CD73 compound

Abstract

Compounds of formula (I); or pharmaceutically acceptable salts thereof, or pharmaceutical compositions wherein various substituents are defined herein, are provided. In some embodiments, the compounds or pharmaceutically acceptable salts thereof provided herein are administered with one or more (e.g., one, two, three, or four) additional therapeutic agents. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of one or more inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. TIFF2025522762000112.tif29128

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 357,948, filed on July 1, 2022, which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] Glycosylphosphatidylinositol - anchored CD73 antigen (also known as cluster of differentiation 73, ecto - 5'-nucleotidase, ecto - 5'-NT, 5'-NT, and NT5E) is thought to be the rate - limiting enzyme in the production of extracellular adenosine (Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene. 2010;29:5346 - 58. doi:10.1038 / onc.2010.292). CD73 is a 70 kDa glycosylphosphatidylinositol (GPI) - anchored protein that is normally expressed on endothelial cells and on subsets of hematopoietic cells. CD73, together with CD39, regulates adenosine triphosphate (ATP) metabolism. CD39 (NTPDase - 1) converts ATP to AMP, releasing trace amounts of ADP, while CD73 catalyzes the conversion of AMP to adenosine (Ado).

[0003] Extracellular Ado accumulates in cancer tissues and constitutes an important mechanism of tumor immune evasion. Among other effects, tumor - derived Ado significantly inhibits infiltrating effector T cells. The breakdown of ATP to Ado by co - expressed CD39 and CD73 on mouse Tregs (regulatory CD4+ T cells) has been shown to cause tumor immunosuppression. CD73 can be found to be structurally expressed at high levels on various types of cancer cells. It is presumed that adenosine produced by CD73 suppresses the anti-tumor adaptive immune response, thereby promoting tumor growth and metastasis. Also, studies in animal models have shown that blocking CD73 activity suppresses tumor growth and prolongs survival by promoting anti-tumor adaptive immunity (Forte et al. (2012) J Immunol. 189(5):2226-33). Considering the need for cancer treatment, there is a need for novel compositions and methods for regulating CD73 activity and related therapeutic agents. The present disclosure meets this need and other needs.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

[0005] The glycosylphosphatidylinositol-anchored CD73 antigen (also known as cluster of differentiation 73, ecto-5'-nucleotidase, ecto-5'-NT, 5'-NT, and NT5E) is thought to be the rate-limiting enzyme in the production of extracellular adenosine (Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene. 2010;29:5346-58. doi:10.1038 / onc.2010.292). CD73 is a 70 kDa glycosylphosphatidylinositol (GPI)-anchored protein that is normally expressed on endothelial cells and on subsets of hematopoietic cells. CD73 regulates adenosine triphosphate (ATP) metabolism together with CD39. CD39 (NTPDase-1) converts ATP to AMP, releasing trace amounts of ADP, while CD73 catalyzes the conversion of AMP to adenosine (Ado).

[0006] In one embodiment of the invention, a compound of formula (I): a.

Chemical formula

[0007] C 3~7 cycloalkyl-C 1~6 alkyl, -C 3~7 cycloalkyl, and the alkyl, cycloalkyl, O-alkyl, or -O-cycloalkyl is optionally substituted with 1 to 4 halogens;

[0008] R 5 is H, C 1~6 alkyl, CN, C 3~7 cycloalkyl, O-C 1~6 alkyl, C 1~6 alkyl-O-C 1~6 alkyl;

[0009] There is provided a compound or a pharmaceutically acceptable salt or stereoisomer thereof. a. In some embodiments, Y is a 4- to 12-membered heteroaryl-O, or a pharmaceutically acceptable salt or stereoisomer thereof. b. In some embodiments, Y is a C 3~7 cycloalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof. c. In some embodiments, Y is a cyclopropyl, or a pharmaceutically acceptable salt or stereoisomer thereof. d. In other embodiments, Y is a 4- to 8-membered heterocyclyl. e. In some embodiments, Y is f.

Chemical Structure

[0010] In one embodiment, a compound of formula (I): a.

Chemical formula

[0011] C 3~7 cycloalkyl-C 1~6 alkyl, -C 3~7 cycloalkyl, and the alkyl, cycloalkyl, O-alkyl, or -O-cycloalkyl is optionally substituted with 1 to 4 halogens

[0012] R 5 is H, C 1~6 alkyl, CN, C 3~7 cycloalkyl, O-C 1~6 alkyl, C 1~6 alkyl-O-C 1~6 alkyl,

[0013] or a pharmaceutically acceptable salt or stereoisomer thereof, and comprises at least one pharmaceutically acceptable excipient, a pharmaceutical composition is provided a. In another embodiment, a method of treating cancer is provided, the method comprising administering to a patient in need of treatment a compound of formula (I): b.

Chemical formula

Mode for Carrying Out the Invention

[0014] I. Definitions "Alkyl" is a straight-chain or branched-chain saturated monovalent hydrocarbon. For example, an alkyl group has 1 to 18 carbon atoms (i.e., C 1~18 alkyl) or 1 to 8 carbon atoms (i.e., C 1~8 alkyl) or 1 to 6 carbon atoms (i.e., C 1~6 alkyl) or 1 to 4 carbon atoms (i.e., C 1~4may have an (alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3) 3. and the like. Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0015] "Alkylene" refers to a straight-chain or branched-chain saturated aliphatic radical having the indicated number of carbon atoms and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same or different atoms of the alkylene group. For example, a straight-chain alkylene can be a divalent radical of -(CH2) n - and can be 、 wherein n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. The alkylene group can be substituted or unsubstituted.

[0016] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least 1 double bond. Alkenyl can contain any number of carbons such as C2, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 , and C6. The alkenyl group can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. The alkenyl group can be substituted or unsubstituted.

[0017] "Alkynyl" refers to any straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least 1 triple bond. Alkynyl can contain any number of carbons such as C2, C 2~3 ,, C 2~4 ,, C 2~5 ,, C 2~6 ,, C 2~7 ,, C 2~8 ,, C 2~9 ,, C 2~10 ,, C3, C 3~4 ,, C 3~5 ,, C 3~6 ,, C4, C 4~5 ,, C 4~6 ,, C5, C 5~6 ,, and C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatriynyl. The alkynyl group can be substituted or unsubstituted.

[0018] "Alkoxy" refers to an alkyl group (alkyl-O-) having an oxygen atom connecting the alkyl group to the point of attachment. Regarding the alkyl group, the alkoxy group can have any suitable number of carbon atoms such as C 1~6 ,. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, etc. The alkoxy group can be further substituted with various substituents described herein. The alkoxy group can be substituted or unsubstituted.

[0019] "Alkoxyalkyl" refers to an alkoxy group linked to an alkyl group that is linked to the rest of the compound, such that the alkyl group is divalent. Alkoxyalkyl has 2 to 6 (C 2~6 alkoxyalkyl), 2 to 5 (C 2~5(alkoxyalkyl), 2 to 4 carbons (C 2~4 (alkoxyalkyl), or 2 to 3 carbons (C 2~3 (alkoxyalkyl) and may have any suitable number of carbons such as those described above. Alkoxy and alkyl are as defined above, and alkyl is divalent and, without limitation, may include methoxymethyl (CH3OCH2-), methoxyethyl (CH3OCH2CH2-), and the like.

[0020] "Alkoxy-alkoxy" refers to an alkoxy group that is linked to a second alkoxy group that is linked to the remainder of the compound. Alkoxy is as defined above and, without limitation, may include methoxy-methoxy (CH3OCH2O-), methoxy-ethoxy (CH3OCH2CH2O-), and others.

[0021] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (I).

[0022] As used herein, "haloalkyl" refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by halo substituents that may be the same or different. For example, C 1~4 haloalkyl is C 1~4 alkyl, wherein one or more of the hydrogen atoms of the C 1~4 alkyl are replaced by halo substituents, and is C1-4 alkyl. Examples of haloalkyl groups include, without limitation, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0023] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to the alkyl group, the haloalkoxy group is C 1~6It may have any suitable number of carbon atoms such as etc. The alkoxy group may be substituted with 1, 2, 3, or more halogens. When all hydrogens are replaced by halogens, for example, fluorine, the compound is oversubstituted, for example, perfluorinated. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0024] "Cycloalkyl" means a saturated or partially unsaturated all-carbon monocyclic ring having 3 to 20 cyclic carbon atoms (i.e., C 3~20 cycloalkyl), for example, 3 to 12 cyclic atoms, for example, 3 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 3 to 4 cyclic atoms. The term "cycloalkyl" also includes saturated and partially unsaturated all-carbon polycondensed ring systems (for example, ring systems containing 2, 3, or 4 carbon rings). Thus, examples of cycloalkyl include polycyclic carbon rings, for example, bicyclic carbon rings (for example, bicyclic carbon rings having 6 to 12 cyclic carbon atoms, for example, bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) and polycyclic carbon rings (for example, tricyclic and tetracyclic carbon rings having up to 20 cyclic carbon atoms). The rings of the polycondensed ring system can be linked to each other by fused bonds, spiro bonds, and bridging bonds when permitted by the valence requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0025] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component is linked to the cycloalkyl component at the point of attachment. The alkyl component is as defined above, except that it is at least a divalent alkylene for the alkyl component to be linked to the cycloalkyl component and the point of attachment. In some cases, the alkyl component may be absent. The alkyl component contains any number of carbons such as C 1~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C 3~6 、C 4~5 、C 4~6 、and C 5~6 etc. The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0026] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic ring system having at least one heteroatom in the ring (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur), where the polycyclic ring system includes at least one non-aromatic ring containing at least one heteroatom. The polycyclic ring system may also include other aromatic and non-aromatic rings. Unless otherwise specified, a heterocyclyl group has from 3 to 20 ring atoms, for example, from 3 to 12 ring atoms, for example, from 3 to 10 ring atoms, or from 3 to 8 ring atoms, or from 3 to 6 ring atoms, or from 3 to 5 ring atoms, or from 4 to 6 ring atoms, or from 4 to 5 ring atoms. Thus, the term encompasses a saturated or partially unsaturated monocyclic ring (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) having from 1 to 6 cyclic carbon atoms and from 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The heteroatom is optionally oxidized to -N(-OH)-, =N(-O) -)-,-S(=O)-, or -S(=O)2- can be formed. The rings of the polycondensed ring (e.g., bicyclic heterocyclyl) system can be linked to each other by fused bonds, spiro bonds, and cross-link bonds when permitted by the valence requirements. Examples of the heterocycle include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, pyrazolidin-3-one, piperazin-2-one, oxazolidin-2-one, and the like.

[0027] Examples of the heterocycloalkyl ring include 9- to 15-membered fused-ring heterocycloalkyl having two, three, or more rings, wherein at least one ring is an aryl ring and at least one ring is a non-aromatic ring containing at least one heteroatom. Representative fused bicyclic heterocycloalkyls include, but are not limited to, as shown in the following structures, indoline (dihydroindole), isoindoline (dihydroisoindole), indazolene (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxole, dihydrobenz[b]dioxin, dihydrobenz[d]oxazole, dihydrobenz[b]thiophene, dihydroisobenz[c]thiophene, dihydrobenz[d]thiazole, dihydrobenz[c]isothiazole, spiro[cyclobutane-1,3'-indoline]-2'-one, spiro[cyclopropane-1,3'-indoline]-2'-one, 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole, benzo[d][1,3]dioxole, and benzo[b][1,4]thiazine: [Chemical formula] The fused bicyclic heterocycloalkyl has the following structure: [Chemical formula] and can also be represented by the formula, wherein X 1 , X 2 , X 3 , and X 4 are each independently absent, -CH2-, -NH-, -O-, or -S-, and at least one of X 1 , X 2 , X 3 , and X 4 is -NH-, -O-, or -S-, and the dashed circle represents a saturated or partially unsaturated non-aromatic ring. The fused bicyclic heterocycloalkyl is optionally substituted.

[0028] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component connects the heterocycloalkyl component at the point of attachment. The alkyl component is as defined above, except that for the alkyl component to connect to the heterocycloalkyl component and the point of attachment, it is at least a divalent alkylene. The alkyl component contains C 0~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 1~6 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C 3~6 、C 4~5 、C 4~6 、and C 5~6 and can contain any number of carbons, such as. In some cases, the alkyl component can be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group can be substituted or unsubstituted.

[0029] As used herein, "aryl" refers to a monocyclic all-carbon aromatic ring or an all-carbon polycondensed ring system in which at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of aryl include phenyl radicals. As aryl, at least one ring may be aromatic, and the other rings may or may not be aromatic (i.e., a carbocyclic ring), and polycondensed ring systems having 9 to 20 carbon atoms (e.g., ring systems containing 2, 3, or 4 rings) are also included. Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups at any carbocyclic ring portion of the polycondensed ring system. The rings of the polycondensed ring system may be linked to each other by fused bonds, spiro bonds, and bridging bonds, where permitted by valence requirements. When referring to aryl having a particular range of atomic numbers (e.g., 6- to 10-membered aryl), it should also be understood that the atomic range is for the total ring atoms of the aryl. For example, 6-membered aryl includes phenyl, and 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0030] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene for the alkyl component to link to the aryl component and the point of attachment. The alkyl component is C 0~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 1~6 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C 3~6 、C4~5 , C 4~6 , and C 5~6 may contain any number of carbons such as. In some cases, the alkyl component may be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethylbenzene. The alkyl-aryl group may be substituted or unsubstituted.

[0031] As used herein, "heteroaryl" refers to a monocyclic aromatic ring having at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur, and "heteroaryl" also encompasses a polycondensed ring system having at least one such aromatic ring, which polycondensed ring system is further described below. Thus, "heteroaryl" encompasses a monocyclic aromatic ring having 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur atoms and nitrogen atoms may be in an oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also encompasses a polycondensed ring system (e.g., a ring system containing 2, 3, or 4 rings), where a heteroaryl group as defined above is condensed with one or more rings selected from heteroaryl (e.g., forming 1,8-naphthyridinyl), heterocycle (e.g., forming 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., forming 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., forming indazolyl) to form a polycondensed ring system. Thus, heteroaryl (a monocyclic or polycondensed aromatic ring system) has 1 to 20 carbon atoms and 1 to 6 heteroatoms in the heteroaryl ring. Such a condensed polycyclic system may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moiety of the condensed ring. The rings of the polycondensed ring system may be linked to each other by fused bonds, spiro bonds, and bridging bonds, where permitted by valence requirements. It should be understood that the individual rings of the polycondensed ring system may be linked to each other in any order. The point of attachment to heteroaryl or a polycondensed ring system of heteroaryl may be at any suitable atom of the heteroaryl or polycondensed ring system of heteroaryl that contains a carbon atom and a heteroatom (e.g., nitrogen). When reference is made to a heteroaryl having a particular range of ring atom numbers (e.g., 5- to 10-membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and is understood to include carbon atoms and heteroatoms.For example, as the 5-membered heteroaryl, thiazolyl can be mentioned, and as the 10-membered heteroaryl, quinolinyl can be mentioned. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolin-4(3H)-one, pyridin-2(1H)-one, isoquinolin-1(2H)-one, and triazolyl.

[0032] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component connects the heteroaryl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene for connecting the heteroaryl component and the point of attachment. The alkyl component can contain any number of carbons such as C 0~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 1~6 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C 3~6 、C 4~5 、C 4~6 、and C 5~6 etc. In some cases, the alkyl component can be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group can be substituted or unsubstituted.

[0033] "The compounds of the present disclosure" include the compounds disclosed herein. For example, the compounds of the present disclosure include the compounds of the examples and the compounds of formula (I).

[0034] As used herein, "composition" is intended to include a product containing specific ingredients in specific amounts, and any product directly or indirectly resulting from the combination of specific amounts of specific ingredients. "Pharmaceutically acceptable" means that a carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[0035] "Pharmaceutically effective amount" refers to the amount of a compound of the present disclosure in a formulation or combination thereof that produces a desired therapeutic or pharmaceutical result.

[0036] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the US Food and Drug Administration as acceptable for use in humans or livestock.

[0037] As used herein, "treatment" or "treating" or "treatment" refers to an approach for obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms, and / or reduction in the degree of symptoms, and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the degree of the disease or condition), b) delaying or preventing the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition), and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the pathological condition, delaying the progression of the disease, improving the quality of life, and / or extending the survival period.

[0038] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount of a compound that is effective to induce a desired biological or medical response, which includes an amount of the compound sufficient to achieve such treatment of the disease when administered to a subject for treating the disease. The effective amount can vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated. The effective amount can include a range of amounts. As is understood in the art, the effective amount can be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. The effective amount can be considered in relation to the administration of one or more therapeutic agents, and a single agent may be administered in an effective amount when used in combination with one or more other agents to achieve a desired or beneficial result, or when such a result is achieved. The preferred dosage of any co-administered compound can optionally be reduced due to the combined action (e.g., additive or synergistic effect) of the compounds.

[0039] "Administering" refers to oral administration to a subject, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini osmotic pump. Administration can be carried out according to a schedule specifying the frequency of administration, the dosage administered, and other factors.

[0040] As used herein, "co - administration" refers to the administration of a unit dose of a compound disclosed herein either before or after the administration of a unit dose of one or more additional therapeutic agents, e.g., administration of a compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by the administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by the administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by the administration of a unit dose of one or more additional therapeutic agents after a period of several hours (e.g., 1 - 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by the administration of a unit dose of a compound of the present disclosure after a period of several hours (e.g., 1 - 12 hours). Co - administration of a compound disclosed herein and one or more additional therapeutic agents generally refers to co - administering or sequentially administering a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0041] "Subject" refers to an animal such as a mammal including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0042] "Disease" or "condition" refers to a physical or health condition of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein. In embodiments, the disease is cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma). The disease can be an autoimmune disease, an inflammatory disease, a cancer disease, an infectious disease, a metabolic disease, a developmental disorder, a cardiovascular disease, a liver disease, an intestinal disease, an endocrine disease, a nervous system disease, or other diseases.

[0043] "Cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

[0044] Additional examples include cancers of the thyroid, endocrine system, brain, breast, cervix, large intestine, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, or medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, Waldenström macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, pre-malignant skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, hypercalcemia of malignancy, endometrial cancer, adrenocortical cancer, neoplasm of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, cancer of pancreatic stellate cells, cancer of hepatic stellate cells, or prostate cancer.

[0045] "Leukemia" generally refers in a broad sense to a progressive malignant disease of the hematopoietic organs, and is generally characterized by abnormal proliferation and generation of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease: acute or chronic; (2) the type of cells involved: myeloid (myelogenous), lymphocyte (lymphogenous), or monocyte; and (3) the increase or non-increase in the number of abnormal cells in the blood: leukemic or aleukemic (subleukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, embryonal cell leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemocytoblastic leukemia, hemoblastocytic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, microblast leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Nägeli type leukemia, plasmacytic leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0046] "Sarcoma" generally refers to a tumor composed of substances such as embryonic connective tissue and generally composed of densely packed cells embedded in fibrous or homogeneous substances. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphoma, melanoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, lipoma, cystosarcoma phyllodes, enamel epithelial sarcoma, embryonal rhabdomyosarcoma, chlorosarcoma, choriocarcinoma, blastoma sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer stellate cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystadenosarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0047] "Melanoma" is considered to mean a tumor arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigo-derived melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0048] "Carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and undergo metastasis. Exemplary carcinomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenocarcinoma of the adrenal cortex, alveolar carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic lung carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, comedocarcinoma, uterine carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, scirrhous carcinoma, durum, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, glandular epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, childhood embryonal carcinoma, carcinoma in situ, carcinoma in situ in epidermis, carcinoma in situ, Chrompecher carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucoepidermoid carcinoma, mucinous carcinoma mucosum, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, cord-like carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinomaExamples include tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinomatosis.

[0049] The terms "metastasis," "metastatic," and "metastatic cancer" may be used interchangeably and refer to the spread of a proliferative disease or disorder, such as cancer, from one organ to another non-adjacent organ or body part. Cancer develops at a site of origin, for example, in the breast, and that site is referred to as the primary tumor, for example, primary breast cancer. Some cancer cells within the primary tumor or site of origin acquire the ability to invade and infiltrate the surrounding normal tissue in the local area and / or to invade the walls of the lymphatic or vascular system and spread through that system to other sites and tissues within the body. A second clinically detectable tumor formed from the cancer cells of the primary tumor is referred to as a metastatic tumor or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be the same as those of the original tumor. Thus, when lung cancer metastasizes to the breast, the secondary tumor at the breast site consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to as metastatic lung cancer. Thus, the term metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrase subject with non-metastatic cancer, or cancer that is not metastatic, refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject who has or has a history of a primary lung tumor and has one or more secondary tumors at a second site or multiple sites, for example, the breast.

[0050] In the context of a substance or the activity or function of a substance related to a disease (e.g., diabetes, cancer (e.g., prostate cancer, kidney cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma)), "related to" or "associated with" means that the disease (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) is (wholly or partially) caused by the substance or the activity or function of the substance, or that the symptoms of the disease are (wholly or partially) caused by it.

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

[0052] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as the free base. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that have the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, a compound containing basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0053] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 +Salts derived from suitable bases such as (wherein X is C1-C4 alkyl) may also be mentioned. Base addition salts such as sodium salts or potassium salts may also be mentioned.

[0054] Also provided are the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, and n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may increase resistance to metabolism and, thus, may be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0055] Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I may also be mentioned. 11 C, 18 F, 15 O, and 13Substitution with a positron-emitting isotope such as N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotope-labeled compounds of formula (I) can generally be prepared using appropriate isotope-labeled reagents in place of the conventionally used unlabeled reagents by conventional techniques known to those skilled in the art or by processes similar to those described in the examples below.

[0056] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and, accordingly, may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- with respect to amino acids. This disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagents or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of a racemic compound (or a racemic compound of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers and are not otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. When the compounds are represented in their chiral forms, it is understood that the embodiments include, but are not limited to, specifically diastereomerically or enantiomerically enriched forms. When chirality is not specified but is present, it is understood that the embodiments are directed to either a specifically diastereomerically or enantiomerically enriched form or a racemic or scaemic mixture of such compounds. As used herein, a "scaemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0057] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0058] "Stereoisomers" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. A compound may exist in stereoisomeric forms if it has one or more asymmetric centers or double bonds with asymmetric substitution and can thus be produced as individual stereoisomers or as mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0059] "Tautomers" refers to alternative forms of compounds in which the position of a proton is different, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both ring-NH- and ring=N-.

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes before or after a chemical group are for convenience only, and the chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of a group. A dashed line indicates an optional bond. Unless required chemically or structurally, the order in which chemical groups are written or the point of attachment to the rest of the molecule indicates neither directionality nor implies it. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be linked in either direction. Similarly, for example, an "arylalkyl" group may be attached to the rest of the molecule by either the aryl or alkyl portion of the group. "C u~v " or (C u ~C vPrefixes such as "etc." indicate that the group that follows has u to v carbon atoms. For example, both "C 1~6 alkyl" and "C1-C6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0061] As used herein, "solvate" refers to the result of the interaction between a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0062] As used herein, "prodrug" refers to a derivative of a drug that is converted to the parent drug by some chemical or enzymatic pathway upon administration to a human body. II. Combinations

[0063] In some embodiments, the compounds or pharmaceutically acceptable salts thereof provided herein are administered with one or more (e.g., one, two, three, or four) additional therapeutic agents. In some embodiments, the additional therapeutic agents are, for example, inhibitory immune checkpoint blockers or inhibitors, stimulatory immune checkpoint stimulators, agonists, or activators, chemotherapeutic agents, anti-cancer agents, radiation therapy agents, anti-neoplastic agents, anti-proliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapy agents, therapeutic antigen-binding molecules (e.g., any form of single-specificity and multispecific antibodies and fragments thereof such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, etc.), bispecific antibodies, non-immunoglobulin antibody mimetics (e.g., including adnectin, affibody molecules, affilins, affimers, affitins, alphabodies, anticalins, peptide aptamers, armadillo repeat proteins (ARM), atrimers, avimers, designed ankyrin repeat proteins (DARPin®), finomers, notchtins, knotted domain peptides, monobodies, and nanoclamps), antibody-drug conjugates (ADC), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editors, cells comprising chimeric antigen receptors (CAR), e.g., T cell immunotherapy agents, NK cell immunotherapy agents, or macrophage immunotherapy agents, engineered T cell receptors (TCR-T), or any combination thereof. Exemplary targets

[0064] In some embodiments, one or more additional therapeutic agents are inhibitors, agonists, antagonists, ligands, regulators, stimulators, blockers, activators or suppressors of targets (e.g., polypeptides or polynucleotides) such as those listed below: 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 (ABL proto-oncogene 1, ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); absent in melanoma 2 (AIM2; NCBI Gene ID: 9447); acetyl-CoA acyltransferase 2 (ACAA2; NCBI Gene ID: 10499); acid phosphatase 3 (ACP3; NCBI Gene ID: 55); adenosine deaminase (ADA, ADA1; NCBI Gene ID: 100); adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI Gene ID: 134, 135, 136, 137); AKT serine / threonine kinase 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase, membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor-type tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha fetoprotein (AFP; NCBI Gene ID: 174); amine oxidase copper-containing (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI Gene ID: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietin (ANGPT1, ANGPT2;NCBI Gene 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 mitochondria associated 1 (AIFM1, AIF; NCBI Gene ID: 9131); arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); asterixis homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI Gene ID: 472); ATP binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI Gene ID: 5243); ATP-dependent Clp-protease (CLPP; NCBI Gene ID: 8192); ATR serine / threonine kinase (ATR; NCBI Gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI Gene ID: 558); B and T lymphocyte associated (BTLA, CD272; NCBI Gene ID: 151888); baculoviral IAP repeat containing protein (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene IDs: 329, 330, 331, 332); basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 682); B-cell lymphoma 2 (BCL2; NCBI Gene ID: 596);BCL2 binding component 3 (BBC3, PUMA; NCBI Gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene ID: 598, 10018); beta-3 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); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain and external domain (BET) bromodomain-containing protein (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene ID: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695); cadherin (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene ID: 1001, 1004); cancer / testis antigen (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene ID: 1485, 30848, 246100); cannabinoid receptor (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene ID: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363); carbonic anhydrase (CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14;NCBI gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677); cancer fetal antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI gene IDs: 1048, 1084, 4680); casein kinase (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2); NCBI gene IDs: 1452, 1457); caspase (e.g., CASP3, CASP7, CASP8; NCBI gene IDs: 836, 840, 841, 864); catenin beta 1 (catenin beta 1, CTNNB1; NCBI gene ID: 1499); cathepsin G (cathepsin G, CTSG; NCBI gene ID: 1511); Cbl proto-oncogene B (Cbl proto-oncogene B, CBLB, Cbl-b; NCBI gene ID: 868); C-C motif chemokine ligand 21 (C-C motif chemokine ligand 21, CCL21; NCBI gene ID: 6366); C-C motif chemokine receptor 2 (C-C motif chemokine receptor 2, CCR2; NCBI gene ID: 729230); C-C motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer binding protein alpha (CCAAT enhancer binding protein alpha, CEBPA, CEBP; NCBI gene ID: 1050); cell adhesion molecule 1 (cell adhesion molecule 1, CADM1; NCBI gene ID: 23705); cell division cycle 7 (cell division cycle 7, CDC7; NCBI gene ID: 8317); cellular communication network factor 2 (cellular communication network factor 2, CCN2; NCBI gene ID: 1490); cereblon (cereblon, CRBN; NCBI gene ID: 51185);Checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene ID: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatomammotropin hormone 1 (CSH1; NCBI Gene ID: 1442); claudin (e.g., CLDN6, CLDN18, NCBI Gene ID: 9074, 51208); markers of the cluster of differentiation (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD beta (TRB), CD gamma (TRG), CD delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLAST1), CD52, CD55 (DAF), CD58 (LFA3), CD74, CD79a, CD79b, CD80 (B7-1), CD84, CD86 (B7-2), CD96 (TACTILE), CD99 (MIC2), CD115 (CSF1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 (IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), CD194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2R), CD223 (LAG3), CD226 (DNAM1), CD244, CD247, CD248, CD276 (B7-H3), CD331 (FGFR1), CD332 (FGFR2), CD333 (FGFR3), CD334 (FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI gene IDs: 2155, 2159); collagen type IV alpha chains (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI gene ID: 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 ID: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI gene ID: 718, 727); COP9 signalosome subunit 5 (COPS5; NCBI gene ID: 10987); C-type lectin domain family member (e.g., , CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371, NCBI Gene ID: 160364, 170482, 283420); C-X-C motif chemokine ligand 12 (C-X-C motif chemokine ligand 12, CXCL12; NCBI Gene ID: 6387); C-X-C motif chemokine receptor (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI Gene ID: 2833, 3577, 3579, 7852); Cyclin D1 (cyclin D1, CCND1, BCL1; NCBI Gene ID: 595); Cyclin-dependent kinase (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI Gene ID: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); Cyclin G1 (cyclin G1, CCNG1; NCBI Gene ID: 900); Cytochrome P450 family member (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene ID: 1565, 1576, 1583, 1585, 1586, 1588, 1595); Cytochrome P450 oxidoreductase (cytochrome P450 oxidoreductase, POR; NCBI Gene ID: 5447); Cytokine inducible SH2 containing protein (cytokine inducible SH2 containing protein, CISH; NCBI Gene ID: 1154); Cytotoxic T-lymphocyte associated protein 4 (cytotoxic T-lymphocyte associated protein 4, CTLA4, CD152; NCBI Gene ID: 1493); DEAD-box helicase (e.g., DDX5, DDX6, DDX58; NCBI Gene ID: 1655, 1656, 23586); Delta-like canonical Notch ligand (e.g., DLL3, DLL4; NCBI Gene ID: 10683, 54567);Diablo IAP-binding mitochondrial protein (DIABLO, SMAC; NCBI Gene ID: 56616); diacylglycerol kinase (e.g., DGKA, DGKZ; NCBI Gene ID: 1606, 8525); dickkopf WNT signaling pathway inhibitor (e.g., DKK1, DKK3; NCBI Gene ID: 22943, 27122); dihydrofolate reductase (NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); discoidin domain receptor tyrosine kinase (e.g., DDR1 (CD167), DDR2; CD167, NCBI Gene ID: 780, 4921); DNA-dependent protein kinase (PRKDC; NCBI Gene ID: 5591); DNA topoisomerase (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI Gene ID: 7150, 7153, 7155, 7156, 8940); dopachrome tautomerase (DCT; NCBI Gene ID: 1638); dopamine receptor D2 (DRD2; NCBI Gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI Gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI Gene ID: 5169); EMAP-like 4 (EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidase (e.g., ERAP1, ERAP2;NCBI Gene ID: 51752, 64167); enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2; NCBI Gene ID: 2146); ephrin receptor (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI Gene ID: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrin (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene ID: 1942, 1945, 1948); epidermal growth factor receptor (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4); NCBI Gene ID: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI Gene ID: 4072); epithelial mitogen (EPGN; NCBI Gene ID: 255324); eukaryotic translation elongation factor (e.g., EEF1A2, EEF2; NCBI Gene ID: 1917, 1938); eukaryotic translation initiation factor (e.g., EIF4A1, EIF5A; NCBI Gene ID: 1973, 1984); exportin-1 (XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fa ligand (FASLG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragment of Ig receptor (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene ID: 2205, 2214, 2217); Fc receptor like 5 (FCRL5, CD307; NCBI Gene ID: 83416);Fibroblast activation protein alpha (FAP; NCBI Gene ID: 2191); fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI Gene ID: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI Gene ID: 2246, 2247, 2249, 2250); fibronectin 1 (FN1, MSF; NCBI Gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI Gene ID: 2321, 2322, 2324); fms-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI Gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI Gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); FURIN (FURIN, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI Gene ID: 2534); galectins (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene ID: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glutamate metabotropic receptor 1 (GRM1; NCBI Gene ID: 2911);Glutaminase (GLS; NCBI Gene ID: 2744); Glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 2950); Glycogen synthase kinase 3 beta (GSK3B; NCBI Gene ID: 2932); Glypican 3 (GPC3; NCBI Gene ID: 2719); Gonadotropin releasing hormone 1 (GNRH1; NCBI Gene ID: 2796); Gonadotropin releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, Osteoactivin; NCBI Gene ID: 10457); Growth differentiation factor 2 (GDF2, BMP9; NCBI Gene ID: 2658); Growth factor receptor-bound protein 2 (GRB2, ASH; NCBI Gene ID: 2885); Guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL, NCBI Gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI Gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK; NCBI Gene ID: 3055); Heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI Gene ID: 3309, 3315, 7184); Heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene ID: 3162, 3163); Heparanase (HPSE; NCBI Gene ID: 10855); Hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366;NCBI Gene ID: 84868); hepatocyte growth factor (HGF; NCBI Gene ID: 3082); HERV-H LTR-associating 2 (HHLA2, B7-H7; NCBI Gene ID: 11148); histamine receptor H2 (HRH2; NCBI Gene ID: 3274); histone deacetylase (e.g., HDAC1, HDAC7, HDAC9; NCBI Gene ID: 3065, 9734, 51564); HRas proto-oncogene, GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factor (e.g., HIF1A, HIF2A (EPAS1); NCBI Gene ID: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI Gene ID: 3551, 3553); IKAROS family zinc finger (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: 2; 3308); Insulin-like growth factor receptors (e.g., IGF1R, IGF2R; NCBI Gene ID: 3480, 3482); Insulin-like growth factors (e.g., IGF1, IGF2; NCBI Gene ID: 3479, 3481); Insulin 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 ID: 3678, 3685, 3688, 3695, 3698); Intercellular adhesion molecule 1 (intercellular adhesion molecule 1, ICAM1, CD54; NCBI Gene ID: 3383); Interleukin 1 receptor-associated kinase 4 (interleukin 1 receptor associated kinase 4, IRAK4; NCBI Gene ID: 51135); Interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI Gene ID: 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 ID: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618); Isocitrate dehydrogenase (NADP(+)) 1 (e.g., IDH1, IDH2; NCBI Gene ID: 3417, 3418); Janus kinases (e.g., JAK1, JAK2, JAK3; NCBI Gene ID: 3716, 3717, 3718); Kallikrein-related peptidase 3 (kallikrein related peptidase 3, KLK3; NCBI Gene ID: 354);Killer cell immunoglobulin-like receptors, Ig domains and long cytoplasmic tails (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI Gene ID: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285); killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene ID: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KISS1; NCBI Gene ID: 3814); KIT 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 ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T-cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / choriogonadotropin receptor (LHCGR; NCBI Gene ID: 3973); LY6 / PLAUR domain containing 3 (LYPD3; NCBI Gene ID: 27076); lymphocyte activating 3 (LAG3; CD223, NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene ID: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytosolic protein 2 (LCP2; NCBI Gene ID: 3937); lysine demethylase 1A (KDM1A; NCBI Gene ID: 23028); lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI Gene ID: 1902); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase like 2 (LOXL2, NCBI Gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 1 receptor (MST1R, CD136;NCBI Gene ID: 4486); MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI Gene ID: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); Major Histocompatibility Complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene ID: 3105, 3133, 3134, 3135); Major Vault Protein (MVP, VAULT1, NCBI Gene ID: 9961); MALT1 Paracaspase (MALT1; NCBI Gene ID: 10892); MAPK-Activated Protein Kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK-Interacting Serine / Threonine Kinase (e.g., MKNK1, MKNK2; NCBI Gene ID: 2872, 8569); Matrix Metallopeptidase (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI Gene ID: 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 Oncogene (MDM2; NCBI Gene ID: 4193); MDM4 Regulator of p53 (MDM4; BMFS6, NCBI Gene ID: 4194); Mechanistic Target of Rapamycin Kinase (MTOR, FRAP1; NCBI Gene ID: 2475);Melan-A (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); mesothelin (MSLN; NCBI Gene ID: 10232); MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI Gene ID: 4233); methionyl aminopeptidase 2 (methionyl aminopeptidase 2, METAP2, MAP2; NCBI Gene ID: 10988); MHC class I polypeptide-related sequence (e.g., MICA, MICB; NCBI Gene ID: 4277, 100507436); mitogen-activated protein kinase (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI Gene ID: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinase kinase (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2), NCBI Gene ID: 4217, 1326); mitogen-activated protein kinase kinase kinase kinase 1 (mitogen-activated protein kinase kinase kinase kinase 1, MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinase kinase (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene ID: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (MPL; NCBI Gene ID: 4352); mucin (e.g., MUC1 (including its splice variants (e.g., including MUC1 / A, C, D, X, Y, Z and REP)), MUC5AC, MUC16 (CA125); NCBI Gene ID: 4582, 4586, 94025); MYC proto-oncogene, bHLH transcription factor (MYC;NCBI Gene ID: 4609); Myostatin (MSTN, GDF8; NCBI Gene ID: 2660); Myristoylated alanine rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082); Natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4883); Natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); Necdin, MAGE family member (NDN; NCBI Gene ID: 4692); Nectin cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4); NCBI Gene ID: 5819, 81607); Neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); Neuropilin (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene ID: 8828, 8829); Neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene ID: 4914, 4915, 4916); NFKB activation ta; Protein (NFKB activating protein, NKAP; NCBI Gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain containing 3 (NLRP3, NALP3; NCBI Gene ID: 114548); Notch receptor (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI Gene ID: 4893); Nuclear factor kappa B (NFKB1, NFKB2; NCBI Gene ID: 4790, 4791); Nuclear factor, erythroid 2 like 2 (NFE2L2; NRF2, NCBI Gene ID: 4780); Nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI Gene ID: 3164); Nucleolin (NCL; NCBI Gene ID: 4691); Nucleophosmin 1 (NPM1; NCBI Gene ID: 4869); Nucleotide binding oligomerization domain containing 2 (NOD2; NCBI Gene ID: 64127); Nudix hydrolase 1 (NUDT1; NCBI Gene ID: 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: 4953); Oxoglutarate dehydrogenase (OGDH; NCBI Gene ID: 4967);Parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); periostin (POSTN; NCBI Gene ID: 10631); peroxisome proliferator-activated receptor (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene ID: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA (PI3K alpha), PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3CG (PI3K gamma); NCBI Gene ID: 5290, 5291, 5293, 5294); phospholipase (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI Gene ID: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogene, serine / threonine kinase (e.g., PIM1, PIM2, PIM3; NCBI Gene ID: 5292, 11040, 415116); placenta growth factor (PGF; NCBI Gene ID: 5228); plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet-derived growth factor receptor (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene ID: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus receptor (PVR) 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 ID: 142, 10038, 10039); Polycomb protein EED (EED; NCBI Gene ID: 8726); Porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcriptional 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); Prosaposin (PSAP; NCBI Gene ID: 5660); Prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); Prostaglandin E synthase (PTGES; NCBI Gene ID: 9536); Prostaglandin endoperoxide synthase (PTGS1(COX1), PTGS2(COX2); NCBI Gene ID: 5742, 5743); Proteasome 20S subunit beta 9 (PSMB9; NCBI Gene ID: 5698); Protein arginine methyltransferase (e.g., PRMT1, PRMT5; NCBI Gene ID: 3276, 10419); Protein kinase N3 (PKN3;NCBI Gene ID: 29941); Protein phosphatase 2A (PPP2CA; NCBI Gene ID: 5515); Protein tyrosine kinase 7 (inactive) (PTK7; NCBI Gene ID: 5754); Protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene ID: 5787, 5788); Prothymosin alpha (PTMA; NCBI Gene ID: 5757); Purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); Purinergic receptor P2X7 (P2RX7; NCBI Gene ID: 5027); PVR-related immunoglobulin domain containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene, serine / threonine kinase (RAF1, c-Raf; NCBI Gene ID: 5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); ras homolog family member C (RHOC); NCBI Gene ID: 389); Ras homolog, mTORC1 binding (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); Receptor-interacting serine / threonine protein kinase 1 (RIPK1; NCBI Gene ID: 8737); Ret proto-oncogene (RET; NCBI Gene ID: 5979); Retinoic acid early transcript (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene ID: 135250, 154064, 353091);Retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene ID: 5914, 5916); retinoid X receptor (e.g., RXRA, RXRB, RXRG; NCBI Gene ID: 6256, 6257, 6258); Rho-associated coiled-coil containing protein kinase (e.g., ROCK1, ROCK2; NCBI Gene ID: 6093, 9475); ribosomal protein S6 kinase B1 (ribosomal protein S6 kinase B1, RPS6KB1, S6K-beta1; NCBI Gene ID: 6198); ring finger protein 128 (ring finger protein 128, RNF128, GRAIL; NCBI Gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROS proto-oncogene 1, ROS1; NCBI Gene ID: 6098); roundabout guidance receptor 4 (roundabout guidance receptor 4, ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX family transcription factor 3, RUNX3; NCBI Gene ID: 864); S100 calcium binding protein A9 (S100 calcium binding protein A9, S100A9; NCBI Gene ID: 6280); secreted frizzled related protein 2 (secreted frizzled related protein 2, SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (secreted phosphoprotein 1, SPP1; NCBI Gene ID: 6696); secretoglobin family 1A member 1 (secretoglobin family 1A member 1, SCGB1A1; NCBI Gene ID: 7356); selectin (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene ID: 6401, 6402, 6403); semaphorin 4D (semaphorin 4D, SEMA4D; CD100, NCBI Gene ID: 10507); sialic acid binding Ig-like lectin (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10;NCBI gene IDs: 27036, 27180, 89790); signal regulatory protein alpha (SIRPA, CD172A; NCBI gene ID: 140885); signal transducers and activators of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI gene IDs: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI gene ID: 23410); signaling lymphocytic activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK like family member 6 (SLITRK6; NCBI gene ID: 84189); smoothened, 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 IDs: 6751, 6752, 67; 53, 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 proto-oncogene, non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); Stabilin 1 (STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family member 1 (STEAP1; NCBI Gene ID: 26872); Steroid sulfatase (STS; NCBI Gene ID: 412); Stimulator of interferon response cGAMP interactor 1 (STING1; NCBI Gene ID: 340061); Superoxide dismutase 1 (SOD1, ALS1; NCBI Gene ID: 6647); Suppressor of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI Gene ID: 8651, 9021); Synapsin 3 (SYN3; NCBI Gene ID: 8224); Syndecan 1 (SDC1, CD138, syndecan; NCBI Gene ID: 6382); Synuclein alpha (SNCA, PARK1; NCBI Gene ID: 6622);T cell immunoglobulin and mucin domain containing 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptor (e.g., TACR1, TACR3; NCBI Gene ID: 6869, 6870); TANK binding kinase 1 (TBK1, NCBI Gene ID: 29110); tankyrase (TNKS, NCBI Gene ID: 8658); TATA-box binding protein associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25976); 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, 11219); thrombomodulin (THBD, CD141; NCBI Gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI Gene ID: 7083, 7084);Thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene ID: 7606, 7608); thyroid stimulating hormone receptor (TSHR; NCBI Gene ID: 7253); TNF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL); NCBI Gene 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 ID: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); transferrin (TF; NCBI Gene ID: 7018); transferrin receptor (TFRC, CD71; NCBI Gene ID: 7037); transforming growth factors (e.g., TGFA, TGFB1; NCBI Gene ID: 7039, 7040); transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI Gene ID: 7046, 7048, 7049); transforming protein E7 (E7; NCBI Gene ID: 1489079);Transglutaminase 5 (TGM5; NCBI Gene ID: 9333); Transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI Gene ID: 7442); Transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); Triggering receptor expressed on myeloid cells (e.g., TREM1 (CD354), TREM2; NCBI Gene ID: 54209, 54210); Trophinin (TRO, MAGED3; NCBI Gene ID: 7216); Trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162); Tryptophan 2,3-dioxygenase (TDO2; NCBI Gene ID: 6999); Tryptophan hydroxylase (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); Tumor associated calcium signal transducer 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 (, CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI gene ID: 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 (tumor protein p53, TP53; NCBI gene ID: 7157); tumor suppressor 2, mitochondrial calcium regulator (tumor suppressor 2, mitochondrial calcium regulator, TUSC2; NCBI gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI gene ID: 7301); tyrosinase (tyrosinase, TYR; NCBI gene ID: 7299); tyrosine hydroxylase (tyrosine hydroxylase, TH; NCBI gene ID: 7054); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI gene ID: 7075); tyrosine-protein phosphatase, non-receptor type 11 (tyrosine-protein phosphatase non-receptor type 11, PTPN11, SHP2; NCBI gene ID: 5781);Ubiquitin-conjugating enzyme E2 I (ubiquitin conjugating enzyme E2 I, UBE2I, UBC9; NCBI gene ID: 7329); ubiquitin C-terminal hydrolase L5 (ubiquitin C-terminal hydrolase L5, UCHL5; NCBI gene ID: 51377); ubiquitin specific peptidase 7 (ubiquitin specific peptidase 7, USP7; NCBI gene ID: 7874); ubiquitin-like modifier activating enzyme 1 (ubiquitin-like modifier activating enzyme 1, UBA1; NCBI gene ID: 7317); UL16-binding protein (e.g., ULBP1, ULBP2, ULBP3; NCBI gene ID: 79465, 80328, 80328); valosin-containing protein (valosin-containing protein, VCP, CDC48; NCBI gene ID: 7415); vascular cell adhesion molecule 1 (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 (vimentin, VIM; NCBI gene ID: 7431); vitamin D receptor (vitamin D receptor, VDR; NCBI gene ID: 7421); V-set domain-containing T cell activation inhibitor 1 (V-set domain containing T cell activation inhibitor 1, VTCN1, B7-H4; NCBI gene ID: 79679); V-set immunoregulatory receptor (V-set immunoregulatory receptor, VSIR, VISTA, B7-H5; NCBI gene ID: 64115); WEE1 G2 checkpoint kinase (WEE1; NCBI gene ID: 7465); WRN RecQ-like helicase (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); X-C motif chemokine ligand 1 (XCL1, ATAC; NCBI gene ID: 6375); X-C motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI gene ID: 2829); Yes1 associated transcriptional regulator (YAP1; NC; BI gene ID: 10413); zeta chain associated protein kinase 70 (ZAP70; NCBI gene ID: 7535).

[0065] In some embodiments, one or more additional therapeutic agents include, for example, 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A receptor (adenosine A 2A receptor, ADORA2A; NCBI gene ID: 135); adenosine A 2BReceptors (adenosine A2B receptor, ADORA2B; NCBI gene ID: 136); C-C motif chemokine receptor 8 (C-C motif chemokine receptor 8, CCR8, CDw198; NCBI gene ID: 1237); cytokine-inducible SH2-containing protein (cytokine inducible SH2 containing protein, CISH; NCBI gene ID: 1154); diacylglycerol kinase alpha (diacylglycerol kinase alpha, DGKA, DAGK, DAGK1, or DGK-α; NCBI gene ID: 1606); fms-like tyrosine kinase 3 (fms like tyrosine kinase 3, FLT3, CD135; NCBI gene ID: 2322); integrin-associated protein (integrin associated protein, IAP, CD47; NCBI gene ID: 961); interleukin-2 (interleukine-2, IL2; NCBI gene ID: 3558); interleukin 2 receptor (interleukine 2 receptor, IL2RA, IL2RB, IL2RG; NCBI gene ID: 3559, 3560, 3561); Kirsten rat sarcoma virus (Kirsten rat sarcoma, KRAS; NCBI gene ID: 3845; including mutations such as KRAS G12C or G12D); mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (Hematopoietic Progenitor Kinase 1, HPK1), NCBI gene ID: 11184)); myeloid cell leukemia sequence 1 apoptosis regulator (myeloid cell leukemia sequence 1 apoptosis regulator, MCL1; NCBI gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta, PIK3CD; NCBI gene ID: 5293);Programmed death-ligand 1 (PD-L1, CD274; NCBI Gene ID: 29126); Programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133); Proto-oncogene c-KIT (KIT, CD117; NCBI Gene ID: 3815); Signal regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); Triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210); Triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209); Tumor-associated calcium signal transducer 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);Drugs targeting Werner RecQ-like helicase (WRN; NCBI Gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807) are included.

[0066] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells in the tumor microenvironment. Activating or stimulating stimulatory immune checkpoints can enhance the effect of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu,., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., as reviewed in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibiting regulatory T-cells (Treg) or Treg depletion can relieve their suppression of anti-tumor immune responses and have an anti-cancer effect (e.g., as reviewed in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0067] As used herein, "prodrug" refers to a derivative of a drug that is converted into the parent drug by some chemical or enzymatic pathways upon administration to the human body. Examples of immune checkpoint proteins or receptors include CD27 (NCBI Gene ID: 939), CD70 (NCBI Gene ID: 970); CD40 (NCBI Gene ID: 958), CD40LG (NCBI Gene ID: 959); CD47 (NCBI Gene ID: 961), SIRPA (NCBI Gene ID: 140885); CD48 (SLAMF2; NCBI Gene ID: 962) transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI Gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI Gene ID: 8832), CD96 (NCBI Gene ID: 10225), CD160 (NCBI Gene ID: 11126), MS4A1 (CD20; NCBI Gene ID; 931), CD244 (SLAMF4; NCBI Gene ID: 51744); CD276 (B7H3; NCBI Gene ID: 80381); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer cell cytotoxicity receptor 3 ligand 1 (natural killer cell cytotoxicity receptor 3 ligand 1, NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-associated 2 (HERV-H LTR-associating 2, HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell co-stimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell co-stimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNF superfamily member 4, TNFSF4, OX40L; NCBI Gene ID: 7292); TNFRSF8 (CD30;NCBI gene ID; 943), TNFSF8 (CD30L; NCBI gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI gene ID; 8797), TNFRSF9 (CD137; NCBI gene ID; 3604), TNFSF9 (CD137L; NCBI gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI gene ID: 8795), TNFRSF10 (TRAIL; NCBI gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI gene ID: 8764), TNFSF14 (HVEML; NCBI gene ID: 8740); CD272 (B and T lymphocyte associated (BTLA), NCBI gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI gene ID: 608), TNFSF13B (BAFF; NCBI gene ID: 10673); TNFRSF18 (GITR; NCBI gene ID: 8784), TNFSF18 (GITRL; NCBI gene ID: 8995); MHC class I polypeptide-related sequence A (MHC class I polypeptide-related sequence A, MICA; NCBI gene ID: 100507436); MHC class I polypeptide-related sequence B (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 (programmed cell death 1, PDCD1, PD1, PD-1; NCBI gene ID: 5133); cytotoxic T-lymphocyte associated protein 4 (cytotoxic T-lymphocyte associated protein 4, CTLA4, CD152; NCBI gene ID: 1493); CD80 (B7-1; NCBI gene ID: 941), CD28 (NCBI gene ID: 940); nectin cell adhesion molecule 2 (nectin cell adhesion molecule 2, NECTIN2, CD112; NCBI gene ID: 5819); CD226 (DNAM-1; NCBI gene ID: 10666);Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4, NCBI Gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); Galectin 9 (galectin 9, LGALS9; NCBI Gene ID: 3965); Lymphocyte activation 3 (LAG3, CD223; NCBI Gene ID: 3902); Signaling lymphocytic activation molecule family member 1 (signaling lymphocytic activation molecule family member 1, SLAMF1, SLAM, CD150; NCBI Gene ID: 6504); Lymphocyte antigen 9 (lymphocyte antigen 9, LY9, CD229, SLAMF3; NCBI Gene ID: 4063); SLAM family member 6 (SLAM family member 6, SLAMF6, CD352; NCBI Gene ID: 114836); SLAM family member 7 (SLAM family member 7, SLAMF7, CD319; NCBI Gene ID: 57823); UL16 binding protein 1 (UL16 binding protein 1, ULBP1; NCBI Gene ID: 80329); UL16 binding protein 2 (UL16 binding protein 2, ULBP2; NCBI Gene ID: 80328); UL16 binding protein 3 (UL16 binding protein 3, ULBP3; NCBI Gene ID: 79465); Retinoic acid early transcript 1E (retinoic acid early transcript 1E, RAET1E; ULBP4, NCBI Gene ID: 135250); Retinoic acid early transcript 1G (retinoic acid early transcript 1G, RAET1G;ULBP5, NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6, NCBI Gene ID: 154064); killer cell immunoglobulin like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1; NCBI Gene ID: 3811, e.g., lirilumab (IPH-2102, IPH-4102)); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A; NCBI Gene ID: 3821); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314; NCBI Gene ID: 22914); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C; NCBI Gene ID: 3822); killer cell lectin like receptor C3 (KLRC3, NKG2E; NCBI Gene ID: 3823); killer cell lectin like receptor C4 (KLRC4, NKG2F; NCBI Gene ID: 8302); killer cell immunoglobulin like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); killer cell immunoglobulin like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803);Killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3; NCBI Gene ID: 3804); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1; NCBI Gene ID: 3824); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI Gene ID: 10219); sialic acid binding Ig like lectin 7 (SIGLEC7; NCBI Gene ID: 27036); and sialic acid binding Ig like lectin 9 (SIGLEC9; NCBI Gene ID: 27180).;

[0068] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include: CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, the following: CD27, CD70; CD40, CD40LG; inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0069] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94), killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-binding Ig-like lectin 7 (SIGLEC7); and sialic acid-binding Ig-like lectin 9 (SIGLEC9). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include the following: CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); 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.

[0070] In some embodiments, the one or more immune checkpoint inhibitors include proteinaceous (e.g., an antibody or fragment thereof, or an antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors include a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of LAG3.

[0071] Examples of inhibitors of CTLA4 that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and bispecific 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).

[0072] Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be administered simultaneously include pembrolizumab, nivolumab, semiprimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanelimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimzumab (CBT-501), LZM-009, prorgolimab (BCD-100), rodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT-502, dostarlimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), enobafolimab (KN-035), sintilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, zimberelimab (AB122), spartalizumab (PDR-001), and the compounds disclosed in International Publication No. WO 2018 / 195321, International Publication No. WO 2020 / 014643, International Publication No. WO 2019 / 160882, or International Publication No. WO 2018 / 195321, and the bispecific inhibitor FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4),MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), TAK-252 (PD-1 / OX40L), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-155 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), bintrafusp alfa (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1) are included. In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor such as CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0073] Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vibostolimab, domvanalimab, domvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0074] Examples of inhibitors of LAG3 that can be co-administered include relatlimab (LAG525).

[0075] Inhibition of regulatory T cell (Treg) activity or Treg depletion can alleviate the suppression of the anti-tumor immune response and have an anti-cancer effect. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more inhibitors of Treg activity or Treg depletion agents. Treg inhibition or depletion can enhance the effect of immune checkpoint inhibitors in cancer treatment.

[0076] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can suppress the migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor can regulate cell phenotype and induce the production of inflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI Gene ID: 1233) antagonists, and 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)).

[0077] Examples of Helios degraders that can be co-administered include, but are not limited to, I-57 (Novartis), and the compounds disclosed in International Publication No. WO2019038717, International Publication No. WO2020012334, International Publication No. WO20200117759, and International Publication No. WO2021101919.

[0078] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more Treg-depleting agents. In some embodiments, the Treg-depleting agent is an antibody. In some embodiments, the Treg-depleting antibody has antibody-dependent cell cytotoxicity (ADCC) activity. In some embodiments, the Treg-depleting antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg-depleting antibody is an antibody-drug conjugate (ADC). Exemplary targets of Treg-depleting agents include, but are not limited to, CD25 (IL2RA; NCBI Gene ID; 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18; NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID; 3604), OX-40 (CD134; NCBI Gene ID; 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).

[0079] In some embodiments, the Treg inhibitor or Treg depleting agent that can be co-administered is C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (selectin L, SELL; CD62L), integrin subunit alpha E (ITGAE; CD103), interleukin 7 receptor (IL7R; CD127), CD40 ligand (CD40 ligand, CD40LG; CD154), folate receptor alpha (folate receptor alpha, FOLR1), folate receptor beta (folate receptor beta, FOLR2), leucine rich repeat containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell co-stimulator (ICOS; CD278), lymphocyte activation 3 (LAG3; CD223), transforming growth factor beta 1 (transforming growth factor beta 1, TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2;It comprises an antibody or an antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of T cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), and combinations thereof.;

[0080] Examples of Treg-depleting anti-CCR8 antibodies that can 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 the antibodies disclosed in International Publication No. WO 2021 / 163064, International Publication No. WO 2020 / 138489, and International Publication No. WO 2021 / 152186.

[0081] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0082] Inhibition, depletion, or reprogramming of non-stimulatory 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; WO 2016 / 049641). Exemplary targets for depleting or reprogramming non-stimulatory myeloid cells include triggering receptors expressed on myeloid cells, TREM-1 (CD354, NCBI Gene ID: 54210) and TREM-2 (NCBI Gene ID: 54209). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more myeloid cell depleting or reprogramming agents such as anti-TREM-1 antibodies (e.g., PY159; antibodies disclosed in WO 2019 / 032624) or anti-TREM-2 antibodies (e.g., PY314; antibodies disclosed in WO 2019 / 118513). Agonist or activator of differentiation cluster

[0083] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an agent that targets a cluster of differentiation (CD) marker. Exemplary agents that target CD markers that can be co-administered include, but are not limited to: A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A2402 / HLA-A0201 restricted epitope peptide vaccine, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranergene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivative, AGX-73, levastinib, NMS-088, lusitanib hydrochloride, midostaurin, cediranib, dovitinib, citravatinib, tiboxanib, masitinib, regorafenib, orberenib dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asunercept (APG-101), APO-010, and International Publication Nos. WO 2016196388, WO 2016033570, WO 2015157386, WO 199203459, WO 199221766, WO 2004080462, WO 2005020921, WO 2006009755, WO 2007078034, WO 2007092403, WO 2007127317, WO 2008005877, WO 2012154480, WO 2014100620, WO 2014039714, WO 2015134536,Compounds disclosed in International Publication No. WO2017167182, International Publication No. WO2018112136, International Publication No. WO2018112140, International Publication No. WO2019155067, International Publication No. WO2020076105, International Application No. US2019063091, International Publication No. WO19173692, International Publication No. WO2016179517, International Publication No. WO2017096179, International Publication No. WO2017096182, International Publication No. WO2017096281, International Publication No. WO2018089628, International Publication No. WO2017096179, International Publication No. WO2018089628, International Publication No. WO2018195321, International Publication No. WO2020014643, International Publication No. WO2019160882, International Publication No. WO2018195321, International Publication No. WO200140307, International Publication No. WO2002092784, International Publication No. WO2007133811, International Publication No. WO2009046541, International Publication No. WO2010083253, International Publication No. WO2011076781, International Publication No. WO2013056352, International Publication No. WO2015138600, International Publication No. WO2016179399, International Publication No. WO2016205042, International Publication No. WO2017178653, International Publication No. WO2018026600, International Publication No. WO2018057669, International Publication No. WO2018107058, International Publication No. WO2018190719, International Publication No. WO2018210793, International Publication No. WO2019023347, International Publication No. WO2019042470, International Publication No. WO2019175218, International Publication No. WO2019183266, International Publication No. WO2020013170, International Publication No. WO2020068752, Cancer Discov. 2019 Jan 9(1):8, and Gariepy J., et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).

[0084] In some embodiments, drugs targeting CD markers that can be co-administered include small molecule inhibitors such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, robrutinib (FGF-401), crizotinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229, teratinib, boralanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blinixafort (TG-0054), X4P-002, mabixafort (X4P-001-IO), Plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0085] In some embodiments, drugs targeting CD markers that can be co-administered include small molecule agonists such as interleukin-2 receptor subunit gamma, eltrombopag, lintetremod, poly ICLC (NSC-301463), riboxon, apoxim, RIBOXXIM (registered trademark), MCT-465, MCT-475, G100, PEPA-10, eftozanermin alpha (ABBV-621), E-6887, motrimod, resiquimod, selgantimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitrimod, tilsotrimod, retinimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatrimod, DIMS-9054, DV-1079, refitrimod (MGN-1703), CYT-003, and PUL-042.

[0086] In some embodiments, agents targeting CD markers that can be co-administered include tafasitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), balstilimab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otrexup (TRU-016), isatuximab, felzartamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX®), TTX-030, serclidemab (RG7876), APX-005M, ABBV-428, ABBV-927, mitazalimab (JNJ-64457107), lenzilumab, alemtuzumab, emactuzumab, AMG-820, FPA-008 (cabiralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simlutec alpha (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, lerotrimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enserelumab (TSR-033), atipolizumab, BrevaRex (Mab-AR-20.5) MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, rituximab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tabalixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006, INBRX-109, GEN-1029, pepinemab (VX-15), boplaterimab (JTX-2011), GSK3359609, cobolimab (TSR-022), MBG-453, INCAGN-2390, and antibodies such as the compounds disclosed in International Publication Nos. WO 2017 / 096179, WO 2017 / 096276, WO 2017 / 096189, and WO 2018 / 089628 are included.

[0087] In some embodiments, agents targeting CD markers that can be co-administered include CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, liso-cel, lisocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), tisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL armored CART cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T cell therapy (acute lymphoblastic leukemia / non-Hodgkin lymphoma, University Hospital Heidelberg), anti-CD19 CAR T cell therapy (silent IL-6 expression, cancer, Shanghai Unicar Therapeutic Biotechnology), 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-CD3zeta-EGFRt expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecleucel-T, CART-19, tisagenlecleucel (CTL-019)), anti-CD20 CAR T cell therapy (non-Hodgkin lymphoma), MB-CART2019.1 (CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01 (NKG2D LIGAND MODULATOR), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, or cell therapies such as those disclosed in International Publication No. 2012079000 or International Publication No. 2017049166, etc. Cluster of differentiation 47 (CD47) inhibitor

[0088] In some embodiments, the antibodies and / or fusion proteins provided herein are inhibitors of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies or CD47 blockers, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), retaplimab (IBI-188), remzoparlimab (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 Nos. WO 97 / 27873, WO 99 / 40940, WO 02 / 092784, WO 05 / 044857, WO 09 / 046541, WO 10 / 070047, WO 11 / 143624, WO 12 / 170250, WO 13 / 109752, WO 13 / 119714, WO 14 / 087248, WO 15 / 191861, WO 16 / 022971, WO 16 / 023040, WO 16 / 024021, WO 16 / 081423, WO 16 / 109415, WO 16 / 141328, WO 16 / 188449, WO 17 / 027422, WO 17 / 049251, WO 17 / 053423, WO 17 / 121771, WO 17 / 194634, WO 17 / 196793, WO 17 / 215585, WO 18 / 075857, WO 18 / 075960, WO 18 / 089508, WO 18 / 095428, WO 18 / 137705,Compounds disclosed in International Publication No. WO 2018 / 233575, International Publication No. WO 2019 / 027903, International Publication No. WO 2019 / 034895, International Publication No. WO 2019 / 042119, International Publication No. WO 2019 / 042285, International Publication No. WO 2019 / 042470, International Publication No. WO 2019 / 086573, International Publication No. WO 2019 / 108733, International Publication No. WO 2019 / 138367, International Publication No. WO 2019 / 144895, International Publication No. WO 2019 / 157843, International Publication No. WO 2019 / 179366, International Publication No. WO 2019 / 184912, International Publication No. WO 2019 / 185717, International Publication No. WO 2019 / 201236, International Publication No. WO 2019 / 238012, International Publication No. WO 2019 / 241732, International Publication No. WO 2020 / 019135, International Publication No. WO 2020 / 036977, International Publication No. WO 2020 / 043188, and International Publication No. WO 2020 / 009725 are included. In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is magrolimab.,

[0089] 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 / 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. Agents targeting SIRPa

[0090] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agent that targets SIRPa (NCBI Gene ID: 140885; UniProt P78324). Examples of agents that target SIRPa include SIRPa inhibitors such as AL-008, RRx-001, and CTX-5861, and anti-SIRPa antibodies such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPa / PD-L1). Additional agents that target SIRPα that may be used are described, for example, in International Publication Nos. WO 200140307, WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO 2011076781, WO 2013056352, WO 2015138600, WO 2016179399, WO 2016205042, WO 2017178653, WO 2018026600, WO 2018057669, WO 2018107058, WO 2018190719, WO 2018210793, WO 2019023347, WO 2019042470, WO 2019175218, WO 2019183266, WO 2020013170, and WO 2020068752. FLT3R agonist

[0091] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an FLT3 agonist. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an FLT3 ligand. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with, for example, the FLT3L-Fc fusion protein described in International Publication No. WO 2020 / 263830. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with GS-3583 or CDX-301. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with GS-3583. An agonist or activator of a member of the TNF Receptor Superfamily (TNFRSF)

[0092] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID; 7293), TNFRSF5 (CD40; NCBI Gene ID; 958), TNFRSF6 (FAS, NCBI Gene ID; 355), TNFRSF7 (CD27, NCBI Gene ID; 939), TNFRSF8 (CD30, NCBI Gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID; 8795), TNFRSF10C (CD263, 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), TNFRSF16 (NGFR, CD271, NCBI Gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID; 608), TNFRSF18 (GITR, CD357, NCBI Gene ID; 8784), TNFRSF19 (NCBI Gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID; 27242), and TNFRSF25 (DR3, NCBI Gene ID; 8718).

[0093] Exemplary anti-TNFRSF4 (OX40) antibodies that can be co-administered include MEDI6469, MEDI6383, tabalixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in International Publication Nos. WO 2016 / 179517, WO 2017 / 096179, WO 2017 / 096182, WO 2017 / 096281, and WO 2018 / 089628.

[0094] Exemplary anti-TNFRSF5 (CD40) antibodies that can be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0095] In some embodiments, the anti-TNFRSF7 (CD27) antibody balstilimab (CDX-1127) is co-administered.

[0096] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0097] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0098] Exemplary anti-TNFRSF18 (GITR) antibodies that can be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication No. WO 2017 / 096179, International Publication No. WO 2017 / 096276, International Publication No. WO 2017 / 096189, and International Publication No. WO 2018 / 089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in International Publication No. WO 2017 / 096179 and WO 2018 / 089628.

[0099] Bispecific antibodies that target TNFRSF family members and can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronexumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), plamotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20). Bispecific T cell engager

[0100] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a bispecific T cell engager (e.g., one that does not have an Fc) or an anti-CD3 bispecific antibody (e.g., one that has an Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvaluxizumab (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), odronexizumab (REGN-1979; CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (heme / CD3), JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), AMG-427 (FLT3 / CD3), AMG-562 (CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-673 (CD33 / CD3), AMG-701 (BCMA / CD3), AMG-757 (DLL3 / CD3), AMG-211 (CEA / CD3), blinatumomab (CD19 / CD3), huGD2-BsAb (CD3 / GD2), ERY974 (GPC3 / CD3), GEMoab (CD3 / PSCA), RG6026 (CD20 / CD3), RG6194 (HER2 / CD3), PF-06863135 (BCMA / CD3), SAR440234 (CD3 / CDw123), JNJ-9383 (MGD-015), AMG-424 (CD38 / CD3), tidutamab (XmAb-18087 (SSTR2 / CD3)), JNJ-63709178 (CD123 / CD3), MGD-007 (CD3 / gpA33), MGD-009 (CD3 / B7H3), IMCgp100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20), tidutamab (XmAb-18087;Examples include sstR2 / CD3), katumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828; CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), GEM-333 (CD3 / CD33). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc. Exemplary bispecific T cell engagers that can be co-administered target CD3 and tumor-associated antigens described herein, such as, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7):e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35):57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403:224-230).; Bispecific and trispecific natural killer (NK) cell engagers

[0101] In some embodiments, the antibodies and / or fusion proteins provided herein are co-administered with a bispecific NK-cell engager (BiKE) or trispecific NK-cell engager (TriKE) (e.g., lacking an Fc), or a bispecific antibody (e.g., having an Fc) against an NK cell activating receptor, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (mediating antibody-dependent cellular 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 (4-1BB). Exemplary anti-CD16 bispecific antibodies, BiKEs, or TriKEs that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK-cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein, for example, these include 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, Fang, et al., Semin Immunol. (2017) 31:37-54. Inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1)

[0102] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of the MCL1 apoptosis regulator, a BCL2 family member (MCL1, TM;EAT;MCL1L, MCL1S, Mcl-1;BCL2L3, MCL1-ES, bcl2-L-3;mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include tapotclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in International Publication No. WO 2018 / 183418, International Publication No. WO 2016 / 033486, and International Publication No. WO 2017 / 147410. SHP2 inhibitor

[0103] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI Gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in International Publication No. WO 2018 / 172984 and International Publication No. WO 2017 / 211303. Hematopoietic progenitor kinase 1 (HPK1) inhibitor and degrader

[0104] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include, but are not limited to, those described in International Publication No. WO 2020 / 092621, International Publication No. WO 2018 / 183956, International Publication No. WO 2018 / 183964, International Publication No. WO 2018 / 167147, International Publication No. WO 2018 / 049152, International Publication No. WO 2020 / 092528, International Publication No. WO 2016 / 205942, International Publication No. WO 2016 / 090300, International Publication No. WO 2018 / 049214, International Publication No. WO 2018 / 049200, International Publication No. WO 2018 / 049191, International Publication No. WO 2018 / 102366, International Publication No. WO 2018 / 049152, and International Publication No. WO 2016 / 090300. Apoptosis Signal-Regulating Kinase (ASK) inhibitor

[0105] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an ASK inhibitor, e.g., an inhibitor of mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI Gene ID: 4217). Examples of ASK1 inhibitors include those described in International Publication No. WO 2011 / 008709 (Gilead Sciences) and International Publication No. WO 2013 / 112741 (Gilead Sciences). Bruton Tyrosine Kinase (BTK) inhibitor

[0106] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315. Cyclin-dependent Kinase (CDK) inhibitor

[0107] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of cyclin dependent kinase 1 (CDK1, CDC2, CDC28A, P34CDC2, NCBI Gene ID: 983); cyclin dependent kinase 2 (CDK2, CDKN2, p33(CDK2); NCBI Gene ID: 1017); cyclin dependent kinase 3 (CDK3; NCBI Gene ID: 1018); cyclin dependent kinase 4 (CDK4, CMM3, PSK-J3; NCBI Gene ID: 1019); cyclin dependent kinase 6 (CDK6, MCPH12, PLSTIRE; NCBI Gene ID: 1021); cyclin dependent kinase 7 (CDK7, CAK, CAK1, HCAK, MO15, STK1, CDKN7, p39MO15; NCBI Gene ID: 1022), or cyclin dependent kinase 9 (CDK9, TAK, C-2k, CTK1, CDC2L4, PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, samuraciclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, simucelitinib hydrate (TAK931), and TG-02. Discoidin Domain Receptor (DDR) inhibitor

[0108] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with inhibitors of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib, as well as those disclosed in International Publication No. WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), 2011-0287011 (Oncomed Pharmaceuticals), International Publication No. WO 2013 / 027802 (Chugai Pharmaceutical), and 2013 / 034933 (Imperial Innovations). Targeted E3 ligase ligand conjugate

[0109] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a target E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survivin) E3 ubiquitin ligase binding moiety, a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, a cereblon E3 ubiquitin ligase binding moiety, a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase the degradation of a targeted protein, e.g., via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting or binding moiety that targets or binds a protein described herein and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting or binding moiety that targets or binds a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and hypoxia inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of, e.g., BTK and an E3 ligase ligand or binding moiety). See, e.g., International Publication No. WO 2018 / 098280.In some embodiments, the targeted E3 ligase ligand conjugate comprises a binding moiety that targets or binds to Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4); rapidly accelerated fibrosarcoma (RAF such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or a BRD protein, and an E3 ligase ligand or binding moiety. See, for example, International Publication No. WO 2019 / 099926, International Publication No. WO 2018 / 226542, International Publication No. WO 2018 / 119448, International Publication No. WO 2018 / 223909, International Publication No. WO 2019 / 079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, for example, in International Publication No. WO 2018 / 237026, International Publication No. WO 2019 / 084026, International Publication No. WO 2019 / 084030, International Publication No. WO 2019 / 067733, International Publication No. WO 2019 / 043217, International Publication No. WO 2019 / 043208, and International Publication No. WO 2018 / 144649. Histone Deacetylase (HDAC) inhibitor

[0110] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of a 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 abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mocetinostat, panobinostat, pracinostat, xenoSTAT (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitor

[0111] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Janus Kinase (JAK) inhibitor

[0112] In some embodiments, the antibodies and / or fusion proteins provided herein are administered 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), lestaurtinib, momelotinib (CYT0387), ilginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019. Lysyl Oxidase-Like Protein (LOXL) inhibitor

[0113] In some embodiments, the antibodies and / or fusion proteins provided herein are administered 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 the antibodies described in International Publication No. WO 2009 / 017833 (Arresto Biosciences), International Publication No. WO 2009 / 035791 (Arresto Biosciences), and International Publication No. WO 2011 / 097513 (Gilead Biologics). Matrix Metalloprotease (MMP) inhibitor

[0114] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of matrix metallopeptidase (MMP), such as an inhibitor of MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), 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), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in International Publication No. WO 2012027721 (Gilead Biologics). RAS and RAS pathway inhibitors

[0115] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of the KRAS oncogene, GTPase (KRAS; aliases, NS; NS3, CFC2, RALD; K-Ras; KRAS1, KRAS2, RASK2, KI-RAS; C-K-RAS; K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B, c-Ki-ras2; NCBI Gene ID: 3845); NRAS oncogene, GTPase (NRAS; aliases, NS6; CMNS; NCMS; ALPS4, N-ras; NRAS1, NCBI Gene ID: 4893) or HRAS oncogene, GTPase (HRAS; aliases, CTLO; KRAS; HAMSV; HRAS1, KRAS2, RASH1, RASK2, Ki-Ras; p21ras, C-H-RAS; c-K-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1, NCBI Gene ID: 3265). The Ras inhibitor can inhibit Ras either at the polynucleotide level (e.g., a transcriptional inhibitor) or at the polypeptide level (e.g., a GTPase enzyme inhibitor). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, e.g., inhibits one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that can be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adagrasib (MRTX-849), ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras (G12D) selective inhibitory peptides (including KRpep-2 and KRpep-2d). Exemplary KRAS mRNA inhibitors include anti-KRAS U1 adapter, AZD-4785, siG12D-LODER™, and siG12D exosomes.Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, labotrasertib, and ulixertib. Exemplary Ras GTPase inhibitors that can be co-administered include rigosertib. Exemplary PI3K inhibitors that can be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pictilisib, inavolisib (RG6114), ASN-003. Exemplary AKT inhibitors that can be co-administered include capivasertib and GSK2141795. Exemplary PI3K / mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapitinib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), racemethyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) having a CDKN2A mutation can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Also, K-RAS and mutant N-RAS can be reduced by the irreversible inhibitor neratinib of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137. Mitogen-activated Protein Kinase (MEK) inhibitor

[0116] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include androquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib. Phosphatidylinositol 3-kinase (PI3K) inhibitor

[0117] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, Buparlisib (BKM120), BYL719 (Alpelisib), CH5132799, Copanlisib (BAY 80-6946), Duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Idelalisib (Zydelig (registered trademark)), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, Rigosertib, RP5090, RP6530, SRX3177, Taselisib, TG100115, TGR-1202 (Umbrelalisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Wortmannin, ZSTK474, and compounds described in International Publication No. WO 2005 / 113556 (ICOS), International Publication No. WO 2013 / 052699 (Gilead Calistoga), International Publication No. WO 2013 / 116562 (Gilead Calistoga), International Publication No. WO 2014 / 100765 (Gilead Calistoga), International Publication No. WO 2014 / 100767 (Gilead Calistoga), and International Publication No. WO 2014 / 201409 (Gilead Sciences). Spleen Tyrosine Kinase (SYK) inhibitor

[0118] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of spleen tyrosine kinase (SYK, p72-Syk, NCBI Gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), enzastaurin, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), those described in U.S. Patent No. 8,450,321 (Gilead Connecticut), and those described in U.S. Patent Application Publication No. 2015 / 0175616. Toll-like Receptor (TLR) agonist

[0119] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agonist of a toll-like receptor (TLR), for example, an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Examples of TLR7 agonists that can be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509 and U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), International Publication No. 2014056953 (Janssen), International Publication No. 2014076221 (Janssen), International Publication No. 2014128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (VentirxCompounds disclosed in U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics) are included. The TLR7 / TLR8 agonist that can be co-administered is NKTR-262. Examples of TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (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 Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (VentirxCompounds disclosed in US Patent Application Publication No. 20140088085 (Ventirx Pharma), US Patent Application Publication No. 20140275167 (Novira Therapeutics), and US Patent Application Publication No. 20130251673 (Novira Therapeutics) are included. Exemplary TLR9 agonists that can be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, retifanlimod, 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 rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Tyrosine-kinase Inhibitor (TKI)

[0120] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a tyrosine kinase inhibitor (TKI). The TKI can 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 include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, clenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, famitinib, L-malate, (MAC-4), tivozanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary agents that target EGFR include neratinib, tucatinib (ONT-380), tesevatinib, mobocertinib (TAK-788), DZD-9008, brivanib, abivertinib (ACEA-0010), EGF816 (nazartinib), ormutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), rifrafenib (BGB-283), bevacizumab, lazertinib (LECLAZA™), and the compounds disclosed in Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.Examples of antibodies that target EGFR include, but are not limited to, matuzumab, cetuximab sarotalocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tositumomab, depatuxizumab (ABT-806), and cetuximab. Chemotherapeutic agent

[0121] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a chemotherapeutic agent or an anti-neoplastic agent.

[0122] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic drug" (or "chemotherapy" when treating with a chemotherapeutic agent) means any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemilolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecin including the synthetic analog topotecan; bryostatin, calicheamycin; CC-1065 including the synthetic analogs adozelesin, carzelesin, and bizelesin; cryptophycins, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin including the synthetic analogs KW-2189 and CBI-TMI; ellipticine; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, cyclophosphamide, glufosfamide, ifosfamide, melphalan, novembicin, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γII and calicheamicin φI1), dynemicin including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as demopterin, methotrexate, pteropterin, and trimethoprim; purine analogs, such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiampurine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyruridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, drostanolone propionate, epitioestanol, mepitiostane, and testolactone; antiadrenal drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; radiotherapy agents such as radium-223; trichothecenes, particularly T-2 toxin, verracurin A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel;Sabizabulin (Veru-111); platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatins; Aceglutamide; Aldophosphamide Glycoside; Aminolevulinic Acid; Eniluracil; Amsacrine; Estramustine; Bisantrene; Edatrexate; Defofamine; Demecortin; Diazicoumarin; Erfolmethine; Elliptinium Acetate; Epothilone; Etoglucid; Gallium Nitrate; Hydroxyurea, Lentinan; Leucovorin; Lonidamine; Maytansinoids such as Maytansine and Ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Phenamet; Pirarubicin; Losoxantrone; Fluoropyrimidine; Folic Acid; Podophyllinic Acid, 2-Ethylhydrazide; Procarbazine; Polysaccharide K (PSK); Razoxane; Rizonixin; Schizophyllan; Spirogermanium; Tenuaazonic Acid; Trabectedin, Triazicoumarin; 2,2’,2’’-Trichlorotriethylamine; Urethane; Vincdesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacitabine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZAR®); 6-Thioguanine; Mercaptopurine; Methotrexate; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Vinorelbine (NAVELBINE®); Novantrone; Teniposide; Edatrexate; Daunomycin, Aminopterin, Xeloda; Ibandronate; CPT-11, Topoisomerase Inhibitor RFS 2000; Difluoromethylornithine (DFMO); Retinoids such as Retinoic Acid; Capecitabine; NUC-1031, FOLFOX (Folic Acid, 5-Fluorouracil, Oxaliplatin); FOLFIRI (Folic Acid, 5-Fluorouracil, Irinotecan);FOLFOXIRI (folic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folic acid, 5-fluorouracil, irinotecan, oxaliplatin), and any pharmaceutically acceptable salts, acids, or derivatives thereof are included. Such agents can be conjugated to an antibody or any targeting agent described herein to produce an antibody-drug conjugate (ADC) or a targeted drug conjugate.; Anti-hormonal agent

[0123] The definition of "chemotherapeutic agent" also includes anti-hormonal agents such as anti-estrogen agents and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgen agents, and any pharmaceutically acceptable salts, acids, or derivatives thereof that act to modulate or inhibit the hormonal action on tumors.

[0124] Examples of anti-estrogen agents and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene ((FARESTON (registered trademark)).

[0125] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE (registered trademark)), exemestane, formestane, fadrozole, vorozole (RIVISOR (registered trademark)), letrozole (FEMARA (registered trademark)), anastrozole (ARIMIDEX (registered trademark)).

[0126] Examples of anti-androgens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprorelin, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (apatocersen).

[0127] Examples of progesterone receptor antagonists include onapristone. Examples of agents targeting additional progesterone include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri-Cyclen), and levonorgestrel. Angiogenesis inhibitor

[0128] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include retinoic acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, neciparib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (curpain), sulfated chitin derivative (prepared from the shell of the Japanese spider crab), sulfated polysaccharide peptide glycan complex (sp-pg), staurosporine, proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thiaproline, 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 (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, epothilone, fumagillin, sodium aurothiomalate, d-penicillamine, β-1~anti-collagenase serum, alpha-2-antiplasmin, bisantrene, robenzarit disodium, n-2-carboxyphenyl-4-chloroanthranyl acid disodium or "CCA", thalidomide, angiogenesis-inhibiting steroid, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenesis growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be co-administered include bevacizumab, ranucizumab, faricimab, zilpascimab (ABT-165; DLL4 / VEGF), or navicixizumab (OMP-305B83; DLL4 / VEGF). Anti-fibrotic agent

[0129] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an anti-fibrotic agent. Anti-fibrotic agents that can be co-administered include compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Patent No. 4,965,288 regarding the use of inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with abnormal deposition of collagen, and U.S. Patent No. 4,997,854 regarding compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, which are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Patent No. 4,943,593, U.S. Patent No. 5,021,456, U.S. Patent No. 5,059,714, U.S. Patent No. 5,120,764, U.S. Patent No. 5,182,297, regarding compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Patent No. 5,252,608 regarding 2-(1-naphthyloxymethyl)-3-fluoroallylamine, and U.S. Patent Application No. 20040248871, which are incorporated herein by reference.

[0130] Exemplary anti-fibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically those that produce a product stabilized by resonance after binding to the carbonyl, such as the following primary amines: emireneamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitrile, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine lactone.

[0131] Other antifibrotic agents are copper chelators 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 thiolamine, in particular D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiol sulfanate, and sodium-4-mercaptobutanesulfinate trihydrate. Anti-inflammatory agent

[0132] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an anti-inflammatory agent. Exemplary 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: 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), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or inhibitors of one or more of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326).In some embodiments, the inhibitor is a dual inhibitor, e.g., a dual inhibitor of COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX.

[0133] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742) that can be co-administered include mofezolac, GLY-230, and TRK-700.

[0134] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that can be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maisosuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, filocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, luteolin, tilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that can be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that can be co-administered include pormacoxib and imrecoxib.

[0135] Examples of inhibitors of secreted phospholipase A2 and prostaglandin E synthase (PTGES, PGES; gene ID: 9536) that can be co-administered include LY3023703, GRC27864, and those described in International Publication Nos. WO2015158204, WO2013024898, WO2006063466, WO2007059610, WO2007124589, WO2010100249, WO2010034796, WO2010034797, WO2012022793, WO2012076673, WO2012076672, WO2010034798, WO2010034799, WO2012022792, WO2009103778, WO2011048004, WO2012087771, WO2012161965, WO2013118071, WO2013072825, WO2014167444, WO2009138376, WO2011023812, WO2012110860, WO2013153535, WO2009130242, WO2009146696, WO2013186692, WO2015059618, WO2016069376, WO2016069374, WO2009117985, WO2009064250, WO2009064251, WO2009082347, WO2009117987, and WO2008071173. Furthermore, metformin has been found to suppress the COX2 / PGE2 / STAT3 axis and can be co-administered. See, for example, Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0136] Examples of inhibitors of carbonic anhydrase (e.g., one or more of CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)) that can be co-administered include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and dichlorphenamide. An example of a COX-2 / CA1 / CA2 dual inhibitor that can be co-administered is CG100649.

[0137] Examples of inhibitors of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) that can be co-administered include sodium meclofenamate and zileuton.

[0138] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that can be co-administered include the compounds described in International Publication No. WO2015148954. Examples of COX-2 / SEH dual inhibitors that can be co-administered include the compounds described in International Publication No. WO2012082647. Examples of dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that can be co-administered include the compounds described in International Publication No. WO2017160861.

[0139] Examples of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) that can be co-administered include GS-4875, GS-5290, BHM-078, and those described in International Publication No. WO 2006 / 124944, International Publication No. WO 2006 / 124692, International Publication No. WO 2014 / 064215, International Publication No. WO 2018 / 005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70, Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35, Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8, Kaila, et al., Bioorg Med Chem. (2007) 15(19):6425-42, and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61. Tumor oxygenating agent

[0140] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agent that promotes or increases tumor oxygenation or reoxygenation, or prevents or reduces tumor hypoxia. Exemplary agents that can be co-administered include, for example, hypoxia inducible factor-1 alpha (HIF-1α) inhibitors such as PT-2977, PT-2385, VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165, and / or oxygen carrier proteins such as OMX-302 and HNOX proteins (e.g., heme nitric oxide and / or oxygen binding protein (HNOX)) described in International Publication No. WO 2007 / 137767, International Publication No. WO 2007 / 139791, International Publication No. WO 2014 / 107171, and International Publication No. WO 2016 / 149562. Immunotherapeutic agent

[0141] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody.Examples of immunotherapeutic agents that can be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bevacizumab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, camidanlumab, canertinib, catumaxomab, CC49, cetuximab, cixutumumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, daratumumab, daratumumab, detumomab, dinutuximab, dombalezumab, dorzigomab, durigotumab, dushigotumab, eculizumab, erlotinib, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, glembatumumab, ibritumomab, igovomab, imiglucerase, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), irinotecan, labelizumab, lexatumumab, lintuzumab, lorbovizumab, lucatumumab, mapatumumab, matuzumab, miratumumab, minretomomab, mitumomab, mogamulizumab, moxetumomab, napatumumab, nalatumumab, nesitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, oraratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatumumab, pasdotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumomab, racoltumomab, radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitumumab, simtuzumab, takatumumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tsukotuzumab, ublituximab, vertuzumab, volociximab, bortezomib, zalutumumab, zimberelimab, and 3F8.Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapeutic agents is particularly effective.

[0142] The exemplified therapeutic antibodies can be further labeled with or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y ibritumomab), or iodine 131.

[0143] In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Exemplary ADCs that can be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein.Examples of ADCs that can be co-administered include gemtuzumab, brentuximab, belantamab (e.g., belantamab mafodotin), camidanlumab (e.g., camidanlumab tesirine), trastuzumab (e.g., trastuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuximab (e.g., mirvetuximab soravtansine), depatuxizumab, batastuximab, labesuximab, radretuximab (e.g., radretuximab vedotin), loncastuximab (e.g., loncastuximab tesirine), sacituzumab (e.g., sacituzumab govitecan), datopotamab (e.g., datopotamab deruxtecan; DS-1062, Dato-DXd), patritumab (e.g., patritumab deruxtecan), rifatuximab, indatuximab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., upifitamab rilsodotin), indatuximab, miratuximab, robatupizumab (e.g., robatupizumab tesirine), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamab ravtansine), dicirumumab (e.g., dicirumumab vedotin), telisotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMGN529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130 and IMMU-140.ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0144] Exemplary therapeutic agents that can be conjugated to a drug-conjugated antibody, a fragment thereof, or an antibody mimetic (e.g., an anti-cancer agent or an anti-tumor agent) include, but are not limited to, monomethyl auristatin E, monomethyl auristatin F, calicheamicin, ansamitocin, maytansine or its analogs (e.g., mertansine / emtansine (DM1), ladansine / sorladansine (DM4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA cross-linking agent SC-DR002 (D6.5), duocarmycin, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or its dimer, duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anti-cancer agents or anti-neoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to the drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anti-cancer agent or an anti-neoplastic agent) that can be conjugated to a drug-conjugated antibody, a fragment thereof, or an antibody mimetic includes an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 includes BPI-002.

[0145] In some embodiments, the ADCs that can be co-administered include antibodies that target tumor-associated calcium signal transducer 2 (TROP-2; TACSTD2, EGP-1, NCBI Gene ID: 4070). 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), 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 FirstHospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and International Publication No. 2020016662 (Abmart), International Publication 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 Publication No. 2015098099 (Daiichi Sankyo), International Publication No. 2017002776 (Daiichi Sankyo), International Publication No. 2020130125 (Daiichi Sankyo), International Publication No. 2020240467 (Daiichi Sankyo), US Patent Application Publication No. 2021093730 (Daiichi Sankyo), US 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 (Immunomedics / Gilead), US Patent Application Publication No. 2017274093 (Immunomedics / Gilead), US Patent Application Publication No. 2018110772 (Immunomedics / Gilead), US Patent Application Publication No. 2018185351 (Immunomedics / Gilead), US Patent Application Publication No. 2018271992 (Immunomedics / Gilead), International Publication No. 2018217227 (Immunomedics / Gilead), US Patent Application Publication No. 2019248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), US Patent Application Publication No. 2021093730 (Immunomedics / Gilead), US Patent Application Publication No. 2021069343 (Immunomedics / Gilead), US Patent No. 8435539 (Immunomedics / Gilead), US Patent No. 8435529 (Immunomedics / Gilead), US 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 KelunThose described in International Publication No. WO2013068946 (Pharma), International Publication No. WO2007095749 (Roche), and International Publication No. WO2020094670 (SynAffix) may be mentioned. 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. Patent Nos. 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anti-cancer agent linked by a linker. In some embodiments, examples of the linker include those disclosed in U.S. Patent No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug moiety of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doxorubicin (DOX), epirubicin, morpholino doxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lutotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanamycin, ansamycin, and epothilone. In some embodiments, the chemotherapeutic moiety is SN-38. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with sacituzumab govitecan.

[0146] In some embodiments, the ADCs that can be co-administered include antibodies that target carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a, NCBI Gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (e.g., as described in International Publication No. WO 1996 / 011013). In some embodiments, the CEACAM1-ADC is as described in International Publication No. WO 2010 / 093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, the antibodies and / or fusion proteins provided herein are co-administered with CEACAM1-ADC IMMU-130.

[0147] In some embodiments, the ADCs that can be co-administered include antibodies that target the MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in International Publication No. WO 2006 / 094192). In some embodiments, the HLA-DR-ADC is as described in International Publication No. WO 2010 / 093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibodies and / or fusion proteins provided herein are co-administered with HLA-DR-ADC IMMU-140. Cancer gene therapy and cell therapy

[0148] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with cancer gene therapy and cell therapy. Cancer gene therapies and cell therapies include: insertion of a normal gene into cancer cells to replace a mutated or altered gene; gene modification to silence a mutated gene; genetic approaches to directly kill cancer cells; for example, infusion of immune cells designed to replace a majority of a patient's own immune system to enhance the immune response against cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells or to find and kill cancer cells; genetic approaches to modify cell activity to further alter the intrinsic immune responsiveness to cancer. Cell therapy

[0149] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with one or more cell therapies. Exemplary cell therapies include, but are not limited to, co-administration of one or more of a population of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocyte (TIL), and / or dendritic cell (DC). In some embodiments, the cell therapy involves co-administration of a population of T cell therapies, such as α / β TCR T cells, γ / δ TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, the cell therapy involves co-administration of an NK cell therapy, such as NK-92 cells. Optionally, the cell therapy can involve co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0150] In some embodiments, cell therapy involves co-administering cells that contain a chimeric antigen receptor (CAR). In such therapies, the population of immune effector cells is engineered to express the CAR, where the CAR includes a tumor antigen binding domain. In T cell therapy, the T cell receptor (TCR) is engineered to target tumor-derived peptides presented on the surface of tumor cells.

[0151] With regard to the structure of the CAR, in some embodiments, the CAR includes an antigen binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain includes a primary signaling domain, a co-stimulatory domain, or both a primary signaling domain and a co-stimulatory domain. In some embodiments, the primary signaling domain includes 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.

[0152] In some embodiments, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, CD83, a ligand that specifically binds to CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI Gene ID: 909), CD1B (NCBI Gene ID: 910), CD1C (NCBI Gene ID: 911), CD1D (NCBI Gene ID: 912), CD1E (NCBI Gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46 and NKG2D.

[0153] In some embodiments, the transmembrane domain comprises the transmembrane domain of a protein selected from the group consisting of 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, 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.

[0154] In some embodiments, the TCR or CAR antigen-binding domains or immunotherapeutic agents (e.g., monospecific or multispecific antibodies or antigen-binding fragments thereof or antibody mimetics) described herein bind to tumor-associated antigens (TAAs). In some embodiments, the tumor-associated antigens are CD19; CD123, CD22, CD30, CD171, CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33, epidermal growth factor receptor variant III (EGFRvIII); 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 (ROR1); tumor-associated glycoprotein 72 (TAG72); CD38, CD44v6, carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin;Interleukin 11 receptor alpha (IL-11Ra); Prostate stem cell antigen (PSCA); Protease serine 21 (testisin or PRSS21); Vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24, Platelet-derived growth factor receptor beta (PDGFR-β); Stage-specific embryonic antigen-4 (SSEA-4); CD20, Delta like 3 (DLL3); Folic acid receptor alpha; Receptor tyrosine protein kinase, ERBB2 (Her2 / neu); Mucin 1, cell surface bound (MUC1); Epidermal growth factor receptor (EGFR); Neural cell adhesion molecule (NCAM); Prostase; Prostatic acid phosphatase (PAP); Elongation factor 2 mutated (ELF2M); Ephrin B2; Fibroblast activation protein alpha (FAP); Insulin-like growth factor 1 receptor (IGF-I receptor), Carbonic anhydrase IX (CAIX); Proteasome (prososome, macropain) subunit, beta type, 9 (LMP2); Glycoprotein 100 (gp100); Cancer gene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); 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 beta; Tumor endothelial marker 1 (TEM1 / CD248); Tumor endothelial marker 7-related (TEM7R); Six transmembrane epithelial antigen of the prostate I (STEAP1); Claudin 6 (CLDN6); Thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); Chromosome X open reading frame 61 (CXORF61); CD97, CD179a, Anaplastic lymphoma kinase (ALK); Polysialic acid; Placenta-specific 1 (PLAC1); Hexasaccharide moiety of globoH glycosphingolipid (GloboH); Breast differentiation antigen (NY-BR-1); Uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); Adrenoceptor beta 3 (ADRB3); Pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); Lymphocyte antigen 6 complex, locus K 9 (LY6K);olfactory receptor 51E2 (ORS1E2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-1a); melanoma associated antigen 1 (MAGE-A1); ETS translocation-variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); angiopoietin binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); fos related antigen 1; tumor protein p53 (p53); p53 variant; prostasin; survivin; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or galectin 8); melanoma antigen 1 recognized by T cells (MelanA or MART1); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1;v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP1B1); CCCTC-binding factor (zinc finger protein) -like (BORIS or Brother of the Regulator of Imprinted Sites); squamous cell carcinoma antigen recognized by T-cells 3 (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89);It is selected from the group consisting of leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen presented by MHC.;

[0155] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, Tumor Necrosis Factor Receptor Superfamily Member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, Human Immunodeficiency Virus type 1 envelope glycoprotein gp120, Human Immunodeficiency Virus type 1 envelope glycoprotein gp41, HLA-DR, HM1.24. Selected from HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1(DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, α-fetoprotein (AFP), angiogenesis factor, exogenous heterologous binding molecule (ExoCBM), cancer gene product, anti-folate receptor, c-Met, carcinoembryonic antigen (CEA), 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, ribin, melanoma-associated antigen, mesothelin, mouse double minute chromosome 2 homolog (MDM2), mucin 16 (mucin 16, MUC16), mutant p53, mutant ras, necrosis antigen, cancer fetal antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenascin, P2-microglobulin, Fc receptor-like 5 (FcRL5).

[0156] In some embodiments, the antigen-binding domain binds to an epitope of a target antigen or tumor-associated antigen (TAA) that is presented by a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer / testis antigen. In some embodiments, the cancer / testis antigen is acrosin binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI Gene ID: 84519), alpha-fetoprotein (AFP; AFPD, FETA, HPAFP; NCBI Gene ID: 174); A-kinase anchoring protein 4 (AKAP4; AKAP82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI Gene ID: 8852), ATPase family AAA domain containing 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI Gene ID: 29028), kinetochore scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI Gene ID: 57082), centrosomal protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI Gene ID: 55165), cancer / testis antigen 1A (CTAG1A; ESO1, CT6.1, LAGE-2, LAGE2A, NY-ESO-1, NCBI Gene ID: 246100), cancer / testis antigen 1B (CTAG1B; CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1; NCBI Gene ID: 1485), cancer / testis antigen 2 (CTAG2; CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B;NCBI Gene ID: 30848), CCCTC-binding factor like (CTCFL; BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20.2; NCBI Gene ID: 140690), catenin alpha 2 (CTNNA2; CAP-R, CAPR, CDCBM9, CT114, CTNR; NCBI Gene ID: 1496), cancer / testis 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 associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI Gene ID: 151871), fetal and adult testis expressed 1 (FATE1; CT43, FATE; NCBI Gene ID: 89885), FMR1 neighbor (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 spermatogenic transposon silencer (MAEL; CT128, SPATA35; NCBI Gene ID: 84944), MAGE family member A1 (MAGEA1; CT1.1, MAGE1; NCBI Gene ID: 4100); MAGE family member A3 (MAGEA3; CT1.3, HIP8, HYPD, MAGE3, MAGEA6; NCBI Gene ID: 4102); MAGE family member A4 (MAGEA4; CT1.4, MAGE-41, MAGE-X2, MAGE4, MAGE4A, MAGE4B; NCBI Gene ID: 4103); MAGE family member A11 (MAGEA11; CT1.11, MAGE-11, MAGE11, MAGEA-11; NCBI Gene ID: 4110); MAGE family member C1 (MAGEC1; CT7, CT7.1; NCBI Gene ID: 9947); MAGE family member C2 (MAGEC2; CT10, HCA587, MAGEE1; NCBI Gene ID: 51438); MAGE family member D1 (MAGED1; DLXIN-1, NRAGE; NCBI Gene ID: 9500); MAGE family member D2 (MAGED2; 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2; NCBI Gene ID: 10916), kinesin family member 20B (KIF20B; CT90, KRMP1, MPHOSPH1, MPP-1, MPP1; NCBI Gene ID: 9585), NDC80 kinetochore complex NUF2 component (NUF2; CDCA1, CT106, NUF2R;NCBI Gene ID: 83540), nuclear RNA export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI Gene ID: 56001), PAS domain-containing repressor 1 (PASD1; CT63, CT64, OXTES1; NCBI Gene ID: 139135), PDZ-binding kinase (PBK; CT84, HEL164, Nori-3, SPK, TOPK; NCBI Gene ID: 55872), piwi-like RNA-mediated gene silencing 2 (PIWIL2; CT80, HILI, PIWIL1L, mili; NCBI Gene ID: 55124), preferentially expressed antigen in melanoma (PRAME; CT130, MAPE, OIP-4, OIP4; NCBI Gene ID: 23532), sperm-associated antigen 9 (SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI Gene ID: 9043), sperm protein associated with the nucleus, X-linked, family member A1 (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;Selected from the group consisting of NCBI Gene ID: 64663), SPANX family member D (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 (SSX family member 1, SSX1; CT5.1, SSRC; NCBI Gene ID: 6756), SSX family member 2 (SSX family member 2, SSX2; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI Gene ID: 6757), synaptonemal complex protein 3 (synaptonemal complex protein 3, SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI Gene ID: 50511), testis expressed 14, intercellular bridge forming factor (TEX14; CT113, SPGF23; NCBI Gene ID: 56155), transcription factor Dp family member 3 (transcription factor Dp family member 3, TFDP3; CT30, DP4, HCA661; NCBI Gene ID: 51270), serine protease 50 (serine protease 50, PRSS50; CT20, TSP50; NCBI Gene ID: 29122), TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI Gene ID: 7272) and zinc finger protein 165 (zinc finger protein 165, ZNF165; CT53, LD65, ZSCAN7; NCBI Gene ID: 7718). T cell receptors (TCRs) and TCR-like antibodies that bind to epitopes of cancer testicular antigens presented by major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer testicular antigens associated with neoplasms are, for example, Gibbs, et al., Trends Cancer 2018 Oct;4(10):701-712, and are summarized in the CT database website at cta.lncc.br / index.php. Exemplary TCRs and TCR-like antibodies that bind to epitopes of NY-ESO-1 presented by MHC are described, for example, in Stewart-Jones, et al., Proc Natl Acad Sci USA. 2009 Apr 7;106(14):5784-8, International Publication No. WO 2005 / 113595, International Publication No. WO 2006 / 031221, International Publication No. WO 2010 / 106431, International Publication No. WO 2016 / 177339, International Publication No. WO 2016 / 210365, International Publication No. WO 2017 / 044661, International Publication No. WO 2017 / 076308, International Publication No. WO 2017 / 109496, International Publication No. WO 2018 / 132739, International Publication No. WO 2019 / 084538, International Publication No. WO 2019 / 162043, International Publication No. WO 2020 / 086158, and International Publication No. WO 2020 / 086647. Exemplary TCRs and TCR-like antibodies that bind to epitopes of PRAME presented by MHC are described, for example, in International Publication No. WO 2011 / 062634, International Publication No. WO 2016 / 142783, International Publication No. WO 2016 / 191246, International Publication No. WO 2018 / 172533, International Publication No. WO 2018 / 234319, and International Publication No. WO 2019 / 109821. Exemplary TCRs and TCR-like antibodies that bind to epitopes of MAGE variants presented by MHC are described, for example, in International Publication No. WO 2007 / 032255, International Publication No. WO 2012 / 054825, International Publication No. WO 2013 / 039889, International Publication No. WO 2013 / 041865, International Publication No. WO 2014 / 118236, International Publication No. WO 2016 / 055785, International Publication No. WO 2017 / 174822, International Publication No. WO 2017 / 174823, International Publication No. WO 2017 / 174824, International Publication No. WO 2017 / 175006, International Publication No. WO 2018 / 097951, International Publication No. WO 2; It is described in WO 2018 / 225732, WO 2019 / 204683, and JP 2018-170338. Exemplary TCRs and TCR-like antibodies that bind to epitopes of alpha-fetoprotein (AFP) presented by MHC are described, for example, in WO 2015 / 011450. Exemplary TCRs and TCR-like antibodies that bind to epitopes of SSX2 presented by MHC are described, for example, in WO 2020 / 063488. Exemplary TCRs and TCR-like antibodies that bind to epitopes of KK-LC-1 (CT83) presented by MHC are described, for example, in WO 2017 / 189254.

[0157] Examples of cell therapies include Algenpantucel-L, Sipuleucel-T, (BPX-501) ribogene reclusel (U.S. Patent No. 9,089,520, WO 2016 / 100236), AU-105, ACTR-087, activated allogeneic natural killer cells (CNDO-109-AANK), MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, imirecel-T, balstilcel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentivirus-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005.

[0158] In some embodiments, one or more additional co-administered therapeutic agents can be classified, by their mechanism of action, for example, into the following groups: · Agents that target adenosine deaminase, such as pentostatin or cladribine; · Agents that target ATM, such as AZD1390; · Agents that target MET, such as servatinib, capmatinib, tepotinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; · Agents that target mitogen-activated protein kinase, such as anthraquinonol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mildabemetinib (PD-0325901), pimasertib, refametinib, or compounds disclosed in WO 2011008709, WO 2013112741, WO 2006124944, WO 2006124692, WO 2014064215, WO 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 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; · Agents that target thymidine kinase, such as aglatimagene besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk); · Agents targeting the interleukin pathway such as peginterferon decakin (AM-0010) (PEGylated IL10) and CA-4948 (IRAK4 inhibitor); · Agents targeting cytochrome P450 family members such as letrozole, anastrozole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); · Agents targeting CD73 such as CD73 inhibitors (e.g., quemriclustat (AB680)) or anti-CD73 antibodies (e.g., oleclumab); · Agents targeting DKK3 such as MTG-201; · Agents targeting EEF1A2 such as platycidin; · Agents targeting EIF4A1 such as rohinitib; · Agents targeting endoglin such as TRC105 (infliximab); · Agents targeting exopolyamine-1 such as eltanexor; · Agents targeting fatty acid amide hydrolase such as the compounds disclosed in International Publication No. 2017 / 160861; · Agents targeting heat shock protein 90 beta family member 1 such as anlotinib; · Agents targeting lactoferrin such as luxotemid (LTX-315); · Agents targeting lysyl oxidase such as the compounds disclosed in U.S. Patent Nos. 4,965,288, 4,997,854, 4,943,593, 5,021,456, 5,059,714, 5,120,764, 5,182,297, or 5,252,608 or U.S. Patent Application Publication No. 2004 / 0248871; · Agents targeting MAGE family members such as KITE-718, MAGE-A10 C796T, or MAGE-A10 TCR; · Agents targeting MDM2 such as ALRN-6924, CMG-097, Milademetan Monotosylate Monohydrate (DS-3032b), or AMG-232; · Agents targeting MDM4 such as ALRN-6924; · Agents targeting Melan-A such as MART-1 F5 TCR engineered PBMC; · Agents targeting Mesothelin such as CSG-MESO or TC-210; · Agents targeting METAP2 such as M8891 or APL-1202; · Agents targeting NLRP3 such as BMS-986299; · Agents targeting Oxoglutarate Dehydrogenase such as Devimistat (CPI-613); · Agents targeting Placenta Growth Factor such as Aflibercept; · Agents targeting SLC10A3 such as the compounds disclosed in International Publication No. WO2015148954, International Publication No. WO2012082647, or International Publication No. WO2017160861; · Agents targeting Transforming Growth Factor Alpha (TGFα) such as the compounds disclosed in International Publication No. WO2019103203; · Agents targeting Tumor Protein p53 such as Kevetrin (Actuator); · Agents targeting Vascular Endothelial Growth Factor A such as Aflibercept; · Agents targeting Vascular Endothelial Growth Factor Receptor such as Fruquintinib or MP0250; · Agents targeting VISTA such as CA-170 or HMBD-002; · Agents targeting WEE1 such as Adavosertib (AZD-1775); · Small molecule inhibitors targeting ABL1, such as imatinib, lestaurtinib, asimicinib, ponatinib (ICLUSIG (registered trademark)); · Small molecule antagonists targeting adenosine receptors, such as CPI-444, AZD-4635, preladenant, etomadenant (AB928), or PBF-509; · Small molecule inhibitors targeting arachidonic acid 5-lipoxygenase, such as sodium meclofenamate or zileuton; · Small molecule inhibitors targeting ATR serine / threonine kinase, such as BAY-937, ceralasertib (AZD6738), AZD6783, VX-803, or VX-970 (bezosertib); · Small molecule inhibitors targeting AXL receptor tyrosine kinase, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); · Small molecule inhibitors targeting Bruton tyrosine kinase (BTK), such as (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, poseclotinib (HM71224), ibrutinib (Imbruvica), M-2951 (evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebrutinib (CC-292), bequabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; · Small molecule inhibitors targeting neurotrophic receptor tyrosine kinase, such as larotrectinib, entrectinib, or selitrectinib (LOXO-195); · Small molecule inhibitors targeting ROS oncogene 1 receptor-type tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; · Small molecule inhibitors targeting the SRC proto-oncogene non-receptor tyrosine kinase, such as VAL-201, tyrphostin (KX2-391), or nilotinib maleate (NS-018); · Small molecule inhibitors targeting B-cell lymphoma 2, such as navitoclax (ABT-263), venetoclax (ABT-199, RG-7601), or AT-101 (gossypol); · Small molecule inhibitors targeting bromodomain and extra-terminal 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), mibebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829; · Small molecule inhibitors targeting carbohydrate sulfotransferase 15, such as STNM-01; · Small molecule inhibitors targeting carbonic anhydrase, such as pormacoxib, acetazolamide, or methazolamide; · Small molecule inhibitors targeting catenin beta-1, such as CWP-291 or PRI-724; · Small molecule antagonists targeting C-C motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (vicriviroc); · Small molecule antagonists targeting C-X-C motif chemokine receptors (e.g., CXCR4), blixafortide; · Small molecule inhibitors targeting cereblon, such as avadomide (CC-122), CC-92480, CC-90009, or iberdomide; · Small molecule inhibitors targeting checkpoint kinase 1, such as SRA737; · Small molecule inhibitors targeting complement components, such as Imprime PGG (Biothera Pharmaceuticals); · Small molecule inhibitors targeting C-X-C motif chemokine ligands (such as CXCL12), such as olaptesed pegol (NOX-A12); · Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; · Small molecule inhibitors targeting DEAD box helicase 5, such as supinoxin (RX-5902); · Small molecule inhibitors targeting DGKa, such as those described in, for example, International Publication No. 2021130638; · Small molecule inhibitors targeting diabro IAP-binding mitochondrial protein, such as BI-891065; · Small molecule inhibitors targeting dihydrofolate reductase, such as pralatrexate or pemetrexed disodium; · Small molecule inhibitors targeting DNA-dependent protein kinase, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastaurin; · Small molecule inhibitors targeting MARCKS, such as BIO-11006; · Small molecule inhibitors targeting RIPK1, such as GSK-3145094; · Small molecule inhibitors targeting Rho-related coiled-coil containing protein kinase, such as AT13148 or KD025; · Small molecule inhibitors targeting DNA topoisomerase, such as irinotecan, filtecanpegol, or amrubicin; · Small molecule inhibitors targeting dopamine receptor D2, such as ONC-201; · Small molecule inhibitors targeting 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 targeting fatty acid synthase such as TVB-2640 (Sagimet Biosciences); · Small molecule inhibitors targeting fibroblast growth factor receptor 2 (FGFR2) such as bemarituzumab (FPA144); · Small molecule inhibitors targeting focal adhesion kinase (FAK, PTK2) such as VS-4718, defactinib, or GSK2256098; · Small molecule inhibitors targeting folate receptor 1 such as pralatrexate; · Small molecule inhibitors targeting FOXM1 such as thiostrepton; · Small molecule inhibitors targeting galectin 3 such as verapectin (GR-MD-02); · Small molecule antagonists targeting glucocorticoid receptor such as relacorilant (CORT-125134); · Small molecule inhibitors targeting glutaminase including, but not limited to, CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES); · Small molecule inhibitors targeting GNRHR such as elagolix, relugolix, or degarelix; · Small molecule inhibitors targeting EPAS1 such as belzutifan (PT-2977 (Merck&Co.)); · Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)) such as restrictedivosidenib (AG-120), borasidenib (AG-881) (IDH1 and IDH2), IDH-305, orenasidenib (AG-221); · Small molecule inhibitors targeting lysine demethylase 1A such as CC-90011; · Small molecule inhibitors targeting MAPK-interacting serine / threonine kinase such as tomivosertib (eFT-508); · Small molecule inhibitors targeting notch receptors such as AL-101 (BMS-906024); · Small molecule inhibitors targeting polo like kinase 1 (PLK1) such as volasertib or onvansertib; · Small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP) such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazolepali (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121 (e-7499)), simmiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP 9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102; · Small molecule inhibitors targeting polycomb protein EED such as MAK683; · Small molecule inhibitors targeting hedgehog O-acyltransferase such as WNT-974; · Small molecule inhibitors targeting prostaglandin-endoperoxide synthase such as HP-5000, rofecoxib, ketorolactromethamine, bromfenac sodium, otenaproxyl (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, reformulated celecoxib (DRGT-46), AAT-076, meisoquine, lumiracoxib, meloxicam, baldecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, filocoxib, rofecoxib, luteolin, tilmacoxib, zaltoprofen, or imrecoxib; · Small molecule inhibitors targeting protein arginine N-methyltransferase such as MS203, PF-06939999, GSK3368715, or GSK3326595; · Small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720), or compounds disclosed in International Publication No. 2018 / 172984 or International Publication No. 2017 / 211303; · Small molecule antagonists targeting retinoic acid receptors, such as tamibarotene (SY-1425); · Small molecule inhibitors targeting ribosomal protein S6 kinase B1, such as MSC2363318A; · Small molecule inhibitors targeting S100 calcium-binding protein A9, such as tasquinimod; · Small molecule inhibitors targeting selectin E, such as uproleselan sodium (GMI-1271); · Small molecule inhibitors targeting SF3B1, such as H3B-8800; · Small molecule inhibitors targeting sirtuin-3, such as YC8-02; · Small molecule inhibitors targeting SMO, such as sonidegib (Odomzo (registered trademark), formerly LDE-225), visidegib (GDC-0449), glasdegib (PF-04449913), itraconazole, or patidegib, taladegib; · Small molecule antagonists targeting somatostatin receptors, such as OPS-201; · Small molecule inhibitors targeting sphingosine kinase 2, such as opaganib (Yeliva (registered trademark), ABC294640); · Small molecule inhibitors targeting STAT3, such as napabucasin (BBI-608); · Small molecule inhibitors targeting tankyrase, such as G007-LK or stenoparib (2X-121 (e-7499)); · Small molecule inhibitors targeting TGFBR1, such as galunisertib, PF-06952229; · Small molecule inhibitors targeting thymidylate synthase, such as idetrexed (ONX-0801); · Small molecule inhibitors targeting tumor protein p53 such as CMG-097; · Small molecule inhibitors targeting valosin-containing protein such as CB-5083; · Small molecule inhibitors targeting WT1 such as ombipepimut-S (DSP-7888); · Small molecule agonists targeting adenosine receptors such as namodenoson (CF102); · Small molecule agonists targeting asparaginase such as crisantasparase (Erwinase®), GRASPA (ERY-001, ERY-ASP), caraspase pegol, or pegaspargase; · Small molecule agonists targeting CCAAT / enhancer-binding protein alpha such as MTL-501; · Small molecule agonists targeting cytochrome P450 family such as mitotane; · Small molecule agonists targeting DExD / H-box helicase 58 such as RGT-100; · Small molecule agonists targeting GNRHR such as leuprolide acetate, leuprolide acetate sustained release depot (ATRIGEL), tryptorelin pamoate, or goserelin acetate; · Small molecule agonists targeting GRB2 such as prexigebersen (BP1001); · Small molecule agonists targeting NFE2L2 such as omaveloxolone (RTA-408); · Small molecule agonists targeting NOD2 such as mifamurtide (liposome); · Small molecule agonists targeting RAR-related orphan receptor gamma such as cintirorgon (LYC-55716); · Small molecule agonists targeting retinoic acid receptor (RAR) such as tretinoin; · Small molecule agonists targeting STING1, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, cyclic GAMP (cGAMP), or cyclic di-AMP; · Small molecule agonists targeting thyroid hormone receptor beta, such as levothyroxine sodium; · Small molecule agonists targeting tumor necrosis factor, such as tasnelmin; · Antisense agents targeting baculovirus IAP repeat containing 5, such as EZN-3042; · Antisense agents targeting GRB2, such as prexigebersen; · Antisense agents targeting heat shock protein 27, such as apatorasen; · Antisense agents targeting STAT3, such as danvatirsen (IONIS-STAT3-2.5Rx); · Gene therapies targeting C-C motif chemokine receptor, such as SB-728-T; · Gene therapies targeting interleukin, such as EGENE-001, tavokinogene telseplasmid, nogapendekin alpha (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55; · Antibodies targeting claudin 18, such as claudiximab; · Antibodies targeting clusterin, such as AB-16B5; · Antibodies targeting complement components, such as ravulizumab (ALXN-1210); · Antibodies targeting C-X-C motif chemokine ligand, such as BMS-986253 (HuMax-Inflam); · Antibodies targeting delta like canonical Notch ligand 4 (DLL4), such as demcizumab and navicixizumab (DLL4 / VEGF); · Antibodies targeting Eph receptor A3, such as fibatuzumab (KB-004); · Antibodies targeting epithelial cell adhesion molecule, such as oportuzumab monatox (VB4-845); · Antibodies targeting fibroblast growth factor, such as GAL-F2 and B-701 (bofatumumab); · Antibodies targeting hepatocyte growth factor, such as MP-0250; · Antibodies targeting interleukin, such as canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), siltuximab, or tocilizumab; · Antibodies targeting LRRC15, such as ABBV-085 or cusatuzumab (ARGX-110); · Antibodies targeting mesothelin, such as BMS-986148, SEL-403, or anti-MSLN-MMAE; · Antibodies targeting myostatin, such as landogrozumab; · Antibodies targeting Notch receptor, such as tarextumab; · Antibodies targeting TGFB1 (TGFb1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA 089, or the compounds disclosed in International Publication No. WO 2019 / 103203; · Vaccines targeting fms-related receptor tyrosine kinase, such as HLA-A2402 / HLA-A0201-restricted epitope peptide vaccine; · Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax); · Vaccines targeting PD-L1, such as IO-120 + IO-103 (PD-L1 / PD-L2 vaccine) or IO-103; · Vaccines targeting tumor protein p53 such as MVA-p53; · Vaccines targeting WT1 such as WT-1 analog peptide vaccine (WT1-CTL); · Cell therapies targeting baculovirus IAP repeat-containing 5 such as dendritic cell vaccine loaded with tumor lysate / MUC1 / survivin PepTivator; · Cell therapies targeting carbonic anhydrase such as DC-Ad-GMCAIX; · Cell therapies targeting C-C motif chemokine receptor such as CCR5-SBC-728-HSPC; · Cell therapies targeting folate hydrolase 1 such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN; · Cell therapies targeting GSTP1 such as CPG3-CAR (GLYCAR); · Cell therapies targeting HLA-A such as FH-MCVA2TCR or NeoTCR-P1; · Cell therapies targeting interleukin such as CST-101; · Cell therapies targeting KRAS such as anti-KRAS G12D mTCR PBL; · Cell therapies targeting MET such as anti-cMet RNA CAR T; · Cell therapies targeting MUC16 such as JCAR-020; · Cell therapies targeting PD-1 such as PD-1 knockout T cell therapy (esophageal cancer / NSCLC); · Cell therapies targeting PRAME such as BPX-701; · Cell therapies targeting transforming protein E7 such as KITE-439; · Cell therapies targeting WT1 such as WT1-CTL, ASP-7517, or JTCR-016. Exemplary combination therapies Lymphoma or leukemia combination therapies

[0159] Several chemotherapeutic agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, albosidib, amifostine trihydrate, aminocamptothecin, chinensin anticarcinogen A10, anticarcinogen AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta-aretin, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, busulfan, Campath-1H, carboplatin, carfilzomib (Kyprolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, drostatins 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium,Mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, ω-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCI-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine tartrate, SAHA (suberoylanilide hydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf (registered trademark)), venetoclax (ABT-199) are mentioned.

[0160] One improved approach is radioimmunotherapy in which monoclonal antibodies are combined with radioisotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR (registered trademark)), yttrium-90 ibritumomab tiuxetan (ZEVALIN (registered trademark)), and BEXXAR (registered trademark) in combination with CHOP.

[0161] The above-mentioned treatment method can be supplemented by or combined with stem cell transplantation or treatment. Treatment means include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibition therapy, total body irradiation, injection of stem cells, bone marrow resection with stem cell support, transplantation of peripherally blood stem cells processed in vitro, umbilical cord blood transplantation, immunoenzymatic techniques, low-LET cobalt-60 γ-ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation. Combined therapy for non-Hodgkin's lymphoma

[0162] For the treatment of non-Hodgkin's lymphoma (NHL), particularly lymphoma of B-cell origin, the use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, prednisone), all optionally including rituximab (R) etc.), radioimmunotherapy, and combinations thereof, particularly the integration of antibody therapy with chemotherapy, are included.

[0163] Examples of unconjugated monoclonal antibodies for the treatment of NHL / B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0164] Examples of experimental antibody drugs used for the treatment of NHL / B-cell cancer include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, miratuzumab, and bevacizumab.

[0165] Examples of standard regimens for chemotherapy of NHL / B cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

[0166] Examples of radioimmunotherapy for NHL / B cell cancer include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®). Combination therapy for mantle cell lymphoma

[0167] Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can be supplemented with the monoclonal antibody rituximab to form R-CHOP, hyperCVAD-R, and R-FCM for combination therapy. Any of the above-mentioned therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0168] An alternative approach to treating MCL is immunotherapy. One type of immunotherapy uses monoclonal antibodies such as rituximab. Another uses cancer vaccines such as GTOP-99 based on the genetic structure of an individual patient's tumor.

[0169] An improved approach to treating MCL is radioimmunotherapy in which monoclonal antibodies are combined with radioisotope particles such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential treatment with CHOP.

[0170] Other approaches for treating MCL include the combined use of autologous stem cell transplantation and high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administration of anti-angiogenic agents such as thalidomide especially in combination with rituximab.

[0171] Another treatment approach is to administer, in combination with other chemotherapeutic agents, a drug that causes degradation of Bcl-2 protein and increases the sensitivity of cancer cells to chemotherapy such as oblimersen.

[0172] A further treatment approach involves the administration of mTOR inhibitors, which can cause inhibition of cell proliferation and even cell death. Non-limiting examples are sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxilaprevir, GSK-2126458, and the combination of temsirolimus with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0173] Other recent treatments for MCL have been disclosed. Such examples include flavopiridol, palbociclib (PD0332991), R-roscovitine (seliciclib, CYC202), styryl sulfone, obatoclax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG). Waldenström's macroglobulinemia combination therapy

[0174] Waldenstrom's macroglobulinemiaTherapeutic agents used for treating macroglobulinemia (WM) include aldesleukin, alemtuzumab, albosidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta-aretin, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, drostatins 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin alpha, epratuzumab (hLL2 - anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (e.g., tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, urolupumab, bertuzumab, vincristine sulfate, vinorelbine tartrate, vorinostat, WT1Examples include 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0175] Examples of treatment means used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibition therapy, total body irradiation, injection of stem cells, marrow ablation with stem cell support, transplantation of peripherally blood stem cells treated in vitro, cord blood transplantation, immunoenzymatic techniques, low LET cobalt-60 γ-ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation. Combination therapy for diffuse large B-cell lymphoma (DLBCL)

[0176] Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof such as ICE and RICE. In some embodiments, therapeutic agents used to treat DLBCL include rituximab (Rituxan®), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin®), prednisone, bendamustine, ifosfamide, carboplatin, etoposide, ibrutinib, polatuzumab vedotin piiq, bendamustine, copanlisib, lenalidomide (Revlimid®), dexamethasone, cytarabine, cisplatin, Yescarta®, Kymriah®, Polivy® (polatuzumab vedotin), BR (bendamustine (Treanda®), gemcitabine, oxaliplatin, oxaliplatin, tafasitamab, polatuzumab, cyclophosphamide, or a combination thereof.In some embodiments, the therapeutic agents used to treat DLBCL include R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone), rituximab + bendamustine, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), rituximab + lenalomide, R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara C) + cisplatin), Polivy® (polatuzumab vedotin) + BR (bendamustine (Treanda®) and rituximab (Rituxan®)), R-GemOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafasitamab + lenalidomide), tafasitamab + Revlimid®, polatuzumab + bendamustine, gemcitabine + oxaliplatin, R-EPOCH (rituximab + etoposide phosphate + prednisone + vincristine sulfate (Oncovin®) + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin)), or CHOP (cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone). In some embodiments, the therapeutic agents used to treat DLBCL include tafasitamab, glofitamab, epcoritamab, Lonca-T (loncastuximab tesirine), Debio-1562, polatuzumab, Yescarta, JCAR017, ADCT-402, brentuximab vedotin, MT-3724, odronexizumab, Auto-03, Allo-501A, or TAK-007. Combined therapy for chronic lymphocytic leukemia

[0177] Therapeutic agents used for treating chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, numerous agents listed for WM, and combination chemotherapy and chemoimmunotherapy including common combination regimens such as CVP, R-CVP, ICE, R-ICE, FCR, and FR. Combination therapy for High Risk Myelodysplastic Syndrome (HR MDS)

[0178] Therapeutic agents used for treating HR MDS include azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, daunorubicin, and combinations thereof. In some embodiments, combinations include cytarabine + daunorubicin and cytarabine + idarubicin. In some embodiments, therapeutic agents used for treating HR MDS include pevonedistat, venetoclax, sabatolimab, guadecitabine, rigosertib,ivosidenib, enasidenib, selinexor, BGB324, DSP-7888, or SNS-301. Combination therapy for Low Risk Myelodysplastic Syndrome (LR MDS)

[0179] Therapeutic agents used for treating LR MDS include lenalidomide, azacitidine, and combinations thereof. In some embodiments, therapeutic agents used for treating LR MDS include roxadustat, luspatercept, imetelstat, LB-100, or rigosertib. Combination therapy for Acute Myeloid Leukemia (AML)

[0180] Therapeutic agents used for treating AML include cytarabine, idarubicin, daunorubicin, midostaurin (Rydapt®), venetoclax, azacitidine, ivosidenib, gilteritinib, enasidenib, low-dose cytarabine (LoDAC), mitozantrone, fludarabine, granulocyte colony-stimulating factor, idarubicin, gilteritinib (Xospata®), enasidenib (Idhifa®), ivosidenib (Tibsovo®), decitabine (Dacogen®), mitozantrone, etoposide, gemtuzumab ozogamicin (Mylotarg®), glasdegib (Daurismo®), and combinations thereof. In some embodiments, therapeutic agents used for treating AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte-colony stimulating factor (G-CSF), and idarubicin), cytarabine + idarubicin, cytarabine + daunorubicin + midostaurin, venetoclax + azacitidine, cytarabine + daunorubicin, or MEC (mitozantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents used for treating AML include pevonedistat, venetoclax, sabatolimab, eprenetapopt, or lenzopalrimab. Combination therapy for multiple myeloma (MM)

[0181] Therapeutic agents used to treat MM include lenalidomide, bortezomib, dexamethasone, daratumumab (Darzalex®), pomalidomide, cyclophosphamide, carfilzomib (Kyprolis®), elotuzumab (Empliciti), and combinations thereof. In some embodiments, the therapeutic agent used to treat MM is RVS (lenalidomide + bortezomib + dexamethasone), RevDex (lenalidomide + dexamethasone), CYBORD (cyclophosphamide + bortezomib + dexamethasone), Vel / Dex (bortezomib + dexamethasone), or PomDex (pomalidomide + low-dose dexamethasone). In some embodiments, the therapeutic agents used to treat MM include JCARH125, TAK-573, belantamab-m, ide-cel (CAR-T). Combination therapy for breast cancer

[0182] Therapeutic agents used for treating breast cancer include albumin-bound paclitaxel, anastrozole, atezolizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used for treating breast cancer (e.g., HR+ / - / HER2+ / -) include trastuzumab (Herceptin®), pertuzumab (Perjeta®), docetaxel, carboplatin, palbociclib (Ibrance®), letrozole, trastuzumab emtansine (Kadcyla®), fulvestrant (Faslodex®), olaparib (Lynparza®), eribulin, tucatinib, capecitabine, lapatinib, everolimus (Afinitor®), exemestane, eribulin mesylate (Halaven®), and combinations thereof. In some embodiments, therapeutic agents used for treating breast cancer include trastuzumab + pertuzumab + docetaxel, trastuzumab + pertuzumab + docetaxel + carboplatin, palbociclib + letrozole, tucatinib + capecitabine, lapatinib + capecitabine, palbociclib + fulvestrant, or everolimus + exemestane. In some embodiments, therapeutic agents used for treating breast cancer include trastuzumab deruxtecan (Enhertu®), datopotamab deruxtecan, DS-1062, enfortumab vedotin (Padcev®), balixafortide, elacestrant, or combinations thereof. In some embodiments, therapeutic agents used for treating breast cancer include balixafortide + eribulin. Combination Therapy for Triple Negative Breast Cancer (TNBC)

[0183] Therapeutic agents used to treat TNBC include atezolizumab, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, therapeutic agents used to treat TNBC include olaparib (Lynparza®), atezolizumab (Tecentriq®), paclitaxel (Abraxane®), eribulin, bevacizumab (Avastin®), carboplatin, gemcitabine, eribulin mesylate (Halaven®), sacituzumab govitecan (Trodelvy®), pembrolizumab (Keytruda®), cisplatin, doxorubicin, epirubicin, or combinations thereof. In some embodiments, therapeutic agents for treating TNBC include atezolizumab + paclitaxel, bevacizumab + paclitaxel, carboplatin + paclitaxel, carboplatin + gemcitabine, or paclitaxel + gemcitabine. In some embodiments, therapeutic agents used to treat TNBC include eliaspargase, capivasertib, alpelisib, rucaparib + nivolumab, atezolumab + paclitaxel + gemcitabine + capecitabine + carboplatin, ipatasertib + paclitaxel, ladiratuzumab vedotin + pembrolizumab, durvalumab + DS-8201a, trilaciclib + gemcitabine + carboplatin. In some embodiments, therapeutic agents used to treat TNBC include trastuzumab deruxtecan (Enhertu®, datopotamab deruxtecan (DS-1062), enfortumab vedotin (Padcev®), balixafortide, adagloxad simolenin, neripeptimut (NeuVax®), nivolumab (Opdivo®), rucaparib, tripalimumab (Tuoyi®), camrelizumab, capivasertib, durvalumab (Imfinzi®), and combinations thereof.In some embodiments, therapeutic agents used to treat TNBC include nivolumab + rucaparib, bevacizumab (Avastin®) + chemotherapy, toripalimab + paclitaxel, toripalimab + albumin-bound paclitaxel, camrelizumab + chemotherapy, pembrolizumab + chemotherapy, balixafortide + eribulin, durvalumab + trastuzumab deruxtecan, durvalumab + paclitaxel, or capivasertib + paclitaxel. Combination therapy for bladder cancer

[0184] Therapeutic agents used to treat bladder cancer include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), erdafitinib, eganelisib, lenvatinib, bempegaldesleukin (NKTR-214), or combinations thereof. In some embodiments, therapeutic agents used to treat bladder cancer include eganelisib + nivolumab, pembrolizumab (Keytruda®) + enfortumab vedotin (Padcev®), nivolumab + ipilimumab, durvalumab + tremelimumab, lenvatinib + pembrolizumab, enfortumab vedotin (Padcev®) + pembrolizumab, and bempegaldesleukin + nivolumab. Combination therapy for colorectal cancer (CRC)

[0185] Therapeutic agents used for treating CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. In some embodiments, the therapeutic agents used for treating CRC include bevacizumab (Avastin®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda®), FOLFIRI, regorafenib (Stivarga®), aflibercept (Zaltrap®), cetuximab (Erbitux®), Lonsurf (Orcantas®), XELOX, FOLFOXIRI, or a combination thereof. In some embodiments, the therapeutic agents used for treating CRC include bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, the therapeutic agents used for treating CRC are binimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabucasin + FOLFIRI + bevacizumab, nivolumab + ipilimumab. Combined Therapy for Esophageal and Esophagogastric Junction Cancers

[0186] Therapeutic agents used for treating esophageal cancer and gastroesophageal junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. In some embodiments, therapeutic agents used for treating gastroesophageal junction cancer (GEJ) include Herceptin, cisplatin, 5-FU, ramicurimab, or paclitaxel. In some embodiments, therapeutic agents used for treating GEJ cancer include ALX-148, AO-176, or IBI-188. Combination therapy for gastric cancer

[0187] Therapeutic agents used for treating gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. Combination therapy for head and neck cancer

[0188] Therapeutic agents used for treating head and neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0189] Therapeutic agents used to treat head and neck squamous cell carcinoma (HNSCC) include pembrolizumab, carboplatin, 5-FU, docetaxel, cetuximab (Erbitux®), cisplatin, nivolumab (Opdivo®), and combinations thereof. In some embodiments, therapeutic agents used to treat HNSCC include pembrolizumab + carboplatin + 5-FU, cetuximab + cisplatin + 5-FU, cetuximab + carboplatin + 5-FU, cisplatin + 5-FU, and carboplatin + 5-FU. In some embodiments, therapeutic agents used to treat HNSCC include durvalumab, durvalumab + tremelimumab, nivolumab + ipilimumab, lobarolimumab, pembrolizumab, pembrolizumab + epacadostat, GSK3359609 + pembrolizumab, lenvatinib + pembrolizumab, retifanlimab, retifanlimab + enobituzumab, ADU-S100 + pembrolizumab, epacadostat + nivolumab + ipilimumab / rilimumab. Combination therapy for non-small cell lung cancer

[0190] Therapeutic agents used for treating non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used for treating NSCLC include alectinib (Alecensa®), dabrafenib (Tafinlar®), trametinib (Mekinist®), osimertinib (Tagrisso®), erlotinib (Tarceva®), crizotinib (Xalkori®), pembrolizumab (Keytruda®), carboplatin, pemetrexed (Alimta®), nab-paclitaxel (Abraxane®), ramucirumab (Cyramza®), docetaxel, bevacizumab (Avastin®), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif®), nivolumab (Opdivo®), gefitinib (Iressa®), and combinations thereof. In some embodiments, therapeutic agents used for treating NSCLC include dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + nab-paclitaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed + carboplatin, cisplatin + pemetrexed, bevacizumab + carboplatin + nab-paclitaxel, cisplatin + gemzar, nivolumab + docetaxel, carboplatin + pemetrexed, carboplatin + nab-paclitaxel, or pemetrexed + cisplatin + carboplatin.In some embodiments, the therapeutic agents used for NSCLC include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), enfortumab vedotin (Padcev®), durvalumab, canakinumab, semipramab, nogapendekin alpha, avelumab, tilagolumab, domvanalimab, vibostrimab, osiprelimab, or combinations thereof. In some embodiments, the therapeutic agents used for treating NSCLC include datopotamab deruxtecan + pembrolizumab, datopotamab deruxtecan + durvalumab, durvalumab + tremelimumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, nogapendekin alpha (N-803) + pembrolizumab, tilagolumab + atezolizumab, vibostrimab + pembrolizumab, or osiprelimab + tislelizumab. Small cell lung cancer combination therapy

[0191] The therapeutic agents used for treating small cell lung cancer (SCLC) include atezolizumab, bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combinations thereof. In some embodiments, the therapeutic agents used for treating SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivolumab, durvalumab, trilaciclib, or combinations thereof. In some embodiments, the therapeutic agents used for treating SCLC include atezolizumab + carboplatin + etoposide, atezolizumab + carboplatin, atezolizumab + etoposide, or carboplatin + paclitaxel. Ovarian cancer combination therapy

[0192] Therapeutic agents used for treating ovarian cancer include 5-fluorouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof. Combination therapy for pancreatic cancer

[0193] Therapeutic agents used for treating pancreatic cancer include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel (Abraxane (registered trademark)), FOLFIRINOX, and combinations thereof. In some embodiments, therapeutic agents used for treating pancreatic cancer include 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, leucovorin + nanoliposomal irinotecan, and gemcitabine + nab-paclitaxel. Combination therapy for prostate cancer

[0194] Therapeutic agents used for treating prostate cancer include enzalutamide (Xtandi®), leuprorelin, trifluridine, tipiracil (Lonsurf), cabazitaxel, prednisone, abiraterone (Zytiga®), docetaxel, mitozantrone, bicalutamide, LHRH, flutamide, ADT, sabizabulin (Veru-111), and combinations thereof. In some embodiments, therapeutic agents used for treating prostate cancer include enzalutamide + leuprorelin, trifluridine + tipiracil (Lonsurf), cabazitaxel + prednisone, abiraterone + prednisone, docetaxel + prednisone, mitoxantrone + prednisone, bicalutamide + LHRH, flutamide + LHRH, leuprorelin + flutamide, and abiraterone + prednisone + ADT. Additional Exemplified Combinations Therapy

[0195] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more therapeutic agents selected from PI3K inhibitors, Trop-2 binders, CD47 antagonists, SIRPα antagonists, FLT3R agonists, PD-1 antagonists, PD-L1 antagonists, MCL1 inhibitors, CCR8 binders, HPK1 antagonists, DGKa inhibitors, CISH inhibitors, PARP-7 inhibitors, Cbl-b inhibitors, KRAS inhibitors (e.g., KRAS G12C or G12D inhibitors), KRAS degraders, beta-catenin degraders, Helios degraders, CD73 inhibitors, adenosine receptor antagonists, TIGIT antagonists, TREM1 binders, TREM2 binders, CD137 agonists, GITR binders, OX40 binders, and CAR-T cell therapy.

[0196] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with one or more therapeutic agents selected from PI3Kd inhibitors (e.g., idealisib), anti-Trop-2 antibody-drug conjugates (e.g., sacituzumab govitecan, datopotamab deruxtecan (DS-1062)), anti-CD47 antibodies or CD47-blocking agents (e.g., magrolimab, DSP-107, AO-176, ALX-148, leptopilimab (IBI-188), remzoparlimab, TTI-621, TTI-622), anti-SIRPα antibodies (e.g., GS-0189), FLT3L-Fc fusion proteins (e.g., GS-3583), anti-PD-1 antibodies (pembrolizumab, nivolumab, zimberelimab), small molecule PD-L1 inhibitors (e.g., GS-4224), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab), small molecule MCL1 inhibitors (e.g., GS-9716), small molecule HPK1 inhibitors (e.g., GS-6451), HPK1 degraders (PROTACs, e.g., ARV-766), small molecule DGKa inhibitors, small molecule CD73 inhibitors (e.g., quemirastat (AB680)), anti-CD73 antibodies (e.g., oleclumab), dual A 2a / A 2b adenosine receptor antagonists (e.g., etrumadenant (AB928)), anti-TIGIT antibodies (e.g., tiragolumab, vibostolimab, domvanalimab, AB308), anti-TREM1 antibodies (e.g., PY159), anti-TREM2 antibodies (e.g., PY314), CD137 agonists (e.g., AGEN-2373), GITR / OX40 binders (e.g., AGEN-1223), and CAR-T cell therapies (e.g., axicabtagene ciloleucel, brexucabtagene autoleucel, tisagenlecleucel).

[0197] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more therapeutic agents selected from idealisib, sacituzumab govitecan, marizomib, GS-0189, GS-3583, zimberelimab, GS-4224, GS-9716, GS-6451, chemiluminescent stat (AB680), etramadenant (AB928), donbanalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicabtagene ciloleucel, and brexucabtagene autoleucel. III. Abbreviations. Certain abbreviations and acronyms are used when describing the details of the experiments. Most of these are understood by those skilled in the art, but Table 1 includes a list of some of these abbreviations and acronyms.

Table 1

[0198] The compounds of the present disclosure can be prepared by various methods. For example, Schemes 1-8 show representative syntheses of the compounds of the present disclosure.

Chemical Structure

[0199] Representative synthetic scheme 1 shows the general synthesis of the compounds of the present disclosure. This method is compatible with a wide variety of functionalities. In representative synthesis 1, a suitably substituted chloropyrimidine, chloropyridazine, or chloropyridine (or the corresponding bromo or iodo compound) is combined with a suitably substituted pyrrolidine in a suitable solvent system (e.g., tert-butanol, DMAc, dioxane, etc.) in the presence of a palladium catalyst (e.g., RuPhos Pd G3, Pd(OAc)2 + XantPhos, etc.) and a base (e.g., Cs2CO3, K3PO4, etc.) at a high temperature (e.g., in the range of about 80 - 120 °C). Subsequently, the resulting suitably substituted 2,4-dimethoxypyrimidine can be treated with an acid (e.g., hydrochloric acid) in a suitable solvent system (e.g., water + methanol, ethanol, etc.) at a high temperature (e.g., in the range of about 60 - 80 °C).

Chemical Structure

[0200] Representative synthetic scheme 2 shows the general synthesis of the compounds of the present disclosure. This method is compatible with a wide variety of functionalities. In representative synthesis 2, a suitably substituted chloropyrimidine, chloropyridazine, or chloropyridine is combined with (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid in a suitable solvent system (e.g., water + dioxane, MeTHF, etc.) in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, Xphos Pd G3, etc.) and a base (e.g., Cs2CO3, K3PO4, etc.) at a high temperature (e.g., in the range of about 70 - 120 °C). Subsequently, the resulting suitably substituted 2,4-di-tert-butoxypyrimidine-containing compound can be treated with an acid (e.g., trifluoroacetic acid) in a suitable solvent system (e.g., DCM, dioxane, etc.).

Chemical Structure

[0201] Representative synthetic scheme 3 shows the general synthesis of the compounds of the present disclosure. This method is compatible with a wide variety of functionalities. In representative synthesis 3, a suitably substituted chloropyrimidine is combined with a suitably substituted pyrrolidine in a suitable solvent system (e.g., NMP, etc.) in the presence of a base (e.g., diisopropylethylamine, etc.) at a high temperature (in the range of about 90 - 110 °C). Subsequently, the resulting suitably substituted 2,4 - di - tert - butoxypyrimidine - containing compound can be treated with an acid (e.g., trifluoroacetic acid) in a suitable solvent system (e.g., DCM, NMP, etc.).

Chemical formula

[0202] Representative synthetic scheme 4 shows the general synthesis of the compounds of the embodiments. This method is compatible with a wide variety of functionalities. In representative synthetic scheme 4, a suitably substituted pyrrolidine alcohol is combined with a suitably substituted aryl bromide, heteroaryl, or bicycloheteroaryl (or the corresponding chloro or iodo compound) in a suitable solvent system (e.g., toluene, dioxane, etc.) in the presence of a palladium or copper catalyst (e.g., Pd(OAc)2 + XPhos Pd G2, CuI + 3,4,7,8 - tetramethyl - 1,10 - phenanthroline, etc.) and a base (e.g., Cs2CO3) at a high temperature (e.g., in the range of about 80 - 120 °C).

Chemical formula

[0203] Representative synthetic scheme 5 shows the general synthesis of the compounds of the embodiments. This method is compatible with a wide variety of functionalities. In representative synthetic scheme 5, a suitably substituted pyrrolidine alcohol is combined with a suitably substituted aryl chloride, heteroaryl, or bicycloheteroaryl (or the corresponding fluoro or OCF3 compound) in a suitable solvent system (e.g., DMF, etc.) in the presence of a base (e.g., NaH, etc.). [Chemistry]

[0204] Representative synthetic scheme 6 shows the general synthesis of the compounds of the embodiments. This method is compatible with a wide variety of functionalities. In representative synthetic scheme 6, a suitably substituted chloropyrimidine, chloropyridazine, or chloropyridine (or the corresponding bromo compound) is combined with a substituted pyrrolidine in a suitable solvent system (e.g., DMF, MeCN, NMP, etc.) in the presence of a base (e.g., diisopropylethylamine, etc.) at a high temperature (in the range of about 60 - 100 °C). Subsequently, the resulting suitably substituted chloropyrimidine, chloropyridazine, or chloropyridine is combined with (2,4 - dimethoxypyrimidin - 5 - yl)boronic acid in a suitable solvent system (e.g., water + dioxane, MeTHF, etc.) in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, Xphos Pd G3, etc.) and a base (e.g., Cs2CO3, K3PO4, etc.) at a high temperature (e.g., in the range of about 70 - 120 °C). [Chemistry]

[0205] Representative synthetic scheme 7 shows the general synthesis of the compounds of the embodiments. This method is compatible with a wide variety of functionalities. In representative synthetic scheme 7, a suitably substituted chloropyrimidine, chloropyridazine, or chloropyridine is combined with (2,4 - dimethoxypyrimidin - 5 - yl)boronic acid in a suitable solvent system (e.g., water + dioxane, MeTHF, etc.) in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, Xphos Pd G3, etc.) and a base (e.g., Cs2CO3, K3PO4, etc.) at a high temperature (e.g., in the range of about 70 - 120 °C). [Chemistry]

[0206] Representative synthetic scheme 8 shows the general synthesis of the compounds of the embodiments. This method is compatible with a wide variety of functionalities. In representative synthetic scheme 8, a suitably substituted aryl bromide, heteroaryl, or bicycloheteroaryl (or the corresponding chloro or iodo compound) is combined with tert-butyl (S)-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate in a suitable solvent system (e.g., toluene, etc.) in the presence of a copper catalyst (e.g., CuI + 3,4,7,8-tetramethyl-1,10-phenanthroline, etc.) and a base (e.g., Cs2CO3, etc.) at elevated temperature (e.g., in the range of about 90 - 135 °C). Subsequently, the resulting suitably substituted pyrrolidine can be treated with an acid (e.g., hydrochloric acid, trifluoroacetic acid, etc.) in a suitable solvent system (e.g., dioxane + DCM, DCM, etc.). Preparation of Intermediates

[0207] Preparation of Intermediate A, 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinonitrile

Chemical Structure

[0208] 4,6-Dichloropicolinonitrile (346 mg, 2.0 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (368 mg, 2.0 mmol, 1 equiv), Pd(dppf)Cl2 DCM (33 mg, 0.04 mmol, 0.02 equiv), and Cs2CO3 (1.63 g, 5 mmol, 2.5 equiv) were added to dioxane (4 mL) and water (4 mL). The mixture was purged with Ar and heated to 70 °C. After 4 h, the mixture was filtered through Celite, diluted with EtOAc (30 mL), washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (0–25% MeOH / DCM) to afford 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinonitrile (387 mg, 70%) as a yellowish-brown solid, which is a 5:1 mixture of isomers. ES / MS m / z: 277.06 [M+H].

[0209] Preparation of Intermediate B, 5-(4-chloro-6-methylpyridin-2-yl)-2,4-dimethoxypyrimidine

Chemical formula

[0210] 4,6-Dichloropicolinonitrile was replaced with 2,4-dichloro-6-methylpyridine, and 5-(4-chloro-6-methylpyridin-2-yl)-2,4-dimethoxypyrimidine was synthesized in the same manner as Intermediate A. ES / MS m / z: 266.00 (M+1). Preparation of Intermediate C, 5-(4-chloro-6-methoxypyridin-2-yl)-2,4-dimethoxypyrimidine

Chemical formula

[0211] 4,6-dichloropicolinonitrile was replaced with 2,4-dichloro-6-methoxypyridine, and 5-(4-chloro-6-methoxypyridin-2-yl)-2,4-dimethoxypyrimidine was synthesized in the same manner as Intermediate A. ES / MS m / z: 266.00 (M+1).

[0212] Preparation of Intermediate D, 5-(4-chloro-6-(trifluoromethyl)pyridin-2-yl)-2,4-dimethoxypyrimidine

Chemical formula

[0213] 4,6-dichloropicolinonitrile was replaced with 2,4-dichloro-6-(trifluoromethyl)pyridine, and 5-(4-chloro-6-(trifluoromethyl)pyridin-2-yl)-2,4-dimethoxypyrimidine was synthesized in the same manner as Intermediate A. ES / MS m / z: 320.00 (M+1).

[0214] Preparation of Intermediate E, 2’,4’-di-tert-butoxy-6-chloro-2-ethyl-4,5’-bipyrimidine

Chemical formula

[0215] 4,6-dichloropicolinonitrile was replaced with 4,6-dichloro-2-ethyl-pyrimidine, and (2,4-dimethoxypyrimidin-5-yl)boronic acid was replaced with (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid, and 2’,4’-di-tert-butoxy-6-chloro-2-ethyl-4,5’-bipyrimidine was synthesized in the same manner as Intermediate A. ES / MS m / z: 252.9 [M-2tBu+1].

[0216] Preparation of Intermediate F, 2’,4’-di-tert-butoxy-6-chloro-2-cyclopropyl-4,5’-bipyrimidine

Chemical formula

[0217] Replace 4,6-dichloropicolinonitrile with 4,6-dichloro-2-cyclopropylpyrimidine and replace (2,4-dimethoxypyrimidin-5-yl)boronic acid with (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid, and synthesize 2’,4’-di-tert-butoxy-6-chloro-2-cyclopropyl-4,5’-bipyrimidine in the same manner as Intermediate A. ES / MS m / z: 264.93 [M - 2tBu + 1]. Preparation of Intermediate G, 2’,4’-di-tert-butoxy-6-chloro-2-(difluoromethyl)-4,5’-bipyrimidine

Chem.

[0218] Replace 4,6-dichloro-2-methylpyrimidine with 4,6-dichloro-2-(difluoromethyl)pyrimidine and replace (2,4-dimethoxypyrimidin-5-yl)boronic acid with (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid, and synthesize 2’,4’-di-tert-butoxy-6-chloro-2-(difluoromethyl)-4,5’-bipyrimidine in the same manner as Intermediate H. ES / MS m / z: 274.90 [M - 2tBu + 1].

[0219] Preparation of Intermediate H, 6-chloro-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chem.

[0220] To a solution of 4,6-dichloro-2-methylpyrimidine (5.0 g, 30.6 mmol, 1.0 eq) in dioxane (50 mL) and H2O (25 mL) were added (2,4-dimethoxypyrimidin-5-yl)boronic acid (5.6 g, 30.6 mmol, 1.0 eq), Pd(dppf)Cl2-DCM (2.5 g, 3.0 mmol, 0.1 eq), and cesium carbonate (29.9 g, 92.0 mmol, 3.0 eq). The reaction mixture was purged and degassed three times with nitrogen and stirred at 80 °C for 12 h. Then, the reaction was diluted with H2O (60 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (0 - 50% ethyl acetate / petroleum ether) to afford 6-chloro-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine (4.7 g, 17.6 mmol, 57.4% yield) as a white solid. ES / MS m / z: 267.1 [M+H]. 1 H NMR (400Mhz, chloroform-d) δ 9.26 (s, 1H), 7.83 (s, 1H), 4.16 (s, 3H), 4.09 (s, 3H), 2.75 (s, 3H). Preparation of Intermediate I, 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0221] To a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (4 g, 20.2 mmol, 1 equiv) in DMF (10 mL) at 0 °C was added Cs2CO3 (6.58 g, 20.2 mmol, 1 equiv), followed by dropwise addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.39 g, 23.2 mmol, 1.15 equiv). The reaction mixture was slowly warmed to room temperature. Then, after 16 h, the reaction mixture was diluted with EtOAc (100 mL), washed with brine (5 × 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (0 - 50% EtOAc / hexane), and the first eluted peak was 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine (3.63 g, 64%) as a pale yellow solid. ES / MS m / z: 279.90 [M+H]. Preparation of Intermediate J, 6-chloro-1-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,5-c]pyridine

Chemical formula

[0222] To a solution of 6-chloropyridine-3,4-diamine (800 mg, 4.4 mmol, 1 equiv HCl) in HCl (10 mL) was added NaNO2 (337.2 mg, 4.9 mmol, 1.1 equiv) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (20 mL) and neutralized with K2CO3 at 0 - 10 °C until pH = 9, then the mixture was filtered and the resulting solid was dried under vacuum to give 6-chloro-1H-1,2,4-triazolo[4,5-c]pyridine (310 mg, 2.0 mmol, 45% yield) as a white solid. ES / MS m / z: 155.2 [M+H].

Chemical formula

[0223] To a solution of 6-chloro-1H-triazolo[4,5-c]pyridine (300 mg, 1.9 mmol, 1 equiv) in DMF (5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (675.7 mg, 2.9 mmol, 1.5 equiv) and K2CO3 (536.5 mg, 3.8 mmol, 2 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (8 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (0 - 13% EtOAc / PE) to afford 6-chloro-1-(2,2,2-trifluoroethyl)triazolo[4,5-c]pyridine (100 mg, 422.6 μmol, 21.78% yield) as a white solid. ES / MS m / z: 237.2 [M+H]. Preparation of Intermediate K, 6-Bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole [Chemical formula]

[0224] To a solution of 6-bromo-5-fluoro-1H-indazole (1 g, 4.6 mmol, 1 equiv) in DMF (10 mL) were added K2CO3 (1.2 g, 9.3 mmol, 2 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.6 g, 6.9 mmol, 1.5 equiv). The reaction mixture was stirred at 80 °C for 1 h. Then, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 - 50% ethyl acetate / petroleum ether) to give 6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole (740 mg, 54% yield) as a yellow solid. Preparation of Intermediate L, 6-Bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine [Chemical formula]

[0225] 6-Bromo-5-fluoro-1H-indazole was replaced with 6-bromo-1H-pyrazolo[4,3-c]pyridine, and 2,2,2-trifluoroethyl trifluoromethanesulfonate was replaced with 2,2-difluoroethyl trifluoromethanesulfonate. However, 6-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine was prepared by the method described for the synthesis of Intermediate K, 6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. Preparation of Intermediate M, 2-chloro-4-(2,2-difluorocyclopropyl)pyridine [Chemical formula]

[0226] Step 1: To a solution of 2-chloro-4-iodopyridine (2.0 g, 8.3 mmol, 1.0 eq) in dioxane (2 mL) and H2O (1 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.2 g, 8.3 mmol, 1.4 mL, 1.0 eq), Cs2CO3 (8.1 g, 25.0 mmol, 3.0 eq), and Pd(dppf)Cl2·CH2Cl2 (1.36 g, 1.67 mmol, 0.2 eq) were added under N2. The resulting suspension was degassed and purged with N2 three times. The reaction mixture was stirred at 80 °C for 12 h. Then, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 - 20% ethyl acetate / petroleum ether) to give 2-chloro-4-vinylpyridine (500 mg, 25% yield) as a yellow oil. [Chemical formula]

[0227] Step 2: To a solution of 2-chloro-4-vinylpyridine (500.0 mg, 3.5 mmol, 1.0 eq) in THF (2 mL) was added NaI (268.4 mg, 1.7 mmol, 0.5 eq), then the mixture was stirred at 70 °C and trimethyl(trifluoromethyl)silane (1.7 g, 12.5 mmol, 3.5 eq) was added, and the reaction was stirred at 70 °C for 12 h. Then, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 - 20% ethyl acetate / petroleum ether) to give 2-chloro-4-(2,2-difluorocyclopropyl)pyridine (480.0 mg, 45% yield) as an orange oil. Intermediate N, 2-bromo-4-(difluoromethyl)-5-fluoropyridine

Chemical formula

[0228] To a solution of 2-bromo-5-fluoropyridine-4-carbaldehyde (1.0 g, 4.9 mmol, 1.0 eq) in DCM (10 mL) was added DAST (1.4 g, 8.8 mmol, 1.1 mL, 1.8 eq) at -20 °C. The mixture was stirred at 20 °C for 2 h. Then, the reaction mixture was diluted with NaHCO3 (15 mL) and extracted with CH2Cl2 (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-bromo-4-(difluoromethyl)-5-fluoropyridine (970.0 mg, crude) as a yellow oil. 1 1H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 7.70 (d, J = 5.0 Hz, 1H), 6.85 (t, J = 53.9 Hz, 1H). Preparation of Intermediate O, tert-butyl (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidine-1-carboxylate

Chemical formula

[0229] To each of four double flasks, 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine (565 mg, 2.0 mmol, 1 equiv), tert-butyl (S)-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.2 mmol, 1.1 equiv), copper(I) iodide (192 mg, 1.0 mmol, 0.5 equiv), 3,4,7,8-tetramethyl-1,10-phenanthroline (95 mg, 0.40 mmol, 0.2 equiv), Cs2CO3 (985 mg, 3.0 mmol, 1.5 equiv), and PhMe (18 mL) were added. The flasks were sealed and heated to 120 °C. After 16 h, the four reactions were combined, diluted with EtOAc, filtered through celite, and concentrated in vacuo. The mixture was purified by silica gel chromatography (0–50% EtOAc / hexane) to afford tert-butyl (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate (2.77 g, 80%) as a white foam. ES / MS m / z: 423.03 [M+H]. Preparation of Intermediate P, (S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride [Chemical formula]

[0230] To a solution of tert-butyl (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate (1.56 g, 3.69 mmol, 1 equiv) in DCM (6 mL) was added 4M HCl in dioxane (3 mL, 12 mmol, 3.25 equiv). After 16 h, the mixture was concentrated in vacuo to afford (S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine; hydrochloride (1.46 g) as a white solid.

[0231] Preparation of Intermediate Q, (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate

Chemical formula

[0232] To a solution of tert-butyl (4S)-3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate (500 mg, 2.2 mmol, 1 equiv) in toluene (10 mL), 4-bromo-2-(difluoromethyl)-1-fluoro-benzene (504.0 mg, 2.2 mmol, 1 equiv), CuI (106.6 mg, 559.9 μmol, 0.25 equiv), 3,4,7,8-tetramethyl-1,10-phenanthroline (105.8 mg, 448.0 μmol, 0.2 equiv), and Cs2CO3 (1.1 g, 3.4 mmol, 1.5 equiv) were added. The reaction mixture was purged and degassed with nitrogen three times, and then the reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column (0 - 20% ethyl acetate / petroleum ether) to give (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate (290 mg, 35% yield) as a colorless oil. 1 1H NMR (chloroform-d, 400 MHz) δ 7.16 (br s, 1H), 7.0 - 7.1 (m, 2H), 6.7 - 7.0 (m, 1H), 4.71 (br s, 1H), 3.6 - 4.0 (m, 4H), 1.49 (br s, 9H). Preparation of Intermediate N, (S)-4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine; hydrochloride

Chemical Structure

[0233] tert-Butyl (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate was replaced with (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate, and (S)-4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine was prepared by the method described for the synthesis of intermediate P, (S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride. Preparation of intermediate R, (S)-tert-butyl 4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate

Chemical formula

[0234] 4-Bromo-2-(difluoromethyl)-1-fluorobenzene was replaced with 2-bromo-4-(difluoromethyl)-5-fluoropyridine, and (S)-tert-butyl 4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate was prepared by the method described for intermediate P, (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate. 1 H NMR (400 MHz, chloroform-d) δ 8.08 (br s, 1H), 7.05 (br s, 1H), 6.82 (t, J = 54.2 Hz, 1H), 5.58 (br s, 1H), 3.92 - 3.75 (m, 4H), 1.48 (br s, 9H). Preparation of intermediate S, (S)-4-(difluoromethyl)-2-((4,4-difluoropyrrolidin-3-yl)oxy)-5-fluoropyridine; hydrochloride

Chemical formula

[0235] (S)-4-(Difluoromethyl)-2-((4,4-difluoropyrrolidin-3-yl)oxy)-5-fluoropyridine; hydrochloride was prepared by the method described for the synthesis of intermediate P, (S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride, but replacing tert-butyl (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate with (S)-tert-butyl 4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate. 1 H NMR (400 MHz, methanol-d4) δ 8.22 (s, 1H), 7.19 - 7.16 (m, 1H), 7.05 - 6.87 (m, 1H), 5.93 - 5.86 (m, 1H), 4.00 - 3.83 (m, 4H), 3.77 (td, J = 2.4, 13.7 Hz, 1H) Preparation of intermediate T, tert-butyl (S)-3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate

Chemical Structure

[0236] 4-Bromo-2-(difluoromethyl)-1-fluoro-benzene was replaced with 2-bromo-4-(trifluoromethyl)-pyridine, and tert-butyl (S)-3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate was prepared by the method described for intermediate P, (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate.

Chemical Structure

[0237] tert-Butyl (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate was replaced with tert-butyl (S)-3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate, and (S)-2-((4,4-difluoropyrrolidin-3-yl)oxy)-4-(trifluoromethyl)pyridine was prepared by the method described for the synthesis of (S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride. SNAr of pyrrolidine ether Preparation of Intermediate U, (S)-6-((1-(6-chloropyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0238] To a solution of 4-chloro-6-fluoro-pyrimidine (36.9 mg, 0.279 mmol, 2 eq) and 6-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine hydrochloride (50.0 mg, 0.139 mmol, 1 eq) in NMP (0.5 mL) was added DIPEA (0.0607 mL, 0.348 mmol, 2.5 eq). The reaction mixture was heated to 100 °C and stirred for 4 h. Then, the reaction mixture was diluted with EtOAc / water and extracted twice with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0 - 70% EtOAc / hexane). ES / MS m / z: 434.90 [M+H]. Preparation of Intermediate V, (S)-6-((1-(6-Chloro-2-methylpyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0239] 4-Chloro-6-fluoropyrimidine was replaced with 4-chloro-6-fluoropyrimidine, and (S)-6-((1-(6-chloro-2-methylpyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was prepared by the method described for Intermediate U. ES / MS m / z: 448.90 [M+H]. Preparation of Intermediate W, (S)-6-((1-(6-Chloro-2-(trifluoromethyl)pyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0240] 4-Chloro-6-fluoropyrimidine was replaced with 4,6-dichloro-2-(trifluoromethyl)pyrimidine, and DMF was used instead of NMP. (S)-6-((1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was synthesized in the same manner as Intermediate U, and the reaction mixture was stirred at 60 °C for 2 hours. ES / MS m / z: 502.80 [M+1]. Preparation of Intermediate X, (S)-4-Chloro-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)pyrimidine-2-carbonitrile [Chemical formula]

[0241] 4-Chloro-6-fluoro-pyrimidine was replaced with 4,6-dichloropyrimidine-2-carbonitrile, and (S)-4-chloro-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)pyrimidine-2-carbonitrile was prepared in the manner described for Intermediate U. ES / MS m / z: 460.00 [M+H]. Preparation of Intermediate Y, 3-((2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)oxy)-2,2-difluoropropan-1-ol [Chemical formula]

[0242] To a solution of 2,2-difluoropropane-1,3-diol (1.0 g, 9.3 mmol, 5.0 eq) in THF (15 mL) was added NaH (224.9 mg, 5.6 mmol, 60% purity, 3.0 eq). The mixture was stirred at 20 °C for 10 minutes. 6-Chloro-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine (500 mg, 1.8 mmol, 1.0 eq) was added and the reaction was stirred at 40 °C for 12 hours. The reaction mixture was quenched by the addition of NH4Cl (10 mL), then diluted with H2O (10 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 - 50% ethyl acetate / petroleum ether) to yield 3-((2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)oxy)-2,2-difluoropropan-1-ol (350 mg, 38% yield) as a white solid. C-N Coupling of Pyrrolidine Ether Preparation of Intermediate Z, (S)-1-(2’,4’-Dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol

Chem.

[0243] To a solution of 6-chloro-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine (200 mg, 749.9 μmol, 1 equiv) in dioxane (5 mL) were added (3S)-4,4-difluoropyrrolidin-3-ol (119.6 mg, 749.9 μmol, 1 equiv, HCl), Pd(OAc)2 (16.8 mg, 75.0 μmol, 0.1 equiv), Cs2CO3 (488.7 mg, 1.5 mmol, 2 equiv), and Xantphos (43.3 mg, 75.0 μmol, 0.1 equiv). The suspension was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 12 h under N2. LCMS indicated complete consumption of the starting material and approximately 50% of the peak with the desired MS was detected. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (8 mL × 2). The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0 - 6% MeOH in DCM, gradient R f = 0.56) to afford (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol (140 mg, 396.2 μmol, 53% yield) as a yellow solid. ES / MS m / z: 354.1 [M+H]. Late-Stage C-N Coupling of Pyrrolidine Ether Preparation of Intermediate AA, (S)-4-(3,3-Difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)picolino-nitrile

Chem.

[0244] 4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinitrile (70 mg, 0.18 mmol, 1 equiv), (S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride (110 mg, 0.31 mmol, 1.2 equiv), RuPhos Pd G3 (13 mg, 0.02 mmol, 0.07 equiv), and K3PO4 (136 mg, 0.64 mmol, 2.5 equiv) were added to DMAc (3.5 mL). The mixture was sparged with Ar for 10 minutes and then heated to 110 °C. After 24 hours, the mixture was diluted with EtOAc, filtered through celite, washed with brine (4 × 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (0–100% EtOAc / hexane) to give (S)-4-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)picolinitrile (31 mg, 20%) as a yellow residue. ES / MS m / z: 563.10 (M+1). Preparation of Intermediate BB, (S)-6-((1-(2-(2,4-Dimethoxypyrimidin-5-yl)-6-methoxypyridin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0245] 4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinitrile was replaced with 5-(4-chloro-6-methoxypyridin-2-yl)-2,4-dimethoxypyrimidine, and (S)-6-((1-(2-(2,4-dimethoxypyrimidin-5-yl)-6-methoxypyridin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was synthesized in the same manner as Intermediate AA. ES / MS m / z: 568.08 (M+1). Preparation of Intermediate CC, (S)-6-((1-(2-(2,4-dimethoxypyrimidin-5-yl)-6-(trifluoromethyl)pyridin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine [Chemical formula]

[0246] 4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinitrile was replaced with 5-(4-chloro-6-(trifluoromethyl)pyridin-2-yl)-2,4-dimethoxypyrimidine, and (S)-6-((1-(2-(2,4-dimethoxypyrimidin-5-yl)-6-(trifluoromethyl)pyridin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was synthesized in the same manner as Intermediate AA. ES / MS m / z: 606.07 (M+1). Preparation of Intermediate DD, (S)-6-((1-(2-(2,4-dimethoxypyrimidin-5-yl)-6-methylpyridin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine [Chemical formula]

[0247] 4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinitrile was replaced with 5-(4-chloro-6-methylpyridin-2-yl)-2,4-dimethoxypyrimidine, and (S)-6-((1-(2-(2,4-dimethoxypyrimidin-5-yl)-6-methylpyridin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was synthesized in the same manner as Intermediate AA. ES / MS m / z: 522.10 (M+1). Preparation of Intermediate EE, (S)-6-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chemical Structure

[0248] To a solution of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine (80.0 mg, 299.9 μmol, 1.0 eq) in dioxane (2 mL) were added 2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-4-(trifluoromethyl)pyridine (80.4 mg, 299.9 μmol, 1.0 eq), Cs2CO3 (195.4 mg, 599.9 μmol, 2.0 eq), Pd(OAc)2 (6.7 mg, 30.0 μmol, 0.1 eq), and Xantphos (17.3 mg, 30.0 μmol, 0.1 eq). The resulting suspension was degassed and purged with N2 three times. The reaction was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC (SiO2, 2:1 petroleum ether / ethyl acetate) to give (S)-6-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine (70.0 mg, 46% yield) as a yellow solid. Preparation of Intermediate FF, 4-[(4S)-4-[[4-(Difluoromethyl)-5-fluoro-2-pyridyl]oxy]-3,3-difluoro-pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine

Chem.

[0249] To a solution of 6-chloro-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine (80 mg, 299.98 μmol, 1 equiv) in dioxane (5 mL) was added 4-(difluoromethyl)-2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-5-fluoro-pyridine (80.4 mg, 299.9 μmol, 1 equiv), Pd(OAc)2 (6.7 mg, 30.0 μmol, 0.1 equiv) and Xantphos (17.3 mg, 30.0 μmol, 0.1 equiv), and Cs2CO3 (195.4 mg, 599.9 μmol, 2 equiv). The mixture was stirred at 100 °C for 12 h under N2. The reaction was concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The combined organics were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (SiO2, 100% ethyl acetate) to give 4-[(4S)-4-[[4-(difluoromethyl)-5-fluoro-2-pyridyl]oxy]-3,3-difluoro-pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine (60 mg, 120.38 μmol, 40.13% yield) as a yellow oil. Preparation of Intermediate GG, (S)-6-(4-(3-(Difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chem.

[0250] 4-(Difluoromethyl)-2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-5-fluoro-pyridine was replaced with (S)-4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidine; hydrochloride, and (S)-6-(4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine was prepared by the method described for Intermediate FF. Preparation of Intermediate HH, (S)-6-(4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chemical formula

[0251] 4-(Difluoromethyl)-2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-5-fluoro-pyridine was replaced with (S)-4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidine; hydrochloride, and (S)-6-(4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine was prepared by the method described for Intermediate FF. ES / MS m / z: 514.1 [M+H]. Preparation of Intermediate II, (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-[4,5’-bipyrimidine]-2-carbonitrile

Chemical formula

[0252] Replace 4,6-dichloropicolinonitrile with (S)-4-chloro-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)pyrimidine-2-carbonitrile, and in the same way as intermediate AA, synthesize (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-[4,5’-bipyrimidine]-2-carbonitrile. ES / MS m / z: 564.10 (M+1). Alcohol SnAr: Preparation of Intermediate JJ, (S)-6-(3,3-difluoro-4-((4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chemical formula

[0253] To a solution of 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)pyridine (62.7 mg, 283.0 μmol, 1.0 equivalent) in DMF (1 mL) was added NaH (22.6 mg, 566.0 μmol, 60% purity, 2.0 equivalents). The mixture was stirred at 20 °C for 10 minutes before the addition of (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidine]-6-yl)-4,4-difluoropyrrolidin-3-ol (100 mg, 283.0 μmol, 1.0 equivalent). The reaction was stirred at 80 °C for 2 hours. The reaction was quenched with NH4Cl (6 mL) and extracted with EtOAc (2 mL × 3). The combined organic layers were washed with brine (2 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-6-(3,3-difluoro-4-((4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine (150 mg, crude product) as a yellow oil. Preparation of Intermediate KK, (S)-6-(3,3-Difluoro-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chemical formula

[0254] 2-Chloro-4-(1-(trifluoromethyl)cyclopropyl)pyridine was replaced with 4-fluoro-2-methylpyridine, and (S)-6-(3,3-difluoro-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine was prepared by the method described for Intermediate JJ. Preparation of Intermediate LL, (S)-6-(3,3-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chemical formula

[0255] 2-Chloro-4-(1-(trifluoromethyl)cyclopropyl)pyridine was replaced with 4-chloro-2-(trifluoromethyl)pyridine, and (S)-6-(3,3-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine was prepared by the method described for Intermediate JJ. Preparation of Intermediate MM, (S)-1-(2’,4’-Di-tert-butoxy-2-methyl-[4,5’-bipyrimidine]-6-yl)-4,4-difluoropyrrolidin-3-yl isopropylcarbamate

Chemical formula

[0256] To a solution of (S)-1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol (100 mg, 228.5 μmol, 1 eq) in DCM (2 mL) were added DIPEA (88.6 mg, 685.7 μmol, 119.4 μL, 3 eq) and 2-isocyanatopropane (194.5 mg, 2.2 mmol, 224.1 μL, 10 eq). The mixture was stirred at 60 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give (S)-1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl isopropylcarbamate (120 mg, crude) as a brown oil, which was used directly without further purification. Preparation of Intermediate NN, 3-((2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)oxy)-2,2-difluoropropyl isopropylcarbamate

Chemical formula

[0257] (S)-1-(2’,4’-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol was replaced with 3-((2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)oxy)-2,2-difluoropropan-1-ol, and 3-((2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)oxy)-2,2-difluoropropyl isopropylcarbamate was prepared by the method described for Intermediate MM. Preparation of Intermediate OO, (S)-1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl (1-(trifluoromethyl)cyclopropyl)carbamate

Chemical formula

[0258] To a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (120 mg, 778.7 μmol, 1 equiv) in toluene (1 mL) were added DPPA (225.0 mg, 817.7 μmol, 177.1 μL, 1.0 equiv) and TEA (104.0 mg, 1.0 mmol, 143.0 μL, 1.3 equiv). The mixture was stirred at 100 °C for 2 h. Then, a solution of (S)-1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol (68.1 mg, 155.7 μmol, 0.2 equiv) and DIPEA (100.6 mg, 778.7 μmol, 135.6 μL, 1 equiv) in DCM (1 mL) was added. The mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl (1-(trifluoromethyl)cyclopropyl)carbamate (260 mg, crude) as a yellow solid. Copper-catalyzed C-O cross-coupling: Preparation of Intermediate PP, (S)-6-((1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole

Chemical formula

[0259] A mixture of (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol (200 mg, 566.0 μmol, 1 equiv), 6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole (184.9 mg, 622.6 μmol, 1.1 equiv), CuI (26.9 mg, 141.5 μmol, 0.2 equiv), 3,4,7,8-tetramethyl-1,10-phenanthroline (26.7 mg, 113.2 μmol, 0.2 equiv), and Cs2CO3 (276.6 mg, 849.0 μmol, 1.5 equiv) in toluene (1.5 mL) was degassed and purged with N2 (3 times), and then the reaction mixture was stirred at 120 °C for 12 h under a N2 atmosphere. Then, the reaction mixture was diluted with 30 mL of H2O, extracted with EtOAc (30 mL × 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1) to give (S)-6-((1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole (60 mg, 19% yield) as a yellow solid. Palladium-catalyzed C-O cross-coupling: Preparation of Intermediate QQ, (S)-6-(4-((4-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine

Chemical Structure

[0260] To a solution of (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol (130 mg, 0.368 mmol, 1 equiv) in toluene (3 mL) were added 2-chloro-4-(difluoromethoxy)pyridine (66.0 mg, 0.368 mmol, 1 equiv), Cs2CO3 (299.7 mg, 0.920 mmol, 2.5 equiv), XPhos-Pd-G2 (28.9 mg, 0.037 mmol, 0.1 equiv), and Pd(OAc)2 (8.2 mg, 0.037 mmol, 0.1 equiv). The resulting suspension was degassed and purged with N2. The reaction mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (8 mL×2). The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0~4% MeOH / DCM) to give 4-[(4S)-4-[[4-(difluoromethoxy)-2-pyridyl]oxy]-3,3-difluoro-pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine. ES / MS m / z: 497.1 [M+H] Preparation of Intermediate RR, (S)-6-((1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazole [Chemical Structure]

[0261] 2-Chloro-4-(difluoromethoxy)pyridine was replaced with 6-bromo-1-(2,2,2-trifluoroethyl)indazole, and (S)-6-((1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazole was prepared by the method described for Intermediate QQ. ES / MS m / z: 552.3 [M+H]. Preparation of Intermediate SS, (S)-6-((1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-[1,2,3]triazolo[4,5-c]pyridine

Chemical Structure

[0262] 2-Chloro-4-(difluoromethoxy)pyridine was replaced with 6-chloro-1-(2,2,2-trifluoroethyl)triazolo[4,5-c]pyridine, and (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol was replaced with (S)-1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol, and (S)-6-((1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazole was prepared by the method described for Intermediate QQ. ES / MS m / z: 638.2 [M+H]. Preparation of Intermediate TT, (2,2-difluoroethyl)-6-((1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0263] 2-Chloro-4-(difluoroethoxy)pyridine was replaced with 6-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine, and (2,2-difluoroethyl)-6-((1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1H-pyrazolo[4,3-c]pyridine was prepared by the method described for Intermediate QQ. Preparation of Intermediate UU, (S)-6-((1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0264] 2-Chloro-4-(difluoromethoxy)pyridine was replaced with 6-chloro-3-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine, and (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol was replaced with (S)-1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol, and (S)-6-((1-(2’,4’-di-tert-butoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was prepared by the method described for Intermediate QQ. Preparation of Intermediate VV, (S)-6-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine [Chem.]

[0265] 2-Chloro-4-(difluoromethoxy)pyridine was replaced with 4-bromo-2-(difluoromethyl)pyridine, and (S)-6-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine was prepared by the method described for Intermediate QQ. Preparation of Intermediate XX, (S)-6-(3,3-Difluoro-4-(pyridin-4-yloxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine [Chem.]

[0266] To a solution of (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol (195 mg, 551.9 μmol, 1 equiv) in dioxane (4 mL) were added 4-bromopyridine (174.4 mg, 1.1 mmol, 2 equiv), Pd(OAc)2 (24.8 mg, 110.3 μmol, 0.2 equiv), Xantphos (63.8 mg, 110.3 μmol, 0.2 equiv), and Cs2CO3 (359.6 mg, 1.10 mmol, 2 equiv). The reaction mixture was bubbled with N2 for 1 minute and then heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and EtOAc, filtered, and the filter cake was washed with EtOAc (3 mL × 3). The combined filtrates were then extracted with ethyl acetate (5 mL × 3). The combined organics were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (25 - 30% EA / PE) to afford (S)-6-(3,3-difluoro-4-(pyridin-4-yloxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine (85 mg, 164.5 μmol, 29.8% yield) as an off-white solid. Preparation of Intermediate YY, (S)-6-(3,3-difluoro-4-((2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-2’,4’-dimethoxy-2-methyl-4,5’-bipyrimidine [Chemical Structure]

[0267] A microwave vial was charged with (S)-1-(2’,4’-dimethoxy-2-methyl-[4,5’-bipyrimidin]-6-yl)-4,4-difluoropyrrolidin-3-ol (60 mg, 0.17 mmol, 1 equiv), 4-bromo-2-(1-(trifluoromethyl)cyclopropyl)pyridine (67.8 mg, 0.255 mmol, 1.5 equiv), Pd(OAc)2 (3.8 mg, 0.017 mmol, 10 mol%), SPhos Pd G3 (12.4 mg, 0.017 mmol, 10 mol%), Cs2CO3 (138 mg, 0.425 mmol, 2.5 equiv), and freshly degassed toluene (1.5 mL) was added. The mixture was purged with nitrogen and heated to 100 °C. After 12 h, the reaction mixture was diluted with EtOAc (30 mL), washed with water (25 mL) and brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product was used in the next step without further purification. ES / MS m / z: 538.92 [M+H]. Preparation of Intermediate ZZ, (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-[4,5’-bipyrimidin]-2’,4’(1’H,3’H)-dione

Chemical formula

[0268] A microwave vial was charged with 5-(5-chloropyridazin-3-yl)-2,4-dimethoxypyrimidine (50.0 mg, 0.198 mmol, 1 equiv), 6-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine hydrochloride (71.0 mg, 0.198 mmol, 1 equiv), RuPhos Pd G3 (14.7 mg, 0.0198 mmol, 10 mol%), and tripotassium phosphate tribasic (126 mg, 0.594 mmol, 3 equiv). Subsequently, prior to the addition of freshly degassed tBuOH (1.06 mL), the reaction vessel was evacuated and refilled with nitrogen. Thereafter, the sealed reaction vessel was heated to 110 °C and stirred for 16 h. The dimethoxypyrimidine was hydrolyzed under the reaction conditions. The reaction mixture was diluted with DMF, filtered, diluted with water, neutralized with 5 drops of TFA, and purified by HPLC (water containing 0–80% ACN / TFA) to afford the title compound. ES / MS m / z: 510.72 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 11.92 (s, 1H), 8.89 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.42 (s, 1H), 7.45 (d, J = 2.9 Hz, 1H), 7.34 (s, 1H), 6.11 (m, 1H), 5.42 (pd, J = 9.1, 4.6 Hz, 2H), 4.41 (m, 2H), 4.00 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -70.14 (t, J = 9.1 Hz, 3F), -74.65 (s, 3F), -108.18 (d, J = 238.3 Hz, 1F), -119.23 (d, J = 238.4 Hz, 1F). SNAr + Deprotection of Pyrrolidine Ether Example 1: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-ethyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

Chemical Structure

[0269] 2,4-Di-tert-butoxy-5-(6-chloro-2-ethyl-pyrimidin-4-yl)pyrimidine (64.9 mg, 0.178 mmol) and 6-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine hydrochloride (58.0 mg, 0.162 mmol) were combined and diluted with NMP (0.8 mL). DIPEA (0.0704 mL, 0.404 mmol) was added and the mixture was stirred at 100 °C overnight. Then, TFA (0.124 mL, 1.62 mmol) was added directly and the mixture was stirred for 1 h. The mixture was diluted with DMF / water and purified by RP-HPLC (H2O containing 10 - 90% MeCN / TFA modifier, Gemini column) to give (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-ethyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione. ES / MS m / z: 538.9 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 11.85 (s, 1H), 8.87 (d, J = 1.0 Hz, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 1.0 Hz, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 6.04 (s, 1H), 5.41 (qt, J = 9.9, 4.8 Hz, 2H), 4.41 - 4.22 (m, 4H), 2.85 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -70.15 (t, J = 9.1 Hz), -75.13, -106.80--110.42 (m), -117.86--120.70 (m). Example 2: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrol...

Claims

1. Compound of formula (I): 【Chemistry 101】 or a pharmaceutically acceptable salt thereof, in the formula, Y becomes independent, C １～６ Alkyl, C ３～７ Cycloalkyl, O-C １～６ Alkyl-O, 4-8 membered heterocyclyl, or O-4-8 membered heterocyclyl, wherein the alkyl, heterocyclyl, O-heterocycle, O-(5-12 membered heteroaryl), O-5-12 membered heteroaryl, or O-alkyl is optionally substituted with a halo. R １ is independently H, -C １～６ alkyl, O-C １～６ alkyl, O-C １～６ alkyl-O, -C ３～７ cycloalkyl, O-(4- to 12-membered heteroaryl), C ６～１０ aryl, 4- to 12-membered heteroaryl, -C １～６ alkyl-C ６～１０ aryl, -C １～６ alkyl-4- to 12-membered heteroaryl, -C(O)N(R ４ )(R ４ ), or -C(O)N(H)C ６～１２ aryl, and the alkyl, O-C １～６ alkyl, O-C １～６ alkyl-O, cycloalkyl, aryl, heteroaryl, O-(4- to 12-membered heteroaryl), or O-heterocyclyl is optionally substituted with 1 to 4 halogens and optionally substituted with 1 or 2 R ３ ; R ２ However, H, Haro, C １～６ Alkyl, or C ３～６ It is a cycloalkyl, and the alkyl or C ３～６ The cycloalkyl group is optionally substituted with a halo. R ３ However, C １～６ Alkyl, -C ３～７ Cycloalkyl, OH, O-C １～６ Alkyl, or -O-C ３～７ It is a cycloalkyl group, and the alkyl, cycloalkyl, O-alkyl, or -O-cycloalkyl group comprises 1 to 4 R ２ It is optionally replaced by, R ４ However, each is independent of H and -C. １～６ Alkyl, -C １～６ Alkyl-C ３～７ Cycloalkyl, -C ３～７ Cycloalkyl-C １～６ Alkyl, -C ３～７ It is a cycloalkyl group, wherein the alkyl, cycloalkyl, O-alkyl, or -O-cycloalkyl group is optionally substituted with 1 to 4 halogens. R ５ However, H, C １～６ Alkyl, CN, C ３～７ Cycloalkyl, O-C １～６ Alkyl, C １～６ Alkyl-O-C １～６ Alkyl, A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound according to claim 1, wherein Y is a 4- to 8-membered heterocyclyl-O, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. Y is C ３～７ The compound according to claim 1, which is a cycloalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The compound according to claim 3, wherein Y is cyclopropyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The compound according to claim 1, wherein Y is a 4- to 8-membered heterocycline.

6. Y, 【Chemical Engineering 102】 The compound according to claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. R １ However, one or two R ４ The compound according to claim 1, which is an azaindole optionally substituted with, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The azaindole contains one or two R ３ The compound according to claim 7, which is substituted with or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The azaindole has one R ３ The compound according to claim 8, which is substituted with or a pharmaceutically acceptable salt or stereoisomer thereof.

10. R １ The compound according to claim 1, wherein the compound is pyridinyl.

11. R １ The compound according to claim 1, wherein the compound is pyrazolo[4,5-c]pyridinyl.

12. Y is C １～６ The compound according to claim 1, wherein the alkyl group is optionally substituted with a halo.

13. The aforementioned compound, 【Chemistry 103】 【Chemical 104】 A compound according to claim 1, selected from the following.

14. A pharmaceutical composition comprising, together with at least one pharmaceutically acceptable carrier, a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. A composition or pharmaceutical composition for treating cancer in a person requiring cancer treatment, wherein the composition comprises a compound according to any one of claims 1 to 13, and the pharmaceutical composition comprises, together with at least one pharmaceutically acceptable carrier, a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

Images