CD73 compounds

Abstract

Provided are compounds of Formula (I): # imgabs0 # (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, wherein the various substituents are as defined herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 USC § 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

[0003] The glycosylphosphatidylinositol-anchored CD73 antigen (also known as cluster of differentiation 73, ecto-5'-nucleotidase, ecto-5'-NT, 5'-NT, and NT5E) is considered to be the rate-limiting enzyme for the generation of extracellular adenosine (Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine incancer. 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 only trace amounts of ADP, while CD73 catalyzes the conversion of AMP to adenosine (Ado).

[0004] Extracellular Ado accumulates in cancer tissues and constitutes an important mechanism of tumor immune escape. Among other effects, tumor-derived Ado significantly suppresses infiltrating effector T cells. Degradation of ATP to Ado by CD39 and CD73 co-expressed on murine Tregs (regulatory CD4+ T cells) has been shown to be responsible for tumor immunosuppression.

[0005] CD73 can be found to be constitutively expressed at high levels on various types of cancer cells. Adenosine produced by CD73 is thought to inhibit adaptive anti-tumor immune responses, thereby promoting tumor growth and metastasis. And studies in animal models have shown that blocking CD73 activity inhibits tumor growth and prolongs survival by promoting anti-tumor adaptive immunity (Forte et al. (2012) J Immunol. 189(5):2226-33). In view of the need for cancer treatment, new compositions and methods for modulating CD73 activity and related therapeutic agents are needed. The present disclosure meets this need and other needs. Summary of the invention

[0006] The glycosylphosphatidylinositol-anchored CD73 antigen (also known as cluster of differentiation 73, ecto-5'-nucleotidase, ecto-5'-NT, 5'-NT, and NT5E) is considered to be the rate-limiting enzyme for the generation of extracellular adenosine (Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine incancer. 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 only trace amounts of ADP, while CD73 catalyzes the conversion of AMP to adenosine (Ado).

[0007] In one embodiment of the present invention, there is provided a compound of formula (I):

[0008] a.

[0009] a.(I),

[0010] b. or a pharmaceutically acceptable salt thereof, wherein:

[0011] cY is independently C 1-6 Alkyl, OC 1-6 Alkyl-O, 4- to 8-membered heterocyclyl, or O-4- to 8-membered heterocyclyl; wherein the alkyl, heterocyclyl, O-heterocyclyl, or O-alkyl is optionally substituted with a halo group;

[0012] dR 1 are independently H, -C 1-6 Alkyl, OC 1-6 Alkyl, OC 1-6 Alkyl-O, -C 3-7 Cycloalkyl, C 6-10 aryl, 5- to 12-membered heteroaryl, O-5- 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; wherein the alkyl, OC 1-6 Alkyl, OC 1-6Alkyl-O, cycloalkyl, aryl, heteroaryl, O-heteroaryl or O-heterocyclyl is optionally substituted with 1 to 4 halogens and optionally with one or two R 3 replace;

[0013] eR 2 is H, halide, C 1-6 Alkyl; or C 3-6 Cycloalkyl, wherein alkyl or C 3-6 Cycloalkyl is optionally substituted with halo; -

[0014] f 3 It is C 1-6 Alkyl, -C 3-7 Cycloalkyl, OH, OC 1-6 Alkyl or -OC 3-7 wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted by 1 to 4 R 2 replace; and

[0015] G JZ 4 Each independently is H, -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-6 Alkyl, -C 3-7 Cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 halogens; and

[0016] R 5 It is H, C 1-6 Alkyl, CN, C 3-7 Cycloalkyl, OC 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 alkyl,

[0017] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0018] a. In some embodiments, Y is 4- to 12-membered heteroaryl-O or a pharmaceutically acceptable salt or stereoisomer thereof.

[0019] b. In some embodiments, Y is C 3-7 Cycloalkyl or a pharmaceutically acceptable salt or stereoisomer thereof.

[0020] c. In some embodiments, Y is cyclopropyl or a pharmaceutically acceptable salt or stereoisomer thereof.

[0021] d. In other embodiments, Y is a 4- to 8-membered heterocyclyl.

[0022] e. In some embodiments, Y is:

[0023] f. , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0024] g. In some embodiments, R 1 is an azaindole, optionally substituted with 1 or 2 R 4 Substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0025] h. In some embodiments, the azaindole is replaced by 1 or 2 R 3 Substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0026] i. In some embodiments, the azaindole is replaced by 1 R 3 Substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0027] j. In some embodiments, R 1 It is pyridyl.

[0028] k. In some embodiments, R 1 It is pyrazolo[4,5-c]pyridinyl.

[0029] 1. In some embodiments, Y is C 1-6 The alkyl group is optionally substituted with a halo group.

[0030] m. In one embodiment, compounds from the Examples are provided.

[0031] In one embodiment, a pharmaceutical composition is provided, comprising a compound of formula (I):

[0032] a.

[0033] a.(I),

[0034] b. or a pharmaceutically acceptable salt thereof, wherein:

[0035] cY is independently C 1-6 Alkyl, OC 1-6 Alkyl-O, 4- to 8-membered heterocyclyl, or O-4- to 8-membered heterocyclyl; wherein the alkyl, heterocyclyl, O-heterocyclyl, or O-alkyl is optionally substituted with a halo group;

[0036] dR 1 are independently H, -C 1-6 Alkyl, OC 1-6 Alkyl, OC 1-6Alkyl-O, -C 3-7 Cycloalkyl, 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; wherein the alkyl, OC 1-6 Alkyl, OC 1-6 Alkyl-O, cycloalkyl, aryl, heteroaryl or O-heterocyclyl is optionally substituted by 1 to 4 halogens and optionally by one or two R 3 replace;

[0037] eR 2 is H, halide, C 1-6 Alkyl; or C 3-6 Cycloalkyl, wherein alkyl or C 3-6 Cycloalkyl is optionally substituted with halo; -

[0038] f 3 It is C 1-6 Alkyl, -C 3-7 Cycloalkyl, OH, OC 1-6 Alkyl or -OC 3-7 wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted by 1 to 4 R 2 replace; and

[0039] G JZ 4 Each independently is H, -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-6 Alkyl, -C 3-7 Cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 halogens; and

[0040] R 5 It is H, C 1-6 Alkyl, CN, C 3-7 Cycloalkyl, OC 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 alkyl,

[0041] or a pharmaceutically acceptable salt or stereoisomer thereof, and the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0042] a. In another embodiment, a method of treating cancer is provided, comprising administering to a patient in need thereof a compound of formula (I):

[0043] b.

[0044] a.(I),

[0045] c. or a pharmaceutically acceptable salt thereof, wherein:

[0046] dY is independently C 1-6 Alkyl, OC 1-6 Alkyl-O, 4- to 8-membered heterocyclyl, or O-4- to 8-membered heterocyclyl; wherein the alkyl, heterocyclyl, O-heterocyclyl, or O-alkyl is optionally substituted with a halo group;

[0047] eR 1 are independently H, -C 1-6 Alkyl, OC 1-6 Alkyl, OC 1-6 Alkyl-O, -C 3-7 Cycloalkyl, 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; wherein the alkyl, OC 1-6 Alkyl, OC 1-6 Alkyl-O, cycloalkyl, aryl, heteroaryl or O-heterocyclyl is optionally substituted by 1 to 4 halogens and optionally by one or two R 3 replace;

[0048] f 2 is H, halide, C 1-6 Alkyl; or C 3-6 Cycloalkyl, wherein alkyl or C 3-6 Cycloalkyl is optionally substituted with halo; -

[0049] G JZ 3 It is C 1-6 Alkyl, -C 3-7 Cycloalkyl, OH, OC 1-6 Alkyl or -OC 3-7 wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted by 1 to 4 R 2 replace; and

[0050] HkD 4 Each independently is H, -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-6 Alkyl, -C 3-7 Cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 halogens; and R 5 It is H, C 1-6 Alkyl, CN, C 3-7 Cycloalkyl, OC 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutically acceptable composition thereof. DETAILED DESCRIPTION

[0051] I. Definitions

[0052] "Alkyl" is a straight or branched chain saturated monovalent hydrocarbon. For example, an alkyl group can have 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 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, isopropyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, sec-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH 3 ) 3), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 )、2-pentyl(-CH(CH 3 )CH 2 CH 2 CH 3 )、3-pentyl(-CH(CH 2 CH 3 ) 2 )、2-methyl-2-butyl(-C(CH 3 ) 2 CH 2 CH 3 )、3-methyl-2-butyl(-CH(CH 3 )CH(CH 3 ) 2 )、3-methyl-1-butyl(-CH 2 CH 2 CH(CH 3 ) 2 )、2-methyl-1-butyl(-CH 2 CH(CH 3 )CH 2 CH 3 )、1-hexyl(-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 )、2-hexyl(-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 )、3-hexyl(-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))、2-methyl-2-pentyl(-C(CH 3 ) 2 CH 2 CH 2 CH 3 )、3-methyl-2-pentyl(-CH(CH 3 )CH(CH 3 )CH 2 CH 3 )、4-methyl-2-pentyl(-CH(CH 3 )CH 2 CH(CH3 ) 2 )、3-methyl-3-pentyl(-C(CH 3 )(CH 2 CH 3 ) 2 )、2-methyl-3-pentyl(-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl(-C(CH 3 ) 2 CH(CH 3 ) 2 ) and 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ). Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0053] "Alkylene" refers to a straight or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having the indicated number of carbon atoms and connecting at least two other groups. The two moieties connected to the alkylene group may be connected to the same atom or to different atoms of the alkylene group. For example, a straight chain alkylene group may be a divalent group -(CH 2 ) n -, 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 may be substituted or unsubstituted.

[0054] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl groups may include any number of carbon atoms, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 and C 6. The alkenyl group may 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 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 may be substituted or unsubstituted.

[0055] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl groups may include any number of carbon atoms, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 and C 6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups may be substituted or unsubstituted.

[0056] "Alkoxy" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. As with alkyl groups, alkoxy groups can have any suitable number of carbon atoms, such as C 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy groups may be further substituted with a variety of substituents as described herein. Alkoxy groups may be substituted or unsubstituted.

[0057] "Alkoxyalkyl" refers to an alkoxy group attached to an alkyl group, which is attached to the rest of the compound, such that the alkyl group is divalent. Alkoxyalkyl groups may have any suitable number of carbon atoms, such as 2 to 6 (C 2-6 alkoxyalkyl), 2 to 5 (C 2-5 alkoxyalkyl), 2 to 4 (C 2-4 alkoxyalkyl), or 2 to 3 (C 2-3 Alkoxy and alkyl are as defined above, wherein alkyl is divalent and may include, but is not limited to, methoxymethyl (CH 3 OCH 2 -), methoxyethyl (CH 3 OCH 2 CH 2 -)wait.

[0058] "Alkoxy-alkoxy" refers to an alkoxy group connected to a second alkoxy group, which is connected to the rest of the compound. Alkoxy is as defined above, and may include, but is not limited to, methoxy-methoxy (CH 3 OCH 2 O-), methoxy-ethoxy (CH 3 OCH 2 CH 2 O-) etc.

[0059] As used herein, "halo" or "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0060] As used herein, "haloalkyl" refers to an alkyl group as defined herein, wherein one or more of the hydrogen atoms of the alkyl group are independently replaced by a halo substituent, which can be the same or different. 1-4 The haloalkyl group is C 1-4 Alkyl, where C 1-4 One or more of the hydrogen atoms of the alkyl group have been replaced by a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0061] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to alkyl groups, haloalkoxy groups can have any suitable number of carbon atoms, such as C 1-6 Alkoxy groups may be substituted with 1, 2, 3 or more halogens. When all hydrogens are replaced with halogens (e.g., fluorine), the compound is fully substituted, e.g., perfluorinated. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

[0062] "Cycloalkyl" refers to a cyclic ring having 3 to 20 carbon atoms (i.e., C 3-20 The term "cycloalkyl" also includes multiple fused, saturated and partially unsaturated all-carbon ring systems (e.g., ring systems containing 2, 3 or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles with 6 to 12 annular carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to 20 annular carbon atoms). When valence requirements permit, the rings of multiple fused ring systems may be connected to each other via fusion, spirocyclic and bridging bonds. Non-limiting examples of monocyclic cycloalkyl groups 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.

[0063] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, wherein the alkyl component is connected to the cycloalkyl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene to be connected to the cycloalkyl component and the point of attachment. In some cases, the alkyl component may not be present. The alkyl component may include any number of carbon atoms, 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 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.

[0064] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or multiple ring systems having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen and sulfur) in the ring, wherein the multiple ring systems include at least a non-aromatic ring containing at least one heteroatom. The multiple ring systems may also include other aromatic rings and non-aromatic rings. Unless otherwise specified, the heterocyclyl group has 3 to 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6- or 7-membered ring) having 1 to 6 ring carbon atoms and 1 to 3 cyclic heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The heteroatom may be optionally oxidized to form -N(-OH)-, =N(- - )-, -S(=O)- or -S(=O) 2 -. When valence requirements permit, the rings of a polycondensed ring (e.g., bicyclic heterocyclyl) system may be connected to one another by fusion, spiro, and bridging bonds. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 6-oxa-1-azaspiro[3.3]heptane-1-yl, 2-thia-6-azaspiro[3.3] heptane-6-yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2-azabicyclo[3.1.0]hexane-2-yl, 3-azabicyclo[3.1.0]hexane-2-yl, 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane-2-yl, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane, pyrazolidin-3-one, piperazin-2-one, oxazolidin-2-one and the like.

[0065] Heterocycloalkyl rings also include 9 to 15 membered fused ring heterocycloalkyls having 2, 3 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, indoline (dihydroindoline), isoindoline (dihydroisoindoline), indazoline (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxole, dihydrobenzo[b]dioxin, dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[d]thiophene, dihydro ... benzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenzo[c]isothiazole, spiro[cyclobutane-1,3'-indolino]-2'-one, spiro[cyclopropane-1,3'-indolino]-2'-one, 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole, benzo[d][1,3]dioxole and benzo[b][1,4]thiazine, as shown in the following structures:

[0066] , , , , , , , , , , , , , , , , , , , .

[0067] Fused bicyclic heterocycloalkyl groups can also be represented by the following structure:

[0068] or

[0069] Where X 1 , X 2 , X 3 and X 4 Each independently does not exist, -CH 2 -, -NH-, -O- or -S-, X 1 , X 2 , X 3 and X 4 At least one of is -NH-, -O- or -S-, and the dotted circle represents a saturated or partially unsaturated non-aromatic ring. The fused bicyclic heterocycloalkyl is optionally substituted.

[0070] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component is connected to the heterocycloalkyl component at a point of attachment. The alkyl component is as defined above except that the alkyl component is an at least divalent alkylene group connected to the heterocycloalkyl component and the point of attachment. The alkyl component may include any number of carbon atoms, 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 In some cases, the alkyl component may not be present. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may be substituted or unsubstituted.

[0071] As used herein, "aryl" refers to a single all-carbon aromatic ring or a polycondensed all-carbon ring system, wherein at least one ring is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having 9 to 20 carbon atoms, wherein at least one ring is aromatic, and wherein the other rings may be aromatic or non-aromatic (i.e., carbocyclic rings). Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the polycondensed ring system. When valence requirements permit, the rings of the polycondensed ring system may be connected to each other via fusion, spirocyclic rings, and bridge bonds. It should also be understood that when a certain atomic range of aryl (e.g., 6-10 aryl) is cited, the atomic range is the total ring atoms of the aryl. For example, a 6-membered aryl group would include phenyl, and a 10-membered aryl group would include 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.

[0072] "Alkyl-aryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component is connected to the aryl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is an at least divalent alkylene group connected to the aryl component and the point of attachment. The alkyl component may include any number of carbon atoms, such as C 0-6 , C 1-2 , C 1-3 , C1-4 , 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 In some cases, the alkyl component may not be present. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. The alkyl-aryl group may be substituted or unsubstituted.

[0073] As used herein, "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes a polycondensed ring system having at least one such aromatic ring, which will be further described below. Thus, "heteroaryl" includes a single aromatic ring of 1 to 6 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Sulfur and nitrogen atoms may also exist in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl or furanyl. "Heteroaryl" also includes poly-fused ring systems (e.g., ring systems containing 2, 3 or 4 rings), wherein the heteroaryl group as defined above is fused to one or more rings selected from heteroaryl (to form, for example, 1,8-naphthyridinyl), heterocyclic (to form, for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocyclic (to form, for example, 5,6,7,8-tetrahydroquinolinyl) and aryl (to form, for example, indazolyl) to form a poly-fused ring system. Thus, the heteroaryl (single aromatic ring or multiple condensed ring systems) has 1-20 carbon atoms and 1-6 heteroatoms within the heteroaryl ring. Such poly-fused ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. When valence requirements permit, the rings of the poly-fused ring systems may be connected to each other via fusion, spirocyclic and bridging bonds. It should be understood that the individual rings of the polycondensed ring system can be connected in any order relative to each other. It should be understood that the point of attachment of the heteroaryl or heteroaryl polycondensed ring system can be located on any suitable atom of the heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when a certain atomic range of heteroaryl (e.g., 5 to 10 yuan heteroaryl) is cited, the atomic range is the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-yuan heteroaryl will include a thiazolyl group, and a 10-yuan heteroaryl will include a quinolinyl group. Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thienyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, pyridin-2(1H)-one, isoquinolin-1(2H)-one, and triazolyl.

[0074] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component is attached to the heteroaryl component at a point of attachment. The alkyl component is as defined above, except that the alkyl component is an at least divalent alkylene group attached to the heteroaryl component and the point of attachment. The alkyl component may include any number of carbon atoms, such as C 0-6 , C1-2 , 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 In some cases, the alkyl component may not be present. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0075] "Compounds of the disclosure" include compounds disclosed herein, for example, compounds of the disclosure include compounds of Formula (I), including the compounds of the Examples.

[0076] As used herein, "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product formed directly or indirectly from combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0077] "Pharmaceutically effective amount" refers to that amount of a compound of the present disclosure in a formulation or combination thereof that provides the desired therapeutic or pharmaceutical result.

[0078] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

[0079] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result. For the purposes of this disclosure, a beneficial or desired result includes, but is not limited to, alleviation of symptoms and / or reduction of the degree of symptoms and / or prevention of deterioration of symptoms associated with a disease or condition. In one embodiment, "treatment" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or reducing the degree of a disease or condition); b) slowing down or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying deterioration or progression of a disease or condition); and c) alleviating a disease or condition, such as causing regression of clinical symptoms, improving the disease state, delaying the progression of a disease, improving quality of life, and / or prolonging survival.

[0080] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective to cause a desired biological or medical response, including an amount of a compound that is sufficient to affect such treatment of a disease when administered to a subject to treat the disease. The effective amount may vary depending on the compound, the disease to be treated and its severity, as well as the age, weight, etc. of the subject. The effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and if combined with one or more other agents, a desired or beneficial result can be achieved or realized, then a single agent may be considered to be administered in an effective amount. The appropriate dose of any co-administered compound may optionally be reduced due to the combined action of the compound (e.g., an additive or synergistic effect).

[0081] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a slow-release device (e.g., a mini-osmotic pump) to a subject. Administration can be carried out according to a schedule specifying the frequency of administration, the dosage of administration, and other factors.

[0082] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by 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 a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents after a few hours (e.g., 1 hour-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein after a few hours (e.g., 1 hour-12 hours). Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the patient.

[0083] "Subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0084] "Disease" or "disorder" refers to the state of being or health of a patient or subject that can be treated with the compounds, pharmaceutical compositions or methods 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 may be an autoimmune disease, an inflammatory disease, a cancer, an infectious disease, a metabolic disease, a developmental disease, a cardiovascular disease, a liver disease, an intestinal disease, an endocrine disease, a neurological disease or other disease.

[0085] "Cancer" refers to all types of cancer, tumors or malignancies found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions or methods provided herein include lymphomas, sarcomas, bladder cancer, bone cancer, brain cancer, 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 resistance, Herceptin resistance, HER2 positive, doxorubicin resistance, tamoxifen resistance, 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 (castration-resistant prostate cancer), breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (for example, of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

[0086] Additional examples include thyroid cancer, cancer of the endocrine system, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiforme myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythaemia, essential macroglobulinemia, primary brain tumor, cancer , malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate cancer.

[0087] "Leukemia" refers broadly to progressive malignant diseases of the blood-forming organs and is generally characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally clinically classified based on: (1) the duration and character of the disease - acute or chronic; (2) the type of cells affected; myeloid (myeloid), lymphoid (lymphocytic), or monocytic; and (3) the presence or absence of an increase in the number of abnormal cells in the blood - leukemic or non-leukemic (meta-leukemic). 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 myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, stem cell leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, stem cell leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, leukemia), hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia leukemia), stem cell leukemia, subleukemic leukemia or undifferentiated cell leukemia.

[0088] "Sarcoma" generally refers to a tumor composed of material such as embryonic connective tissue, and is generally composed of closely packed cells embedded in a fibrillar or uniform material. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar sarcoma of soft tissue, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriosarcoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, fibroblastic ... Sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma of the cutaneous, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, periosteal sarcoma, reticular cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0089] "Melanoma" refers to 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's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma or superficial spreading melanoma.

[0090] "Carcinoma" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and produce metastases. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, cystic adenoid carcinoma, adenoid cystic carcinoma, adenoma carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchial protocarcinoma, gyriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine body carcinoma, cribriform carcinoma, thoracic carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, dural carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, carcinoma epithelial adenoides), explanted carcinoma, ulcerative carcinoma, fibrous carcinoma (carcinoma fibrosum), gelatinous carcinoma, colloid carcinoma, giant cell carcinoma (carcinomagigantocellulare), adenocarcinoma, granular cell carcinoma, pilomatrix carcinoma, hematogenous carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, clear carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma (carcinoma lenticulare), lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma (carcinoma medullare, medullary carcinoma), melanoma, soft carcinoma, mucinous carcinoma (carcinomamuciparum), mucous cell carcinoma, mucoepidermoid carcinoma, colloid carcinoma, mucous carcinoma (mucouscarcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteocarcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthotic cell carcinoma, comedo carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongy carcinoma (carcinomaspongiosum), squamous carcinoma, squamous cell carcinoma, rope-shaped carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0091] "Metastasis", "metastatic" and "metastatic cancer" are used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., cancer) from one organ or another non-adjacent organ or body part. Cancer occurs at a starting site, such as the breast, which is called a primary tumor, such as primary breast cancer. Some cancer cells in the primary tumor or starting site acquire the ability to penetrate and infiltrate surrounding normal tissues in a local area and / or the ability to penetrate the walls of the lymphatic system or vascular system, thereby circulating to other parts and tissues in the body through the system. The second clinically detectable tumor formed by the cancer cells of the primary tumor is called a metastatic or secondary tumor. When cancer cells metastasize, it is presumed that the metastatic tumor and its cells are similar to those of the original tumor and its cells. Therefore, if lung cancer metastasizes to the breast, the secondary tumor at the breast site is composed of abnormal lung cells rather than abnormal breast cells. Secondary tumors in the breast are called metastatic lung cancer. Therefore, the phrase metastatic cancer refers to a disease in which a subject suffers from or has a primary tumor and has one or more secondary tumors. The phrase non-metastatic cancer or a subject with a 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 with a primary lung tumor or a history of a primary lung tumor and one or more secondary tumors at a secondary location or locations (e.g., in the breast).

[0092] "Associated with" or "associated with..." in the context of a substance or a substance activity or function associated with 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., head, neck or esophageal), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma or multiple myeloma)) 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 caused (in whole or in part) by the substance or substance activity or function, or that the symptoms of the disease are caused (in whole or in part) by the substance or substance activity or function.

[0093] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0094] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or as free bases when appropriate. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound, which have the desired pharmacological activity of the free base. These salts can be derived from inorganic acids, organic acids or bases. For example, compounds containing basic nitrogen can be prepared into pharmaceutically acceptable salts by contacting the compound with an inorganic acid or an organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyrates, succinate ... The pharmaceutically acceptable salts of the present invention are benzoic acid salts, benzoic acid salts, chlorobenzoic acid salts, methylbenzoic acid salts, dinitrobenzoic acid salts, hydroxybenzoic acid salts, methoxybenzoic acid salts, phthalates, sulfonates, methylsulfonates, propylsulfonates, benzenesulfonates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates and mandelates. The list of other suitable pharmaceutically acceptable salts can be found in "Remington: The Science and Practice of Pharmacy", 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0095] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include those derived from suitable bases such as alkali metals (eg, sodium, potassium), alkaline earth metals (eg, magnesium), ammonium and NX 4 + (where X is C 1 -C 4 Base addition salts such as sodium or potassium salts are also included.

[0096] Also provided are compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be substituted by deuterium atoms or D, wherein n is the number of hydrogen atoms in the molecule. As known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and can therefore be used to increase the half-life of compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527, 1984. Such compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0097] Examples of isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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. Use of positron emitting isotopes such as 11 C. 18 F. 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples listed below, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0098] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may include one or more asymmetric centers and may thus produce enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- in terms of absolute stereochemistry or as (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, and unless otherwise specified, it is intended that the compounds include E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where a compound is represented in its chiral form, it is understood that the embodiment encompasses but is not limited to a specific diastereomeric or enantiomerically enriched form. Where chirality is not specified but present, it is understood that the embodiment relates to a specific diastereomeric or enantiomerically enriched form; or a racemic or non-racemic mixture of such a compound. As used herein, a "non-racemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0099] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0100] One or more "stereoisomers" refer to compounds with different chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. If a compound has one or more asymmetric centers or has asymmetrically substituted double bonds, these compounds can exist in stereoisomeric forms and can therefore be prepared as individual stereoisomers or as mixtures. Unless otherwise indicated, this specification is intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry 4th edition, J. March, John Wiley and Sons, New York, 1992).

[0101] "Tautomer" refers to alternative forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both ring -NH- and ring =N-, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0102] 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 at the front or end of a chemical group are for convenience; a chemical group can be depicted without one or more dashes without loss of its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. A dotted line represents an optional bond. Unless chemically or structurally required, the order in which chemical groups are written or their points of attachment to the rest of the molecule do not indicate or imply directionality. For example, the group "-SO 2 CH 2 -" is equivalent to "-CH 2 SO 2 -", and both may be attached in either direction. Similarly, an "arylalkyl" group may be attached to the remainder of the molecule, for example, at either the aryl or alkyl portion of the group. A prefix such as "C u-v " or (C u -C v ) means that the following group has u to v carbon atoms. For example, "C 1-6 Alkyl" and "C 1 -C 6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms.

[0103] As used herein, "solvate" refers to the result of the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0104] As used herein, a "prodrug" is a derivative of a drug that is converted to the parent drug according to some chemical or enzymatic pathway when administered to the human body.

[0105] II. Combination

[0106] In some embodiments, the compounds or pharmaceutical compositions 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 include, for example, inhibitory immune checkpoint blockers or inhibitors, stimulatory immune checkpoint stimulators, agonists, or activators, chemotherapeutic agents, anticancer agents, radiotherapeutic agents, antitumor agents, antiproliferative agents, antiangiogenic agents, anti-inflammatory agents, immunotherapeutic agents, therapeutic antigen binding molecules (e.g., monospecific and multispecific antibodies or fragments thereof in any form, such as DARTs, ® , Duobody ® 、BiTE ® 、BiKE、TriKE、XmAb ® 、TandAb ®, scFv, Fab, Fab derivatives), bispecific antibodies, non-immunoglobulin antibody mimetics (including, for example, adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein (DARPin ® ), fynomers, knottins, Kunitz domain peptides, single antibodies and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or gene editors, cells containing chimeric antigen receptors (CARs) (e.g., including T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics), cells containing engineered T cell receptors (TCR-T), or a combination thereof.

[0107] Exemplary Targets

[0108] In some embodiments, the one or more additional therapeutic agents include, for example, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators, or suppressors of a target (e.g., a polypeptide or polynucleotide), such as: 2'-5'-oligoadenylate synthetase (OAS1; NCBI gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI gene ID: 54464); 5'-ectonucleotidase (NT5E, CD73; NCBI gene ID: 4907); ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-A BL, v-ABL; NCBI Gene ID: 25); melanoma deficiency factor 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 IDs: 134, 135, 136, 137); AKT serine / threonine kinase enzyme 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha-fetoprotein (AFP; NCBI Gene ID: 174); copper-containing amine oxidases (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI Gene IDs: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietin (ANGPT1, ANGPT2; NCBI Gene IDs: 284, 285); Angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); mitochondria-associated apoptosis-inducing factor 1 (AIFM1, AIF; NCBI Gene ID: 9131); arachidonic acid 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); steroid 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 protein (BTLA, CD272; NCBI Gene ID: 151888); baculovirus IAP repeat-containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP5); P3), BIRC5 (survivin); NCBI Gene IDs: 329, 330, 331, 332); basic glycoprotein (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 IDs: 598, 10018); β3-adrenergic receptor (ADRB3; NCBI Gene ID : 155); bone gamma-carboxyglutamate protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein 10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI Gene IDs: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain-containing and extracellular domain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 234 76, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695); cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004); cancer / testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363);Carbonic anhydrase (e.g., CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677); carcinoembryonic antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI gene ID: 1048 , 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2); NCBI Gene IDs: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene IDs: 836, 840, 841, 864); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); CC motif chemokine ligand 21 (CCL21 ; NCBI Gene ID: 6366); CC motif chemokine receptor 2 (CCR2; NCBI Gene ID: 729230); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI Gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NC BI Gene ID: 8317); cell communication network factor 2 (CCN2; NCBI Gene ID: 1490); cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatostatin 1 (CSH1; NCBI Gene ID: 1442); claudin (e.g., CLDN6, CLDN18; NCBI Gene IDs: 9074, 51208);Cluster of differentiation markers (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3α (TRA), CDβ (TRB), CDγ (TRG), CDδ (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLAST1), CD52, CD55 (DAF), CD58 (LFA3) ), CD74, CD79a, CD79b, CD80 (B7-1), CD84, CD86 (B7-2), CD96 (TACTILE), CD99 (MIC2), CD115 (CSF1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 ( IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), C D194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2R), CD223 (LAG3), CD226 (DNAM1), CD244, CD247, CD248, CD276 (B7-H3), CD331 (FGFR1), CD332 (FGFR2), CD333 (FGFR3), CD334 (FGFR4); NCBI gene ID: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 9 53, 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); Type IV collagen alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI Gene IDs: 1282, 1284, 1285, 1286, 1287); Collagen lectin subfamily member 10 (COLEC10; NCBI Gene ID: 10584); Colony stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI Gene IDs: 1435, 1437, 1440); Complement factors (e.g., C3, C5; NCBI Gene ID: 71 8, 727); COP9 signalosome subunit 5 (COPS5; NCBI gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371; NCBI gene IDs: 160364, 170482, 283420); CXC motif chemokine ligand 12 (CXCL12; NCBI gene ID: 6387); CXC motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R ), CXCR4 (CD184; NCBI Gene IDs: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI Gene ID: 595); cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI Gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (CCNG1; NCBI Gene ID: 900); cytochrome P 450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidoreductase (POR; NCBI Gene ID: 5447); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD box helicases (e.g., DDX5, DDX6, DDX58;NCBI Gene IDs: 1655, 1656, 23586); Delta-like canonical Notch ligands (e.g., DLL3, DLL4; NCBI Gene IDs: 10683, 54567); DiabloIAP-binding mitochondrial protein (DIABLO, SMAC; NCBI Gene ID: 56616); Diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI Gene IDs: 1606, 8525); Dickkopf WNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI Gene IDs: 22943, 27122); Dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); Dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); Dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); Discoidin domain receptor tyrosine 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: 2 022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene IDs: 51752, 64167); enhancer of zeste homolog 2 polycomb repressive complex 2 subunit (EZH2; NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI Gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4);NCBI Gene IDs: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI Gene ID: 4072); epithelial mitogen (EPGN; NCBI Gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI Gene IDs: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI Gene IDs: 1973, 1984); exportin-1 (XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fas ligand (FAS LG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragments of Ig receptors (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene IDs: 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., FG FR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI gene IDs: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGFα), FGF2 (FGFβ), FGF4, FGF5; NCBI gene IDs: 2246, 2247, 2249, 2250); fibronectin 1 (FN1, MSF; NCBI gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI gene IDs: 2336, 2337, 2338); BI 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 IDs: 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: 2744). :2950); glycogen synthase kinase 3β (GSK3B; NCBI Gene ID: 2932); phosphatidylinositol glycan 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: 10457); I gene ID: 2658); growth factor receptor binding protein 2 (GRB2, ASH; NCBI gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL, NCBI gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI gene ID: 283120); HCK proto-oncogene Src family tyrosine kinase (HCK; NCBI gene ID: 3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI Gene IDs: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene IDs: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cell receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatocyte growth factor (HGF; NCBI Gene ID: 3082); HERV-H LTR-associated 2 (HHLA2, B7-H7; NCBI Gene ID: 11148); histamine receptor H2 (HRH2; NCBI Gene ID: 3274); histone 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 IDs: 2034, 3091); I-κ-β kinase (IKKβ; NCBI gene IDs: 3551, 3553); IKAROS family zinc fingers (IKZF1 (LYF1), IKZF3; NCBI gene IDs: 10320, 22806); immunoglobulin superfamily member 11 (IGSF11; NCBI gene ID: 152404); indoleamine 2,3-dioxygenases (e.g., IDO1, IDO2; NCBI gene IDs: 3620, 169355); inducible T cell costimulators (ICOS, CD278; NCBI gene ID: 29851); inducible T cell costimulator ligands (ICOSLG, B 7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptors (e.g., IGF1R, IGF2R; NCBI Gene IDs: 3480, 3482); insulin-like growth factors (e.g., IGF1, IGF2; NCBI Gene IDs: 3479, 3481); insulin receptors (INSR, CD220; NCBI Gene ID: 3643); integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene IDs: 3678, 3685, 3688, 3695, 3697 8); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI gene ID: 3383); interleukin 1 receptor-associated kinase 4 (IRAK4; NCBI gene ID: 51135); interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6 (HGF), IL7, IL8 ( CXCL8), IL10 (TGIF), IL12A, IL12B, IL15, IL17A (CTLA8), IL18, IL23A, IL24, IL-29 (IFNL1); NCBI Gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618); Isocitrate dehydrogenase (NADP(+)1) (e.g., IDH1, IDH2; NCBI Gene IDs: 3417, 3418); Janus kinases (e.g., JAK1, JAK2, JAK3;NCBI gene IDs: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI gene ID: 354); killer cell immunoglobulin-like receptor Ig domain and long cytoplasmic tail (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI gene ID: 3 802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285); killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptors (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family Member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KISS1; NCBI Gene ID: 3814); KIT proto-oncogene receptor tyrosine kinase (KIT, C-KIT, CD117; NCBI Gene ID: 3815); KRAS proto-oncogene GTPase (KRAS; NCBI Gene ID: 3845); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 4035); Leucine repeat-containing protein 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene IDs: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); adaptor for activated T cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NCBI Gene ID: 3973); LY6 / PLAUR domain-containing 3 (LYPD3; NCBI Gene ID: 27076);Lymphocyte activation 3 (LAG3; CD223; NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene IDs: 4063, 17076); LYN proto-oncogene Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytoplasmic protein 2 (LCP2; NCBI Gene ID: 3937); lysine demethylase 1A (KDM1A; NCBI Gene ID: 23028); lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI Gene ID: 19 02); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase-like 2 (LOXL2; NCBI Gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 1 receptor (MST1R, CD136; NCBI Gene ID: 4486); MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI Gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); major histocompatibility complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene IDs: 3105, 3133, 3134, 3135); major vault protein (MVP, VAULT1; NCBI Gene ID: 9961); MALT1-like caspase (paracaspase) (MALT1; NCBI Gene ID: 108 92); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene IDs: 2872, 8569); matrix metalloproteinases (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 proto-oncogene (MDM2; NCBI gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI gene ID: 4194); Rapamycin stimulator Mechanistic targets of enzymes (MTOR, FRAP1; NCBI Gene ID: 2475); melanin-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene ID: 4157, 4148); MER proto-oncogene tyrosine kinase (MERTK; NCBI Gene ID: 10461); mesothelin (MSLN; NCBI Gene ID: 10232); MET proto-oncogene receptor tyrosine kinase (MET, c-Met, HGFR; NCBI Gene ID: 4233); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI Gene ID: 10988); MHC Class I polypeptide-related sequences (e.g., MICA, MICB; NCBI Gene IDs: 4277, 100507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38β), MAPK12; NCBI Gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI Gene IDs: 4217, 1326 ); mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein 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); mucins (e.g., MUC1 (including its splice variants (e.g., including MUC1 / A, C, D, X, Y, Z and REP)), MUC5AC, MUC16 (CA125); NCBI Gene ID: 4582, 4586, 94025);MYC proto-oncogene bHLH transcription factor (MYC; NCBI Gene ID: 4609); myostatin (MSTN, GDF8; NCBI Gene ID: 2660); 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 IDs: 5819, 81607); neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); neuropilin (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene IDs: 8828, 8829); neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene IDs: 4914, 4915, 4916); NFKB activated protein (NKAP; NCBI Gene ID: 7 9576); NIMA-associated kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain-containing protein 3 (NLRP3, NALP3; NCBI Gene ID: 114548); notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene IDs: 4851, 4853, 4854, 4855); NRAS proto-oncogene GTPase (NRAS; NCBI Gene ID: 4893); nuclear factor kappa B (NFKB1, NFKB2; NCBI Gene IDs: 4790, 4791); nuclear factor erythroid 2-like 2 (e.g., 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); nucleolar phosphatidylcholine 1 (NPM1; NCBI Gene ID: 4869); nucleotide-binding oligomerization domain-containing protein 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); ketoglutarate dehydrogenase (OGDH; NCBI Gene ID: 4967); parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); periostin (POSTN; NCBI Gene ID: 10631); peroxisome proliferator-activated receptors (e.g., PPARA (PPARα), PPARD (PPARδ), PPARG (PPARγ); NCBI Gene IDs: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinases (PIK3CA (PI3Kα), PIK3CB (PI3Kβ), PIK3CD (PI3Kδ), PIK3CG (PI3Kγ); NCBI gene IDs: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84 647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI Gene IDs: 5292, 11040, 415116); Placental growth factor (PGF; NCBI Gene ID: 5228); Plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); Platelet-derived growth factor receptor (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene IDs: 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) polymerases (e.g., PARP1, PARP2, PARP3; NCBI Gene IDs: 142, 10038, 10039); polycomb protein EED (EED; NCBI Gene ID: 8726); porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcriptional regulator (PRAME; NCBI Gene ID: 23532); premelanosomal 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 β9 (PSMB9; NCBI Gene ID: 5698); protein arginine phosphatase (e.g., PRMT1, PRMT5; NCBI Gene IDs: 3276, 10419); protein kinase N3 (PKN3; NCBI Gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI Gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI Gene ID: 5754); protein tyrosine phosphatase receptors (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene IDs: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X 7 (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); mTORC1-bound Ra s homolog (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); receptor-interacting serine / threonine-protein kinase 1 (RIPK1; NCBI Gene ID: 8737); ret proto-oncogene (RET; NCBI Gene ID: 5979); retinoic acid early transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091);Retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene IDs: 5914, 5916); retinoid X receptor (e.g., RXRA, RXRB, RXRG; NCBI Gene IDs: 6256, 6257, 6258); Rho-associated coiled-coil containing protein kinase (e.g., ROCK1, ROCK2; NCBI Gene IDs: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-β1; NCBI Gene ID: 6198); RING finger protein 128 (RNF128, GRAIL; NCBI Gene ID: 79589); ROS proto-oncogene 1 receptor tyrosine kinase (ROS1; NCBI Gene ID: 79589); Gene ID: 6098); roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium binding protein A9 (S100A9; NCBI Gene ID: 6280); secreted frizzled-related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID: 6696); secretory globulin family 1A member 1 (SCGB1A1; NCBI Gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene ID: 6401, 6402, 6403); semaphorin 4D (SEMA4D; CD100; NCBI gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI gene 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); longevity protein-3 (S IRT3; NCBI Gene ID: 23410); signaling lymphocyte activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI Gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI Gene ID: 84189); 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, 6753, 6754, 6755); hedgehog signaling molecule (SHH; NCBI Gene ID: 6469); Sp1 transcription factor (SP1; NCBI Gene ID: 6667); sphingosine kinases (e.g., SPHK1, SPHK2; NCBI Gene IDs: 8877, 56848); sphingosine-1-phosphate receptor 1 (S1PR1, CD363; NCBI Gene ID: 1901); spleen-associated tyrosine kinase (SYK; NCBI Gene ID: 6850); splicing factor 3B factor 1 (SF3B1; NCBI Gene ID: 23451); SRC proto-oncogene non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); stabilin 1 (STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family member 1 (STEAP1; NCBI Gene ID: 26872); steroid sulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interacting factor 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 protein 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene IDs: 6869, 6870); TANK binding kinase 1 (TBK1; NCBI Gene ID: 29110); tankyrase (TNKS; NCBI Gene ID: 8658);TATA-box binding protein-associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD-inducible poly (ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25976); 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 ); Triple repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); Thrombomodulin (THBD, CD141; NCBI Gene ID: 7056); Thymidine kinases (e.g., TK1, TK2; NCBI Gene IDs: 7083, 7084); Thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); Thymidylate synthase (TYMS; NCBI Gene ID: 7298); Thyroid hormone receptors (THRA, THRB; NCBI Gene IDs: 7606, 7608); Thyroid stimulating hormone receptor (TSHR; NCBI Gene ID: 7253); TNF superfamily members (e.g., For example, TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF 11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL); NCBI gene ID: 9 44, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995); Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); Transferrin (TF; NCBI gene ID: 7018);Transferrin receptor (TFRC, CD71; NCBI gene ID: 7037); transforming growth factor (e.g., TGFA, TGFB1; NCBI gene ID: 7039, 7040); transforming growth factor receptor (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 protein 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptor expressed on myeloid cells (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 hydroxylases (e.g., TPH1, TPH2; NCBI Gene ID: 716 6, 121278); tumor-associated calcium signal transducer 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); tumor necrosis factor (TNF; NCBI gene ID: 7124); members of the tumor necrosis factor (TNF) receptor superfamily (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD137, 4-1BB ), TNFRSF10A (CD261), TNFRSF10B (TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B (OPG), TNFRSF12A, TNFRSF13B, TNFR1 3C (CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25;NCBI Gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); tumor protein p53 (TP53; NCBI Gene ID: 7157); tumor suppressor 2 mitochondrial calcium regulator (TUSC2; NCBI Gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI Gene ID: 7301); tyrosinase (TYR; NCBI Gene ID: 7299); tyrosine hydroxylase (TH; NCBI Gene ID: 7054); tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin-conjugating enzyme E2 I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI Gene ID: 51377); ubiquitin-specific peptidase 7 (USP7; NCBI Gene ID: 7874); ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI Gene ID: 7317); UL16 binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene IDs: 79465, 80328, 80328); valosin-containing proteins (VCP, CDC48; NCBI Gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI Gene ID: 7412); vascular endothelial growth factor (e.g., VEGFA, VEGFB; NCBI Gene IDs: 7422, 7423); vimentin (VIM; NCBI Gene ID: 7431); vitamin D receptor (VDR; NCBI Gene ID: 7421); V-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunomodulatory receptor (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1 G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRN RecQ-like helicase (WRN; RECQ3; NCBI Gene ID: 7486); WT1 transcription factor (WT1; NCBI Gene ID: 7490); WW domain-containing transcription regulator 1 (WWTR1; TAZ; NCBI Gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI Gene ID: 6375);XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI Gene ID: 2829); Yes1-associated transcriptional regulator (YAP1; NCBI Gene ID: 10413); ζ chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535). ;

[0109] In some embodiments, the one or more additional therapeutic agents include, for example, agents targeting: 5'-ectonucleotidase (NT5E or CD73; NCBI Gene ID: 4907); adenosine A 2A Receptor (ADORA2A; NCBI Gene ID: 135); Adenosine A 2Breceptor (ADORA2B; NCBI Gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-α; NCBI Gene ID: 1606); fms-like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); integrin-associated protein (IAP, CD47; NCBI Gene ID: 961); interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin-2 receptors (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (KRAS; NCBI Gene ID: 3845; including mutants such as KRAS G12C or G12D); mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator (MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293); programmed death ligand 1 (PD-L1, CD274; NCBI Gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 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, PAR P7; 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);WRN RecQ-like helicase (WRN; NCBI Gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807). ;

[0110] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune escape of cancer cells in the tumor microenvironment. Activation or stimulation of stimulatory immune checkpoints can enhance the effect of immune checkpoint inhibitors in cancer treatment. In some embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., in Xu et al., J Exp Clin Cancer Res. (2018) 37: 110). In some embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., in Davis et al., Semin Immunol. (2017) 31: 64-75 and Chiossone et al., Nat Rev Immunol. (2018) 18 (11): 671-688). Inhibition of regulatory T cells (Tregs) or depletion of Tregs can alleviate their suppression of anti-tumor immune responses and have anti-cancer effects (e.g., reviewed in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0111] As used herein, "prodrug" is a derivative of a drug that is converted to the parent drug according to some chemical or enzymatic pathway when administered 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 (NC 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 immunomodulatory 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 (NCR3LG1, B7H6; NCBI gene ID: 374383); HERV-H LTR-associated 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 (TNFSF4, OX40L; NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 7293); 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 (MICA; NCBI Gene ID: 100507436); Class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI Gene ID: 5133); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); CD80 (B7-1; NCBI Gene ID: 941), CD28 (N CBI gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI gene ID: 5819); CD226 (DNAM-1; NCBI gene ID: 10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI gene ID: 5817); PVR-related immunoglobulin domain (PVRIG, CD112R; NCBI gene ID: 79037); with Ig and I T cell immunoreceptor with TIM domain (TIGIT; NCBI Gene ID: 201633); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4; NCBI Gene ID: 91937); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); galectin 9 (LGALS9; NCBI Gene ID: 3965); lymphocyte activation 3 (LAG3, CD223; NCBI Gene ID: 3902); signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI gene ID: 6504); lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI gene ID: 57823);UL16 binding protein 1 (ULBP1; NCBI Gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI Gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI Gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI Gene ID: 154064 ); Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1; NCBI Gene ID: 3811, e.g., lirelumab (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: 22914); : 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 (KIR 2DL3; 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). ;

[0112] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more blockers or inhibitors of one or more 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 immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin protein domains (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, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell 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, e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0113] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell NK 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 together with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis et al., Semin Immunol. (2017) 31: 64-75; Fang et al., Semin Immunol. (2017) 31: 37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18 (11): 671-688.

[0114] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimetic) inhibitors of LAG3.

[0115] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zeflalimab (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 the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0116] Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that may be co-administered include pembrolizumab, nivolumab, cemiplizumab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, coxilimab (CK-301), saxalizumab (PF-06801591), tislelizumab (BGB-A317), G LS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, Rivulimab (MGA-012), BI-754091, Batilizumab (AGEN-2034), AMG-404, Teplizumab (JS-001), Cetrilimab (JNJ-63723283), Genolizumab (CBT-501), LZM-009, Parolizumab (BCD-100), Lodalizumab Anti-(LY-3300054), SHR-1201, Camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT-502, dotalimumab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3 155, Envolizumab (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, Sepalimab (AB122), Spartalizumab (PDR-001), and compounds disclosed in WO 2018195321, WO2020014643, WO 2019160882 or WO 2018195321,As well as the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1) , RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), TAK-252 (PD-1 / OX40L), XmAb-20717 (PD-1 / CTLA4), AK-10 4 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-155 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), bintrafusp α (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor, such as CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0117] Examples of TIGIT inhibitors that may be co-administered include tisleliumab (RG-6058), vembrolizumab, dunalimab, dunalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0118] Examples of LAG3 inhibitors that may be co-administered include, but are not limited to, elalimumab (LAG525).

[0119] Inhibition of regulatory T cell (Treg) activity or Treg depletion can reduce their suppression of anti-tumor immune responses and have anti-cancer effects. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4: 459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49: 1140-1146. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more Treg activity inhibitors or Treg depletion agents. Treg inhibition or depletion can enhance the effect of immune checkpoint inhibitors in cancer therapeutics.

[0120] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more Treg inhibitors. In some embodiments, Treg inhibitors can inhibit Treg migration into the tumor microenvironment. In some embodiments, Treg inhibitors can reduce the immunosuppressive function of Treg. In some embodiments, Treg inhibitors can regulate cell phenotypes and induce the production of proinflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI gene ID: 1233) antagonists and degraders of Ikaros zinc finger proteins (e.g., Ikaros (IKZF1; NCBI gene ID: 10320), Helios (IKZF2; NCBI gene ID: 22807), Aiolos (IKZF3; NCBI gene ID: 22806), and Eos (IKZF4; NCBI gene ID: 64375).

[0121] Examples of Helios degraders that may be co-administered include, but are not limited to, I-57 (Novartis) and compounds disclosed in WO2019038717, WO2020012334, WO20200117759, and WO2021101919.

[0122] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more Treg depletion agents. In some embodiments, the Treg depletion agent is an antibody. In some embodiments, the Treg depletion antibody has antibody-dependent cellular cytotoxicity (ADCC) activity. In some embodiments, the Treg depletion antibody is Fc engineered to have enhanced ADCC activity. In some embodiments, the Treg depletion 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).

[0123] In some embodiments, the co-administered Treg inhibitor or Treg depleting agent comprises an antibody or antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of: CC motif chemokine receptor 4 (CCR4), CC motif chemokine receptor 7 (CCR7), CC motif chemokine receptor 8 (CCR8), CXC motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, extracellular nucleotide triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit αE (ITGAE; CD103), interleukin 7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), leucine-rich repeat-containing protein 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 β1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), or a combination thereof.

[0124] 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 antibodies disclosed in WO 2021163064, WO 2020138489, and WO 2021152186.

[0125] Examples of Treg-depleting anti-CCR4 antibodies that can be administered include moglizumab.

[0126] Inhibiting, depleting or reprogramming non-stimulatory myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5): 541-550; WO 2016049641). Exemplary targets for depleting or reprogramming 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 together with one or more myeloid cell depleting or reprogramming agents such as anti-TREM-1 antibodies (e.g., PY159; antibodies disclosed in WO2019032624) or anti-TREM-2 antibodies (e.g., PY314; antibodies disclosed in WO2019118513).

[0127] Cluster of differentiation agonists or activators

[0128] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an agent targeting a cluster of differentiation (CD) marker. Exemplary agents targeting CD markers that can be co-administered include, but are not limited to, A6, AD-IL24, neratinib, tocatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN ®), trastuzumab biosimilars (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 malate), AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, rebastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, duvitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverembatinib dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate L-malate), CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asunercept (APG-101), APO-010, and compounds disclosed in the following documents: WO 2016196388, WO 2016033570, WO 2015157386, WO 199203459, WO199221766, WO 2004080462, WO 2005020921, WO 2006009755, WO 2007078034, WO2007092403, WO 2007127317, WO 2008005877, WO 2012154480、WO 2014100620、WO2014039714、WO 2015134536、WO 2017167182、WO 2018112136、WO 2018112140、WO2019155067、WO2020076105, PCT / US 2019 / 063091, WO 19173692, WO 2016179517, WO2017096179, WO 2017096182, WO 2017096281, WO 2018089628, WO 2017096179, WO2018089628, WO 2018195321, WO 2020014643, WO 2019160882, WO 2018195321, WO200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO2011076781, WO 2013056352, WO 2015138600, WO 2016179399, WO 2016205042, WO2017178653, WO 2018026600, WO 2018057669, WO 2018107058, WO 2018190719, WO2018210793, WO 2019023347, WO 2019042470, WO 2019175218, WO 2019183266, WO2020013170, WO 2020068752, Cancer Discov.2019 January 9(1):8; Gariepy J. Tototo 106th Annu Meet Am Assoc Immunologists (AAI) (May 9th to 13th, San Diego, 2019, Abst71.5).

[0129] In some embodiments, agents 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, roblitinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-1 91. BLU-263, CD117-ADC, AZD3229, telatinib, vorolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, burixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0130] In some embodiments, agents targeting CD markers that may be co-administered include small molecule agonists such as interleukin-2 receptor subunit gamma, eltrombopag, retamod, polyICLC (NSC-301463), Riboxxon, Apoxxim, RIBOXXIM ® , MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, resiquimod, selgantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0131] In some embodiments, agents targeting CD markers that may be co-administered include antibodies such as tafasitamab (MOR208; MorphoSys AG), Inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilars (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzartamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX ®), TTX-030, selicrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, mitazalimab (JNJ-64457107), lenziluma, alemtuzuma, emactuzumab, AMG-820, FPA-008 (cabiralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simlukafusp α alfa)(RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatlimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, encelimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20.5), MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, lirilumab (IPH-2102), lacutamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), apamistamab (131I) (131I-BC8 (lomab-B)), MEDI0562 (tavolixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX -518, BMS-986156, MK-1248, GWN-323, CTB-006, INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, cobolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in WO 2017096179, WO 2017096276, WO2017096189, and WO 2018089628. .

[0132] In some embodiments, agents targeting CD markers that can be co-administered include cell therapies such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, liso-cel, lisocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta ®), KTE-X19, US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), tisagenlecleucel-T (CTL019), T cells expressing CD19CAR-CD28-CD3ζ-EGFRt, CD19 / 4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζ T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T cell therapy (acute lymphoblastic leukemia / non-Hodgkin's lymphoma, University Hospital Heidelberg, Germany), anti-CD19 CAR T cell therapy (silenced IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19 / APRIL), ICG-134, ICG-132 (CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20 CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), Tn / mem expressing CD19CAR-CD28-CD3ζ-EGFRt, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, Tesaran-T, CART-19, Tesaran (CTL-019)), anti-CD20 CAR T cell therapy (non-Hodgkin's lymphoma), MB-CART2019.1 (CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CART cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01 (NKG2D ligand modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, and therapies disclosed in WO 2012079000 or WO 2017049166. .

[0133] Cluster of differentiation 47 (CD47) inhibitors

[0134] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with inhibitors of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 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), IBI-188 (letaplimab), lemzoparlimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or in WO 199727873, WO 199940940, WO 2002092784, WO2005044857, WO 2009046541, WO 2010070047, WO 2011143624, WO 2012170250, WO2013109752, WO 2013119714, WO 2014087248, WO 2015191861, WO 2016022971, WO2016023040, WO 2016024021, WO 2016081423, WO 2016109415, WO 2016141328, WO2016188449, WO 2017027422, WO 2017049251, WO 2017053423, WO 2017121771, WO2017194634, WO 2017196793, WO 2017215585, WO 2018075857, WO 2018075960, WO2018089508, WO 2018095428, WO 2018137705, WO 2018233575, WO 2019027903, WO2019034895, WO 2019042119, WO 2019042285, WO 2019042470, WO 2019086573, WO2019108733, WO 2019138367, WO Compounds disclosed in WO 2019144895, WO 2019157843, WO 2019179366, WO 2019184912, WO 2019185717, WO 2019201236, WO 2019238012, WO 2019241732, WO2020019135, WO 2020036977, WO 2020043188 and WO 2020009725.In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPα-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is mololimab.

[0135] 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 / FLT 3), 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.

[0136] SIRPa targeting agents

[0137] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with: a SIRPα targeting agent (NCBI gene ID: 140885; UniProt P78324). Examples of SIRPα targeting agents include SIRPα inhibitors (such as AL-008, RRx-001, and CTX-5861) and anti-SIRPα antibodies (such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPα / PD-L1)). Additional SIRPα targeting agents of use are described, for example, in WO 200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO2010083253, WO 2011076781, WO 2013056352, WO 2015138600, WO 2016179399, WO2016205042, WO 2017178653, WO 2018026600, WO 2018057669, WO 2018107058, WO 2018190719, WO 2018210793, WO 2019023347, WO 2019042470, WO 2019175218, WO2019183266, WO 2020013170 and WO 2020068752.

[0138] FLT3R agonists

[0139] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a FLT3R agonist. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a FLT3 ligand. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a FLT3L-Fc fusion protein (e.g., as described in WO2020263830). In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with GS-3583 or CDX-301. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with GS-3583.

[0140] TNF receptor superfamily (TNFRSF) member agonists or activators

[0141] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agonist of one or more TNF receptor superfamily (TNFRSF) members, such as an agonist of one or more of the following: 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: 961), TNFRSF7 (TNFRSF8; NCBI gene ID: 962), TNFRSF9 (TNFRSF10; NCBI gene ID: 963), TNFRSF11 (TNFRSF12; NCBI gene ID: 964), TNFRSF13 (TNFRSF14; NCBI gene ID: 965), TNFRSF15 (TNFRSF16; NCBI gene ID: 966), TNFRSF17 (TNFRSF18; NCBI gene ID: 967), TNFRSF19 (TNFRSF11; NCBI gene ID: 968), TNFRSF20 (TNFRSF21; NCBI gene ID: 969), TNFRSF22 (TNFRSF23; NCBI gene ID: 970), TNFRSF24 (TNFRSF25; NCBI gene ID: 971), TNFRSF25 (TNFRSF26; NCBI gene ID: 969), TNFRSF27 (TNFRSF28; NCBI gene ID: 972), TNFRSF29 (TNFRSF29; NCBI gene ID: 973), TNFRSF28 (TNFRSF29; NCBI gene ID: 969), TNFRSF29 (TNFRSF21 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, TRAIL R3, 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: 23496), and TNFRSF14A (CD269, NCBI gene ID: 3761). 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).

[0142] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tavolizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO 2016179517, WO 2017096179, WO 2017096182, WO 2017096281, and WO 2018089628.

[0143] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0144] In some embodiments, the anti-TNFRSF7 (CD27) antibody varilumab (CDX-1127) is co-administered.

[0145] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include usurelumab, utolumab (PF-05082566), AGEN-2373, and ADG-106.

[0146] In some embodiments, co-administration

[0147] Anti-TNFRSF17 (BCMA) antibody GSK-2857916.

[0148] 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 those described in WO 2017096179, WO 2017096276, WO2017096189, and WO 2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO 2017096179 and WO2018089628.

[0149] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronextamab (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).

[0150] Bispecific T cell engagers

[0151] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a bispecific T cell engager (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), onituzumab (odronextamab) (REGN-1979; CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (heme / CD3), JNJ-7564 (CD3 / heme), AMG-757 (DLL3-C D3), ​​AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), AMG-427 (FLT3 / CD3), AMG-562 (CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-673 (CD3 3 / 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 / CDw 123), JNJ-9383 (MGD-015), AMG-424 (CD38 / CD3), tidutamab (XmAb-18087 (SSTR2 / CD3)), JNJ-63709178 (CD123 / CD3), MGD-0 07 (CD3 / gpA33), MGD-009 (CD3 / B7H3), IMCgp100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20) Titumumab (XmAb-18087;SSTR2 / CD3), catumaxomab (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). The anti-CD3 binding bispecific molecule may or may not have an Fc, as appropriate. Exemplary bispecific T cell engagers that can be co-administered target CD3 and a tumor-associated antigen as described herein, including, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil et al., Oncoimmunology. (2017) May 17; 6(7):e1326437); PD-L1 (Horn et al., Oncotarget. 2017 Aug 3; 8(35):57964-57980); and EGFRvIII (Yang et al., Cancer Lett. 2017 Sep 10; 403:224-230). ;

[0152] Bispecific and trispecific natural killer (NK) cell engagers

[0153] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a bispecific NK cell engager (BiKE) or a trispecific NK cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc) against: NK cell activating receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates 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 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKEs or TriKEs that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Depending on the circumstances, 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 as described herein, including, for example, 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.

[0154] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0155] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO 2018183418, WO 2016033486, and WO 2017147410.

[0156] SHP2 inhibitors

[0157] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in WO 2018172984 and WO 2017211303.

[0158] Hematopoietic progenitor kinase 1 (HPK1) inhibitors and degraders

[0159] In some embodiments, an antibody and / or fusion protein provided herein is administered with an inhibitor of mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of hematopoietic progenitor kinase 1 (HPK1) inhibitors include, but are not limited to, those described in WO 2020092621, WO 2018183956, WO 2018183964, WO 2018167147, WO 2018049152, WO 2020092528, WO 2016205942, WO 2016090300, WO2018049214, WO 2018049200, WO 2018049191, WO 2018102366, WO 2018049152, and WO2016090300.

[0160] Apoptosis signal-regulating kinase (ASK) inhibitors

[0161] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of ASK, e.g., mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO 2011008709 (Gilead Sciences) and WO 2013112741 (Gilead Sciences).

[0162] Bruton's tyrosine kinase (BTK) inhibitors

[0163] 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 GeneID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (Ibrutinib), and PD-1 inhibitors. evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0164] Cyclin-dependent kinase (CDK) inhibitors

[0165] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with inhibitors 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 CDK 1, 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, simurosertib hydrate (TAK931), and TG-02.

[0166] Discoidin domain receptor (DDR) inhibitors

[0167] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with an inhibitor of the following kinases: discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO 2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0168] Targeting E3 ligase ligand conjugates

[0169] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a targeting E3 ligase ligand conjugate. Such conjugates have a target protein binding portion and an E3 ligase binding portion (e.g., inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce and survivin) E3 ubiquitin ligase binding portion, Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding portion, cereblon E3 ubiquitin ligase binding portion, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding portion), and can be used, for example, to promote or increase degradation of the targeted protein via the ubiquitin pathway. In some embodiments, the targeting E3 ligase ligand conjugate comprises: a targeting or binding portion that targets or binds to a protein described herein, and an E3 ligase ligand or binding portion. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting or binding moiety that targets or binds to a protein selected from the group consisting of: 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, such as BTK and a small molecule kinase inhibitor of an E3 ligase ligand or binding moiety). See, e.g., WO2018098280. In some embodiments, the targeted E3 ligase ligand conjugate comprises: targeting or binding to interleukin-1 (IL-1) receptor associated kinase-4 (IRAK-4); a binding moiety of rapidly accelerated fibrosarcoma (RAF, such as c-RAF, A-RAF and / or B-RAF), c-Met / p38 or BRD protein; and an E3 ligase ligand or binding moiety. See, for example, WO 2019099926, WO 2018226542, WO 2018119448, WO 2018223909, WO 2019079701. Additional targeted E3 ligase ligand conjugates that may be co-administered are described, for example, in WO 2018237026, WO 2019084026, WO 2019084030, WO2019067733, WO 2019043217, WO 2019043208, and WO 2018144649.

[0170] Histone deacetylase (HDAC) inhibitors

[0171] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of a histone deacetylase, such as an inhibitor of 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, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0172] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0173] 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 vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0174] Janus kinase (JAK) inhibitors

[0175] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10; THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), igratinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasocitinib citrate), INCB052793, and XL019.

[0176] Lysyl oxidase-like protein (LOXL) inhibitors

[0177] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of a LOXL protein, such as LOXL1 (NCBI Gene ID: 4016), LOXL2 (NCBI Gene ID: 4017), LOXL3 (NCBI Gene ID: 84695), LOXL4 (NCBI Gene ID: 84171), and / or LOX (NCBI Gene ID: 4015). Examples of LOXL2 inhibitors include antibodies described in WO 2009017833 (Arresto Biosciences), WO 2009035791 (Arresto Biosciences), and WO 2011097513 (Gilead Biologics).

[0178] Matrix metalloproteinase (MMP) inhibitors

[0179] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of a matrix metalloproteinase (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), simaxastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012027721 (Gilead Biologics).

[0180] RAS and RAS pathway inhibitors

[0181] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of KRAS proto-oncogene GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene GTPase ( NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or HRAS proto-oncogene GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). Ras inhibitors can inhibit Ras at the level of polynucleotides (e.g., transcription inhibitors) or polypeptides (e.g., GTPase inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, such as inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that can be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adagrasib (MRTX-849), ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 and KRpep-2d. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 aptamers, AZD-4785, siG12D-LODER ™and siG12D exosomes. Exemplary MEK inhibitors that may be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that may be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that may be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that may be co-administered include ligotinib. Illustrative PI3K inhibitors that may be co-administered include Zydelig ® ), aboliciib, bupariciib, pictilisib, inavolisib (RG6114), ASN-003. Exemplary AKT inhibitors that can be co-administered include capasitinib and GSK2141795. Exemplary PI3K / mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, GSK-2126458, inariciib (RG6114), sapanisertib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), racemic tyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL ® , CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administering the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou et al., Cancer Lett. 2017 Nov 1;408:130-137. Moreover, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1 / 2 / 4 inhibitor neratinib. See, e.g., Booth et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0182] Mitogen-activated protein kinase (MEK) inhibitors

[0183] 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, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include antroquinonol, bimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimacitinib, LTT462, AS703988, CC-90003, and refametinib.

[0184] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0185] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of the following substances: 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, P110DELTA, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, Bupalixib (BKM120), BYL719 (arbolixib), CH5132799, copanlixib (BAY 80-6946), duvelixib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Zydelig ®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, regoratinib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and in WO 2005113556 (ICOS), WO 2013 / 052699 (Gilead Calistoga), WO 2013116562 (Gilead Calistoga), WO 2014100765 (Gilead Calistoga), WO 2014100767 (Gilead Calistoga) and WO 2014201409 (Gilead Sciences).

[0186] Spleen tyrosine kinase (SYK) inhibitors

[0187] In some embodiments, an antibody and / or fusion protein provided herein is administered with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI Gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in US8450321 (Gilead Connecticut) and US 20150175616.

[0188] Toll-like receptor (TLR) agonists

[0189] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agonist of a toll-like receptor (TLR), such as 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).Exemplary TLR7 agonists that can be co-administered include DS-0509, GS-9620 (visamod), visamod 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 US 20100143301 (Gilead Sciences), US 20110098248 (Gilead Sciences), and US 20090047249 (Gilead Sciences). 20140045849 (Janssen), US 20140073642 (Janssen), WO 2014056953 (Janssen), WO 2014076221 (Janssen), WO 2014128189 (Janssen), US 20140350031 (Janssen), WO 2014023813 (Janssen), US 20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US 20100029585 (Ventirx Pharma), US 20110092485 (Ventirx Pharma), US 20110118235 (Ventirx Pharma), US 20120082658 (VentirxPharma), US Compounds disclosed in US 20120219615 (Ventirx Pharma), US 20140066432 (Ventirx Pharma), US 20140088085 (Ventirx Pharma), US 20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). A TLR7 / TLR8 agonist that may be co-administered is NKTR-262.Exemplary 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 US 20140045849 (Janssen), US 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), US 20140350031 (Janssen), WO 2014 / 023813 (Janssen), US Compounds disclosed in US 20080234251 (Array Biopharma), US 20080306050 (Array Biopharma), US 20100029585 (Ventirx Pharma), US 20110092485 (Ventirx Pharma), US 20110118235 (Ventirx Pharma), US 20120082658 (Ventirx Pharma), US 20120219615 (Ventirx Pharma), US 20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US 20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). Example TLR9 agonists that can be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include retasimide, polyICLC, RIBOXXON. ® 、Apoxxim、RIBOXXIM ® , IPH-33, MCT-465, MCT-475 and ND-1.1.

[0190] Tyrosine kinase inhibitors (TKIs)

[0191] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a tyrosine kinase inhibitor (TKI). TKIs can target receptors for epidermal growth factor receptor (EGFR) as well as 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 (drazentinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, clenonib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib tinib, KX2-391 (Src), lapatinib, lestautinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib L-malate (MAC-4), tivanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary agents targeting EGFR include neratinib, tocatinib (ONT-380), tefatinib, mobotinib (TAK-788), DZD-9008, valitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA ®) and compounds disclosed in Booth et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137. Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab sarotalocan (RM-1929), seribantumab, nesimumab, depatuxizumab mafodotin (ABT-414), tomozutuximab, depatuxizumab (ABT-806), and cetuximab.

[0192] Chemotherapeutic agents

[0193] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a chemotherapeutic or anti-tumor agent.

[0194] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is intended to encompass any non-proteinaceous (e.g., non-peptide) compound that can be used to treat cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN ®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodepa, carboquinone, metodepa and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; lactones such as brassic acid and brassinone; camptothecins, including the synthetic analogue topotecan; bryostatin, callystatin; CC-1065, including its synthetic analogues adolesin, carzelesin and biszelesin; scutellarin, especially scutellarin 1 and scutellarin 8; caudate phytosine; duocarmycins, including the synthetic analogues KW -2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, cyclophosphamide, glufosfamide, ivophosphamide, bendamustine, estramustine, ifosfamide, dichloromethyl diethylamine, dichloromethyl diethylamine hydrochloride, melphalan, nembixin, phenamic acid, prednimustine, trolofosamide and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as Edenediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma II and calicheamicin phiI), danimycins (including danimycin A), bisphosphonates (such as clodronate), espammycins, neostatin chromophores and related chromophores, enediyne antibiotic chromophores, aclarubicin, actinomycin, authramycin, azaserine, bleomycin, actinomycin, carabicin, carrninomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detopicin, 6-diazo-5-oxo-L-norleucine acid, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolo-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogamycin, olivetomycin, peplomycin, porfibrinocin, puromycin, quinamycin, rhodorubicin, streptomycin, streptozotocin, tuberculocidin, ubenimex, zoloft and daunorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as norpterin, methotrexate, pteropterin and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiabendazole and thioguanine;Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as caprotestosterone, drostanolone propionate, cyclothiocarb, melastane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; radiotherapeutic agents such as radium-223; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxanes such as paclitaxel; ® ), albumin-bound paclitaxel (abraxane), docetaxel (TAXOTERE ® ), cabazitaxel, BIND-014, tesetaxel; sabizabulin (Veru-111); platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; acetoglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatrexate; fosfoamide; colcemid; diazocone; elformthine; elliptolide; epothilone; epothilone; etoglucose; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansine alkaloids such as maytansine and ansamitocin; Mitoguanidine; mitoxantrone; mopidarol; diamine nitrazol; pentostatin; methamine nitrogen mustard; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizoran; spirogermanamine; tricholomaric acid; trabectedin, triazoquinone; 2,2',2''-trichlorotrimethylamine; carbamate; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine (GEMZAR ® ); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE ®)。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。 )。

[0195] Antihormonal agents

[0196] Also included in the definition of "chemotherapeutic agent" are anti-hormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), aromatase inhibitors, antiandrogens, and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing, which are used to modulate or inhibit the effects of hormones on tumors.

[0197] Examples of antiestrogens and SERMs include tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, troloxifene, raloxifene hydrochloride, LY117018, onapristone, and toremifene (FARESTON ® ).

[0198] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE ® ), exemestane, formestane, fadrozole, vorazole (RIVISOR ® ), letrozole (FEMARA ® ) and anastrozole (ARIMIDEX ® ).

[0199] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galactron, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antisense).

[0200] Examples of progesterone receptor antagonists include onapristone. Additional progesterone-targeting agents include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri-Cyclen), and levonorgestrel.

[0201] Anti-angiogenic agents

[0202] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include retinoids and their derivatives, 2-methoxyestradiol, ANGIOSTATIN ® ENDOSTATIN ® , regorafenib, nivolumab, 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 (herring protamine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators (including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thioproline), α,α'-bipyridine, β-amino Propionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken metalloproteinase 3 inhibitor (ChIMP-3), chymosin inhibitor, β-cyclodextrin tetradecansulfate, epothilone, fumagillin, gold sodium thiomalate, d-penicillamine, β-1-anticollagenase-serum, α-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthranilic acid disodium or "CCA", thalidomide, antiangiogenic steroids, carboxyaminoimidazoles, metalloproteinase inhibitors such as BB-94, S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies to these angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2. Examples of anti-VEGFA antibodies that may be co-administered include bevacizumab, vanucizumab, faricimab, dilpacimab (ABT-165; DLL4 / VEGF), or navicixizumab (OMP-305B83; DLL4 / VEGF).

[0203] Antifibrotic agents

[0204] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an anti-fibrotic agent. Anti-fibrotic agents that can be co-administered include compounds such as β-aminopropionitrile (BAPN), and compounds disclosed in US4965288 involving lysyl oxidase inhibitors and their use in treating diseases and conditions associated with abnormal collagen deposition and compounds disclosed in US4997854 involving inhibition of LOX to treat various pathological fibrotic states, the patents are incorporated herein by reference. Additional exemplary inhibitors are described in US4943593 involving compounds such as 2-isobutyl-3-fluoro-, chloro- or bromo-allylamine, US5021456, US5059714, US5120764, US5182297, US5252608, and US 20040248871 involving 2-(1-naphthyloxymethyl)-3-fluoroallylamine, which are incorporated herein by reference.

[0205] Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of lysyl oxidase, and more specifically, those that produce products stabilized by resonance upon binding to the carbonyl group, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated halogenated amines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine ​​lactone.

[0206] Other anti-fibrotic agents are copper chelators that infiltrate or do not infiltrate cells. Exemplary compounds include indirect inhibitors that block aldehyde derivatives derived from lysyl oxidase to lysyl and hydroxylysyl residues oxidative deamination. Examples include thiolamines (particularly D-penicillamine) and analogs thereof, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetylaminoethyl) dithio) butyric acid, p-2-amino-3-methyl-3-((2-aminoethyl) dithio) butyric acid, 4-((p-1-dimethyl-2-amino-2-carboxylethyl) dithio) butane sodium sulfate, 2-acetylaminoethyl-2-acetylaminoethanethiol sulfate and 4-mercaptobutanesulfinate sodium trihydrate.

[0207] Anti-inflammatory agents

[0208] 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, inhibitors of one or more of the following: arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), C A12 (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), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, such as a dual inhibitor of COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX.

[0209] Examples of inhibitors of prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742) that may be co-administered include mofetil, GLY-230, and TRK-700.

[0210] Examples of inhibitors of prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, mesosulide, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anizafine, alicoxib, cimicoxib, deracoxib, fluumidazole, firocoxib, mavalocoxib, NS-398, pamigrelbrine, parecoxib, robacoxib, rofecoxib, evodiamine, temoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that may 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 may be co-administered include pomacoxib and ericoxib.

[0211] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that may be co-administered include LY3023703, GRC 27864, and WO 2015158204, WO 2013024898, WO2006063466, WO 2007059610, WO 2007124589, WO 2010100249, WO 2010034796, WO2010034797, WO 2012022793, WO 2012076673, WO 2012076672, WO 2010034798, WO 2010034799, WO 2012022792, WO 2009103778, WO 2011048004, WO 2012087771, WO2012161965, WO 2013118071, WO 2013072825, WO 2014167444, WO 2009138376, WO2011023812, WO 2012110860, WO 2013153535, WO 2009130242, WO 2009146696, WO2013186692, WO 2015059618, WO 2016069376, WO 2016069374, WO 2009117985, WO2009064250, WO Compounds described in WO 2009064251, WO 2009082347, WO 2009117987, and WO 2008071173. Metformin has also been found to inhibit the COX2 / PGE2 / STAT3 axis, and metformin can be co-administered. See, e.g., Tong et al., Cancer Lett. (2017) 389:23-32; and Liu et al., Oncotarget. (2016) 7(19):28235-46.

[0212] 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 may be co-administered include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and dichlorobenzenesulfonamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0213] Examples of inhibitors of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) that may be co-administered include meclofenamic acid sodium, zileuton.

[0214] Dual inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that may be co-administered include compounds described in WO 2015148954. Dual inhibitors of COX-2 / SEH that may be co-administered include compounds described in WO2012082647. Dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that may be co-administered include compounds described in WO2017160861.

[0215] Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression site 2, TPL2; NCBI gene ID: 1326) that may be co-administered include GS-4875, GS-5290, BHM-078, and those described in WO 2006124944, WO 2006124692, WO 2014064215, WO 2018005435; Teli et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila et al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0216] Tumor oxygenator

[0217] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with agents that promote or increase tumor oxygenation or reoxygenation or prevent or reduce tumor hypoxia. Exemplary agents that can be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors, such as PT-2977, PT-2385; VEGF inhibitors, such as bevasizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen binding protein (HNOX)), such as OMX-302 and HNOX proteins described in WO 2007137767, WO2007139791, WO 2014107171, and WO 2016149562.

[0218] Immunotherapeutic agents

[0219] 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. Exemplary immunotherapeutics that can be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bectumomab, bevacizumab , bivatuzumab, blinatumomab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab , dalotuzumab, daratumumab, detumomab, dinutuximab, domvanalimab, drozitumab, duligotumab, dusigitumab, ecoromeximab, elotuzumab, emibetuzumab, ensituximab, ertuximab rtumaxomab), etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab,imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY, ® , MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, necitumumab, nimotuzumab, nof etumomab), OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab (Cyramza ®), rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, tapitumomab, tenatumomab The following are some of the drugs that can be used to treat B-cell cancers: rituximab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, 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.

[0220] The exemplified therapeutic antibodies may be further labeled or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y-clituzumab), or iodine-131.

[0221] In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Exemplary ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics targeting proteins or antigens listed above and herein. Exemplary ADCs that may be co-administered include gemtuzumab, brentuximab, belantamab (e.g., belantamab mofortin), camidanlumab (e.g., camidanlumab teslin), trastuzumab (e.g., trastuzumab-drunotecan; trastuzumab-emtansine), inotuzumab, glenbarumab, anetumab, mirvetuximab (e.g., mirvetuximab ... mirvetuximab soravtansine), depatuxizumab, vadastuximab, labetuximab, laditratuzumab (e.g., laditratuzumab vedotin), loncastuximab (e.g., loncastuximab teslin), sacituzumab (e.g., sacituzumab govitecan), datopotuzumab (e.g., datopotuzumab drutilecan; DS-1062;Dato-DXd), pertuzumab (e.g., pertuzumab derugent), rifatuzumab, indusatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., risorbazine), rilsodotin), indalatuximab, milatuzumab, rofopilizumab (e.g., rofopilizumab teslin), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamab lavtansine), disitamab (e.g., disitamab vedotin), terituzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK28 57916, Humax-TF-ADC, IMGN289, IMGN151, IMGN529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, P F-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. ;

[0222] Exemplary therapeutic agents (e.g., anticancer agents or antitumor agents) that can be conjugated to the drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethylreoxetine E (MMAE), monomethylreoxetine F (MMAF), calicheamicin, ansamitocin, maytansine or its analogs (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM2), sirolimus / ... M4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinker SC-DR002 (D6.5), duocarmycin, microtubule inhibitors (MTI) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or its dimer, duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or antitumor 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., anticancer or antitumor agent) that can be conjugated to the drug-conjugated antibody, its fragment or antibody mimetic includes an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 includes BPI-002.

[0223] In some embodiments, the ADC that can be co-administered includes an antibody targeting 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, TROP2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datobotanumab derunotecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou Duoxi Biotechnology Co., Ltd., Shanghai Junshi Biopharmaceuticals Co., Ltd.), sacizumab govinotecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech / Zhangjiang, Yakult Honsha, Shanghai Henlius Biotech Co., Ltd.), LIV-2008b (LivTech / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Shijian Biotechnology Co., Ltd., TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan Zhangjiang Biopharmaceutical Co., Ltd.), SKB-264 (Sichuan Kelun Pharmaceutical Co., Ltd.), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing Kaidi Biotechnology Co., Ltd.), WO 2020016662 (Abmart), WO 2020249063 (Bio-TheraSolutions), US 20190048095 (Bio-Thera Solutions), WO2013077458(LivTech / Chiome)、EP20110783675(Chiome)、WO 2015098099(Daiichi Sankyo)、WO 2017002776(DaiichiSankyo)、WO 2020130125(Daiichi Sankyo)、WO 2020240467(Daiichi Sankyo)、US2021093730(Daiichi Sankyo)、US9850312(Daiichi Sankyo)、CN112321715(Biosion)、US2006193865(Immunomedics / Gilead)、WO 2011068845(Immunomedics / Gilead)、US2016296633(Immunomedics / Gilead)、US 2017021017(Immunomedics / Gilead)、US2017209594(Immunomedics / Gilead)、US 2017274093(Immunomedics / Gilead)、US2018110772(Immunomedics / Gilead)、US 2018185351(Immunomedics / Gilead)、US2018271992(Immunomedics / Gilead)、WO 2018217227(Immunomedics / Gilead)、US2019248917(Immunomedics / Gilead)、CN111534585(Immunomedics / Gilead)、US2021093730(Immunomedics / Gilead)、US 2021069343(Immunomedics / Gilead)、US8435539(Immunomedics / Gilead)、US8435529(Immunomedics / Gilead)、US9492566(Immunomedics / Gilead)、WO 2003074566(Gilead)、WO 2020257648(Gilead)、US 2013039861(Gilead)、WO2014163684(Gilead)、US9427464(LivTech / Chiome)、US 10501555(Abruzzo Theranostic / Oncoxx)、WO2018036428 (Sichuan Kelun Pharmaceutical Co., Ltd.), WO 2013068946 (Pfizer), WO2007095749 (Roche), and WO 2020094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Patent Nos. 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anticancer agent connected by a linker. In some embodiments, the linker includes a linker disclosed in USPN 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug portion of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doxorubicin (DOX), epirubicin, morpholino doxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolinyl-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lurtotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxanes, geldanamycin, ansamycin and epothilone. In some embodiments, the chemotherapeutic portion is SN-38. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with sacetuzumab govitecan.

[0224] In some embodiments, the ADC that can be co-administered includes targeting carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a; NCBI Gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (e.g., as described in WO1996011013). In some embodiments, the CEACAM1-ADC is as described in WO 2010093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the CEACAM1-ADC IMMU-130.

[0225] In some embodiments, the ADC that can be co-administered includes an antibody targeting an MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO2006094192). In some embodiments, the HLA-DR-ADC is as described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the HLA-DR-ADC IMMU-140.

[0226] Cancer gene therapy and cell therapy

[0227] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; genetic modification of silencing mutated genes; genetic methods that directly kill cancer cells; including infusions of immune cells designed to replace most of the patient's own immune system to enhance the immune response to cancer cells, or activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells, or find and kill cancer cells; genetic methods that change cell activity to further change the endogenous immune response to cancer.

[0228] Cell therapy

[0229] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with one or more cell therapies. Exemplary cell therapies include, but are not limited to, co-administering 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 lymphocytes (TILs), and / or dendritic cells (DCs). In some embodiments, the cell therapy requires T cell therapy, such as co-administering α / β TCR T cells, γ / δ TCR T cells, regulatory T (Treg) cells, and / or TRuC ™ A population of T cells. In some embodiments, cell therapy requires NK cell therapy, such as co-administration of NK-92 cells. Depending on the circumstances, cell therapy may require co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0230] In some embodiments, cell therapy requires co-administration of cells containing a chimeric antigen receptor (CAR). In such therapies, a population of immune effector cells is engineered to express a CAR, wherein the CAR comprises a tumor antigen binding domain. In T cell therapy, a T cell receptor (TCR) is engineered to target a tumor-derived peptide presented on the surface of a tumor cell.

[0231] In terms of the structure of CAR, in some embodiments, CAR comprises an antigen binding domain, a transmembrane domain and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of the following items: CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (Fcε Rlb), CD79a, CD79b, FcγRIIa, DAP10 and DAP12.

[0232] In some embodiments, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NK p80 (KLRFI), CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, I TGA6, 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, CRTA M, 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.

[0233] In some embodiments, the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: alpha, beta, or zeta chain of a 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, CD 1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD1 8), 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, CD15 0, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and NKG2C.

[0234] In some embodiments, a TCR or CAR antigen binding domain or an immunotherapeutic described herein (e.g., a monospecific or multispecific antibody or antigen-binding fragment thereof, or an antibody mimetic) binds a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); 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); folate receptor alpha; receptor tyrosine protein kinase, ERBB2 (Her2 / neu); cell surface-associated mucin 1 (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostate enzyme; prostatic acid phosphatase (PAP); mutated elongation factor 2 (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (Prosome, Macropain) subunit beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein composed of the breakpoint cluster region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl) (bcr-abl); tyrosinase;Ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); occludin 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 glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenal receptor β3 (ADRB3); pan-nexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCRγ alternate reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-la); 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 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); fos-related antigen 1; tumor protein p53, (p53); p53 mutants; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); rat sarcoma (Ras) mutants; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints ; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosamine transferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytoma viral oncogene neuroblastoma-derived homolog (MYCN); ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI);CCCTC-binding factor (zinc finger protein)-like (BORIS or brother of regulator of imprinted sites factor), squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box protein Pax-5 (PAX5); pre-acrosin binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchoring protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitin 1 (RUI); renal ubiquitin 2 (RU2); legumin; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; mutant heat shock protein 70-2 (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module containing mucin-like hormone receptor 2 (EMR2); lymphocyte antigen 75 (LY75); phosphatidylinositol glycan-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 in MHC. ;

[0235] In some embodiments, the tumor antigen is selected from CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD 80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, α-fetoprotein (AFP), angiogenic factors, exogenous cognate binding molecules (ExoCBM), oncogene products, antifolate receptor, c-Met, cancer Embryonic antigen (CEA), cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, activin, melanoma associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate specific antigen, tEGFR, tenascin, P2-Microgiobuiin, Fc receptor-like 5 (FcRL5).

[0236] In some embodiments, the antigen binding domain binds to an epitope of a target or tumor-associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer testis antigen. In some embodiments, the cancer testis antigen is selected from the group consisting of sperm acrogranulin 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; AKAP 82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI gene ID: 8852), ATPase family AAA domain protein 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI gene ID: 29028), centromere scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI gene ID: 57082), 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 protein 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI Gene ID: 151871), fetal and adult testis expressed protein 1 (FATE1; CT43, FATE; NCBI Gene ID: 89885), FMR1 neighbor (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI Gene ID: 158521), HORMA domain-containing protein 1 (HORMAD1; CT46, NOHMA; NCBI Gene ID: 84072), insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3; CT98, IMP-3, IMP3, 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), whirlpool spermatogenesis transposon silencer (MAEL; CT128, SPATA35; NCBI gene ID: 84944), MAGE family member A1 (MAGEA1; CT1.1, MAGE1; NCBI gene ID: 41 00); 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; N CBI gene ID: 9585), NUF2 component of the NDC80 centromere complex (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 R NA-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 nucleus, X-linked family member A1 (SPANXA1; CT11.1, CT11.3, NAP-X, S PAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A; NCBI gene ID: 30014), SPANX family member A2 (SPANXA2; CT11.1, CT11.3, SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC; NCBI gene ID: 728712), SPANX family member C (SPANXC; CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE; NCBI gene ID: 64663), SPANX family member D (SPANXD; CT11.3, CT11.4, SPANX-C, SPANX-D, SPANX-E, SPANXC, SPANXE, dJ171K16.1; NCBI gene ID: 64648), SSX family member 1 (SSX1; CT5.1, SSRC; NCBI gene ID: 6756), SSX family member 2 (SSX2; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI gene ID: 6757), synaptonemal complex protein 3 (SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI gene ID: 50511), testis expressed 14 intercellular bridge The invention relates to a novel cytokine synthase (TEX14; CT113, SPGF23; NCBI gene ID: 56155), a transcription factor Dp family member 3 (TFDP3; CT30, DP4, HCA661; NCBI gene ID: 51270), a serine protease 50 (PRSS50; CT20, TSP50; NCBI gene ID: 29122), a TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI gene ID: 7272), and a 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 testis antigens presented in major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer testis antigens associated with neoplasia are summarized, for example, in Gibbs et al., Trends Cancer; 2018 Oct; 4(10):701-712 and the CT database website cta.lncc.br / index.php. Exemplary TCRs and TCR-like antibodies that bind to epitopes of NY-ESO-1 presented in MHC are described, for example, in Stewart-Jones et al., Proc Natl Acad Sci USA.April 7, 2009; 106(14):5784-8; WO 2005113595, WO 2006031221, WO2010106431, WO 2016177339, WO 2016210365, WO 2017044661, WO 2017076308, WO2017109496, WO 2018132739, WO 2019084538, WO 2019162043, WO 2020086158 and WO2020086647. Exemplary TCR and TCR-like antibodies that bind to an epitope of PRAME presented in MHC are described, for example, in WO2011062634, WO 2016142783, WO 2016191246, WO 2018172533, WO 2018234319 and WO2019109821. Exemplary TCR and TCR-like antibodies that bind to MAGE epitopes presented in MHC are described, e.g., in WO2007032255, WO 2012054825, WO 2013039889, WO 2013041865, WO 2014118236, WO2016055785, WO 2017174822, WO 2017174823, WO 2017174824, WO 2017175006, WO2018097951, WO 2018170338, WO 2018225732, and WO 2019204683. Exemplary TCRs and TCR-like antibodies that bind to epitopes of alpha-fetoprotein (AFP) presented in MHC are described, for example, in WO 2015011450. Exemplary TCRs and TCR-like antibodies that bind to epitopes of SSX2 presented in MHC are described, for example, in WO 2020063488. Exemplary TCRs and TCR-like antibodies that bind to epitopes of KK-LC-1 (CT83) presented in MHC are described, for example, in WO 2017189254. .

[0237] Examples of cell therapy include Algenpantucel-L, Sipuleucel-T, rivogenlecleucel (BPX-501) US9089520, WO 2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBLCAR 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.

[0238] In some embodiments, one or more additional co-administered therapeutic agents can be categorized according to their mechanism of action into, for example, the following groups:

[0239] •Agents that target adenosine deaminase, such as pentostatin or cladribine;

[0240] •Agents targeting ATM, such as AZD1390;

[0241] • Agents that target MET, such as savolitinib, capmatinib, tepotinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115;

[0242] • Agents targeting mitogen-activated protein kinases, such as antroquinol, bimetinib, cobimetinib, selumetinib, trametinib, eupressor, mirdametinib (PD-0325901), pimacitinib, refactinib, or compounds disclosed in WO 2011008709, WO 2013112741, WO 2006124944, WO2006124692, 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;

[0243] •Agents that target thymidine kinase, such as aglatimagene besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk);

[0244] • Agents targeting the interleukin pathway, such as Pegilodecakin (AM-0010) (PEGylated IL10), CA-4948 (IRAK4 inhibitor);

[0245] • Agents that target members of the cytochrome P450 family, such as letrozole, anastrozole, aminoglutethimide, megestrol acetate (MEGACE ® ), exemestane, formestane, fadrozole, vorazole (RIVISOR ® ), letrozole (FEMARA ® ) or anastrozole (ARIMIDEX ® );

[0246] • Agents that target CD73, such as CD73 inhibitors (e.g., quemliclustat (AB680)) or anti-CD73 antibodies (e.g., oleclumab);

[0247] • Agents targeting DKK3, such as MTG-201;

[0248] •Agents that target EEF1A2, such as priligy;

[0249] •Agents that target EIF4A1, such as lorlatinib;

[0250] • Agents that target endoglin, such as TRC105 (carotuximab);

[0251] •Agents that target exportin 1, such as eltanexor;

[0252] • Agents targeting fatty acid amide hydrolases, such as the compounds disclosed in WO 2017160861;

[0253] •Agents that target heat shock protein 90 beta family member 1, such as anlotinib;

[0254] •Agents that target lactotransferrin, such as ruxotemitide (LTX-315);

[0255] • Agents targeting lysyl oxidase, such as compounds disclosed in US4965288, US4997854, US4943593, US5021456, US5059714, US5120764, US5182297, US5252608 or US 20040248871;

[0256] •Agents that target MAGE family members, such as KITE-718, MAGE-A10C796T, or MAGE-A10 TCR;

[0257] • Agents that target MDM2, such as ALRN-6924, CMG-097, milademetan monotosylate monohydrate (DS-3032b), or AMG-232;

[0258] •Agents that target MDM4, such as ALRN-6924;

[0259] •Agents targeting melanin A, such as MART-1 F5 TCR-engineered PBMCs;

[0260] •Agents that target mesothelin, such as CSG-MESO or TC-210;

[0261] •Agents that target METAP2, such as M8891 or APL-1202;

[0262] •Agents that target NLRP3, such as BMS-986299;

[0263] •Agents that target ketoglutarate dehydrogenase, such as devimistat (CPI-613);

[0264] •Agents that target placental growth factor, such as aflibercept;

[0265] • Agents targeting SLC10A3, such as compounds disclosed in WO 2015148954, WO 2012082647 or WO 2017160861;

[0266] • Agents targeting transforming growth factor alpha (TGF), such as the compounds disclosed in WO2019103203;

[0267] •Agents that target the tumor protein p53, such as kevetrin (stimulator);

[0268] •Agents that target vascular endothelial growth factor A, such as aflibercept;

[0269] •Agents that target the vascular endothelial growth factor receptor, such as fruquintinib or MP0250;

[0270] •Agents that target VISTA, such as CA-170 or HMBD-002;

[0271] • Agents that target WEE1, such as adavosertib (AZD-1775);

[0272] • Small molecule inhibitors targeting ABL1, such as imatinib, ribatinib, asciminib, or ponatinib (ICLUSIG ® );

[0273] • Small molecule antagonists targeting adenosine receptors, such as CPI-444, AZD-4635, predinanide, edradine (AB928), or PBF-509;

[0274] • Small molecule inhibitors targeting arachidonic acid 5-lipoxygenase, such as meclofenamic acid or zileuton;

[0275] • Small molecule inhibitors targeting ATR serine / threonine kinases, such as BAY-937, ceralasertib (AZD6738), AZD6783, VX-803, or VX-970 (berzosertib);

[0276] • Small molecule inhibitors targeting the AXL receptor tyrosine kinase, such as bemcentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3);

[0277] • Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posetinib (HM71224), ibrutinib (Imbruvica), M-2951 (ivubrutinib), telabrutinib (ONO-4059), rizabrutinib (PRN-1008), sepretinib (CC-292), vecabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315;

[0278] • Small molecule inhibitors targeting neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or selitrectinib (LOXO-195);

[0279] • Small molecule inhibitors targeting the ROS proto-oncogene 1 receptor tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib;

[0280] • Small molecule inhibitors targeting the non-receptor tyrosine kinase of the SRC proto-oncogene, such as VAL-201, tirbanibulin (KX2-391), or ilginatinib maleate (NS-018);

[0281] • Small molecule inhibitors targeting B-cell lymphoma 2, such as navitoclax (ABT-263), venetoclax (ABT-199, RG-7601), or AT-101 (gossypol);

[0282] • Small molecule inhibitors targeting proteins containing bromodomains and extracellular domains (BET) bromodomains, such as ABBV-744, INCB-054329, INCB057643, AZD-5153, ABT-767, BMS-986158, CC-90010, NHWD-870, ODM-207, ZBC246, ZEN3694, CC-95775 (FT-1101), mivebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829;

[0283] • Small molecule inhibitors targeting carbohydrate sulfotransferase 15, such as STNM-01;

[0284] • Small molecule inhibitors targeting carbonic anhydrase, such as polmacoxib, acetazolamide, or methazolamide;

[0285] • Small molecule inhibitors targeting β-catenin, such as CWP-291 or PRI-724;

[0286] • Small molecule antagonists targeting CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (virivirox);

[0287] • Small molecule antagonists targeting CXC motif chemokine receptors (e.g., CXCR4), blixafortide;

[0288] • Small molecule inhibitors targeting cereblon, such as avadomide (CC-122), CC-92480, CC-90009, or iberdomide;

[0289] • Small molecule inhibitors targeting checkpoint kinase 1, such as SRA737;

[0290] • Small molecule inhibitors targeting complement components, such as Imprime PGG (Biothera Pharmaceuticals);

[0291] • Small molecule inhibitors targeting CXC motif chemokine ligands (e.g., CXCL12), such as olaptesed pegol (NOX-A12);

[0292] • Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone or abiraterone acetate;

[0293] • Small molecule inhibitors targeting DEAD box helicase 5, such as supinoxin (RX-5902);

[0294] • Small molecule inhibitors targeting DGKa, for example, such as described in WO2021130638;

[0295] • Small molecule inhibitors targeting diablo IAP-binding mitochondrial proteins, such as BI-891065;

[0296] • Small molecule inhibitors targeting dihydrofolate reductase, such as pralatrexate or pemetrexed disodium;

[0297] • Small molecule inhibitors targeting DNA-dependent protein kinases, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastuzumab;

[0298] • Small molecule inhibitors targeting MARCKS, such as BIO-11006;

[0299] • Small molecule inhibitors targeting RIPK1, such as GSK-3145094;

[0300] • Small molecule inhibitors targeting Rho-associated coiled-coil containing protein kinases, such as AT13148 or KD025;

[0301] • Small molecule inhibitors targeting DNA topoisomerases, such as irinotecan, firtecanpegol, or amrubicin;

[0302] • Small molecule inhibitors targeting dopamine receptor D2, such as ONC-201;

[0303] • Small molecule inhibitors targeting DOT1-like histone lysine methyltransferases, such as pinometostat (EPZ-5676);

[0304] • Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497;

[0305] • Small molecule inhibitors targeting fatty acid synthase, such as TVB-2640 (Sagimet Biosciences);

[0306] • Small molecule inhibitors targeting fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144);

[0307] • Small molecule inhibitors targeting focal adhesion kinases (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098;

[0308] • Small molecule inhibitors targeting folate receptor 1, such as pralatrexate;

[0309] • Small molecule inhibitors targeting FOXM1, such as thiostrepton;

[0310] • Small molecule inhibitors targeting galectin-3, such as belapectin (GR-MD-02);

[0311] • Small molecule antagonists that target the glucocorticoid receptor, such as relacorilant (CORT-125134);

[0312] • Small molecule inhibitors targeting glutaminase include but are not limited to CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES);

[0313] • Small molecule inhibitors targeting the GNRHR, such as elagrolimus, relugolix, or degarelix;

[0314] • Small molecule inhibitors targeting EPAS1, such as belzutifan (PT-2977 (Merck & Co.));

[0315] • Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)), such as limited to ivosidenib (AG-120), vorasidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221);

[0316] • Small molecule inhibitors targeting lysine demethylase 1A, such as CC-90011;

[0317] • Small molecule inhibitors targeting MAPK-interacting serine / threonine kinases, such as tomivosertib (eFT-508);

[0318] • Small molecule inhibitors targeting notch receptors, such as AL-101 (BMS-906024);

[0319] • Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as volasertib or onvansertib;

[0320] • 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, CEP9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102;

[0321] • Small molecule inhibitors targeting Polycomb EED, such as MAK683;

[0322] • Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974;

[0323] • Small molecule inhibitors targeting prostaglandin-endoperoxide synthase, such as HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, otenaproxesul (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, reconstituted Celecoxib (DRGT-46), AAT-076, meisuoshuli, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anizafine, alicoxib, cimicoxib, deracoxib, flumidazole, firocoxib, mavacoxib, pamigrelor, parecoxib, robenacoxib, rofecoxib, evodiamine, temacoxib, zaltoprofen or imrecoxib;

[0324] • Small molecule inhibitors targeting protein arginine N-methyltransferase, such as MS203, PF-06939999, GSK3368715, or GSK3326595;

[0325] • Small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720), or compounds disclosed in WO 2018172984 or WO 2017211303;

[0326] • Small molecule antagonists targeting retinoic acid receptors, such as tamibarotene (SY-1425);

[0327] • Small molecule inhibitors targeting ribosomal protein S6 kinase B1, such as MSC2363318A;

[0328] • Small molecule inhibitors targeting S100 calcium-binding protein A9, such as tasquinimod;

[0329] • Small molecule inhibitors targeting selectin E, such as uproleselan sodium (GMI-1271);

[0330] • Small molecule inhibitors targeting SF3B1, such as H3B-8800;

[0331] • Small molecule inhibitors targeting Sirtuin-3, such as YC8-02;

[0332] • Small molecule inhibitors targeting SMO, such as sonidegib (Odomzo ® , formerly known as LDE-225), vismodegib (GDC-0449), glasdegib (PF-04449913), itraconazole, patidegib, or taladegib;

[0333] • Small molecule antagonists targeting somatostatin receptors, such as OPS-201;

[0334] • Small molecule inhibitors targeting sphingosine kinase 2, such as opaganib (Yeliva ® , ABC294640);

[0335] • Small molecule inhibitors targeting STAT3, such as napabucasin (BBI-608);

[0336] • Small molecule inhibitors targeting tankyrase, such as G007-LK or stenoparib (2X-121(e-7499));

[0337] • Small molecule inhibitors targeting TFGBR1, such as galunisertib and PF-06952229;

[0338] • Small molecule inhibitors targeting thymidylate synthase, such as idetrexed (ONX-0801);

[0339] • Small molecule inhibitors targeting the tumor protein p53, such as CMG-097;

[0340] • Small molecule inhibitors targeting valosin-containing proteins, such as CB-5083;

[0341] • Small molecule inhibitors targeting WT1, such as ombipepimut-S (DSP-7888);

[0342] • Small molecule agonists targeting adenosine receptors, such as namodenoson (CF102);

[0343] • Small molecule agonists targeting asparaginase, such as crisantaspase (Erwinase ® ), GRASPA (ERY-001, ERY-ASP), calaspargase pegol, or pegaspargase;

[0344] • Small molecule agonists targeting CCAAT enhancer binding protein α, such as MTL-501;

[0345] • Small molecule agonists targeting the cytochrome P450 family, such as mitotane;

[0346] • Small molecule agonists targeting DExD / H-box helicase 58, such as RGT-100;

[0347] • Small molecule agonists that target the GNRHR, such as leuprolide acetate, leuprolide acetate extended-release depot (ATRIGEL), triptorelin pamoate, or goserelin acetate;

[0348] • Small molecule agonists targeting GRB2, such as prexigebersen (BP1001);

[0349] • Small molecule agonists targeting NFE2L2, such as omaveloxolone (RTA-408);

[0350] • Small molecule agonists targeting NOD2, such as mifamotide (liposomal);

[0351] • Small molecule agonists targeting RAR-related orphan receptor γ, such as syntropin (LYC-55716);

[0352] • Small molecule agonists targeting retinoic acid receptors (RARs), such as retinoic acid;

[0353] • 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;

[0354] • Small molecule agonists targeting thyroid hormone receptor β, such as levothyroxine sodium;

[0355] • Small molecule agonists targeting TNF, such as tasonamine;

[0356] • Antisense agents targeting baculoviral IAP repeat-containing protein 5, such as EZN-3042;

[0357] • Antisense agents targeting GRB2, such as prexigebersen;

[0358] • Antisense agents targeting heat shock protein 27, such as apatorsen;

[0359] • Antisense agents targeting STAT3, such as danvatirsen (IONIS-STAT3-2.5Rx);

[0360] • Gene therapy targeting CC motif chemokine receptors, such as SB-728-T;

[0361] • Gene therapies targeting interleukins, such as EGENE-001, tavokinogene telseplasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55;

[0362] • Antibodies targeting claudin 18, such as claudiximab;

[0363] •Antibodies targeting clusterin, such as AB-16B5;

[0364] • Antibodies that target complement components, such as ravulizumab (ALXN-1210);

[0365] • Antibodies targeting CXC motif chemokine ligands, such as BMS-986253 (HuMax-Inflam);

[0366] • Antibodies targeting delta-like canonical Notch ligand 4 (DLL4), such as demcizumab and navicula (DLL4 / VEGF);

[0367] •Antibodies targeting EPH receptor A3, such as fibatuzumab (KB-004);

[0368] •Antibodies targeting epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845);

[0369] • Antibodies targeting fibroblast growth factor, such as GAL-F2, B-701 (vofatamab);

[0370] •Antibodies targeting hepatocyte growth factor, such as MP-0250;

[0371] • Antibodies that target interleukins, such as canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), siltuximab, or tocilizumab;

[0372] •Antibodies targeting LRRC15, such as ABBV-085 or cusatuzumab (ARGX-110);

[0373] •Antibodies targeting mesothelin, such as BMS-986148, SEL-403, or anti-MSLN-MMAE;

[0374] • Antibodies targeting myostatin, such as landogrozumab;

[0375] • Antibodies targeting the notch receptor, such as tarextumab;

[0376] •Antibodies targeting TGFB1 (TGFb1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA089, or compounds disclosed in WO2019103203;

[0377] • Vaccines targeting fms-related receptor tyrosine kinases, such as HLA-A2402 / HLA-A0201-restricted epitope peptide vaccines;

[0378] • Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax);

[0379] • Vaccines targeting PD-L1, such as IO-120 + IO-103 (PD-L1 / PD-L2 vaccine) or IO-103;

[0380] • Vaccines targeting the tumor protein p53, such as MVA-p53;

[0381] • Vaccines targeting WT1, such as WT-1 analog peptide vaccine (WT1-CTL);

[0382] • Cell therapies targeting baculovirus IAP repeat-containing protein 5, such as the tumor lysate / MUC1 / survivin PepTivator-loaded dendritic cell vaccine;

[0383] • Cell therapies targeting carbonic anhydrase, such as DC-Ad-GMCAIX;

[0384] • Cell therapy targeting CC-motif chemokine receptors, such as CCR5-SBC-728-HSPC;

[0385] • Cell therapies targeting folate hydrolase 1, such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN;

[0386] • Cell therapies targeting GSTP1, such as CPG3-CAR (GLYCAR);

[0387] • Cell therapies targeting HLA-A, such as FH-MCVA2TCR or NeoTCR-P1;

[0388] •Cell therapies targeting interleukins, such as CST-101;

[0389] • Cell therapy targeting KRAS, such as anti-KRAS G12D mTCR PBL;

[0390] • Cell therapy targeting MET, such as anti-cMet RNA CAR T;

[0391] • Cell therapies targeting MUC16, such as JCAR-020;

[0392] • Cell therapy targeting PD-1, such as PD-1 knockout T cell therapy (esophageal cancer / NSCLC);

[0393] • Cell therapies targeting PRAME, such as BPX-701;

[0394] • Cell therapies targeting transforming protein E7, such as KITE-439;

[0395] •Cell therapies targeting WT1, such as WT1-CTL, ASP-7517 or JTCR-016.

[0396] Exemplary Combination Therapies

[0397] Combination therapy for lymphoma or leukemia

[0398] Some chemotherapeutic agents are useful in treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplastic A10, antineoplastic AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta alethine, BMS-345541, bortezomib (VELCADE ® ), bortezomib (VELCADE ® , PS-341), bryostatin 1, bulsulfan, 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, Aplysia 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin alfa, 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 alfa-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, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), ethylenediaminetetracycline, ethylenediaminetetracycline liposomal doxorubicin hydrochloride, perifosine, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab monoclonal antibody and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE) and R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine bitartrate, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide and hydroxamic acid), vemurafenib (Zelboraf ® ), venetoclax (ABT-199).

[0399] 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 ® ), Yttrium-90 Ibritumomab (ZEVALIN ® ) and BEXXAR ® with CHOP.

[0400] The above therapies may be supplemented or combined with stem cell transplantation or therapy. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole body irradiation, stem cell infusion, bone marrow ablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic technology, low LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0401] Combination therapy for non-Hodgkin lymphoma

[0402] Treatment of non-Hodgkin lymphoma (NHL), especially those of B-cell origin, includes the use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, prednisolone), all optionally including rituximab (R), etc.), radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy with chemotherapy.

[0403] Examples of unconjugated monoclonal antibodies used to treat NHL / B-cell cancers 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.

[0404] Examples of experimental antibody agents used to treat NHL / B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumizumab, apolizumab, milatuzumab, and bevacizumab.

[0405] Examples of standard regimens for chemotherapy for NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R MCP.

[0406] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90 ibritumomab (ZEVALIN ® ) and iodine-131 tositumomab (BEXXAR ® ).

[0407] Combination therapy for mantle cell lymphoma

[0408] Curative treatments for mantle cell lymphoma (MCL) include combination chemotherapy such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0409] 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, which are based on the genetic makeup of an individual patient's tumor.

[0410] An improved approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles (such as iodine-131 tositumomab (BEXXAR ® ) and Y-90 Ibritumomab tiuxetan (ZEVALIN ® ) combination. In another example, BEXXAR ® For sequential treatment with CHOP.

[0411] Other approaches to treat MCL include autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (VELCADE ® or PS-341) or administration of anti-angiogenic agents such as thalidomide, especially in combination with rituximab.

[0412] Another treatment approach is to administer drugs that cause degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents.

[0413] Another treatment method includes the administration of mTOR inhibitors that can lead to inhibition of cell growth or even cell death. Non-limiting examples are sirolimus, temsirolimus, and mTOR inhibitors. ® , CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and RITUXAN ® 、VELCADE ® or temsirolimus in combination with other chemotherapeutic agents.

[0414] Other recent MCL therapies have been published. Examples include flavopiridol, palbociclib (PD0332991), R-roscovitine (celicilib, CYC202), styrylsulfone, obaclava (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).

[0415] Combination therapy for Waldenstrom's macroglobulinemia

[0416] Therapeutic agents used to treat Waldenstrom's macroglobulinemia (WM) include aldesleukin, alemtuzumab, avosidix, amifostine trihydrate, aminocamptothecin, antineoplastic A10, antineoplastic AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, β-alexin, bortezomib (VELCADE ® ), bryostatin 1, busufan, Campas-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin, dexamethasone, docetaxel, Aplysia 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, 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 (such as 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, perifosin, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA ® ), simvastatin, sirolimus, tacrolimus, tanspiramycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, ulocuplumab, veltuzumab, vincristine sulfate, vinorelbine tartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0417] Examples of therapeutic procedures used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole body irradiation, stem cell infusion, myeloablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic techniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0418] Combination therapy for diffuse large B-cell lymphoma (DLBCL)

[0419] 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, cupranisib, lenalidomide (Revlimid ® ), dexamethasone, cytarabine, cisplatin, Yescarta ® , Kymriah ® ,Polivy ® (Polatumumab vedotin), BR (Bendamustine (Treanda ® )), gemcitabine, oxaliplatin, oxaliplatin, tafacitumomab, polatuzumab, cyclophosphamide, or a combination thereof. In some embodiments, the therapeutic agent used to treat DLBCL includes R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin ® ) + prednisone), rituximab + bendamustine, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), rituximab + lenalidomide, R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara C) + cisplatin), Polivy ® (Polatumumab vedotin) + BR (Bendamustine (Treanda ® ) and rituximab (Rituxan ®), R-GemOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafacitumab + lenalidomide), tafacitumab + 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 agent used to treat DLBCL includes tafamidis, glofitamab, epcoritamab, Lonca-T (telantuximab teslin), Debio-1562, polatuzumab, Yescarta, JCAR017, ADCT-402, brentuximab vedotin, MT-3724, onituzumab, Auto-03, Allo-501A, or TAK-007.

[0420] Combination therapy for chronic lymphocytic leukemia

[0421] Therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0422] Combination therapy for high-risk myelodysplastic syndrome (HR MDS)

[0423] Therapeutic agents used to treat HR MDS include azacitidine (Vidaza ® ), decitabine (Dacogen ® ), Revlimid ® ), cytarabine, idarubicin, daunorubicin, and combinations thereof. In some embodiments, the combination includes cytarabine + daunorubicin and cytarabine + idarubicin. In some embodiments, the therapeutic agent for treating HR MDS includes mololimab, pevonistat, venetoclax, sabatolizumab, guacitabine, ligotinib, ivosidenib, ensidipine, selinexor, BGB324, DSP-7888, or SNS-301.

[0424] Combination therapy for low-risk myelodysplastic syndrome (LR MDS)

[0425] Therapeutic agents used to treat LR MDS include lenalidomide, azacytidine, and combinations thereof. In some embodiments, the therapeutic agent used to treat LR MDS includes roxadustat, luspatercept, imetelstat, LB-100, or ligotinib.

[0426] Combination therapy for acute myeloid leukemia (AML)

[0427] Therapeutic agents used to treat AML include cytarabine, idarubicin, daunorubicin, midostaurin (Rydapt ® ), venetoclax, azacitidine, ivasidenib, gilteritinib, ensidipine, low-dose cytarabine (LoDAC), mitoxantrone, fludarabine, granulocyte colony-stimulating factor, idarubicin, gilteritinib (Xospata ® ), Ensidipine (Idhifa ® ), Ivonib (Tibsovo ® ), decitabine (Dacogen ® ), mitoxantrone, etoposide, gemtuzumab ozogamicin (Mylotarg ® ), Glasgibb (Daurismo ® ) and combinations thereof. In some embodiments, therapeutic agents used to treat AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF), and idarubicin), cytarabine + idarubicin, cytarabine + daunorubicin + midostaurin, venetoclax + azacitidine, cytarabine + daunorubicin, or MEC (mitoxantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents used to treat AML include pevonistat, venetoclax, sabatolizumab, eprenetapopt, or leszolimab.

[0428] Combination therapy for multiple myeloma (MM)

[0429] Therapeutic agents used to treat MM include lenalidomide, bortezomib, dexamethasone, daratumumab (Darzalex ® ), pomalidomide, cyclophosphamide, carfilzomib (Kyprolis ®), Elotuzumab (Empliciti), and combinations thereof. In some embodiments, therapeutic agents for treating MM include RVS (lenalidomide + bortezomib + dexamethasone), RevDex (lenalidomide plus dexamethasone), CYBORD (cyclophosphamide + bortezomib + dexamethasone), Vel / Dex (bortezomib plus dexamethasone), or PomDex (pomalidomide + low-dose dexamethasone). In some embodiments, therapeutic agents for treating MM include JCARH125, TAK-573, belantamab mofortin, ide-cel (CAR-T).

[0430] Combination therapy for breast cancer

[0431] Therapeutic agents used to treat breast cancer include nab-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, the therapeutic agent used to treat breast cancer (e.g., HR+ / - / HER2+ / -) includes trastuzumab (Herceptin ® ), Perjeta ® ), docetaxel, carboplatin, palbociclib (Ibrance ® ), letrozole, trastuzumab-emtansine (Kadcyla ® ), Fulvestrant (Faslodex ® ), Lynparza ® ), eribulin, tucatinib, capecitabine, lapatinib, everolimus (Afinitor ® ), exemestane, eribulin mesylate (Halaven ® ) and combinations thereof. In some embodiments, therapeutic agents for treating breast cancer include trastuzumab + pertuzumab + docetaxel, trastuzumab + pertuzumab + docetaxel + carboplatin, palbociclib + letrozole, tucatinib + capecitabine, lapatinib + capecitabine, palbociclib + fulvestrant, or everolimus + exemestane. In some embodiments, therapeutic agents for treating breast cancer include trastuzumab-drutec, datopotamusab drutec (DS-1062), enfutumab vedotin (Padcev ®), balixafortide, elastrant, or a combination thereof. In some embodiments, the therapeutic agent for treating breast cancer includes balixafortide + eribulin.

[0432] Combination therapy for triple-negative breast cancer (TNBC)

[0433] Therapeutic agents used to treat TNBC include atezolizumab, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, the therapeutic agent used to treat TNBC includes olaparib (Lynparza ® ), atezolizumab (Tecentriq ® ), paclitaxel (Abraxane ® ), Eribulin, Avastin, Carboplatin, Gemcitabine, Eribulin Mesylate (Halaven ® ), Trodelvy ® ), pembrolizumab (Keytruda ® ), cisplatin, doxorubicin, epirubicin, or a combination thereof. In some embodiments, therapeutic agents for treating TNBC include atezolizumab + paclitaxel, bevacizumab + paclitaxel, carboplatin + paclitaxel, carboplatin + gemcitabine, or paclitaxel + gemcitabine. In some embodiments, therapeutic agents for treating TNBC include eryaspase, capasitinib, abrocitabine, rucaparib + nivolumab, atezolizumab + paclitaxel + gemcitabine + capecitabine + carboplatin, pataseti + paclitaxel, ladizumab vedotin + pembrolizumab, durvalumab + DS-8201a, trasiksib + gemcitabine + carboplatin. In some embodiments, therapeutic agents for treating TNBC include trastuzumab-drutican (Enhertu ® ), datobotulinumab drutilecan (DS-1062), enfutumomab vedotin (Padcev ® ), balisafortide, adagloxad simolenin, nelipepimut-s (NeuVax ® ), Opdivo ® ), rucaparib, toripalimab (Tuoyi ® ), carrelizumab, capasitinib, durvalumab (Imfinzi ® ) and combinations thereof. In some embodiments, therapeutic agents for treating TNBC include nivolumab + rucaparib, bevacizumab (Avastin ®) + chemotherapy, toripalizumab + paclitaxel, toripalizumab + nab-paclitaxel, camrelizumab + chemotherapy, pembrolizumab + chemotherapy, balixafortide + eribulin, durvalumab + trastuzumab-derutec, durvalumab + paclitaxel, or capasitinib + paclitaxel.

[0434] Combination therapy for bladder cancer

[0435] Therapeutic agents used to treat bladder cancer include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu ® ), erdafitinib, eganelisib, lenvatinib, bempegaldesleukin (NKTR-214), or a combination thereof. In some embodiments, the therapeutic agent used to treat bladder cancer includes eganelisib + nivolumab, pembrolizumab (Keytruda ® ) + Enfutumab vedotin (Padcev ® ), nivolumab + ipilimumab, durvalumab + tremelimumab, lenvatinib + pembrolizumab, enfutumomab vedotin (Padcev ® ) + pembrolizumab and bempegaldesleukin + nivolumab.

[0436] Combination therapy for colorectal cancer (CRC)

[0437] Therapeutic agents used to treat CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, aflibercept, and any combination thereof. In some embodiments, the therapeutic agent used to treat CRC includes 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, therapeutic agents 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, therapeutic agents for treating CRC include bimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, nabucasin + FOLFIRI + bevacizumab, nivolumab + ipilimumab.

[0438] Combination therapy for esophageal and esophagogastric junction cancer

[0439] Therapeutic agents for treating esophageal and esophagogastric junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. In some embodiments, therapeutic agents for treating gastroesophageal junction cancer (GEJ) include Herceptin, cisplatin, 5-FU, ramucirumab, or paclitaxel. In some embodiments, therapeutic agents for treating GEJ cancer include ALX-148, AO-176, or IBI-188.

[0440] Gastric cancer combination therapy

[0441] Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0442] Combination therapy for head and neck cancer

[0443] Therapeutic agents used to treat head and neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0444] 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 for treating HNSCC include pembrolizumab + carboplatin + 5-FU, cetuximab + cisplatin + 5-FU, cetuximab + carboplatin + 5-FU, cisplatin + 5-FU and carboplatin + 5-FU. In some embodiments, therapeutic agents for treating HNSCC include durvalumab, durvalumab + tremelimumab, nivolumab + ipilimumab, rovaluecel, pembrolizumab, pembrolizumab + icandrostat, GSK3359609 + pembrolizumab, lenvatinib + pembrolizumab, rivulizumab, rivulizumab + enobituzumab, ADU-S100 + pembrolizumab, icandrostat + nivolumab + ipilimumab / lirelumab.

[0445] Combination therapy for non-small cell lung cancer

[0446] Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, nab-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, the therapeutic agent used to treat NSCLC includes alectinib (Alecensa ® ), Tafinlar ® )、Mekinist ® ), osimertinib (Tagrisso ® ), entrectinib (Tarceva ® ), crizotinib (Xalkori ® ), pembrolizumab (Keytruda ® ), carboplatin, pemetrexed (Alimta ® ), Abraxane ® ), Cyramza ® ), docetaxel, bevacizumab (Avastin ® ), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif ® ), Opdivo ® ), gefitinib (Iressa ®) and combinations thereof. In some embodiments, therapeutic agents 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 + gemcitabine, nivolumab + docetaxel, carboplatin + pemetrexed, carboplatin + nab-paclitaxel, or pemetrexed + cisplatin + carboplatin. In some embodiments, therapeutic agents for NSCLC include datopotamusab derutec (DS-1062), trastuzumab-derutec (Enhertu ® ), Enfutumomab Vedotin (Padcev ® ), durvalumab, canakinumab, cemiplizumab, norgeleukin alpha, avelumab, tisleliumab, dunalimab, vembrolizumab, ospelimab, or a combination thereof. In some embodiments, the therapeutic agent used to treat NSCLC includes datopotamumab drutilecan + pembrolizumab, datopotamumab drutilecan + durvalumab, durvalumab + tremelimumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, norgeleukin alpha (N-803) + pembrolizumab, tisleliumab + atezolizumab, vembrolizumab + pembrolizumab, or ospelimab + tislelizumab.

[0447] Combination therapy for small cell lung cancer

[0448] Therapeutic agents 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 combination thereof. In some embodiments, the therapeutic agents for treating SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivolumab, durvalumab, tracillin, or a combination thereof. In some embodiments, the therapeutic agents for treating SCLC include atezolizumab + carboplatin + etoposide, atezolizumab + carboplatin, atezolizumab + etoposide, or carboplatin + paclitaxel.

[0449] Combination therapy for ovarian cancer

[0450] Therapeutic agents used to treat ovarian cancer include 5-fluorouracil, nab-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.

[0451] Combination therapy for pancreatic cancer

[0452] Therapeutic agents used to treat pancreatic cancer include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel (Abraxane ® ), FOLFIRINOX and combinations thereof. In some embodiments, the therapeutic agents for treating pancreatic cancer include 5-FU+leucovorin+oxaliplatin+irinotecan, 5-FU+nanoliposome irinotecan, leucovorin+nanoliposome irinotecan and gemcitabine+nab-paclitaxel.

[0453] Combination therapy for prostate cancer

[0454] Therapeutic agents used to treat prostate cancer include enzalutamide (Xtandi ® ), leuprolide, trifluridine, tipiracil (Lonsurf), cabazitaxel, prednisone, abiraterone (Zytiga ® ), docetaxel, mitoxantrone, bicalutamide, LHRH, flutamide, ADT, sabizabulin (Veru-111), and combinations thereof. In some embodiments, therapeutic agents used to treat prostate cancer include enzalutamide + leuprolide, trifluridine + tipiracil (Lonsurf), cabazitaxel + prednisone, abiraterone + prednisone, docetaxel + prednisone, mitoxantrone + prednisone, bicalutamide + LHRH, flutamide + LHRH, leuprolide + flutamide, and abiraterone + prednisone + ADT.

[0455] Additional Exemplary Combination Therapies

[0456] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more therapeutic agents selected from the group consisting of a PI3K inhibitor, a Trop-2 binder, a CD47 antagonist, a SIRPα antagonist, a FLT3R agonist, a PD-1 antagonist, a PD-L1 antagonist, a MCL1 inhibitor, a CCR8 binder, a HPK1 antagonist, a DGKa inhibitor, a CISH inhibitor, a PARP-7 inhibitor, a Cbl-b inhibitor, a KRAS inhibitor (e.g., a KRAS G12C or G12D inhibitor), a KRAS degrader, a β-catenin degrader, a helios degrader, a CD73 inhibitor, an adenosine receptor antagonist, a TIGIT antagonist, a TREM1 binder, a TREM2 binder, a CD137 agonist, a GITR binder, an OX40 binder, and a CAR-T cell therapy.

[0457] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more therapeutic agents selected from the group consisting of a PI3Kd inhibitor (e.g., idealisib), an anti-Trop-2 antibody drug conjugate (e.g., sacetuzumab govitecan, datopotamumab derutecan (DS-1062)), an anti-CD47 antibody or CD47 blocker (e.g., mololimab, DSP-107, AO-176, ALX-148, letaprilimab (IBI-188), leszolimab, TTI-621, TTI-622), an anti-SIRPα antibody (e.g., GS-0189), FL T3L-Fc fusion proteins (e.g., GS-3583), anti-PD-1 antibodies (pembrolizumab, nivolumab, sepalizumab), 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., quetiapine (AB680)), anti-CD73 antibodies (e.g., olerumumab), dual A 2a / A 2bAdenosine receptor antagonists (e.g., eltridinam (AB928)), anti-TIGIT antibodies (e.g., tisellimumab, vembryomab, dunalimab, 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).

[0458] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more therapeutic agents selected from the group consisting of idelalisib, sacetuzumab govitecan, mololimab, GS-0189, GS-3583, sepalizumab, GS-4224, GS-9716, GS-6451, quiliclazumab (AB680), edrinan (AB928), dunalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, akilencilam, and briginumab.

[0459] III. Abbreviations. Certain abbreviations and acronyms are used to describe the experimental details. Although most of these abbreviations and acronyms are understood by those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

[0460] Table 1. List of abbreviations and acronyms .

[0461]

[0462] IV. Experimental Procedure

[0463] General approach

[0464] Preparation method :

[0465] The compounds of the present disclosure can be prepared by a variety of methods. For example, Schemes 1 to 8 show representative syntheses of the compounds of the present disclosure.

[0466] Solution 1.

[0467]

[0468] Representative Synthesis Scheme 1 shows the general synthesis of the compounds of the present disclosure. This method is compatible with a variety of functions. In Representative Synthesis 1, a palladium catalyst (e.g., RuPhos Pd G3, Pd(OAc)2+XantPhos, etc.) and a base (e.g., Cs 2 CO 3 , K 3 PO 4 The appropriately substituted chloropyrimidine, chloropyridazine or chloropyridine (or the corresponding brominated or iodinated compound) is mixed with the appropriately substituted pyrrolidine in a suitable solvent system (e.g., tert-butanol, DMAc, dioxane, etc.) at an elevated temperature (e.g., in the range of about 80° C. to 120° C.) in the presence of an amine. Subsequently, the resulting appropriately substituted 2,4-dimethoxypyrimidine-containing compound can be treated with an acid (e.g., hydrochloric acid) in a suitable solvent system (e.g., water+methanol) at an elevated temperature (e.g., in the range of about 60° C. to 80° C.).

[0469] Solution 2.

[0470]

[0471] Representative Synthesis Scheme 2 shows the general synthesis of compounds of the present disclosure. This approach is compatible with a variety of functions. In Representative Synthesis 2, in the presence of a palladium catalyst (e.g., Pd(dppf)Cl 2 , Xphos Pd G3, etc.) and bases (such as Cs 2 CO 3 , K 3 PO 4 The appropriately substituted chloropyrimidine, chloropyridazine or chloropyridine is mixed with (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid in a suitable solvent system (e.g., water + dioxane, MeTHF, etc.) at elevated temperature (e.g., in the range of about 70° C. to 120° C.) in the presence of a 2,4-di-tert-butoxypyrimidine, chloropyridazine or chloropyridine. Subsequently, the resulting appropriately 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.).

[0472] Solution 3.

[0473]

[0474] Representative Synthesis Scheme 3 shows the general synthesis of compounds of the present disclosure. This method is compatible with a variety of functions. In Representative Synthesis 3, an appropriately substituted chloropyrimidine is mixed with an appropriately substituted pyrrolidine in a suitable solvent system (e.g., NMP, etc.) in the presence of a base (e.g., diisopropylethylamine, etc.) at elevated temperature (in the range of about 90° C. to 110° C.). Subsequently, the resulting appropriately 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.).

[0475] Solution 4.

[0476]

[0477] Representative Synthesis Scheme 4 shows the general synthesis of compounds of the embodiments. This method is compatible with a variety of functions. In Representative Synthesis Scheme 4, 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 bases (such as Cs 2 CO 3 The appropriately substituted pyrrolidinol is mixed with an appropriately substituted aryl, heteroaryl or bicyclic heteroaryl bromide (or the corresponding chlorinated or iodinated compound) in a suitable solvent system (e.g. toluene, dioxane, etc.) at an elevated temperature (e.g. about 80°C to 120°C) in the presence of an oxidizing agent (e.g., chlorinated or iodinated agent).

[0478] Solution 5.

[0479]

[0480] Representative Synthesis Scheme 5 shows the general synthesis of compounds of the embodiments. This approach is compatible with a variety of functions. In Representative Synthesis Scheme 5, an appropriately substituted pyrrolidinol is reacted with an appropriately substituted aryl, heteroaryl or bicyclic heteroaryl chloride (or the corresponding fluoro or OCF) in the presence of a base (e.g., NaH, etc.). 3 -compound) in a suitable solvent system (such as DMF, etc.).

[0481] Solution 6.

[0482]

[0483] Representative Synthesis Scheme 6 shows the general synthesis of compounds of the embodiment. This method is compatible with a variety of functions. In Representative Synthesis Scheme 6, an appropriately substituted chloropyrimidine, chloropyridazine or chloropyridine (or the corresponding bromo compound) is mixed 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 an elevated temperature (about 60° C. to 100° C.). Subsequently, a palladium catalyst (e.g., Pd(dppf)Cl 2 , XphosPd G3, etc.) and bases (such as Cs 2 CO 3 , K 3 PO 4 The resulting appropriately substituted chloropyrimidine, chloropyridazine or chloropyridine is mixed with (2,4-dimethoxypyrimidin-5-yl)boronic acid in a suitable solvent system (e.g., water + dioxane, MeTHF, etc.) at an elevated temperature (e.g., about 70° C. to 120° C.) in the presence of a chlorinated solvent.

[0484] Solution 7.

[0485]

[0486] Representative Synthesis Scheme 7 shows the general synthesis of compounds of the embodiments. This approach is compatible with a variety of functions. In Representative Synthesis Scheme 7, in the presence of a palladium catalyst (e.g., Pd(dppf)Cl 2 , Xphos Pd G3, etc.) and bases (such as Cs 2 CO 3 , K 3 PO 4 The appropriately substituted chloropyrimidine, chloropyridazine or chloropyridine is mixed with (2,4-dimethoxypyrimidin-5-yl)boronic acid in a suitable solvent system (e.g., water + dioxane, MeTHF, etc.) at an elevated temperature (e.g., about 70° C. to 120° C.) in the presence of an amine.

[0487] Solution 8.

[0488]

[0489] Representative Synthesis Scheme 8 shows the general synthesis of compounds of the embodiment. This method is compatible with a variety of functions. In Representative Synthesis Scheme 8, a copper catalyst (e.g., CuI+3,4,7,8-tetramethyl-1,10-phenanthroline, etc.) and a base (e.g., Cs 2 CO 3The appropriately substituted aryl, heteroaryl or bicyclic heteroaryl bromide (or the corresponding chloro or iodinated compound) is mixed with (S)-tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate in a suitable solvent system (e.g., toluene, etc.) at elevated temperature (e.g., about 90° C. to 135° C.) in the presence of an ether, such as d-H-(S) ...

[0490] Preparation of intermediates

[0491] Preparation of Intermediate A, 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridinecarbonitrile

[0492]

[0493] 4,6-Dichloropyridinecarbonitrile (346 mg, 2.0 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (368 mg, 2.0 mmol, 1 eq), Pd(dppf)Cl 2 DCM (33 mg, 0.04 mmol, 0.02 eq), Cs 2 CO 3 To 1.63 g, 5 mmol, 2.5 equiv. was added 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), and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The mixture was purified by silica gel chromatography (0% to 25% MeOH / DCM) to give 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinonitrile (387 mg, 70%) as a tan solid as a 5:1 mixture of isomers. ES / MS m / z: 277.06 [M+H].

[0494] Preparation of Intermediate B, 5-(4-chloro-6-methylpyridin-2-yl)-2,4-dimethoxypyrimidine

[0495]

[0496] 5-(4-chloro-6-methylpyridin-2-yl)-2,4-dimethoxypyrimidine was synthesized in a similar manner to Intermediate A, except that 2,4-dichloro-6-methylpyridine was used instead of 4,6-dichloropyridinecarbonitrile. ES / MS m / z: 266.00 (M+1).

[0497] Preparation of Intermediate C, 5-(4-chloro-6-methoxypyridin-2-yl)-2,4-dimethoxypyrimidine

[0498]

[0499] 5-(4-Chloro-6-methoxypyridin-2-yl)-2,4-dimethoxypyrimidine was synthesized in a similar manner to Intermediate A, except that 2,4-dichloro-6-methoxypyridine was used instead of 4,6-dichloropyridinecarbonitrile. ES / MS m / z: 266.00 (M+1).

[0500] Preparation of Intermediate D, 5-(4-chloro-6-(trifluoromethyl)pyridin-2-yl)-2,4-dimethoxypyrimidine

[0501]

[0502] 5-(4-Chloro-6-(trifluoromethyl)pyridin-2-yl)-2,4-dimethoxypyrimidine was synthesized in a similar manner to Intermediate A, except that 2,4-2,4-dichloro-6-(trifluoromethyl)pyridine was used instead of 4,6-dichloropyridinecarbonitrile. ES / MS m / z: 320.00 (M+1).

[0503] Preparation of Intermediate E, 2',4'-di-tert-butoxy-6-chloro-2-ethyl-4,5'-bipyrimidine

[0504]

[0505] 2',4'-di-tert-butoxy-6-chloro-2-ethyl-4,5'-bipyrimidine was synthesized in a similar manner to Intermediate A, except that 4,6-dichloro-2-ethylpyrimidine was used instead of 4,6-dichloropyridinecarbonitrile, and (2,4-dimethoxypyrimidin-5-yl)boronic acid was used instead of (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid. ES / MS m / z: 252.9 [M-2tBu+1].

[0506] Preparation of Intermediate F, 2',4'-di-tert-butoxy-6-chloro-2-cyclopropyl-4,5'-bipyrimidine

[0507]

[0508] 2',4'-di-tert-butoxy-6-chloro-2-cyclopropyl-4,5'-bipyrimidine was synthesized in a similar manner to Intermediate A, except that 4,6-dichloro-2-cyclopropylpyrimidine was used instead of 4,6-dichloropyridinecarbonitrile, and (2,4-dimethoxypyrimidin-5-yl)boronic acid was used instead of (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid. ES / MS m / z: 264.93 [M-2tBu+1].

[0509] Preparation of Intermediate G, 2',4'-di-tert-butoxy-6-chloro-2-(difluoromethyl)-4,5'-bipyrimidine

[0510]

[0511] 2',4'-di-tert-butoxy-6-chloro-2-(difluoromethyl)-4,5'-bipyrimidine was synthesized in a similar manner to Intermediate H, except that 4,6-dichloro-2-(difluoromethyl)pyrimidine was used instead of 4,6-dichloro-2-methylpyrimidine, and (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid was used instead of (2,4-dimethoxypyrimidin-5-yl)boronic acid. ES / MS m / z: 274.90 [M-2tBu+1].

[0512] Preparation of intermediate H, 6-chloro-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0513]

[0514] 4,6-Dichloro-2-methylpyrimidine (5.0 g, 30.6 mmol, 1.0 equiv) was dissolved in dioxane (50 mL) and H 2 O (25 mL) was added with (2,4-dimethoxypyrimidin-5-yl)boronic acid (5.6 g, 30.6 mmol, 1.0 equiv), Pd(dppf)Cl 2 -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 with nitrogen three times and stirred at 80 °C for 12 h. The reactants were then treated with H 2 O (60 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3) and purified by Na 2 SO 4 The crude product was purified by silica gel chromatography (0% to 50% ethyl acetate / petroleum ether) to give 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 HNMR (400 MHz, CHLOROFORM-d) δ 9.26 (s, 1H), 7.83 (s, 1H), 4.16 (s, 3H), 4.09 (s, 3H), 2.75 (s, 3H).

[0515] Preparation of Intermediate I, 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

[0516]

[0517] To a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (4 g, 20.2 mmol, 1 eq.) in DMF (10 mL) was added Cs 2 CO 3(6.58 g, 20.2 mmol, 1 eq.) was then added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.39 g, 23.2 mmol, 1.15 eq.). The reaction was allowed to slowly warm to room temperature. After 16 h, the reaction mixture was diluted with EtOAc (100 mL), washed with brine (5 × 50 mL), and washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. The mixture was purified by silica gel chromatography (0% to 50% EtOAc / hexanes) and the first eluting peak was 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine (3.63 g, 64%) as a light yellow solid. ES / MS m / z: 279.90 [M+H].

[0518] Preparation of Intermediate J, 6-chloro-1-(2,2,2-trifluoroethyl)triazolo[4,5-c]pyridine

[0519]

[0520] To a solution of 6-chloropyridine-3,4-diamine (800 mg, 4.4 mmol, 1 eq. HCl) in HCl (10 mL) was added NaNO at 0 °C. 2 (337.2 mg, 4.9 mmol, 1.1 eq.). The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (20 mL) and heated at 0 °C to 10 °C with K 2 CO 3 Neutralize until pH = 9, then filter the mixture and dry the resulting solid under vacuum to give 6-chloro-1H-triazolo[4,5-c]pyridine (310 mg, 2.0 mmol, 45% yield) as a white solid. ES / MS m / z: 155.2 [M+H]

[0521]

[0522] To a solution of 6-chloro-1H-triazolo[4,5-c]pyridine (300 mg, 1.9 mmol, 1 eq) in DMF (5 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (675.7 mg, 2.9 mmol, 1.5 eq) and K 2 CO 3 (536.5 mg, 3.8 mmol, 2 eq.). The reaction 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 organics were washed with brine (10 mL) and purified by Na 2 SO 4The crude product was purified by silica gel chromatography (0% to 13% EtOAc / PE) to give 6-chloro-1-(2,2,2-trifluoroethyl)triazolo[4,5-c]pyridine (100 mg, 422.6 umol, 21.78% yield) as a white solid. ES / MS m / z: 237.2 [M+H].

[0523] Preparation of Intermediate K, 6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole

[0524]

[0525] To a solution of 6-bromo-5-fluoro-1H-indazole (1 g, 4.6 mmol, 1 eq.) in DMF (10 mL) was added K 2 CO 3 (1.2 g, 9.3 mmol, 2 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.6 g, 6.9 mmol, 1.5 eq). The reaction was stirred at 80 °C for 1 h. The reaction mixture was then heated with H 2 O (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by silica gel chromatography (0% to 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.

[0526] Preparation of intermediate L, 6-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine

[0527]

[0528] 6-Bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine was prepared in the manner described for the synthesis of intermediate K, 6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole, but substituting 6-bromo-1H-pyrazolo[4,3-c]pyridine for 6-bromo-5-fluoro-1H-indazole and 2,2-difluoroethyl trifluoromethanesulfonate for 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0529] Preparation of Intermediate M, 2-chloro-4-(2,2-difluorocyclopropyl)pyridine

[0530]

[0531] Step 1: In N 2 2-Chloro-4-iodopyridine (2.0 g, 8.3 mmol, 1.0 equiv) was dissolved in dioxane (2 mL) and H 2O (1 mL) was added with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.2 g, 8.3 mmol, 1.4 mL, 1.0 equiv), Cs 2 CO 3 (8.1 g, 25.0 mmol, 3.0 equiv) and Pd(dppf)Cl 2 .CH 2 Cl 2 (1.36 g, 1.67 mmol, 0.2 eq.). The resulting suspension was treated with N 2 Degas and purge 3 times. The reaction was stirred at 80 °C for 12 h. The reaction mixture was then washed with H 2 O (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The crude product was purified by silica gel chromatography (0% to 20% ethyl acetate / petroleum ether) to afford 2-chloro-4-vinylpyridine (500 mg, 25% yield) as a yellow oil.

[0532]

[0533] Step 2: To a solution of 2-chloro-4-vinylpyridine (500.0 mg, 3.5 mmol, 1.0 equiv) in THF (2 mL) was added NaI (268.4 mg, 1.7 mmol, 0.5 equiv), then stirred at 70 ° C, and trimethyl (trifluoromethyl) silane (1.7 g, 12.5 mmol, 3.5 equiv) was added and stirred at 70 ° C for 12 hours. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0% to 20% ethyl acetate / petroleum ether) to give 2-chloro-4-(2,2-difluorocyclopropyl) pyridine (480.0 mg, 45% yield) as an orange oil.

[0534] Intermediate N,2-bromo-4-(difluoromethyl)-5-fluoropyridine

[0535]

[0536] To a solution of 2-bromo-5-fluoroisonicotinaldehyde (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. The reaction mixture was then washed with NaHCO 3 (15 mL) and diluted with CH 2 Cl 2 (15 mL × 3) extraction. The combined organic layers were purified by Na2 SO 4 Dry, filter and concentrate under reduced pressure to give 2-bromo-4-(difluoromethyl)-5-fluoropyridine (970.0 mg, crude product) as a yellow oil.

[0537] 1 H 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).

[0538] Preparation of intermediate O, (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine- tert-Butyl 6-(6-yl)oxy)pyrrolidine-1-carboxylate

[0539]

[0540] To four identical containers were added 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine (565 mg, 2.0 mmol, 1 eq), (S)-tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.2 mmol, 1.1 eq), copper iodide (192 mg, 1.0 mmol, 0.5 eq), 3,4,7,8-tetramethyl-1,10-phenanthroline (95 mg, 0.40 mmol, 0.2 eq), Cs 2 CO 3 (985 mg, 3.0 mmol, 1.5 equiv) and PhMe (18 mL). The vessel was sealed and heated to 120 ° C. After 16 hours, the four reactants were combined, diluted with EtOAc, filtered through celite and concentrated in vacuo. The mixture was purified by silica gel chromatography (0% to 50% EtOAc / hexanes) to give (S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.77 g, 80%) as a white foam. ES / MS m / z: 423.03 [M+H].

[0541] Preparation of intermediate P, (S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H- Pyrazolo[4,3-c]pyridine hydrochloride

[0542]

[0543] To a solution of (S)-tert-butyl 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 eq) in DCM (6 mL) was added 4M HCl in dioxane (3 mL, 12 mmol, 3.25 eq). After 16 h, the mixture was concentrated in vacuo to give (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.

[0544] Preparation of Intermediate Q, (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate ester

[0545]

[0546] To a solution of (4S)-3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.2 mmol, 1 eq.) in toluene (10 mL) were added 4-bromo-2-(difluoromethyl)-1-fluoro-benzene (504.0 mg, 2.2 mmol, 1 eq.), CuI (106.6 mg, 559.9 umol, 0.25 eq.), 3,4,7,8-tetramethyl-1,10-phenanthroline (105.8 mg, 448.0 umol, 0.2 eq.) and Cs 2 CO 3 (1.1 g, 3.4 mmol, 1.5 eq.). The reaction mixture was purged and degassed with nitrogen three times, and then the reaction mixture was stirred at 120 °C for 12 hours. 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), and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified by flash column (0% to 20% ethyl acetate / petroleum ether) to afford (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate (290 mg, 35% yield) as a colorless oil. 1 H NMR (chloroform-d, 400MHz) 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).

[0547] Preparation of intermediate N, (S) -4- (3- (difluoromethyl) -4-fluorophenoxy) -3,3-difluoropyrrolidine; hydrochloride

[0548]

[0549] (S)-4-(3-(Difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine was prepared using the procedure 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 substituting (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate for tert-butyl 3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate.

[0550] Preparation of intermediate R, (S)-4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidine- 1-tert-Butyl formate

[0551]

[0552] (S)-tert-Butyl 4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate was prepared in the manner described for Intermediate P, (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate, but using 2-bromo-4-(difluoromethyl)-5-fluoropyridine in place of 4-bromo-2-(difluoromethyl)-1-fluoro-benzene. 1 H NMR (400MHz, chloroform-d) δ 8.08 (br s, 1H), 7.05 (br s, 1H), 6.82 (t, J = 54.2Hz, 1H), 5.58 (br s, 1H), 3.92 - 3.75 (m, 4H), 1.48 (br s, 9H).

[0553] Preparation of intermediate S, (S)-4-(difluoromethyl)-2-((4,4-difluoropyrrolidin-3-yl)oxy)-5-fluoropyridine; Hydrochloride

[0554]

[0555] (S)-4-(Difluoromethyl)-2-((4,4-difluoropyrrolidin-3-yl)oxy)-5-fluoropyridine; hydrochloride was prepared in the manner 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 substituting (S)-tert-butyl 4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate for (S)-tert-butyl 3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate. 1 H NMR (400 MHz, methanol-d 4 ) 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, 13.7Hz, 1H)

[0556] Preparation of Intermediate T, (S)-3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylic acid Tert-butyl ester

[0557]

[0558] (S)-tert-Butyl 3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate was prepared in the manner described for Intermediate P, (S)-tert-butyl 4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1-carboxylate, but using 2-bromo-4-(trifluoromethyl)pyridine in place of 4-bromo-2-(difluoromethyl)-1-fluoro-benzene.

[0559]

[0560] (S)-2-((4,4-difluoropyrrolidin-3-yl)oxy)-4-(trifluoromethyl)pyridine was prepared using the procedure 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, except that (S)-tert-butyl 3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate was used in place of tert-butyl 3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate.

[0561] SNAr of pyrrolidine ether

[0562] 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

[0563]

[0564] 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 was heated to 100 °C and stirred for 4 h. The reaction mixture was then diluted with EtOAc / water, extracted twice with EtOAc, and the combined organics were purified by MgSO 4 Dry, filter and concentrate in vacuo. The crude product was purified by silica gel chromatography (0% to 70% EtOAc / hexanes). ES / MS m / z: 434.90 [M+H].

[0565] 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

[0566]

[0567] (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 in the manner described for Intermediate U, except that 4-chloro-6-fluoro-pyrimidine was used instead of 4-chloro-6-fluoro-pyrimidine. ES / MS m / z: 448.90 [M+H].

[0568] Preparation of Intermediate W, (S)-6-((1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-4,4-difluoropyrrolidine-3-yl)- 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

[0569]

[0570] (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 a manner similar to Intermediate U except that 4,6-dichloro-2-(trifluoromethyl)pyrimidine was substituted for 4-chloro-6-fluoro-pyrimidine, DMF was substituted for NMP, and the reaction was stirred at 60 °C for 2 h. ES / MS m / z: 502.80 [M+1].

[0571] 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

[0572]

[0573] (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, but substituting 4,6-dichloropyrimidine-2-carbonitrile for 4-chloro-6-fluoro-pyrimidine. ES / MS m / z: 460.00 [M+H].

[0574] Preparation of intermediate Y, 3-((2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)oxy)-2,2-dimethoxy Fluoropropane-1-ol

[0575]

[0576] 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 min. 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 h. By adding NH 4 The reaction mixture was quenched with Cl (10 mL) and then with H 2 O (10 mL), and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with Na 2 SO 4 The crude product was purified by silica gel chromatography (0% to 50% ethyl acetate / petroleum ether) to give 3-((2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)oxy)-2,2-difluoropropan-1-ol (350 mg, 38% yield) as a white solid.

[0577] CN coupling of pyrrolidine ethers

[0578] Preparation of intermediate Z, (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoro Pyrrolidin-3-ol

[0579]

[0580] To a solution of 6-chloro-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine (200 mg, 749.9 umol, 1 eq.) in dioxane (5 mL) were added (3S)-4,4-difluoropyrrolidin-3-ol (119.6 mg, 749.9 umol, 1 eq., HCl), Pd(OAc) 2 (16.8 mg, 75.0 umol, 0.1 equivalent), Cs 2 CO 3 (488.7 mg, 1.5 mmol, 2 eq.) and Xantphos (43.3 mg, 75.0 umol, 0.1 eq.). The suspension was washed with N 2 Degas and purge 3 times. 2 The mixture was stirred at 100 °C for 12 hours. LCMS showed that the starting material was completely consumed and about 50% of the peak with the desired MS was detected. The reaction mixture was cooled to room temperature and diluted with water (5 mL) and extracted with ethyl acetate (8 mL*2). The combined organics were washed with brine (15 mL) and purified by Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0% to 6% MeOH in DCM, gradient 20 min R f =0.56) to give (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidine]-6-yl)-4,4-difluoropyrrolidin-3-ol (140 mg, 396.2 umol, 53% yield) as a yellow solid. ES / MS m / z: 354.1 [M+H].

[0581] Late-stage CN coupling of pyrrolidine ethers

[0582] 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)picolinonitrile

[0583]

[0584] To 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinonitrile (70 mg, 0.18 mmol, 1 eq), (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 eq), RuPhos Pd G3 (13 mg, 0.02 mmol, 0.07 eq) and K 3 PO 4(136 mg, 0.64 mmol, 2.5 equiv) was added DMAc (3.5 mL). The mixture was sparged with Ar for 10 min and then heated to 110 °C. After 24 h, the mixture was diluted with EtOAc, filtered through celite, washed with brine (4 × 20 mL), and washed with Na 2 SO 4 The mixture was dried, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (0% to 100% EtOAc / hexanes) 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)picolinonitrile (31 mg, 20%) as a yellow residue. ES / MS m / z: 563.10 (M+1).

[0585] 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

[0586]

[0587] (S)-6-((1-(2-(2,4-dimethoxypyrimidin-5-yl)-6-methoxypyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was synthesized in a manner similar to Intermediate AA except that 5-(4-chloro-6-methoxypyridin-2-yl)-2,4-dimethoxypyrimidine was used instead of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinonitrile. ES / MS m / z: 568.08 (M+1).

[0588] Preparation of Intermediate CC, (S)-6-((1-(2-(2,4-dimethoxypyrimidin-5-yl)-6-(trifluoromethyl)pyridine-4-yl)- 4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

[0589]

[0590] (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 a manner similar to Intermediate AA, but with 5-(4-chloro-6-(trifluoromethyl)pyridin-2-yl)-2,4-dimethoxypyrimidine replacing 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinonitrile. ES / MS m / z: 606.07 (M+1).

[0591] 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

[0592]

[0593] (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 a similar manner to Intermediate AA, but with 5-(4-chloro-6-methylpyridin-2-yl)-2,4-dimethoxypyrimidine instead of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)picolinonitrile. , ES / MS m / z: 522.10 (M+1).

[0594] Preparation of Intermediate EE, (S)-6-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-yl 2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0595]

[0596] To a solution of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine (80.0 mg, 299.9 umol, 1.0 equiv) in dioxane (2 mL) was added 2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-4-(trifluoromethyl)pyridine (80.4 mg, 299.9 umol, 1.0 equiv), Cs 2 CO 3 (195.4 mg, 599.9 umol, 2.0 equivalents), Pd(OAc) 2 (6.7 mg, 30.0 umol, 0.1 eq.) and Xantphos (17.3 mg, 30.0 umol, 0.1 eq.). The resulting suspension was washed with N 2 Degas and purge 3 times. 2 The mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and analyzed by preparative TLC (SiO 2 , 2:1 petroleum ether / ethyl acetate) to afford (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.

[0597] Preparation of intermediate FF, 4-[(4S)-4-[[4-(difluoromethyl)-5-fluoro-2-pyridinyl]oxy]-3,3-difluoro-pyridinyl [pyrimidine]-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine

[0598]

[0599] To a solution of 6-chloro-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine (80 mg, 299.98 umol, 1 eq.) in dioxane (5 mL) was added 4-(difluoromethyl)-2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-5-fluoro-pyridine (80.4 mg, 299.9 umol, 1 eq.), Pd(OAc) 2 (6.7mg, 30.0umol, 0.1 equivalent) and Xantphos (17.3mg, 30.0umol, 0.1 equivalent) and Cs 2 CO 3 (195.4 mg, 599.9 umol, 2 equivalents). The mixture was stirred at N 2 The mixture was stirred at 100 °C for 12 hours. The reaction was concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic matter was washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was analyzed by preparative TLC (SiO 2 , 100% ethyl acetate) to give 4-[(4S)-4-[[4-(difluoromethyl)-5-fluoro-2-pyridinyl]oxy]-3,3-difluoro-pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine (60 mg, 120.38 umol, 40.13% yield) as a yellow oil.

[0600] Preparation of intermediate GG, (S)-6-(4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)- 2',4'-Dimethoxy-2-methyl-4,5'-bipyrimidine

[0601]

[0602] (S)-6-(4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine was prepared as described for Intermediate FF, but substituting (S)-4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidine for 4-(difluoromethyl)-2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-5-fluoropyridine; hydrochloride.

[0603] Preparation of intermediate HH, (S)-6-(4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidine-1- 2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0604]

[0605] (S)-6-(4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine was prepared as described for Intermediate FF, but substituting (S)-4-(3-(difluoromethoxy)-4-fluorophenoxy)-3,3-difluoropyrrolidine for 4-(difluoromethyl)-2-[(3S)-4,4-difluoropyrrolidin-3-yl]oxy-5-fluoropyridine; hydrochloride. ES / MS m / z: 514.1 [M+H].

[0606] 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

[0607]

[0608] The synthesis 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',4'-dimethoxy-[4,5'-bipyrimidine]-2-carbonitrile was similar to Intermediate AA, but 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 replacing 4,6-dichloropyridinecarbonitrile. ES / MS m / z: 564.10 (M+1).

[0609] Alcohol SnAr :

[0610] Preparation of Intermediate JJ, (S)-6-(3,3-difluoro-4-((4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)oxy 2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0611]

[0612] To a solution of 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)pyridine (62.7 mg, 283.0 umol, 1.0 equiv) in DMF (1 mL) was added NaH (22.6 mg, 566.0 umol, 60% purity, 2.0 equiv). The mixture was stirred at 20 °C for 10 minutes, then (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol (100 mg, 283.0 umol, 1.0 equiv) was added. The reaction was stirred at 80 °C for 2 hours. The reaction was washed with NH 4 The solution was quenched with Cl (6 mL) and extracted with EtOAc (2 mL × 3). The combined organic layers were washed with brine (2 mL × 3) and purified by Na 2 SO 4The reaction mixture was dried, 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.

[0613] 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

[0614]

[0615] (S)-6-(3,3-Difluoro-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine was prepared in the manner described for Intermediate JJ, except that 4-fluoro-2-methylpyridine was used in place of 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)pyridine.

[0616] Preparation of Intermediate LL, (S)-6-(3,3-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyrrolidine-1-yl 2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0617]

[0618] (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 in the manner described for Intermediate JJ, except that 4-fluoro-2-(trifluoromethyl)pyridine was used in place of 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)pyridine.

[0619] Preparation of intermediate MM, (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4- Difluoropyrrolidin-3-yl isopropylcarbamate

[0620]

[0621] To a solution of (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol (100 mg, 228.5 umol, 1 eq) in DCM (2 mL) was added DIPEA (88.6 mg, 685.7 umol, 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'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-yl isopropylcarbamate (120 mg, crude) as a brown oil which was used without further purification.

[0622] Preparation of intermediate NN, 3-((2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)oxy)-2,2- Difluoropropyl isopropyl carbamate

[0623]

[0624] 3-((2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)oxy)-2,2-difluoropropyl isopropylcarbamate was prepared in the manner described for Intermediate MM, except that 3-((2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)oxy)-2,2-fluoropropan-1-ol was used instead of (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol.

[0625] Preparation of intermediate OO, (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4- Difluoropyrrolidin-3-yl(1-(trifluoromethyl)cyclopropyl)carbamate

[0626]

[0627] To a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (120 mg, 778.7 umol, 1 eq.) in toluene (1 mL) was added DPPA (225.0 mg, 817.7 umol, 177.1 µL, 1.0 eq.) and TEA (104.0 mg, 1.0 mmol, 143.0 µL, 1.3 eq.). The mixture was stirred at 100 °C for 2 hours. Then, a solution of (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol (68.1 mg, 155.7 umol, 0.2 eq.) and DIPEA (100.6 mg, 778.7 umol, 135.6 µL, 1 eq.) in DCM (1 mL) was added. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was treated with H 2 O (3 mL), and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-yl(1-(trifluoromethyl)cyclopropyl)carbamate (260 mg, crude product) as a yellow solid.

[0628] Copper-catalyzed CO cross-coupling:

[0629] Preparation of intermediate PP, (S)-6-((1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidine]-6-yl)-4, 4-difluoropyrrolidin-3-yl)oxy)-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole

[0630]

[0631] (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol (200 mg, 566.0 umol, 1 equivalent), 6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole (184.9 mg, 622.6 umol, 1.1 equivalent), CuI (26.9 mg, 141.5 umol, 0.2 equivalent), 3,4,7,8-tetramethyl-1,10-phenanthroline (26.7 mg, 113.2 umol, 0.2 equivalent) and Cs 2 CO 3 A mixture of (276.6 mg, 849.0 umol, 1.5 eq.) in toluene (1.5 mL) was stirred with N 2 After degassing and purging (3 times), the reaction mixture was placed under N 2 The mixture was stirred at 120 °C for 12 h under a HCl atmosphere. 2 O 30mL, extracted with EtOAc (30mL×3), and the combined organic layers were purified by Na 2 SO 4 The crude product was purified by preparative TLC (SiO 2 , petroleum ether / ethyl acetate = 0 / 1) to give (S)-6-((1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidine]-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.

[0632] Palladium-catalyzed CO cross-coupling :

[0633] Preparation of intermediate QQ, (S)-6-(4-((4-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidine- 1-yl)-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0634]

[0635] To a solution of (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol (130 mg, 0.368 mmol, 1 eq) in toluene (3 mL) were added 2-chloro-4-(difluoromethoxy)pyridine (66.0 mg, 0.368 mmol, 1 eq), Cs 2 CO 3(299.7 mg, 0.920 mmol, 2.5 eq), XPhos-Pd-G2 (28.9 mg, 0.037 mmol, 0.1 eq) and Pd(OAc) 2 (8.2 mg, 0.037 mmol, 0.1 eq.). The resulting suspension was washed with N 2 Degassing and purging were performed. The reaction mixture was placed under N 2 The mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature and diluted with water (5 mL), extracted with ethyl acetate (8 mL x 2). The combined organics were washed with brine (15 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by silica gel chromatography (0% to 4% MeOH / DCM) to give 4-[(4S)-4-[[4-(difluoromethoxy)-2-pyridinyl]oxy]-3,3-difluoro-pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-pyrimidine. ES / MS m / z: 497.1 [M+H]

[0636] Preparation of intermediate RR, (S)-6-((1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidine]-6-yl)-4, 4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazole

[0637]

[0638] (S)-6-((1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazole was prepared in the manner described for Intermediate QQ, except that 6-bromo-1-(2,2,2-trifluoroethyl)indazole was used instead of 2-chloro-4-(difluoromethoxy)pyridine. ES / MS m / z: 552.3 [M+H].

[0639] Preparation of intermediate SS, (S)-6-((1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)- 4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-[1,2,3]triazolo[4,5-c]pyridine

[0640]

[0641] (S)-6-((1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazole was prepared in the manner described for intermediate QQ, except that 6-chloro-1-(2,2,2-trifluoroethyl)triazolo[4,5-c]pyridine was used instead of 2-chloro-4-(difluoromethoxy)pyridine, and (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol was used instead of (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol. ES / MS m / z: 638.2 [M+H].

[0642] Preparation of intermediate TT, (2,2-difluoroethyl)-6-((1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidine pyridine]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1H-pyrazolo[4,3-c]pyridine

[0643]

[0644] (2,2-Difluoroethyl)-6-((1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1H-pyrazolo[4,3-c]pyridine was prepared in the manner described for Intermediate QQ, except that 6-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine was used in place of 2-chloro-4-(difluoromethoxy)pyridine.

[0645] Preparation of intermediate UU, (S)-6-((1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)- 4,4-difluoropyrrolidin-3-yl)oxy)-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

[0646]

[0647] (S)-6-((1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-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 procedure described for intermediate QQ, except using 6-chloro-3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl 2-chloro-4-(difluoromethoxy)pyridine was replaced with oxazolo[4,3-c]pyridine, and (S)-1-(2',4'-di-tert-butoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol was replaced with (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol.

[0648] Preparation of Intermediate VV, (S)-6-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidine-1-yl 2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0649]

[0650] (S)-6-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine was prepared in the manner described for Intermediate QQ, but substituting 4-bromo-2-(difluoromethyl)pyridine for 2-chloro-4-(difluoromethoxy)pyridine.

[0651] Preparation of Intermediate XX, (S)-6-(3,3-difluoro-4-(pyridin-4-yloxy)pyrrolidin-1-yl)-2',4'-dimethyl Oxy-2-methyl-4,5'-bipyrimidine

[0652]

[0653] To a solution of (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol (195 mg, 551.9 umol, 1 eq) in dioxane (4 mL) were added 4-bromopyridine (174.4 mg, 1.1 mmol, 2 eq), Pd(OAc) 2 (24.8 mg, 110.3 umol, 0.2 equivalent), Xantphos (63.8 mg, 110.3 umol, 0.2 equivalent) and Cs 2 CO 3 (359.6 mg, 1.10 mmol, 2 eq.). The reaction mixture was washed with N 2 Bubble for 1 minute, then heat to 100°C and stir for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and EtOAc, filtered, and the filter cake was rinsed with EtOAc (3 mL*3). The combined filtrate was then extracted with ethyl acetate (5 mL*3). The combined organics were washed with brine (5 mL) and purified by Na 2 SO 4 The crude product was purified by silica gel chromatography (25% to 30% EA / PE) to give (S)-6-(3,3-difluoro-4-(pyridin-4-yloxy)pyrrolidin-1-yl)-2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine (85 mg, 164.5 umol, 29.8% yield) as an off-white solid.

[0654] Preparation of Intermediate YY, (S)-6-(3,3-difluoro-4-((2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)oxy 2',4'-dimethoxy-2-methyl-4,5'-bipyrimidine

[0655]

[0656] A microwave vial was charged with (S)-1-(2',4'-dimethoxy-2-methyl-[4,5'-bipyrimidinyl]-6-yl)-4,4-difluoropyrrolidin-3-ol (60 mg, 0.17 mmol, 1 eq), 4-bromo-2-(1-(trifluoromethyl)cyclopropyl)pyridine (67.8 mg, 0.255 mmol, 1.5 eq), Pd(OAc) and 4-bromo-2-(1-(trifluoromethyl)cyclopropyl)pyridine (67.8 mg, 0.255 mmol, 1.5 eq). 2 (3.8mg, 0.017mmol, 10mol%), SPhos Pd G3 (12.4mg, 0.017mmol, 10mol%), Cs 2 CO 3 (138 mg, 0.425 mmol, 2.5 equiv) and freshly degassed toluene (1.5 mL) were 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), and precipitated over MgSO 4 Dry, filter and concentrate in vacuo. The crude mixture was used in the next step without further purification. ES / MS m / z: 538.92 [M+H].

[0657] 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'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0658]

[0659] A microwave vial was charged with 5-(5-chloropyridazin-3-yl)-2,4-dimethoxy-pyrimidine (50.0 mg, 0.198 mmol, 1 eq), 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 eq), RuPhos Pd G3 (14.7 mg, 0.0198 mmol, 10 mol%) and tripotassium phosphate (126 mg, 0.594 mmol, 3 eq). The reaction vessel was then evacuated and backfilled with nitrogen followed by the addition of freshly degassed tBuOH (1.06 mL). The sealed reaction vessel was subsequently 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 (0% to 80% ACN / water w / TFA) to afford the title compound. ES / MS m / z: 510.72 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 12.19 (s, 1H), 11.92 (s, 1H), 8.89 (s, 1H), 8.74 (d, J = 2.8Hz, 1H), 8.47 (d, J = 5.4Hz, 1H), 8.42 (s, 1H), 7.45 (d, J = 2.9Hz, 1H), 7.34 (s,1H), 6.11 (m, 1H), 5.42 (pd, J = 9.1, 4.6Hz, 2H), 4.41 (m, 2H), 4.00 (m, 2H). 19F NMR (376MHz, DMSO-d6) δ -70.14 (t, J = 9.1Hz, 3F), -74.65 (s, 3F), -108.18 (d, J = 238.3Hz, 1F), -119.23 (d, J = 238.4Hz, 1F).

[0660] SNAr+ Deprotection of Pyrrolidine Ethers

[0661] Example 1: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyrrolidone (pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-ethyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0662]

[0663] 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 mixed 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. TFA (0.124 mL, 1.62 mmol) was then added directly and the mixture was stirred for 1 hour. The mixture was diluted with DMF / water and purified by RP-HPLC (10% to 90% MeCN / H 2 (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 (400MHz, DMSO-d 6 ) δ 12.10 (s, 1H), 11.85 (s, 1H), 8.87 (d, J =1.0Hz, 1H), 8.50 (d, J = 4.9Hz, 1H), 8.41 (d, J = 1.0Hz, 1H), 7.33 (s, 1H),7.21 (s, 1H), 6.04 (s, 1H), 5.41 (qt, J = 9.9, 4.8Hz, 2H), 4.41 – 4.22 (m,4H), 2.85 (q, J = 7.6Hz, 2H), 1.28 (t, J = 7.5Hz, 3H). 19 F NMR (376MHz, DMSO-d 6 ) δ -70.15 (t, J = 9.1Hz), -75.13, -106.80 - -110.42 (m), -117.86 - -120.70(m).

[0664] Example 2: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyrrolidone (pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-(difluoromethyl)-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0665]

[0666] (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-(difluoromethyl)-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione was prepared using the procedure described for Example 1, except that 2',4'-di-tert-butoxy-6-chloro-2-(difluoromethyl)-4,5'-bipyrimidine was used instead of 2,4-di-tert-butoxy-5-(6-chloro-2-ethyl-pyrimidin-4-yl)pyrimidine. ES / MS m / z: 560.80 [M+1]. 1H NMR (400MHz, DMSO-d6) δ 11.60 (dd, J = 6.5, 2.0Hz, 1H), 11.49 (d, J = 2.0Hz, 1H), 8.87 (d,J = 1.0Hz, 1H), 8.44 (d, J = 6.5Hz, 1H), 8.40 (d, J = 1.0Hz, 1H), 7.65 (s,1H), 7.33 (d, J = 1.1Hz, 1H), 6.67 (t, J = 54.5Hz, 1H), 5.97 (s, 1H), 5.40(qd, J = 9.1, 1.8Hz, 2H), 4.27 - 4.01 (m, 3H), 3.79 (m, 1H). 19F NMR (376MHz, DMSO-d6) δ -70.16 (t, J = 9.0Hz, 3F), -75.44 (s, 3F), -108.70 (m, 1F), -119.19 (m, 1F), -119.47 (d, J = 54.6Hz, 2F).

[0667] Deprotected SNAr of pyrrolidine ether

[0668] Example 3: Preparation of (S)-2-cyclopropyl-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[2-yl] ... [4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0669]

[0670] (S)-2-Cyclopropyl-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione was prepared using the procedure described for Example 1, except that 2',4'-di-tert-butoxy-6-chloro-2-cyclopropyl-4,5'-bipyrimidine was used instead of 2,4-di-tert-butoxy-5-(6-chloro-2-ethyl-pyrimidin-4-yl)pyrimidine. ES / MS m / z: 550.90 [M+1]. 1H NMR (400MHz, DMSO-d6) δ11.98 (s, 1H), 11.77 (s, 1H), 8.87 (d, J = 1.0Hz, 1H), 8.43 (d, J = 5.0Hz, 1H), 8.40 (d, J = 1.0Hz, 1H), 7.32 (d, J = 1.1Hz, 1H), 7.14 (s, 1H), 6.01 (d,J = 7.5Hz, 1H), 5.40 (qt, J = 10.1, 4.8Hz, 2H), 4.23 (q, J = 35.1, 24.7Hz,6H), 3.90 (d, J = 13.3Hz, 1H), 2.22 (s, 1H), 1.17 (s, 4H). 19F NMR (376MHz, DMSO-d6) δ -70.15 (t, J = 9.1Hz, 3F), -75.04 (s, 3F), -108.40 (t, J =254.5Hz, 1F), -118.90 (d, J = 267.5Hz, 1F).

[0671] Example 4: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyrrolidone (pyridine-6-yl)oxy)pyrrolidin-1-yl)-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0672]

[0673] A microwave vial was charged with (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (43.5 mg, 0.162 mmol, 1.5 equiv), Pd Cl 2 (dppf)-CH 2 Cl 2(4.41 mg, 0.00541 mmol, 5 mol%) and cesium carbonate (70.4 mg, 0.216 mmol, 2 eq). The reaction vessel was then evacuated and backfilled with nitrogen before adding a freshly degassed solution of 6-[(3S)-1-(6-chloropyrimidin-4-yl)-4,4-difluoro-pyrrolidin-3-yl]oxy-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine (47.0 mg, 0.108 mmol, 1 eq) in dioxane / water (5:1, 1.2 mL). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was then diluted with EtOAc / water, extracted twice with EtOAc, and the combined organics were purified by MgSO 4 Dry, filter and concentrate in vacuo. The crude product was dissolved in DCM (4 mL), TFA (0.5 mL) was added and the resulting solution was stirred at room temperature for 30 minutes and then concentrated in vacuo. The resulting pyrimidinedione was purified by HPLC (0% to 80% ACN / water w / TFA) to give the title compound. ES / MS m / z: 510.88 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 12.01 (s, 1H),11.75 (s, 1H), 8.87 (d, J = 1.0Hz, 1H), 8.68 (s, 1H), 8.58 (d, J = 4.9Hz,1H), 8.40 (d, J = 1.0Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 6.03 (s, 1H), 5.41(qd, J = 9.2, 2.6Hz, 2H), 4.39 - 4.10 (m, 3H), 3.91 (d, J = 12.9Hz, 1H). 19FNMR (376MHz, DMSO-d6) δ -70.15 (t, J = 9.1Hz, 3F), -75.16 (s, 3F), -108.46 (m, 1F), -118.96 (m, 1F).

[0674] Example 5: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyrrolidone (pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-methyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0675]

[0676] (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-methyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione was prepared as described for Example 4, except using (S)-6-((1-(6-chloro-2-methylpyrimidin-4-yl)oxy)pyrrolidin-1-yl)-2-methyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione. (S)-6-((1-(6-chloropyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine was replaced with (S)-6-((1-(6-chloropyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine and the reaction was stirred at 100° C. for 16 hours. ES / MS m / z: 524.9 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 12.08 (s, 1H), 11.83 (s, 1H), 8.87 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.41 (s, 1H), 7.33 (s, 1H), 7.20 (s, 1H), 6.02 (s, 1H), 5.41 (qd, J = 9.1, 3.1Hz, 2H), 4.40 - 4.15 (m,4H), 2.57 (s, 3H). 19F NMR (376MHz, DMSO-d6) δ -70.14 (t, J = 9.2Hz, 3F), -75.09 (s, 3F), -109.49 (m, 1F), -119.09 (m, 1F).

[0677] Example 6: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyrrolidone (6-pyridinyl)oxy)pyrrolidin-1-yl)-2-(trifluoromethyl)-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0678]

[0679] (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)pyrrolidin-1-yl)-2-(trifluoromethyl)-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione was prepared as described for Example 4, except that (S)-6-((1-(6-chloro- 6-[(3S)-1-(6-chloropyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl]oxy-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine was replaced by 6-[(3S)-1-(6-chloropyrimidin-4-yl)-4,4-difluoropyrrolidin-3-yl]oxy-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine. ES / MS m / z: 578.85[M+H]. 1H NMR (400MHz, DMSO-d6) δ 11.62 (dd, J = 6.6, 2.0Hz, 1H), 11.54 (d, J= 2.0Hz, 1H), 8.87 (d, J = 0.9Hz, 1H), 8.51 - 8.33 (m, 2H), 7.74 (s, 1H), 7.33 (s, 1H), 5.98 (s, 1H), 5.40 (qd, J = 9.0, 2.2Hz, 2H), 4.28 - 4.03 (m,3H), 3.81 (s, 1H). 19F NMR (376MHz, DMSO-d6) δ -70.17 (t, J = 9.0Hz, 3F), -70.52 (s, 3F), -75.52 (s, 3F), -108.51 (dd, J = 411.5, 237.5Hz, 1F), -118.89(dd, J = 410.6, 237.6Hz, 1F).

[0680] Example 7: Preparation of (S)-6-(3,3-difluoro-4-((2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)oxy) Pyrrolidin-1-yl)-2-methyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione

[0681]

[0682] To a solution of (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 (91 mg, 0.169 mmol, 1 eq) in MeOH (1.3 mL) was added 2N HCl (1.3 mL). The reaction mixture was stirred at 80 °C for 1.5 hours and then concentrated in vacuo. The crude product was purified by RP-HPLC (10% to 90% MeCN / H 2(S)-6-(3,3-difluoro-4-((2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-2-methyl-[4,5'-bipyrimidine]-2',4'(1'H,3'H)-dione. ES / MS m / z: 510.90 (M+1). 1H NMR (400MHz, DMSO-d6) δ 12.01(s, 1H), 11.78 (s, 1H), 8.47 (dd, J = 5.4, 0.8Hz, 1H), 8.44 (d, J = 5.7Hz,1H), 7.22 (s, 1H), 7.19 - 7.09 (m, 2H), 5.70 (m, 1H), 4.37 - 4,10 (m, 4H), 2.55 (s, 3H), 1.44 - 1.28 (m, 4H). 19F NMR (376MHz, DMSO-d6) δ -66.61 (s, 3F), -75.04 (s, 3F), -106.70 (m, 1F), -120.47 (m, 1F).

[0683] Example 8: Preparation of (S)-4-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyrrolidone (2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pyridinecarbonitrile

[0684]

[0685] (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-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)picolinonitrile was synthesized in a manner similar to Example 7, except that (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-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)picolinonitrile was used. (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. ES / MS m / z: 535.02 (M+1). 1 H NMR (400MHz, DMSO-d 6) δ 11.44 (d, J = 6.4Hz, 1H), 11.41 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.21 (d, J = 6.1Hz, 1H), 7.73 (d, J = 2.3Hz, 1H), 7.33 (s, 1H), 7.17 (d, J = 2.3Hz, 1H), 6.04 - 5.95 (m,1H), 5.40 (q, J = 9.4, 9.0Hz, 2H), 4.15 - 3.94 (m, 3H), 3.69 (d, J = 11.5Hz,1H). 19 F NMR (377MHz, DMSO-d 6 ) δ -70.16 (t, J = 9.1Hz), -75.22, -108.08 (dtd, J= 236.7, 16.6, 7.6Hz), -118.53 - -119.58 (m).

[0686] Example 9: Preparation of (S)-6-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyrrolidone pyrrolidine-6-yl)oxy)pyrrolidin-1-yl)-2',4'-dioxo-1',2',3',4'-tetrahydro-[4,5'-bipyrimidine]-2-carbonitrile

[0687]

[0688] (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'-dioxo-1',2',3',4'-tetrahydro-[4,5'-bipyrimidine]-2-carbonitrile was synthesized in a manner similar to Example 7, except that (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'-dioxo...

Claims

1. A compound of formula (I): (I) ， or a pharmaceutically acceptable salt thereof, wherein: Y is independently C 1-6 Alkyl, C 3-7 Cycloalkyl, OC 1-6 Alkyl-O, 4- to 8-membered heterocyclyl, or O-4- to 8-membered heterocyclyl; wherein the alkyl, heterocyclyl, O-heterocyclyl, O-(5- to 12-membered heteroaryl), O-5- to 12-membered heteroaryl, or O-alkyl is optionally substituted with a halo group; R 1 are independently H, -C 1-6 Alkyl, OC 1-6 Alkyl, OC 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; wherein the alkyl, OC 1-6 Alkyl, OC 1-6 Alkyl-O, cycloalkyl, aryl, heteroaryl, O-(4-membered to 12-membered heteroaryl) or O-heterocyclyl is optionally substituted with 1 to 4 halogens and optionally substituted with one or two R 3 replace; R 2 is H, halide, C 1-6 Alkyl; or C 3-6 Cycloalkyl, wherein the alkyl or C 3-6 Cycloalkyl is optionally substituted with halo; - R 3 It is C 1-6 Alkyl, -C 3-7 Cycloalkyl, OH, OC 1-6 Alkyl or -OC 3-7 wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted by 1 to 4 R 2 replace; and R 4 Each independently is H, -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-6 Alkyl, -C 3-7 Cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 halogens; and R 5 It is H, C 1-6 Alkyl, CN, C 3-7 Cycloalkyl, OC 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 alkyl, 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. The compound according to claim 1, wherein Y is C 3-7 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. The compound according to claim 1 , wherein Y is a 4- to 8-membered heterocyclic group.

6. The compound according to claim 5, wherein Y is: , or a pharmaceutically acceptable salt or stereoisomer thereof.

7. A compound according to any one of claims 1 to 6, wherein R 1 is an azaindole, optionally substituted with 1 or 2 R 4 Substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The compound according to claim 7, wherein the azaindole is replaced by 1 or 2 R 3 Substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The compound according to claim 8, wherein the azaindole is replaced by 1 R 3 Substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. A compound according to any one of claims 1 to 6, wherein R 1 It is pyridyl.

11. A compound according to any one of claims 1 to 6, wherein R 1 It is pyrazolo[4,5-c]pyridinyl.

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

13. The compound according to claim 1, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

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

15. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 13 or a composition according to claim 14.

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