targeted E3 ligase ligand conjugates that can be administered concurrently are described, for example, in International Publications 2018237026, 2019084026, 2019084030, 2019067733, 2019043217, 2019043208, and 2018144649.

[0186] Histone deacetylase (HDAC) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with inhibitors of histone deacetylase, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR, gene ID: 9734). Examples of HDAC inhibitors include avexinostat, ACY-241, AR-42, BEBT-908, bellinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, dibinostat, mosetinostat, panobinostat, prasinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamstine, remetinostat, and entinostat.

[0187] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1, NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrhodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919 vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0188] Janus kinase (JAK) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with inhibitors of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3, NCBI gene ID: 3716), Janus kinase 2 (JAK2, JTK10, THCYT3, NCBI gene ID: 3717), and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK, NCBI gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restaurtinib, momerotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0189] Lysyl oxidase-like protein (LOXL) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with inhibitors of LOXL proteins, such as LOXL1 (NCBI gene ID: 4016), LOXL2 (NCBI gene ID: 4017), LOXL3 (NCBI gene ID: 84695), LOXL4 (NCBI gene ID: 84171), and / or LOX (NCBI gene ID: 4015). Examples of LOXL2 inhibitors include antibodies described in International Publication No. 2009017833 (Arresto Biosciences), No. 2009035791 (Arresto Biosciences), and No. 2011097513 (Gilead Biologics).

[0190] Matrix metalloproteinase (MMP) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are inhibitors of matrix metallopeptidases (MMPs), such as MMP1 (NCBI gene ID: 4312), MMP2 (NCBI gene ID: 4313), MMP3 (NCBI gene ID: 4314), MMP7 (NCBI gene ID: 4316), MMP8 (NCBI gene ID: 4317), MMP9 (NCBI gene ID: 4318), MMP10 (NCBI gene ID: 4319), MMP11 (NCBI gene ID: 4320), MMP12 (NCBI gene ID: 4321), MMP13 (NCBI gene ID: 4312). It is administered together with inhibitors of MMP14 (NCBI gene ID: 4323), MMP15 (NCBI gene ID: 4324), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP19 (NCBI gene ID: 4327), MMP20 (NCBI gene ID: 9313), MMP21 (NCBI gene ID: 118856), MMP24 (NCBI gene ID: 10893), MMP25 (NCBI gene ID: 64386), MMP26 (NCBI gene ID: 56547), MMP27 (NCBI gene ID: 64066), and / or MMP28 (NCBI gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), cipestat (Ro 32-3555), GS-5745 (andecaliximab), and those described in International Publication No. 2012027721 (Gilead Biologics).

[0191] RAS and RAS pathway inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are KRAS proto-oncogenes, GTPases (KRAS, also known as NS, NS3, CFC2, RALD, K-Ras, KRAS1, KRAS2, RASK2, KI-RAS, CK-RAS, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B, c-Ki-ras2, NCBI gene ID: 3845), NRAS proto-oncogenes, GTPases (NR Ras inhibitors are administered together with inhibitors of the AS (also known as NS6, CMNS, NCMS, ALPS4, N-ras, NRAS1, NCBI gene ID: 4893) or HRAS proto-oncogene, or GTPase (HRAS, also known as CTLO, KRAS, HAMSV, HRAS1, KRAS2, RASH1, RASK2, Ki-Ras, p21ras, CH-RAS, cK-ras, H-RASIDX, c-Ki-ras, C-BAS / HAS, C-HA-RAS1, NCBI gene ID: 3265). Ras inhibitors can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of the following: EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Examples of K-Ras inhibitors that can be administered concurrently include sotrasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adaglasib (MRTX-849), ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides including KRpep-2 and KRpep-2d. Examples of KRAS mRNA inhibitors include anti-KRAS U1 adapters, AZD-4785, siG12D-LODER®, and siG12D exosomes.Examples of MEK inhibitors that can be administered concurrently include binimetinib, cobimetinib, PD-0325901, pimacertib, RG-7304, selumetinib, trametinib, and those described below and in this specification. Examples of Raf dimer inhibitors that can be administered concurrently include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Examples of ERK inhibitors that can be administered concurrently include LTT-462, LY-3214996, MK-8353, labocertinib, and urixertinib. Examples of Ras GTPase inhibitors that can be administered concurrently include rigosertib. Examples of PI3K inhibitors that can be administered concurrently include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Examples of AKT inhibitors that can be administered concurrently include capivacertib and GSK2141795. Examples of PI3K / mTOR inhibitors that can be administered concurrently include dactricib, omiparicib, voxtalisib, gedatricib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanicertib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), racemethyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatacertib (CC-223), SF-1126, and PQR-309 (vimiralisib). In some embodiments, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, for example, Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. In addition, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1 / 2 / 4 inhibitor neratinib. See, for example, Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0192] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with inhibitors of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4, NCBI gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib + trametinib, PD-0325901, pimacertib, LTT462, AS703988, CC-90003, and refametinib.

[0193] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, for example, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α, NCBI gene ID: 5290), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β ( It is administered together with inhibitors of PIK3CB (P110β, PI3K, PI3KBETA, PIK3C1, NCBI gene ID: 5291), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K, gene ID: 5494), and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D, NCBI gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, buparlisib (BKM120), BYL719 (alperisib), CH5132799, and copanlisib (BAY 80-6946), Duverisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, R G7604, ligoseltib, RP5090, RP6530, SRX3177, tasericib, TG100115, TGR-1202 (umbralicib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Waltmannin, ZSTK474, and International Publication No. 2005113556 (ICOS), and International Publication No. 2013 / 052699 (Gilead Examples include the compounds described in Calistoga, Gilead Calistoga (No. 2013116562), Gilead Calistoga (No. 2014100765), Gilead Calistoga (No. 2014100767), and Gilead Sciences (No. 2014201409).

[0194] Spleen tyrosine kinase (SYK) inhibitors In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine, BAY-61-3606, celduratinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Patent No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 20150175616.

[0195] Toll-like receptor (TLR) agonist In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with agonists of Toll-like receptors (TLRs), such as TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793).Examples of TLR7 agonists that can be administered concurrently include DS-0509, GS-9620 (besatrimod), besatrimod analogues, LHC-165, TMX-101 (imiquimod), GSK-2245035, reciquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509, and U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). (Sciences), and Patent No. 20090047249 (Gilead Sciences), Patent No. 20140045849 (Janssen), Patent No. 20140073642 (Janssen), International Publication No. 2014056953 (Janssen), International Publication No. 2014076221 (Janssen), International Publication No. 2014128189 (Janssen), US Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014023813 (Janssen), US Patent Application Publication No. 20080234251 (Array Biopharma), International Publication No. 20080306050 (Array Biopharma), International Publication No. 20100029585 (Ventirx Examples of compounds disclosed include those listed in (Pharma), (Ventirx Pharma) No. 20110092485, (Ventirx Pharma) No. 20110118235, (Ventirx Pharma) No. 20120082658, (Ventirx Pharma) No. 20120219615, (Ventirx Pharma) No. 20140066432, (Ventirx Pharma) No. 20140088085, (Ventirx Pharma) No. 20140275167, and (Novira Therapeutics) No. 20130251673. The TLR7 / TLR8 agonist that can be administered concurrently is NKTR-262.Examples of TLR8 agonists that can be administered concurrently include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motlimod, reciquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 20140045849 (Janssen), No. 201400736. 42 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Examples of compounds disclosed in Biopharma, No. 20080306050 (Array Biopharma), No. 20100029585 (Ventirx Pharma), No. 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), No. 20140088085 (Ventirx Pharma), No. 20140275167 (Novira Therapeutics), and No. 20130251673 (Novira Therapeutics). Examples of TLR9 agonists that can be administered concurrently include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042.Examples of TLR3 agonists include lintatrimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0196] Tyrosine kinase inhibitors (TKIs) In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with a tyrosine kinase inhibitor (TKI). The TKI may target the epidermal growth factor receptor (EGFR), as well as the receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs, though not limited to them, include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cejiranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, and imatinib. Examples include KX2-391(Src), lapatinib, restaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rosiletinib, sulfatinib (HMPL-012), sunitinib, famitinib, L-malate (MAC-4), tiboanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Examples of EGFR-targeting drugs include neratinib, tucatinib (ONT-380), tesevatinib, mobocertinib (TAK-788), DZD-9008, baritinib, avivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), rifirafenib (BGB-283), vectibix, razertinib (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 sarotalocan (RM-1929), cerivanthumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab.

[0197] Chemotherapy agents In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with chemotherapeutic agents or antineoplastic agents.

[0198] As used herein, the terms “chemotherapeutic agent” or “chemotherapeutic drug” (or “chemotherapy” when referring to treatment with a chemotherapeutic agent) mean to encompass any non-proteinogenic (e.g., non-peptidogenic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents, e.g., thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g., benzodepa, carboquan, meturedepa, and uredepa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemiloromelamamine; acetogenins, e.g., bratacin and bratacinone; camptothecin, including the synthetic analog topotecan; bryostatin, callistatin; CC-1065, including adzeresin, karzeresin, and bizeresin synthetic analogs; cryptophycin, in particular, Liptophycin 1 and cryptophycin 8; dorastatin; duocalmycin including synthetic analogs KW-2189 and CBI-TMI; eloiterobin; 5-azacitidine; pancratistatin; sarcodictiin; spongstatin; nitrogen mustards, e.g., chlorambucil, chlornafadin, cyclophosphamide, gluphosphamide, evophosphamide, bendamustine, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenesterine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., carmustine, chlorozotosine, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, for example, engine antibiotics (e.g., calichemycin, especially calichemycin γII and calichemycin φI1), dinemycin including dinemycin A, bisphosphonates such as clodronate, esperamycin, neocardinostatin chromophores and related chromoprotein engine antibiotic chromophores, acrasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kactinomycin, carabicin, carninomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, Detorubicin, 6-diazo-5-C=OL-norleucine, doC=O rubicin (including morpholino-doC=O rubicin, cyanomorpholino-doC=O rubicin, 2-pyrrolino-doC=O rubicin, and deoxide-C=O rubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenime Phosphates, dinostatins, and zolubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folate analogs, e.g., demopterin, methotrexate, pteropterin, and trimethrexate; purine analogs, e.g., cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; an Drogens, e.g., carsterone, dromostanolone propionate, epithiostanol, mepithiostan, and testotractone; anti-adrenal drugs, e.g., aminoglutethimide, mitotane, and trilostane; folic acid supplements, e.g., floric acid; radiotherapy agents such as radium-223; trichothecenes, especially T-2 toxin, beraclin A, loridine A, and anguidin; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Sabizabrin (Veru-111), platinum analogs, e.g., cisplatin and carboplatin, NC-6004 nanoplatin; acegraton; aldofamide glycoside; aminolevulinic acid; enyluracil; amsacrin; hestrabusyl; bisanthren; edatraxate; defofamine; demecoltin; diaziquan; elformutin; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea; lentinan; leucovorin; ronidamine; meitansinoids, e.g., meitansin and ansamitosine; mitogwazone; mitoxantrone; mopidamol; nitracrin; pentostatin; fenamet; pirarubicin; losoxantrone; fluoropyrimidine; folic acid; podophyllic acid, 2-ethylhydrazide; procarbazine; polysaccharide K (PSK); ra Zoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Trabectedin, Triadiquan; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiopeta; Chlorambucil; Gemcitabine (GEMZAR (Registered Trademark)); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; bancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; zeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031; FOLFOX (folic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folic acid, 5-fluorouracil, irinotecan);Examples include, but are not limited to, FOLFOXIRI (folic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folic acid, 5-fluorouracil, irinotecan, oxaliplatin), and any pharmaceutically acceptable salts, acids, or derivatives of the above. Such agents may be conjugated to an antibody or any targeted agent described herein to create an antibody-drug conjugate (ADC) or a targeted drug conjugate.

[0199] Anti-hormone drugs The definition of "chemotherapeutic agents" includes anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), enzyme aromatase inhibitors, anti-androgens, and any pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to modulate or inhibit the hormonal effects on tumors.

[0200] Examples of anti-estrogen agents and SERMs include tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (FARESTON®).

[0201] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal gland. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestan, fadrozole, borozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0202] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enovotherm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antisense).

[0203] An example of a progesterone receptor antagonist is onapristone. Additional progesterone-targeting drugs include TRI-CYCLEN LO (norethindrone + ethinylestradiol), norgestimate + ethinylestradiol (Tri-Cyclen), and levonorgestrel.

[0204] Anti-angiogenic agents In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with anti-angiogenic agents. Anti-angiogenic agents that can be administered concurrently include retinoid acids and their derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, nekparanib, suramin, squalamine, metalloproteinase-1 tissue inhibitors, metalloproteinase-2 tissue inhibitors, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clepein), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, and thiap. Examples include lorine, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin serum, chicken inhibitor of metalloproteinase-3 (cChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagiline, sodium aurantithiomalate, d-penicillamine, β-1-anticollagenase serum, α-2-antiplasmin, bisantren, lobenzarit disodium, n-2-carboxyphenyl-4-chloroantonylate disodium or "CCA", thalidomide, angiogenesis-inhibiting steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tascinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against angiogenic growth factors such as β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be administered concurrently include bevacizumab, vanucizumab, falisimab, zilpasimab (ABT-165, DLL4 / VEGF), or nabisikizumab (OMP-305B83, DLL4 / VEGF).

[0205] Antifibrotic agents In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an antifibrotic agent. Antifibrotic agents that may be administered concurrently include compounds such as β-aminopropionitrile (BAPN), as well as compounds disclosed in U.S. Patent No. 4,965,288, relating to lysyl oxidase inhibitors and their use in the treatment of diseases and conditions associated with abnormal collagen deposition, and U.S. Patent No. 4,997,854, relating to compounds that inhibit LOX for the treatment of various pathological fibrous conditions, which are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Patents 4,943,593, 5021,456, 5059,714, 5120,764, and 5182,297 relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Patent 5,252,608 relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application Publication 20040248871, which are incorporated herein by reference.

[0206] Examples of antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that, after binding to carbonyl, produce resonance-stabilized products, such as emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazides and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and primary amines such as selenohomocysteine ​​lactone.

[0207] Other antifibrotic agents are copper chelating agents that either penetrate or do not penetrate cells. Exemplary compounds include indirect inhibitors that inhibit aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamins, particularly D-penicillamine and its analogues, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiol sulfanate, and sodium-4-mercaptobutane sulfinate trihydrate.

[0208] Anti-inflammatory drugs In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an anti-inflammatory agent. Examples of anti-inflammatory agents include, but are not limited to, arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: Examples of inhibitors include one or more of the following: 377677), CA14 (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), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES, gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX, NCBI gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH, NCBI gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2, NCBI gene ID: 1326). In some embodiments, the inhibitor is a biinhibitor, such as a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, or COX-2 / 5-LOX biinhibitor.

[0209] Examples of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1, NCBI gene ID: 5742) inhibitors that can be administered concurrently include mofezolac, GLY-230, and TRK-700.

[0210] Examples of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2, NCBI gene ID: 5743) inhibitors that can be administered concurrently include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maesoshri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimeslid, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, firocoxib, mavacoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, lutecarpine, chilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that can be administered concurrently include HP-5000, lornoxicam, ketrolactromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that can be administered concurrently include polmacoxib and imurecoxib.

[0211] Examples of inhibitors of secretory phospholipase A2 and prostaglandin E synthase (PTGES, PGES, gene ID: 9536) that can be administered concurrently include LY3023703, GRC27864, and International Publication Nos. 2015158204, 2013024898, 2006063466, 2007059610, and 20071. 24589, 2010100249, 2010034796, 2010034797, 2012022793, 2012076673, 2012076672, 2010034798, 2010034799, 2012022792, 2009103778, 201104800 No. 4, No. 2012087771, No. 2012161965, No. 2013118071, No. 2013072825, No. 2014167444, No. 2009 138376, 2011023812, 2012110860, 2013153535, 2009130242, 2009146696, Examples of compounds listed are those described in Nos. 2013186692, 2015059618, 2016069376, 2016069374, 2009117985, 2009064250, 2009064251, 2009082347, 2009117987, and 2008071173. Metformin has been further found to inhibit the COX2 / PGE2 / STAT3 axis and can be administered concurrently. See, for example, Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0212] Carbonic anhydrases that can be administered simultaneously (e.g., CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), C Examples of inhibitors for one or more of the following: A9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), and CA14 (NCBI gene ID: 23632) include acetazolamide, metazolamide, dorzolamide, zonisamide, brinzolamide, and diclofenamide. CG100649 is an example of a dual COX-2 / CA1 / CA2 inhibitor that can be administered concurrently.

[0213] Examples of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX, NCBI gene ID:240) inhibitors that can be administered concurrently include meclofenamate sodium and dilauton.

[0214] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH, NCBI gene ID: 2053) that can be administered concurrently include compounds described in International Publication No. 2015148954. Examples of COX-2 / SEH dual inhibitors that can be administered concurrently include compounds described in International Publication No. 2012082647. Examples of SEH and fatty acid amide hydrolase dual inhibitors (FAAH, NCBI gene ID: 2166) that can be administered concurrently include compounds described in International Publication No. 2017160861.

[0215] Examples of mitogen-activated protein kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2, NCBI gene ID: 1326) inhibitors that can be administered concurrently include GS-4875, GS-5290, BHM-078, and international publications 2006124944, 2006124692, 2014064215, 2018005435, 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, and Kaila, et al., Bioorg Med Examples include those described in Chem. (2007) 15(19):6425-42 and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0216] Tumor oxygenation agent In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Illustrative agents that may be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors such as PT-2977 and PT-2385, VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165, and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding protein (HNOX)) such as OMX-302 and HNOX proteins described in International Publication Nos. 2007137767, 2007139791, 2014107171, and 2016149562.

[0217] Immunotherapy agents In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with an immunotherapy agent. In some embodiments, the immunotherapy agent is an antibody.Examples of immunotherapeutic agents that can be administered concurrently include avagovomab, AB308, ABP-980, adecatumumab, aftumumab, alemtuzumab, altumomab, amatsuximab, anatumomab, alsitumomab, atezolizumab, bavituximab, vectumomab, bevacizumab, vibatuzumab, blinatumomab, brentuximab, camidanlumab, cantuzumab, catumakisomab, CC49, cetuximab, sitatuzumab, xixtumumab, cribatuzumab, conatumumab, dacetuzumab, darotuzumab, daratumumab, detumomab. Dinutuximab, dombanarimab, dorodizumab, durigotumab, dusigitumab, eclomeximab, elotuzumab, emibetuzumab, encituximab, erzumaxomab, etalacizumab, falletuzumab, ficratuzumab, figitumumab, frambotumab, futuximab, ganituzumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igobomab, imugatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-7) 34016, and MDX-101), Iratumumab, Labetuzumab, Lexatumumab, Lintuzumab, Rorbotuzumab, Lucatumumab, Mapatumumab, Matuzumab, Miratuzumab, Minretumomab, Mitsumomab, Mogamulizumab, Moxetumomab, Naptumomab, Narunatumumab, Necitumumab, Nimotuzumab, Nofetumomab, OBI-833, Obinutuzumab, Okalatuzumab, Ofatumumab, Oraratumumab, Onarutuzumab, Oporutuzumab, Olegobomab, Panitumumab, Pulsatuzumab, Pasdotox, Patrizumab, Pem Examples include tumomab, pertuzumab, pintumomab, pritumumab, lacotumomab, radretumumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samarizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, takatuzumab, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotsuzumab, ubirituximab, bertuzumab, borsetuzumab, botumumab, zaltumumab, zimbererimab, and 3F8.Rituximab can be used to treat slow chronic B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0218] Exemplary therapeutic antibodies may be further labeled or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y cribatuzumab), or iodine-131.

[0219] In some embodiments, the immunotherapy agent is an antibody-drug conjugate (ADC). Illustrative ADCs that may be administered concurrently include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimes targeting proteins or antigens listed above and herein.Examples of ADCs that can be administered concurrently include gemtuzumab, brentuximab, verantamab (e.g., verantamab mahodotin), camidanrumab (e.g., camidanrumab tesirin), tratuzumab (e.g., tratuzumab deruxtecan, trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, milbetuxizumab (e.g., milbetuxizumab solvetansine), depatuxizumab, vadasotuximab, rabetuzumab, radilatuzumab (e.g., radilatuzumab vedotin), and roncatuximab. For example, roncatuximab tecilin), sacituzumab (for example, sacituzumab govitecan), datopotomab (for example, datopotomab deruxtecan, DS-1062, Dato-DXd), patrizumab (for example, patrizumab deruxtecan), rifastuzumab, indosatumab, polatuzumab (for example, polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (for example, upifitamab brilsodotin), indatuximab, milatuzumab, lovalpituzumab (for example, lovalpituzumab tecilin), Enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamab tansine), disitamab (e.g., disitamab vedotin), terisotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMGN529 Examples include 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 administered concurrently 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.

[0220] Examples of exemplary therapeutic agents (e.g., anticancer agents or antitumor agents) that can be conjugated to drug-conjugated antibodies, fragments thereof, or antibody mimics include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, mytansine or its analogues (e.g., meltansine / emtansine (DM1), labtansine / solabtansine (DM4)), and anthracyclines (e.g., d-C). Examples include rubicin (=O rubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD), DNA crosslinking agent SC-DR002 (D6.5), duocalmycin, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epotilone), pyrrolobenzodiazepine (PBD) or its dimers, duocalmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or antineoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to a drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anticancer or antineoplastic agent) that can be conjugated to a drug-conjugated antibody, its fragments, or antibody mimetic includes immune checkpoint inhibitors. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 includes BPI-002.

[0221] In some embodiments, ADCs that may be administered concurrently include tumor-associated calcium signaling factors 2 (TROP-2, TACSTD2, EGP-1, NCBI gene ID: 4070). Examples of exemplary anti-TROP-2 antibodies include, but are not limited to, TROP-2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Shanghai DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP-2-TRACTr (Janux Therapeutics), and LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius). BioTech), LIV-2008b (Shanghai / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University ofWisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and international publications No. 2020016662 (Abmart), No. 2020249063 (Bio-Thera Solutions), US patent application publication No. 20190048095 (Bio-Thera Solutions), international publication No. 2013077458 (LivTech / Chiome), European patent application publication No. 20110783675 (Chiome), international publications No. 2015098099 (Daiichi Sankyo), No. 2017002776 (Daiichi Sankyo), No. 2020130125 (Daiichi Sankyo), Patent No. 2020240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021093730 (Daiichi Sankyo), U.S. Patent No. 9850312 (DaiichiSankyo, Chinese Patent No. 112321715 (Biosion), US Patent Application Publication No. 2006193865 (Immunomedics / Gilead), International Publication No. 2011068845 (Immunomedics / Gilead), US Patent Application Publication No. 2016296633 (Immunomedics / Gilead), US Patent Application Publication No. 2017021017 (Immunomedics / Gilead), US Patent Application Publication No. 2017209594 Publication No. (Immunomedics / Gilead), No. 2017274093 (Immunomedics / Gilead), No. 2018110772 (Immunomedics / Gilead), No. 2018185351 (Immunomedics / Gilead), No. 2018271992 (Immunomedics / Gilead), International Publication No. 2018217227 (Immunomedics / Gilead), US National Patent Application Publication No. 2019248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), US Patent Application Publication No. 2021093730 (Immunomedics / Gilead), US Patent No. 2021069343 (Immunomedics / Gilead), US Patent No. 8435539 (Immunomedics / Gilead), US Patent No. 8435529 (I (Immunomedics / Gilead), Patent No. 9492566 (Immunomedics / Gilead), International Publication No. 2003074566 (Gilead), International Publication No. 2020257648 (Gilead), US Patent Application Publication No. 2013039861 (Gilead), International Publication No. 2014163684 (Gilead), US Patent No. 9427464 (LivTech / Chiome), US Patent No. 10501555 (Abruzzo Theranostic / Oncoxx), International Publication No. 2018036428 (Sichuan KelunExamples include those described in U.S. Patent No. 2013068946 (Pfizer), No. 2007095749 (Roche), and No. 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. Patents No. 7,238,785, No. 7,517,964, and No. 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anticancer agent linked by a linker. In some embodiments, the linker is as disclosed in U.S. Patent No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug portion of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from dC=Orubicin (DOX), epirubicin, morpholino-dC=O-rubicin (morpholino-DOX), cyanomorpholino-dC=O-rubicin (cyanomorpholino-DOX), 2-pyrroline-dC=O-rubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, rootecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanmycin, ansamycin, and epotilon. In some embodiments, the chemotherapeutic portion is SN-38. In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with sacituzumab govitecan.

[0222] In some embodiments, the ADC that may be co-administered includes an antibody against carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1, CD66a, NCBI gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (for example, as described in International Publication No. 1996011013). In some embodiments, the CEACAM1-ADC is as described in International Publication No. 2010093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with CEACAM1-ADC IMMU-130.

[0223] In some embodiments, the ADC that may be co-administered includes an antibody that targets MHC class II cell surface receptors encoded by human leukocyte antigen complexes (HLA-DRs). In some embodiments, the HLA-DR antibody is hL243 (for example, as described in International Publication No. 2006094192). In some embodiments, the HLA-DR-ADC is as described in International Publication No. 2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered together with HLA-DR-ADC IMMU-140.

[0224] Cancer gene therapy and cell therapy In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered in conjunction with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include: insertion of normal genes into cancer cells to replace mutated or modified genes; gene modification to silence mutated genes; genetic approaches to directly kill cancer cells; injection of immune cells designed to replace a large portion of the patient's own immune system, for example, to enhance the immune response against cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill or detect and kill cancer cells; and genetic approaches to modify cell activity to further alter the intrinsic immune responsiveness to cancer.

[0225] cell therapy In some embodiments, the compounds disclosed herein or the antibodies and / or fusion proteins provided herein are administered in conjunction with one or more cell therapies. Illustrative cell therapies include, but are not limited to, the co-administration of one or more populations of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor-infiltrating lymphocytes (TILs), and / or dendritic cells (DCs). In some embodiments, the cell therapy involves the co-administration of T cell therapy, e.g., populations of α / βTCR T cells, γ / δTCR T cells, regulatory T (Treg) cells, and / or TRuC® T cells. In some embodiments, the cell therapy involves the co-administration of NK cell therapy, e.g., NK-92 cells. If necessary, the cell therapy may involve the co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0226] In some embodiments, cell therapy involves the co-administration of cells containing a chimeric antigen receptor (CAR). In such therapies, a population of immune effector cells is genetically engineered to express a CAR, which contains a tumor antigen-binding domain. In T-cell therapy, the T cell receptor (TCR) is genetically engineered to target tumor-derived peptides present on the surface of tumor cells.

[0227] Regarding the structure of CAR, in some embodiments, CAR includes an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain includes a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain includes the signaling functional domain of one or more proteins selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0228] In some embodiments, the co-stimulatory domain is a ligand that specifically binds to CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD 4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 9 12), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL 1. It contains one or more functional domains of proteins selected from the group consisting of CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0229] In some embodiments, the transmembrane domain is the α, β, or ζ chain of the T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rβ, IL2Rγ, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E It contains a transmembrane domain of a protein selected from the group consisting of ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0230] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapy agent described herein (e.g., monospecific or multispecific antibodies or their antigen-binding fragments or antibody mimes) binds to tumor-associated antigens (TAAs). In some embodiments, tumor-associated antigens include CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); type C lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit α-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor α (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testicin or PR SS21); Vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; Platelet-derived growth factor receptor β (PDGFR-β); Stage-specific fetal antigen-4 (SSEA-4); CD20; Delta-like 3 (DLL3); Folate receptor α; Receptor tyrosine protein kinase, ERBB2 (Her2 / neu); Mucin 1, cell surface binding (MUC1); Epidermal growth factor receptor (EGFR); Neuronal cell adhesion molecule (NCAM); Prostase; Prostatic acid phosphatase (PAP); Elongation factor 2 variant (ELF2M); Ephrin B2; Fibroblast-activating protein α (FAP);Insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, β-type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of cleavage cluster region (BCR) and Abelson mouse leukemia virus oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); prostate I 6 Transmembrane epithelial antigen (STEAP1); Claudin 6 (CLDN6); Thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); X chromosome open reading frame 61 (CXORF61); CD97; CD179a; Anaplastic lymphoma kinase (ALK); Polysialic acid; Placenta-specific antigen 1 (PLAC1); Hexasaccharide moiety of globoH glycoceramide (GloboH); Mammary gland differentiation antigen (NY-BR-1); Uloplakin 2 (UPK2); Hepatitis A virus cell receptor 1 (HAVCR1); Adrenergic receptor β3 (ADRB3); Panexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); Lymphocyte antigen 6 complex, locus K9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCRγ Alternative Reading Frame Protein (TARP); Wilms Tumor Protein (WT1); Cancer / Testicular Antigen 1 (NY-ESO-1); Cancer / Testicular Antigen 2 (LAGE-la); Melanoma-Associated Antigen 1 (MAGE-A1); ETS Translocation Variant Gene 6 (ETV6-AML) located on chromosome 12p; Sperm Protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); Angiopoietin-Binding Cell Surface Receptor 2 (Tie2); Melanoma Cancer Testicular Antigen-1 (MADCT-1); Melanoma Cancer Testicular Antigen-2 (MADCT-2); Fos-Associated Antigen 1; Tumor Protein p53 (p53); p53 Variant; Prostein; Sulbibin; Telomerase;Prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma apoptosis inhibitor (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myeloma virus oncogene neuroblastoma-derived homolog (MYCN); ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC binding factor (zinc finger protein)-like (BORIS or brother of the Regulator of Imprinted Sites)) Squamous cell carcinoma antigen 3 (SART3) recognized by T cells; paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-section 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous protein 1 (RUI); renal ubiquitous protein 2 (RU2); regmine; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); enteric carboxylesterase; heat shock protein 70-2 variant (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); Bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); Lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5);The target is selected from the group consisting of immunoglobulin λ-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen present in the MHC.

[0231] In some embodiments, the tumor antigens are CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD4 6, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1(DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, G protein-binding receptor, alpha-fetoprotein (AFP), angiogenic factor, exogenous alloconjugate molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA) The following are selected: cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate-binding protein, gp100, hepatitis B surface antigen, κ chain, κ light chain, kdr, λ chain, livin, melanoma-associated antigen, mesoserin, mouse double microchromosome 2 homolog (MDM2), mucin 16 (MUC16), variant p53, variant ras, necrotic antigen, tumor-fetal antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenacin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0232] In some embodiments, the antigen-binding domain binds to an epitope of a target antigen or tumor-associated antigen (TAA) present on a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer-testicular antigen. In some embodiments, cancer testicular antigens include acrosin-binding proteins (ACRBP, CT23, OY-TES-1, SP32, NCBI gene ID: 84519), alpha-fetoproteins (AFP, AFPD, FETA, HPAFP, NCBI gene ID: 174), A kinase anchor proteins 4 (AKAP4, AKAP82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82, NCBI gene ID: 8852), ATPase family AAA domain-containing proteins 2 (ATAD2, ANCCA, CT137, PRO2000, NCBI gene ID: 29028), kinetochore scaffolds 1 (KNL1, AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105, NCBI gene ID: 8852), ATPase family AAA domain-containing proteins 2 (ATAD2, ANCCA, CT137, PRO2000, NCBI gene ID: 29028), and kinetochore scaffolds 1 (KNL1, AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105, NCBI gene ID: 84519). Gene ID: 57082), Centrosolecular protein 55 (CEP55, C10orf3, CT111, MARCH, URCC6, NCBI gene ID: 55165), Cancer / testicular antigen 1A (CTAG1A, ESO1, CT6.1, LAGE-2, LAGE2A, NY-ESO-1, NCBI gene ID: 246100), Cancer / testicular antigen 1B (CTAG1B, CT6.1, CTAG, CTAG1, E SO1, LAGE-2, LAGE2B, NY-ESO-1, NCBI gene ID: 1485), cancer / testicular antigen 2 (CTAG2, CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B, NCBI gene ID: 30848), CCCTC binding factor-like (CTCFL, BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20).2. NCBI gene ID: 140690), Catenin α2 (CTNNA2, CAP-R, CAPR, CDCBM9, CT114, CTNR, NCBI gene ID: 1496), Cancer / Testicular Antigen 83 (CT83, CXorf61, KK-LC-1, KKLC1, NCBI gene ID: 203413), Cyclin A1 (CCNA1, CT146, NCBI gene ID: 8900), DEAD Box Helicase 43 (DDX43, CT13, HAGE, NCBI gene ID: 55510) ), Developmental pluripotency-related 2 (DPPA2, CT100, ECAT15-2, PESCRG1, NCBI gene ID: 151871), Fetal and adult testicular expression 1 (FATE1, CT43, FATE, NCBI gene ID: 89885), FMR1 adjacent (FMR1NB, CT37, NY-SAR-35, NYSAR35, NCBI gene ID: 158521), HORMA domain-containing 1 (HORMAD1, CT46, NOHMA, NCBI gene ID: 84072), Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3, CT98, IMP-3, IMP3, KOC, KOC1, VICKZ3, NCBI gene ID: 10643), leucine zipper protein 4 (LUZP4, CT-28, CT-8, CT28, HOM-TES-85, NCBI gene ID: 51213), lymphocyte antigen 6 family member K (LY6K, CT97, HSJ001348, URLC10, ly-6K, NCBI gene ID: 54742), maelstrom spermatogenesis transposon silencer (MAEL, CT128, SPATA35) MAGE family member A1 (MAGEA1, CT1.1, MAGE1, NCBI gene ID: 4100), MAGE family member A3 (MAGEA3, CT1.3, HIP8, HYPD, MAGE3, MAGEA6, NCBI gene ID: 4102), MAGE family member A4 (MAGEA4, CT1.4, MAGE-41, MAGE-X2, MAGE4, ​​MAGE4A, MAGE4B, NCBI gene ID: 4103), MAGE family member A11 (MAGEA11, CT1.11, MAGE-11, MAGE11, MAGEA-11, NCBI gene ID: 4110), MAGE family member C1 (MAGEC1, CT7, CT7.1, NCBI gene ID: 9947), MAGE family member C2 (MAGEC2, CT10, HCA587, MAGEE1; NCBI gene ID: 51438); MAGE family member D1 (MAGED1, DLXIN-1, NRAGE, NCBI gene ID: 9500), MAGE family member D2 (MAGED2, 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2, NCBI gene ID: 10916), Kinesin family member 20B (KIF20B, CT90, KRMP1, MPHOSPH1, MPP-1, MPP1, NCBI gene ID: 9585), NUF2 component of the NDC80 kinetochore complex (NUF2, CDCA1, CT106, NUF2R, NCBI gene ID: 83540), Nuclear RNA transport factor 2 (NXF2, CT39, TAPL-2, TCP11X2, NCBI gene ID: 5600) 1) PAS domain-containing repressor 1 (PASD1, CT63, CT64, OXTES1; NCBI gene ID: 139135), PDZ-binding kinase (PBK, CT84, HEL164, Nori-3, SPK, TOPK, NCBI gene ID: 55872), piwi-like RNA-mediated gene silencing 2 (PIWIL2, CT80, HILI, PIWIL1L, mili, NCBI gene ID: 55124), melanoma preferential expression antigen (PRAME, CT130, MAPE, OIP-4, OIP4, NCBI Gene ID: 23532), sperm-associated antigens 9 (SPAG9, CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6, NCBI gene ID: 9043), nuclear X-binding family member A1-associated sperm proteins (SPANXA1, CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A, NCBI gene ID: 30014), SPANX family member A2 (SPANXA2, CT11.1, CT11.3. SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC (NCBI gene ID: 728712), SPANX family member C (SPANXC, CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE, NCBI gene ID: 64663), SPANX family member D (SPANXD, CT11.3, CT11.4, SPANX-C, SPANX-D, SPANX-E, SPANXC, SPANXE, dJ171K16.1, NCBI gene ID: 64648), SSX family member 1 (SSX1, CT5.1, SSRC, NCBI gene ID: 6756), SSX family member 2 (SSX2, CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX, NCBI gene ID: 6757), The group is selected from the following: synaptonema complex proteins 3 (SYCP3, COR1, RPRGL4, SCP3, SPGF4, NCBI gene ID: 50511), 14 intercellular bridge-forming factors expressed in the testes (TEX14, CT113, SPGF23, NCBI gene ID: 56155), Dp family member 3 transcription factors (TFDP3, CT30, DP4, HCA661, NCBI gene ID: 51270), serine proteases 50 (PRSS50, CT20, TSP50, NCBI gene ID: 29122), TTK protein kinases (TTK, CT96, ESK, MPH1, MPS1, MPS1L1, PYT, NCBI gene ID: 7272), and zinc finger proteins 165 (ZNF165, CT53, LD65, ZSCAN7, NCBI gene ID: 7718). T cell receptors (TCRs) and TCR-like antibodies that bind to epitopes of cancer-testis antigens present in major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer-testis antigens associated with neoplasms are summarized, for example, in Gibbs, et al., Trends Cancer 2018 Oct;4(10):701-712, and on the CT database website cta.lncc.br / index.php. Exemplary TCRs and TCR-like antibodies that bind to the NY-ESO-1 epitope present in MHC are, for example, in Stewart-Jones, et al.This is described in Proc Natl Acad Sci USA. 2009 Apr 7;106(14):5784-8, International Publication Nos. 2005113595, 2006031221, 2010106431, 2016177339, 2016210365, 2017044661, 2017076308, 2017109496, 2018132739, 2019084538, 2019162043, 2020086158, and 2020086647. Exemplary TCRs and TCR-like antibodies that bind to PRAME epitopes present in MHC are described, for example, in International Publication Nos. 2011062634, 2016142783, 2016191246, 2018172533, 2018234319, and 2019109821. Exemplary TCRs and TCR-like antibodies that bind to epitopes of MAGE variants present in MHC are described, for example, in International Publication Nos. 2007032255, 2012054825, 2013039889, 2013041865, 2014118236, 2016055785, 2017174822, 2017174823, 2017174824, 2017175006, 2018097951, 2018170338, 2018225732, and 2019204683. Exemplary TCRs and TCR-like antibodies that bind to the alpha-fetoprotein (AFP) epitope present in MHC are described, for example, in International Publication No. 2015011450. Exemplary TCRs and TCR-like antibodies that bind to the SSX2 epitope present in MHC are described, for example, in International Publication No. 2020063488. Exemplary TCRs and TCR-like antibodies that bind to the KK-LC-1 (CT83) epitope present in MHC are described, for example, in International Publication No. 2017189254.

[0233] Examples of cell therapies include Algenpantucel-L, Sipuleucel-T, (BPX-501) Ribogen Recrucel (US Patent No. 9089520, International Publication No. 2016100236), AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Imi Recrucel-T, Baltaluce-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral transducer huCART-mesocells, CART-22 cells, EGFRt / 19-28z / 4-1BBL Examples include CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

[0234] In some embodiments, one or more additional concurrently administered therapeutic agents may be classified into the following groups, for example, based on their mechanism of action. • Drugs that target adenosine deaminase, such as pentostatin or cladribine. • Drugs that target ATMs, such as AZD1390, Drugs targeting METs such as savolitinib, capmatinib, tetoponitib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115. Antroquinonol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mildametinib (PD-0325901), pimacertib, refametinib, or International Publication Nos. 2011008709, 2013112741, 2006124944, 2006124692, 2014064215, 2018005435, Zhou, et al., Cancer Lett. 2017 Nov 1, 408:130-137, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4): 558-70, Gangwall, et al., Curr Top Med Drugs that target mitogen-activated protein kinases, such as compounds disclosed in Chem. (2013) 13(9): 1015-35, Wu, et al., Bioorg Med Chem Lett. (2009) 19(13): 3485-8, Kaila, et al., Bioorg Med Chem. (2007) 15(19): 6425-42, or Hu, et al., Bioorg Med Chem Lett. (2011) 21(16): 4758-61. Drugs that target thymidine kinases, such as agratimazin besadenovek (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk), Drugs that target the interleukin pathway, such as pegylodecaquin (AM-0010) (PEGylated IL-10) and CA-4948 (IRAK4 inhibitor). Drugs that target cytochrome P450 family members, such as letrozole, anastrozole, aminoglutethimide, medystrol acetate (MEGACE®), exemestane, formestan, fadrozol, borozol (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®), • CD73-targeting drugs such as CD73 inhibitors (e.g., quemliculstat (AB680)) or anti-CD73 antibodies (e.g., oleculumab), • Drugs that target DKK3, such as MTG-201, Drugs that target EEF1A2, such as platidisin. • Drugs that target EIF4A1, such as rohinitib. • Endoglin-targeting drugs such as TRC105 (carotuximab) Drugs that target exportin-1, such as ertanexol. Drugs that target fatty acid amide hydrolases, such as compounds disclosed in International Publication No. 2017160861, • Drugs that target heat shock protein 90β family member 1, such as anlotinib. • Drugs that target lactoferrin, such as ruxotemitide (LTX-315) • Agents that target lysyl oxidase, such as compounds disclosed in U.S. Patent Nos. 4,965288, 4,997854, 4943593, 5021456, 5059714, 5120764, 5182297, 5252608, or U.S. Patent Publication No. 20040248871. Drugs targeting MAGE family members such as KITE-718, MAGE-A10C796T, or MAGE-A10 TCR. • MDM2-targeting drugs such as ALRN-6924, CMG-097, mirademethane monotosylate monohydrate (DS-3032b), or AMG-232. • MDM4-targeting drugs such as ALRN-6924, • Drugs targeting melan-A, such as MART-1 F5 TCR gene-modified PBMCs. • Drugs targeting mesothelin, such as CSG-MESO or TC-210. • METAP2-targeting drugs such as M8891 or APL-1202, • Drugs that target NLRP3, such as BMS-986299, Drugs that target C=O glutarate dehydrogenase, such as devimit (CPI-613), Drugs that target placental growth factors, such as aflibercept. • Drugs targeting SLC10A3, such as compounds disclosed in International Publication No. 2015148954, No. 2012082647, or No. 2017160861. • Drugs that target transforming growth factor α (TGFa), such as compounds disclosed in International Publication No. 2019103203, Drugs that target the tumor protein p53, such as kebetrin (stimulator), Drugs that target vascular endothelial growth factor A, such as aflibercept. • Drugs that target vascular endothelial growth factor receptors, such as fluquinotinib or MP0250. • VISTA-targeting drugs such as CA-170 or HMBD-002, • Drugs that target WEE1, such as adavocertib (AZD-1775) • Small molecule inhibitors targeting ABL1, such as imatinib, levatinib, aciminib, and ponatinib (ICLUSIG®). • Small molecule antagonists that target adenosine receptors, such as CPI-444, AZD-4635, preradiant, etrumandent (AB928), or PBF-509. • Small molecule inhibitors that target arachidonic acid 5-lipoxygenase, such as sodium meclofenamate or diloton. • Small molecule inhibitors targeting ATR serine / threonine kinases, such as BAY-937, ceraracertib (AZD6738), AZD6783, VX-803, or VX-970 (belzocertib), • Small molecule inhibitors that target AXL receptor tyrosine kinases, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3). Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as (S)-6-amino-9-(1-(buto-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posertinib (HM71224), ibrutinib (Imbruvica), M-2951 (evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebralutinib (CC-292), becabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315. • Small molecule inhibitors that target neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or ceritrectinib (LOXO-195), • Small molecule inhibitors targeting ROS proto-oncogene 1 receptor tyrosine kinases, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib. • Small molecule inhibitors targeting SRC oncogene nonreceptor tyrosine kinases, such as VAL-201, tilvanibrin (KX2-391), or irginatinib maleate (NS-018). • Small molecule inhibitors targeting B-cell lymphoma 2, such as Navitoclax (ABT-263), Venetoclax (ABT-199, RG-7601), and AT-101 (Gossypol). Small molecule inhibitors targeting bromodomain and extracellular domain (BET) bromodomain-containing proteins such as ABBV-744, INCB-054329, INCB057643, AZD-5153, ABT-767, BMS-986158, CC-90010, NHWD-870, ODM-207, ZBC246, ZEN3694, CC-95775 (FT-1101), mibeblesib, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829. • Small molecule inhibitors that target carbohydrate sulfotransferase 15, such as STNM-01, • Small molecule inhibitors that target carbonic anhydrase, such as polmacoxib, acetazolamide, or metazolamide. • Small molecule inhibitors targeting catenin β1, such as CWP-291 or PRI-724. • Small molecule antagonists that target CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Bicribiroc). • Blixafortide, a small molecule antagonist that targets CXC-motif chemokine receptors (e.g., CXCR4), • Small molecule inhibitors targeting cereblon, such as abbamide (CC-122), CC-92480, CC-90009, or iverdamide. • Small molecule inhibitors that target checkpoint kinase 1, such as SRA737, • Small molecule inhibitors that target complement components, such as Imprime PGG (Biothera Pharmaceuticals) • Small molecule inhibitors that target CXC motif chemokine ligands (e.g., CXCL12), such as oraptesedo pegol (NOX-A12). • Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, ceviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate. • Small molecule inhibitors that target DEAD box helicase 5, such as spinoxin (RX-5902), For example, small molecule inhibitors that target DGKa, such as those described in International Publication No. 2021130638, • Small molecule inhibitors that target diablo IAP-binding mitochondrial proteins, such as BI-891065. • Small molecule inhibitors that target dihydrofolate reductase, such as pralatrexate or pemetrexed disodium. • Small molecule inhibitors that target DNA-dependent protein kinases, such as MSC2490484A (Nedicertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastaurin. • Small molecule inhibitors that target MARCKS, such as BIO-11006 • Small molecule inhibitors that target RIPK1, such as GSK-3145094 • Small molecule inhibitors targeting Rho-related coiled-coil protein kinases such as AT13148 or KD025, • Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, filtecan pegol, or amrubicin. • Small molecule inhibitors that target dopamine receptor D2, such as ONC-201, • Small molecule inhibitors that target DOT1-like histone lysine methyltransferase, such as pinometostat (EPZ-5676) • Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497. • Small molecule inhibitors that target fatty acid synthases, such as TVB-2640 (Sagimet Biosciences) • Small molecule inhibitors that target fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144) • Small molecule inhibitors targeting adhesion plaque kinases (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098. • Small molecule inhibitors that target folate receptor 1, such as pralatrexate. • Small molecule inhibitors that target FOXM1, such as thiostrepton. • Small molecule inhibitors that target galectin-3, such as belapectin (GR-MD-02) • Small molecule antagonists that target glucocorticoid receptors, such as relacorirant (CORT-125134), • Small molecule inhibitors that target glutaminase, including but not limited to CB-839 (teragrenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazole-2-yl)ethyl sulfide (BPTES), • Small molecule inhibitors that target GNRHR, such as elagolyx, relugolix, or degarelix. • Small molecule inhibitors targeting EPAS1, such as verzutifan (PT-2977 (Merck & Co.)), • Restrictions: Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)), such as ivosidenib (AG-120), boracidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221). • Small molecule inhibitors that target lysine demethylase 1A, such as CC-90011, • Small molecule inhibitors that target MAPK-interacting serine / threonine kinases, such as tomibocertib (eFT-508), • Small molecule inhibitors that target Notch receptors, such as AL-101 (BMS-906024) • Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as borasertib or onvansertib. • Small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), lucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazolepali (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121(e-7499)), simmiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP 9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102. • Small molecule inhibitors that target Polycomb protein EEDs such as MAK683, • Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974. HP-5000, lornoxicam, ketrolactromethamine, bromfenac sodium, otenaproxul (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, re-prescription celecoxib (DRGT-46), AAT-076, meisosuri, lumiracoxib, me Small molecule inhibitors that target prostaglandin-endoperoxide synthase, such as roxicam, valdecoxib, zaltoprofen, nimeslid, anitrazafen, apricoxib, simicoxib, delacoxib, flumizol, firocoxib, mavacoxib, pamicogrel, parecoxib, robenacoxib, rofecoxib, lutecarpi...

Claims

1. Compound of formula (I) 【Chemistry 81】 or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein the formula, J is, 【Chemistry 82】 And, X １ N, CR ４ , or CR ４ R ４ And, X ２ CR ５ And, X ３ CR ５ And, X ４ is N or CR ５ and X ５ CR ５ And, X ６ CR ５ And, A is either O or NH, R １ H, C １ - ６ Alkyl and C ３－１２ Selected from cycloalkyl, where C １ - ６ Alkyl is one or more R ６ Replaced by optional selection, R ２ H, Halo, C １ - ６ Alkyl, -OH, -O(C) １－６ Selected from alkyl and cyclopropyl, R ３ａ and R ３ｂ These are H, halo, -OH, and C, respectively, independently. １ - ６ Alkyl and -O(C) １－６ Selected from alkyl, where each C １ - ６ Alkyl independently comprises one or more R ６ Replaced by optional selection, Z is one or more R ７ 5- to 12-membered heteroaryls, one or more R, which are optionally substituted. ７ C is replaced by an optional choice. ６－１０ aryl, one or more R ７ C is replaced by an optional choice. ３－１２ Cycloalkyl, and one or more R ７ A selection is made from 4- to 12-membered heterocyclines that are optionally substituted, where a 5- to 12-membered heteroaryl or C ６－１０ Aryls are monocyclic or bicyclic, C ３－１２ Cycloalkyl or 4-12 membered heterocyclils are monocyclic, bicyclic, condensed bicyclic, spirocyclic, or crosslinked. Each R ４ These are H, Halo, and C, which are independent of each other. １－６ Alkyl, C ３－１２ Cycloalkyl and -O(C １－６ Selected from alkyl, Each R ５ These are H, Halo, and C, which are independent of each other. １－６ Alkyl, C ４－１０ Cycloalkyl, -OH, and -O(C) １－６ Selected from alkyl, Each R ６ These are independently H, halo, -OH, -O(C) １－６ Haloalkyl), and -O(C) １－６ Selected from alkyl, Each R ７ It is independent, Haro, C １－６ Alkyl, -NH ２ , -SO ２ (C １－６ Alkyl), -O (C １－６ Alkyl), and C ３－１２ Selected from cycloalkyl, where each C １－６ Alkyl is optionally substituted with one or more halos, -OH groups, or CN groups. The aforementioned compound, 2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 5-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 5-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 6-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-2-[5-(trifluoromethyl)pyridine-2-yl]-1,6-naphthyridine-5-one, 6-[5-(difluoromethoxy)pyridine-2-yl]-8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 8-Fluoro-6-(5-Fluoropyridine-2-yl)-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyrazine-2-yl]isoquinoline-1-one, 7-Fluoro-6-(5-methoxypyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1-benzofuran-7-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1,4-benzodioxin-5-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]aminopentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-pyridine-2-ylisoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethoxy)pyridine-2-yl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-6-(5-Fluoropyrimidine-2-yl)-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-6-(5-Fluoropyridine-2-yl)-2-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]butyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 8-Fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(2,2,2-trifluoroethyl)pyridin-2-yl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyridine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-Chloro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 4-methyl-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyridin-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-6-(5-fluoropyridine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-6-(5-fluoropyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[5-(trifluoromethyl)pyridine-2-yl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethoxy)pyridine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-[5-(trifluoromethyl)pyridine-2-yl]quinazolin-4-one, 6-Fluoro-7-(5-Fluoropyridine-2-yl)-3-[(4S)-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-(5-Fluoropyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-(7H-pyrrolo[2,3-d]pyrimidine-2-yl)quinazolin-4-one, 6-Fluoro-7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-cyclopropylpyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-methoxypyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(4-amino-5-fluoropyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-hydroxy-5-methyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]hexyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-6-[5-(2-hydroxypropan-2-yl)pyrimidine-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(1,1-difluoro-2-hydroxyethyl)pyridine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-methylpyrimidine-2-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-(4-amino-5-methylpyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(2-amino-5-methylpyrimidine-4-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(2-amino-5-methylpyrimidine-4-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-(5-cyclopropylpyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-Fluoro-6-(5-methylsulfonylpyrimidine-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7,8-difluoro-2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4R)-4-deuterio-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7,8-difluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4S)-4-Duterio-4-[[6-Oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7,8-Difluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, (S)-2-(2,2-difluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 6-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-7-(5-methylpyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(5-amino-4-fluoropyridine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[5-amino-4-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5-chloropyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-fluoropyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[2-amino-5-(difluoromethyl)pyrimidine-4-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(4-amino-5-cyclopropylpyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 7-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5,5-dimethyl-6,7-dihydropyrrolo[2,3-d]pyrimidine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[2-amino-5-(difluoromethyl)pyrimidine-4-yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinoline-1-one, 6-Fluoro-7-(5-methylsulfonylpyrimidine-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 6-Fluoro-7-[5-(2-hydroxyethoxy)pyrimidine-2-yl]-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one, 7-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]quinazolin-4-one, 7-Fluoro-6-[5-(2-hydroxyethoxy)pyrimidine-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-5-methoxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]oxy]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-(4-amino-5-methoxypyrimidine-2-yl)-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-7-fluoroisoquinoline-1-one, 6-Fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]quinazolin-4-one, 7-(5-chloropyrimidine-2-yl)-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]hexyl]quinazolin-4-one, 7,8-difluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 6-Fluoro-3-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]aminopentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-(5-chloropyrimidine-2-yl)-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 6-[6-amino-5-(trifluoromethyl)pyridin-2-yl]-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, 2-[(4R)-5-(difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]aminopentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-6-[4-(trifluoromethyl)pyrazole-1-yl]isoquinoline-1-one, 2-[(4R)-5-ethoxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]aminopentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, 7-Fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]-5-(triduteriomethoxy)pentyl]-6-[5-(trifluoromethyl)pyrimidine-2-yl]isoquinoline-1-one, (S)-6-(4-amino-5-ethoxypyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-ethoxypyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-methoxypyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, 6-[4-amino-5-(triduteriomethoxy)pyrimidine-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]pentyl]isoquinoline-1-one, (S)-6-(4-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(5-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-aminopyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-fluoro-7-(4-morpholino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)quinazoline-4(3H)-one, (S)-6-(6-amino-5-(difluoromethyl)pyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(thieno[2,3-d]pyrimidine-2-yl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-chloropyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-chloropyridine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(1H-pyrazolo[3,4-d]pyrimidine-6-yl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-(difluoromethyl)thiazole-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-(pyrazolo[1,5-a]pyridine-2-yl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(imidazo[1,2-a]pyridine-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-([1,2,4]triazolo[1,5-a]pyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(benzo[d]oxazole-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(benzo[d]thiazole-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(trifluoromethyl)thiazole-2-yl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloro-6-methylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-fluoro-6-(6-fluoroquinazolin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(4-(trifluoromethyl)oxazole-2-yl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(difluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-isopropylpyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methyl-5-(trifluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(3-amino-5-(trifluoromethyl)pyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(5-(difluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(6-(difluoromethyl)-5-fluoropyridine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(8-aminoimidazo[1,2-a]pyrazine-6-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(thiazolo[5,4-b]pyridine-5-yl)isoquinoline-1(2H)-one, (S)-6-([1,2,4]triazolo[1,5-a]pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-fluoro-6-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-7-(5-(difluoromethyl)pyridine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-(5-(difluoromethoxy)pyridine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-chloropyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-methoxypyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-7-(5-(difluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-methoxypyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-chloropyrazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(6-amino-5-chloropyrazine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)quinazoline-4(3H)-one, (S)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (S)-4-amino-6'-fluoro-3'-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-[2,7'-biquinazoline]-4'(3'H)-one, (S)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5,7-dihydrofl[3,4-d]pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-7,7-dimethyl-5,7-dihydrofluoro[3,4-d]pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-chloropyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)hexyl)isoquinoline-1(2H)-one, (S)-6-(4-aminoquinazolin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)quinazoline-4(3H)-one, (S)-6-(4-amino-1,3,5-triazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-6-(4-amino-6-methyl-1,3,5-triazine-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinoline-1(2H)-one, (S)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)quinazoline-4(3H)-one, (R)-6-(6-amino-5-(difluoromethyl)pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-methoxypyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-6-(5-(difluoromethoxy)pyrazine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyrazine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-7-(5-(difluoromethoxy)pyrazine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7,8-difluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-6-fluoro-7-(5-(trifluoromethyl)pyrimidine-2-yl)quinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyrimidine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-2-(5-(trifluoromethyl)pyridine-2-yl)-1,6-naphthyridine-5(6H)-one, (R)-6-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyrimidine-2-yl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(4-amino-5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-6-(5-chloropyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(4-amino-5-methoxypyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(5-chloropyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(6-amino-5-(difluoromethyl)pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-7-fluoro-6-(5-(trifluoromethyl)thiazole-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(3,4-dihydro-2H-pyran-6-yl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-fluoro-6-(5-(trifluoromethyl)pyridine-2-yl)isoquinoline-1(2H)-one, (R)-6-(5-amino-6-(trifluoromethyl)pyridine-3-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyridine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-(5-(difluoromethyl)pyridine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-fluoro-7-(5-(trifluoromethyl)pyridine-2-yl)quinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-7-(5-(trifluoromethyl)pyridine-2-yl)pyrido[2,3-d]pyrimidine-4(3H)-one, (R)-2-(6-amino-5-(trifluoromethyl)pyridine-2-yl)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-1,6-naphthyridine-5(6H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyridine-2-yl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7,8-difluoro-6-(5-(trifluoromethyl)pyridine-2-yl)isoquinoline-1(2H)-one, (R)-6-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-2-(5-(difluoromethyl)pyridine-2-yl)-1,6-naphthyridine-5(6H)-one, (R)-6-(6-amino-5-fluoropyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-chloropyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-methylpyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-7-(5-cyclopropylpyrazine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloro-6-cyclopropylpyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-6-(6-amino-5-methoxypyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrazine-2-yl)isoquinoline-1(2H)-one, (R)-6-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7,8-difluoroisoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-6-fluoro-7-(5-(trifluoromethyl)pyrazine-2-yl)quinazoline-4(3H)-one, (R)-6-(5-amino-1H-1,2,4-triazole-3-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-6-(5-(difluoromethyl)pyrazine-2-yl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)aminopentyl)-7-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloropyrimidine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)-6-fluoroquinazoline-4(3H)-one, 6-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-[5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]-5-(triduteriomethoxy)pentyl]isoquinoline-1-one, 6-Fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]-5-(triduteriomethoxy)pentyl]-7-[5-(trifluoromethyl)pyrimidine-2-yl]quinazolin-4one, 7-[5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazine-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-[4-amino-5-(trifluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-[4-amino-5-(difluoromethyl)pyrimidine-2-yl]-6-fluoro-3-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]-5-(triduteriomethoxy)pentyl]quinazolin-4-one, 7-Fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]-5-(triduteriomethoxy)pentyl]-6-[5-(trifluoromethyl)-2-pyridyl]isoquinoline-1-one, (R)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)-5-(trifluoromethoxy)pentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((3S,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((3R,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-7-fluoro-2-(6,6,6-trifluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-7-(6-amino-5-(trifluoromethyl)pyrazine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-chloropyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethyl)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-2-(6-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-2-(6-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)hexyl)-7-fluoroisoquinoline-1(2H)-one, (R)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)butyl)-7-(5-(difluoromethyl)pyrimidine-2-yl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(4-amino-5-(trifluoromethyl)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-7-(5-chloropyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, (R)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoro-7-(5-(trifluoromethyl)pyrimidine-2-yl)quinazoline-4(3H)-one, (R)-7-(4-amino-5-(difluoromethoxy)pyrimidine-2-yl)-3-(4-cyclopropyl-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-fluoroquinazoline-4(3H)-one, 7-Fluoro-2-((4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((2S,4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, 7-Fluoro-2-((2R,4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-(5-(trifluoromethyl)pyrimidine-2-yl)isoquinoline-1(2H)-one, (R)-6-([1,2,4]triazolo[1,5-a]pyridine-2-yl)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-7-fluoroisoquinoline-1(2H)-one, (R)-7-([1,2,4]triazolo[1,5-a]pyridine-2-yl)-3-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)aminopentyl)-6-fluoroquinazoline-4(3H)-one, 6-Fluoro-7-(5-methoxypyrimidine-2-yl)-3-[[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]methyl]quinazolin-4-one, or Compounds other than (S)-7-fluoro-6-(5-methyl-6-(trifluoromethyl)pyridine-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)pentyl)isoquinoline-1(2H)-one, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof.

2. R １ It is methyl, ethyl, -CH ２ OCF ２ H, -CH ２ OCH ３ , -CF ３ , or -CH ２ The compound according to claim 1, which is an OH group, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

3. R ２ H, Halo, C １－６ Alkyl, -OH, or -O(C) １－６ A compound according to claim 1 or 2, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

4. R ３ａ and R ３ｂ These are H, F, -OH, and -OCH, respectively, independently. ３ A compound according to any one of claims 1 to 3, which is methyl, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

5. J is, 【Chemistry 83】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

6. Z is one or more R ７ A compound according to any one of claims 1 to 5, which is a 5 to 12-membered heteroaryl substituted with , or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

7. Z is, 【Chemical 84】 In the formula, w is 0 to 3 including both ends, t is 0 to 4 including both ends, and R ７ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein is bonded at any substitutable position on Z.

8. Z is, 【Chemical 85】 That is, A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

9. R ３ａ H is R ３ｂ A compound according to any one of claims 1 to 8, wherein F is F, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

10. R ３ａ H is R ３ｂ The compound according to any one of claims 1 to 8, wherein is -OH or methyl, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

11. A is NH, a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

12. A is O, the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

13. J is, 【Chemical 86】 A compound according to claim 4, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

14. J is given by the following equation 【Transformation 87】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

15. J is given by the following equation 【Chemical 88】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

16. J is given by the following equation 【Chemical 89】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

17. R １ The compound according to any one of claims 13 to 16, wherein is methyl, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

18. Z is, 【Chemistry 90】 That is, A compound according to any one of claims 13 to 17, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

19. A is NH, a compound according to any one of claims 13 to 18, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

20. A is O, the compound according to any one of claims 13 to 18, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

21. R ２ A compound according to any one of claims 13 to 20, wherein is H, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

22. R ２ A compound according to any one of claims 13 to 20, wherein is -OH, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

23. R ３ａ H is R ３ｂ A compound according to any one of claims 13 to 22, wherein F is F, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

24. R ３ａ H is R ３ｂ The compound according to any one of claims 13 to 22, wherein is -OH or methyl, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

25. J is, 【Chemistry 91】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

26. J is given by the following equation 【Chemistry 92】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

27. R １ is ethyl or -CH ２ (OCHF) ２ The compound according to claim 25 or 26, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

28. Z is, 【Chemistry 93】 That is, A compound according to any one of claims 25 to 27, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

29. A is NH, a compound according to any one of claims 25 to 28, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

30. A is O, the compound according to any one of claims 25 to 28, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

31. R ２ is H, a compound according to any one of claims 25 to 30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof.

32. R ２ A compound according to any one of claims 25 to 30, wherein is -OH, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

33. R ３ａ H is R ３ｂ A compound according to any one of claims 25 to 32, wherein F is a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog.

34. R ３ａ H is R ３ｂ The compound according to any one of claims 25 to 32, wherein is -OH or methyl, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

35. R ３ａ and R ３ｂ is H, a compound according to any one of claims 25 to 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. 【Request Item 36】 【Table 22-1】 Table 22-2 Table 22-3 A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

37. Compounds selected from Table 1 or Table 2, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a pharmaceutically acceptable excipient.

39. A method for treating cancer, comprising administering to a patient in need of treatment for cancer an effective amount of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers or deuterated analog thereof, or a pharmaceutical composition according to claim 38.

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