2,4-Dioxopyrimidine compounds that inhibit CD73

Abstract

The present disclosure provides pyrimidinedione compounds and pharmaceutical compositions thereof for treating cancers including solid tumors. The compounds can be used alone or in combination with other anticancer agents.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 018,774, filed on May 1, 2020, and U.S. Provisional Application No. 63 / 149,803, filed on February 16, 2021, which are hereby incorporated by reference in their 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 hematopoietic cell subsets. 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 inhibits infiltrating effector T cells. The degradation of ATP to Ado by CD39 and CD73 co-expressed on murine Tregs (regulatory CD4+ T cells) has been shown to be the cause of tumor immunosuppression.

[0005] It can be found that CD73 is constitutively expressed at high levels on various types of cancer cells. Adenosine produced by CD73 is believed 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 regulating CD73 activity and related therapeutic agents are needed. The present disclosure meets this need and other needs. Summary of the invention

[0006] In one embodiment, the present disclosure provides a compound of formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein

[0009] Y is a bond, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-O-, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkyl-O-, -C 3-7 Cycloalkyl-O-, -OC 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-3 Alkyl, -S(=O) 2 -、-S(=O) 2 CH 2 -、-CH 2 S(=O) 2 -、-N(R a )-、-N(R a )CH 2 -、-C 1-6 Alkyl-N(R b )-、-C 3-7 Cycloalkyl-N(R b )-、-N(R a )C(=O)-、-C 1-3 Alkyl N(R a )C(=O)-, heterocycloalkyl-C(=O)-, heterocycloalkyl-N(H)C(=O)-, heterocycloalkyl, heterocycloalkyl-C 1-6 alkyl-O- or heterocycloalkyl-O-, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one to four halogens and further optionally substituted with one or two independently selected from -CN, -C 1-3 Alkyl and -C 1-3 haloalkyl radical substitution;

[0010] Z 1 , Z 2 and Z 3 One or both of them are CR 2 , and Z 1 , Z 2 and Z 3 The remaining one or both of are N;

[0011] W 1 and W 2One of them is N, and the other is C;

[0012] R 1 It is hydrogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6-12 Aryl, -C 1-6 Alkyl-C 6-12 Aryl, -C 1-6 Alkyl-heteroaryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 replace;

[0013] R 2 are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a , -C(=O)heterocycloalkyl, -C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )heteroaryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6-12 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace;

[0014] R 3 It is halogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 1-3 Alkyl-C 3-7 Cycloalkyl, -C 1-3 Alkyl-heterocycloalkyl, -N(R b )(R b )、-N(H)C(=O)OR c 、-C(=O)N(R b )(R b ), -C(=O)OC 1-6 Alkyl, -C(=O)OC1-6 Alkyl C 6-12 Aryl, -C(=O)C 1-3 Alkyl, -C(=O)C 3-7 Cycloalkyl, -C(=O)heterocycloalkyl, -OC(=O)heterocycloalkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)N(H)C 3-7 Cycloalkyl, -OC(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 6-12 Aryl or -OR c , wherein each alkyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted with one to three halogens and further optionally substituted with one or two R c replace;

[0015] R 4 Halogen, -CN, -OR c , -C 1-6 Alkyl, -N(R b )(R b ) or -C 1-6 Haloalkyl;

[0016] R a are independently hydrogen or -C 1-3 alkyl;

[0017] R b are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -C 3-7 Halogenated cycloalkyl or -C(=O)C 1-6 Alkyl; and

[0018] R c are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -C 1-3 Alkyl-C 3-7 Cycloalkyl, -C 1-3 Alkyl-C 3-7 Cyclohaloalkyl, -OC 1-6 Alkyl or -C 3-7 halocycloalkyl; and

[0019] wherein each heterocycloalkyl or heteroaryl group has one to four heteroatoms independently selected from N, O and S;

[0020] wherein each heterocycloalkyl group has 4 to 15 ring members; and

[0021] wherein each heteroaryl group has 5 to 15 ring members.

[0022] In another embodiment, the present disclosure provides a compound of formula (I):

[0023]

[0024] or a pharmaceutically acceptable salt thereof, wherein

[0025] Y is a bond, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-O-, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-7 Cycloalkyl-O-, -OC 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-3 Alkyl-, -S(=O) 2 -、-S(=O) 2 CH 2 -、-CH 2 S(=O) 2 -、-N(R a )-、-N(R a )CH 2 -、-C 1-6 Alkyl-N(R b )-、-C 3-7 Cycloalkyl-N(R b )-、-N(R a )C(=O)-、-C 1-3 Alkyl N(R a )C(=O)-, heterocycloalkyl-C(=O)-, heterocycloalkyl or heterocycloalkyl-O-, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one to four halogens and further optionally substituted with one or two independently selected from -CN and -C 1-3 Alkyl radical substitution;

[0026] Z 1 , Z 2 and Z 3 One or both of them are CR 2 , and Z 1 , Z 2 and Z3 The remaining one or both of are N;

[0027] W 1 and W 2 One of them is N, and the other is C;

[0028] R 1 It is hydrogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6-12 Aryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 replace;

[0029] R 2 are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )heteroaryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace;

[0030] R 3 It is halogen, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -N(R b )(R b ), -C(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)OC 1-6 Alkyl or -OR c ;

[0031] R 4Halogen, -CN, -OR c , -C 1-6 Alkyl, -N(R b )(R b ) or -C 1-6 Haloalkyl;

[0032] R a are independently hydrogen or -C 1-3 alkyl;

[0033] R b are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl, -C 3-7 Halogenated cycloalkyl or -C(=O)C 1-6 Alkyl; and

[0034] R c are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl or -C 3-7 halocycloalkyl; and

[0035] wherein each heterocycloalkyl or heteroaryl group has one to four heteroatoms independently selected from N, O and S;

[0036] wherein each heterocycloalkyl group has 4 to 10 ring members; and

[0037] wherein each heteroaryl group has 5 to 10 ring members.

[0038] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0039] In another embodiment, the present disclosure provides a method of inhibiting CD73 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0040] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION

[0041] I. Definitions

[0042] "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 (-CH2 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(CH 3 ) 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.

[0043] "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 can be connected to the same atom or to different atoms of the alkylene group. For example, a straight chain alkylene group can be a divalent radical -(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.

[0044] "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 vinyl / ethenyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hexatrienyl. The alkenyl group may be substituted or unsubstituted.

[0045] "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 , C2-6 , 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.

[0046] "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.

[0047] "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 can 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.

[0048] "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.

[0049] As used herein, "halo" or "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0050] 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 may 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.

[0051] "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.

[0052] "Cycloalkyl" refers to a cyclic ring having 3 to 20 carbon atoms (i.e., C 3-20The term "cycloalkyl" also includes a single saturated or partially unsaturated full carbon ring of a cycloalkyl (e.g., 3 to 12 cyclic atoms, such as 3 to 10 cyclic atoms or 3 to 8 cyclic atoms or 3 to 6 cyclic atoms or 3 to 5 cyclic atoms or 3 to 4 cyclic atoms). The term "cycloalkyl" also includes multiple fused, saturated and partially unsaturated full carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Therefore, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles with 6 to 12 cyclic 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 cyclic carbon atoms). When valence requirements allow, the rings of multiple fused ring systems can be connected to each other via fusion, spirocycles and bridge 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.

[0053] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, wherein the alkyl component connects the cycloalkyl component to 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 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.

[0054] 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 indicated, the heterocyclyl group has 3 to 20 cyclic atoms, such as 3 to 12 cyclic atoms, such as 3 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from 1 to 6 annular carbon atoms and from 1 to 3 annular heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroatoms may be optionally oxidized to form -N(-OH)-, =N(-OH)-, or -N(-OH)-. - )-, -S(=O)- or –S(=O) 2 -. When valence requirements allow, the rings of the polycondensed ring (e.g., bicyclic heterocyclic group) system can be connected to each other by fusion, spiro ring, 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-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.

[0055] 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 (dihydroindole), isoindoline (dihydroisoindole), indazoline (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxole, dihydrobenzo[b]dioxole, Indole, dihydrobenzo[d] oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[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:

[0056]

[0057] A fused bicyclic heterocycloalkyl group can also be represented by the following structure:

[0058]

[0059] 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.

[0060] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component connects the heterocycloalkyl component to 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 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.

[0061] 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 (for example, ring systems comprising 2, 3 or 4 rings) with 9 to 20 carbon atoms, wherein at least one ring is aromatic, and wherein other rings may be aromatic or not aromatic (i.e., carbocyclic rings). Such polycondensed ring systems are optionally substituted by one or more (for example, 1, 2 or 3) oxo groups on any carbocyclic ring portion of the polycondensed ring system. When valence requirements allow, the rings of the polycondensed ring systems may be connected to each other via fusion, spirocycles and bridge bonds. It should also be understood that when a certain atomic range yuan aryl (for example, 6-10 yuan 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.

[0062] "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 , 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 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.

[0063] 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 oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, which are 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. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, "Heteroaryl" also includes polycondensed 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), heterocycle (to form, for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryl (to form, for example, indazolyl) to form a polycondensed ring system. Therefore, heteroaryl (single aromatic ring or multiple condensed ring systems) has 1-20 carbon atoms and 1-6 heteroatoms in the heteroaryl ring. Such polycondensed ring systems can be optionally substituted by one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portion of the condensed ring. When valence requirements allow, the rings of the polycondensed ring system can be connected to each other via fusion, spirocycle and bridge bond. It should be understood that the various rings of the polycondensed ring system can be connected in any order relative to each other. It should be understood that the connection point 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 unit 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-membered heteroaryl will include thiazolyl, and a 10-membered heteroaryl will include quinolyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, Azolyl, iso Azolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzo Azolyl, indazolyl, quinol quinolinyl, 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.

[0064] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component connects the heteroaryl component to 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 heteroaryl 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 heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0065] "Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), including the compounds of the Examples.

[0066] 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.

[0067] "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.

[0068] "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.

[0069] As used herein, "treatment" or "treat" or "treating" 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 extent of symptoms and / or prevention of worsening of symptoms associated with a disease or disorder. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms caused by a disease or disorder, and / or reducing the extent of a disease or disorder); b) slowing down or preventing the development of one or more symptoms associated with a disease or disorder (e.g., stabilizing a disease or disorder, delaying worsening or progression of a disease or disorder); and c) alleviating a disease or disorder, such as causing regression of clinical symptoms, improving the disease state, delaying progression of the disease, improving quality of life, and / or prolonging survival.

[0070] 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).

[0071] "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., mini-osmotic pump) to a subject. Administration can be performed according to a schedule specifying the frequency of administration, the dosage of administration, and other factors.

[0072] 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 within 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 within 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.

[0073] "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.

[0074] "Disease" or "disorder" refers to the state of being or health of a patient or subject that can be treated with a compound, pharmaceutical composition or method as provided herein. In embodiments, the disease is cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma). The disease can be an autoimmune disease, inflammatory disease, cancer, infectious disease, metabolic disease, developmental disease, cardiovascular disease, liver disease, intestinal disease, endocrine disease, neurological disease or other disease.

[0075] "Cancer" refers to all types of cancers, 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 (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

[0076] 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.

[0077] "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 involved; 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.

[0078] "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 fibril 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.

[0079] "Melanoma" refers to a tumor produced by 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.

[0080] "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, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial protocarcinoma, gyriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus 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 carcinomacarcinoma, 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, spongiosum carcinoma, squamous carcinoma, squamous cell carcinoma, cord carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0081] "Metastasis", "metastatic" and "metastatic cancer" can be 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 speculated that the metastatic tumor and its cells are similar to those tumors and cells of the original tumor. 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 second location or locations (e.g., in the breast).

[0082] "Associated with" or "associated with..." in the context of a substance or 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.

[0083] 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.

[0084] 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.

[0085] 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 Also included are base addition salts such as sodium or potassium salts.

[0086] 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 replaced 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.

[0087] 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.

[0088] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may include one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- according to absolute stereochemistry or as (D)- or (L)- for amino acids. The 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 / separating 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 indicated, it is intended that the compounds include E and Z geometric isomers. Likewise, it is also intended to include all tautomeric forms. 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.

[0089] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0090] 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, the compound can exist in stereoisomeric forms, and can therefore be prepared as a single stereoisomer or as a mixture. Unless otherwise indicated, this specification is intended to include single 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).

[0091] "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.

[0092] 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 can be attached in either direction. Similarly, an "arylalkyl" group can be attached to the rest of the molecule, for example, at 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.

[0093] 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.

[0094] 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.

[0095] II.Compounds

[0096] The present disclosure provides compounds that are inhibitors of CD73. In some embodiments, the present disclosure provides compounds of formula (I) as described herein and / or pharmaceutically acceptable salts thereof. In some embodiments, compounds having the structure of formula (I) are provided,

[0097]

[0098] And / or a pharmaceutically acceptable salt thereof. Some embodiments provide a compound having the structure of Formula (I).

[0099] In some embodiments, the compound of formula (I) is

[0100]

[0101] or a pharmaceutically acceptable salt thereof, wherein

[0102] Y is a bond, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-O-, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkyl-O-, -C 3-7 Cycloalkyl-O-, -OC 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-3 Alkyl, -S(=O) 2 -、-S(=O) 2 CH 2 -、-CH 2 S(=O) 2 -、-N(R a )-、-N(R a )CH 2 -、-C 1-6 Alkyl-N(R b )-、-C 3-7 Cycloalkyl-N(R b )-、-N(R a )C(=O)-、-C 1-3 Alkyl N(R a )C(=O)-, heterocycloalkyl-C(=O)-, heterocycloalkyl-N(H)C(=O)-, heterocycloalkyl, heterocycloalkyl-C 1-6 alkyl-O- or heterocycloalkyl-O-, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one to four halogens and further optionally substituted with one or two independently selected from -CN, -C 1-3 Alkyl and -C 1-3 haloalkyl radical substitution;

[0103] Z 1 , Z 2 and Z 3 One or both of them are CR 2 , and Z 1 , Z 2 and Z 3 The remaining one or both of are N;

[0104] W 1 and W 2 One of them is N, and the other is C;

[0105] R 1 It is hydrogen, -CN, -C 1-6Alkyl, -C 3-7 Cycloalkyl, -C 6-12 Aryl, -C 1-6 Alkyl-C 6-12 Aryl, -C 1-6 Alkyl-heteroaryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 replace;

[0106] R 2 are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a , -C(=O)heterocycloalkyl, -C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )heteroaryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6-12 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace;

[0107] R 3 It is halogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 1-3 Alkyl-C 3-7 Cycloalkyl, -C 1-3 Alkyl-heterocycloalkyl, -N(R b )(R b )、-N(H)C(=O)OR c 、-C(=O)N(R b )(R b ), -C(=O)OC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl C 6-12 Aryl, -C(=O)C 1-3 Alkyl, -C(=O)C 3-7Cycloalkyl, -C(=O)heterocycloalkyl, -OC(=O)heterocycloalkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)N(H)C 3-7 Cycloalkyl, -OC(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 6-12 Aryl or -OR c , wherein each alkyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted with one to three halogens and further optionally substituted with one or two R c replace;

[0108] R 4 Halogen, -CN, -OR c , -C 1-6 Alkyl, -N(R b )(R b ) or -C 1-6 Haloalkyl;

[0109] R a are independently hydrogen or -C 1-3 alkyl;

[0110] R b are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -C 3-7 Halogenated cycloalkyl or -C(=O)C 1-6 Alkyl; and

[0111] R c are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -C 1-3 Alkyl-C 3-7 Cycloalkyl, -C 1-3 Alkyl-C 3-7 Cyclohaloalkyl, -OC 1-6 Alkyl or -C 3-7 halocycloalkyl; and

[0112] wherein each heterocycloalkyl or heteroaryl group has one to four heteroatoms independently selected from N, O and S;

[0113] wherein each heterocycloalkyl group has 4 to 15 ring members; and

[0114] wherein each heteroaryl group has 5 to 15 ring members.

[0115] In some embodiments, the compound of formula (I) is

[0116]

[0117] and / or a pharmaceutically acceptable salt thereof, wherein

[0118] Y is a bond, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-O-, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-7 Cycloalkyl-O-, -OC 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-3 Alkyl-, -S(=O) 2 -、-S(=O) 2 CH 2 -、-CH 2 S(=O) 2 -、-N(R a )-、-N(R a )CH 2 -、-C 1-6 Alkyl-N(R b )-、-C 3-7 Cycloalkyl-N(R b )-、-N(R a )C(=O)-、-C 1-3 Alkyl N(R a )C(=O)-, heterocycloalkyl-C(=O)-, heterocycloalkyl or heterocycloalkyl-O-, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one to four halogens and further optionally substituted with one or two independently selected from -CN and -C 1-3 Alkyl radical substitution;

[0119] Z 1 , Z 2 and Z 3 One or both of them are CR 2 , and Z 1 , Z 2 and Z 3 The remaining one or both of are N;

[0120] W 1 and W 2One of them is N, and the other is C;

[0121] R 1 It is hydrogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6-12 Aryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 replace;

[0122] R 2 are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )heteroaryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace;

[0123] R 3 It is halogen, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -N(R b )(R b ), -C(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)OC 1-6 Alkyl or -OR c ;

[0124] R 4 Halogen, -CN, -OR c , -C 1-6 Alkyl, -N(R b )(R b) or -C 1-6 Haloalkyl;

[0125] R a are independently hydrogen or -C 1-3 alkyl;

[0126] R b are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl, -C 3-7 Halogenated cycloalkyl or -C(=O)C 1-6 Alkyl; and

[0127] R c are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl or -C 3-7 halocycloalkyl; and

[0128] wherein each heterocycloalkyl or heteroaryl group has one to four heteroatoms independently selected from N, O and S;

[0129] wherein each heterocycloalkyl group has 4 to 10 ring members; and

[0130] wherein each heteroaryl group has 5 to 10 ring members.

[0131] In some embodiments, the present disclosure provides compounds having a structure of formula (I) and / or a pharmaceutically acceptable salt thereof, wherein

[0132] Y is a bond, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-O-, -OC 1-6 Alkyl, -C 3-7 Cycloalkyl-O-, -OC 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-3 Alkyl-, -S(=O) 2 -、-S(=O) 2 CH 2 -、-CH 2 S(=O) 2 -、-N(R a )-、-N(R a )CH 2 -、-C1-6 Alkyl-N(R b )-、-C 3-7 Cycloalkyl-N(R b )-、-N(R a )C(=O)-、-C 1-3 Alkyl N(R a )C(=O)-, heterocycloalkyl-C(=O)-, -OC 1-6 Alkyl-O-, heterocycloalkyl-N(H)C(=O)-, heterocycloalkyl-C 1-6 wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one to four halogens and further optionally substituted with one or two independently selected from -CN, -C 1-3 Alkyl and -C 1-3 haloalkyl radical substitution;

[0133] R 1 It is hydrogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6-12 Aryl, -C 1-6 Alkyl-C 6-12 Aryl, -C 1-6 Alkyl-heteroaryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 replace;

[0134] R 3 It is halogen, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -C 1-3 Alkyl-C 3-7 Cycloalkyl, -C 1-3 Alkyl-heterocycloalkyl, -N(R b )(R b )、-N(H)C(=O)OR c 、-C(=O)N(R b )(R b ), -C(=O)OC 1-6 Alkyl C 6-12 Aryl, -C(=O)C 1-3 Alkyl, -C(=O)C 3-7 Cycloalkyl, -C(=O)heterocycloalkyl, -OC(=O)heterocycloalkyl, -OC(=O)N(H)C 3-7 Cycloalkyl, -OC(=O)N(H)C6-12 Aryl or -OR c ;

[0135] R b are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -C 3-7 Halogenated cycloalkyl or -C(=O)C 1-6 Alkyl; and

[0136] Where Z 1 , Z 2 , Z 3 , W 1 , W 2 , R 2 , R 4 , R a and R c As described in this article.

[0137] In some embodiments, the present disclosure provides compounds having a structure of formula (I) and / or a pharmaceutically acceptable salt thereof, wherein

[0138] Y is a bond, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-O-, -OC 1-6 Alkyl, -C 3-7 Cycloalkyl-O-, -OC 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-3 Alkyl-, -S(=O) 2 -、-S(=O) 2 CH 2 -、-CH 2 S(=O) 2 -、-N(R a )-、-N(R a )CH 2 -、-C 1-6 Alkyl-N(R b )-、-C 3-7 Cycloalkyl-N(R b )-、-N(R a )C(=O)-、-C 1-3 Alkyl N(R a )C(=O)-, heterocycloalkyl-C(=O)- or heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one to four halogens and further optionally substituted by one or two independently selected from -CN and -C1-3 Alkyl radical substitution;

[0139] R 1 It is hydrogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6 Aryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 replace;

[0140] R 3 It is halogen, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -N(R b )(R b ) or -OR c ;

[0141] R b are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -C 3-7 Halogenated cycloalkyl or -C(=O)C 1-6 Alkyl; and

[0142] Where Z 1 , Z 2 , Z 3 , W 1 , W 2 , R 2 , R 4 , R a and R c As described in this article.

[0143] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-a):

[0144]

[0145] and / or a pharmaceutically acceptable salt thereof, wherein Y, R 1 , R 2a and R 2b As described in this article.

[0146] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-a):

[0147]

[0148] Where R 2a and R 2b are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a , -C(=O)heterocycloalkyl, -C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6-12 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace,

[0149] And where R 1 and Y as described herein.

[0150] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-a):

[0151]

[0152] and / or a pharmaceutically acceptable salt thereof,

[0153] Where R 2a and R 2b are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R4 replace,

[0154] And where R 1 and Y as described herein.

[0155] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-b):

[0156]

[0157] and / or a pharmaceutically acceptable salt thereof, wherein Y, R 1 and R 2b As described in this article.

[0158] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-b):

[0159]

[0160] and / or a pharmaceutically acceptable salt thereof,

[0161] Where R 2b It is hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )heteroaryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace,

[0162] And where R 1 and Y as described herein.

[0163] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-c):

[0164]

[0165]

[0166] and / or a pharmaceutically acceptable salt thereof, wherein Y, R 1 , R 2a and R 2b As described in this article.

[0167] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-c):

[0168]

[0169] and / or a pharmaceutically acceptable salt thereof,

[0170] Where R 2a and R 2b are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace,

[0171] And where R 1 and Y as described herein.

[0172] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-d):

[0173]

[0174] and / or a pharmaceutically acceptable salt thereof, wherein Y, R 1 and R 2a As described in this article.

[0175] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-d):

[0176]

[0177] and / or a pharmaceutically acceptable salt thereof,

[0178] Where R 2a It is hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace,

[0179] And where R 1 and Y as described herein.

[0180] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-e):

[0181]

[0182] and / or a pharmaceutically acceptable salt thereof, wherein Y, R 1 and R 2a As described in this article.

[0183] In some embodiments, the present disclosure provides compounds having the structure of Formula (II-e):

[0184]

[0185] and / or a pharmaceutically acceptable salt thereof,

[0186] Where R 2a are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace,

[0187] And where R 1 and Y as described herein.

[0188] Some embodiments provide compounds having the structure of Formula (II-a), (II-b), (II-c), (II-d) or (II-e), wherein R 1 Optionally one or two R 3 substituted; and wherein R 2a and R 2b are independently hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace.

[0189] In some embodiments, the compounds of the present disclosure are compounds wherein R 1 Yes-C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6-12 Aryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 In some embodiments, the compounds of the present disclosure are compounds wherein R 1 Yes-C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C6-12 Aryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 Alkyl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to four halogens.

[0190] In some embodiments, the compounds of the present disclosure are compounds wherein R 1 Yes-C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6 Aryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 alkyl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 3 In some embodiments, the compounds of the present disclosure are compounds wherein R 1 Yes-C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 6 Aryl, heterocycloalkyl, heteroaryl or -C 1-6 Alkyl-OC 1-6 Alkyl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to four halogens.

[0191] In some embodiments, the compounds of the present disclosure are compounds wherein R 1 isopropyl, -F, -CF 3 , pyrrolidinyl, morpholinyl, imidazolyl, phenyl, pyridyl, -CH 2 OCH 3 、-C(CH 3 ) 3 or cyclopropyl, each of which is optionally substituted with one to three halogens and further optionally with one or two R 3 In some embodiments, the compound of the present disclosure is a compound or a pharmaceutically acceptable salt thereof: wherein R 1 isopropyl, -F, -CF 3 , pyrrolidinyl, morpholinyl, imidazolyl, phenyl, pyridyl, -CH 2 OCH 3 、-C(CH 3 ) 3 or cyclopropyl, each of which is optionally substituted with one to three halogens within the range permitted by valence. In some embodiments, the compounds of the present disclosure are compounds or pharmaceutically acceptable salts thereof: wherein R 1 isopropyl, -F, -CF3 , pyrrolidinyl, morpholinyl, imidazolyl, phenyl, pyridyl, -CH 2 OCH 3 、-C(CH 3 ) 3 Or cyclopropyl.

[0192] In some embodiments, the compounds of the present disclosure are compounds wherein R 1 yes:

[0193]

[0194] In some embodiments, the compounds of the present disclosure are compounds wherein R 1 yes:

[0195]

[0196]

[0197] In some embodiments, the compounds of the present disclosure are compounds wherein R 2 Selected from hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C 6-12 Aryl, -C(=O)N(R b )heteroaryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace.

[0198] In some embodiments, the compounds of the present disclosure are compounds wherein R 2a and R 2b Each is selected from hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -OC 1-6 Alkyl, -C(=O)OR a 、-C(=O)N(R b )C6-12 Aryl, -C(=O)N(R b )heteroaryl, -C(=O)N(R b )(R b ),-C 1-6 Alkyl-S(=O) 2 C 6 Aryl, -N(R b )(R b ),-C 6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to three halogens and further optionally substituted with one to three R 4 replace.

[0199] In some embodiments, the compounds of the present disclosure are compounds wherein R 2 , R 2a and R 2b are independently hydrogen, halogen, -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -C(=O)OR a , -C 1-6 Alkyl-S(=O) 2 C 6 Aryl, heteroaryl or -C 6 Aryl, wherein each alkyl, cycloalkyl, heteroaryl or aryl is optionally substituted with one to three halogens and further optionally substituted with one or two R 4 replace.

[0200] In some embodiments, the compounds of the present disclosure are compounds wherein R 2 , R 2a and R 2b are independently -H, -F, -CH 3 、-CH 2 CH 3 , -CF 3 , phenyl, -CH 2 SO 2 Ph, -C(=O)OCH 2 CH 3 , cyclopropyl or

[0201] In some embodiments, the compounds of the present disclosure are compounds wherein R 2 , R 2a or R 2b yes:

[0202]

[0203] In some embodiments, the compounds of the present disclosure are compounds wherein R 2 , R 2a or R 2b yes:

[0204]

[0205] In some embodiments, the compounds of the present disclosure are compounds wherein R 2 , R 2a or R 2b yes:

[0206]

[0207] In some embodiments, the compounds of the present disclosure are compounds wherein R 3 Yes-CH 3 、-CH 2 CH 3 , -F, -Cl, -CF 3 , cyclopropyl, -OCF 3 or -CN.

[0208] In some embodiments, the compounds of the present disclosure are compounds wherein R 3 Yes-O-CH 3 or

[0209] In some embodiments, the compounds of the present disclosure are compounds wherein R 4 Is -F or -CF 3 .

[0210] In some embodiments, the compounds of the present disclosure are those wherein Y is a bond.

[0211] In some embodiments, the compounds of the present disclosure are compounds wherein Y is:

[0212]

[0213] In some embodiments, the compounds of the present disclosure are compounds wherein YR 1 yes:

[0214] -CH 3 、-CH 2 CH 3 , isopropyl, -O-isopropyl, -OPh,

[0215]

[0216] Each of these groups is optionally substituted by one or two R3 replace.

[0217] In some embodiments, the compounds of the present disclosure are compounds wherein YR 1 yes:

[0218]

[0219]

[0220] In some embodiments, the compounds of the present disclosure are compounds wherein YR 1 yes:

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (II-f):

[0237]

[0238] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a and R 2bAs described in this article.

[0239] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (II-f):

[0240]

[0241] or a pharmaceutically acceptable salt thereof,

[0242] Where R 1 is phenyl or heteroaryl, each of which is optionally substituted by one to three halogens and further optionally substituted by one or two R 3 Replacement, R 2a and R 2b are each independently hydrogen or halogen.

[0243] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-a):

[0244]

[0245] or a pharmaceutically acceptable salt thereof, wherein R 1 As described in this article.

[0246] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-a):

[0247]

[0248] or a pharmaceutically acceptable salt thereof,

[0249] Where R 1 is phenyl or heteroaryl, each of which is optionally substituted by one to three halogens and further optionally substituted by one or two R 3 replace.

[0250] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (II-g):

[0251]

[0252] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a and R 2b As described in this article.

[0253] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (II-g):

[0254]

[0255] or a pharmaceutically acceptable salt thereof,

[0256] Where R 1 is phenyl or heteroaryl, each of which is optionally substituted by one to three halogens and further optionally substituted by one or two R 3 Replacement, R 2a and R 2b are each independently hydrogen or halogen.

[0257] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-b):

[0258]

[0259] or a pharmaceutically acceptable salt thereof, wherein R 1 As described in this article.

[0260] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-b):

[0261]

[0262] or a pharmaceutically acceptable salt thereof,

[0263] Where R 1 is phenyl or heteroaryl, each of which is optionally substituted by one to three halogens and further optionally substituted by one or two R 3 replace.

[0264] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (II-h):

[0265]

[0266] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a and R 2b As described in this article.

[0267] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (II-h):

[0268]

[0269] or a pharmaceutically acceptable salt thereof,

[0270] Where R 1 It is C 3-7 Cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one to three halogens and further optionally substituted by one or two R 3 Replacement, R2a and R 2b are each independently hydrogen or halogen.

[0271] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-c):

[0272]

[0273] or a pharmaceutically acceptable salt thereof, wherein m, R 5 , R 2a and R 2b As described in this article.

[0274] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-c):

[0275]

[0276] in

[0277] Each R 5 are independently halogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-N(R d )(R d ),-OR c 、-N(R b )(R b ), -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)OC 1-6 Alkyl, -OC 6-12 Aryl, -O-heteroaryl or -C 1-6 Haloalkyl, or two R 5 The moieties are joined together to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring, wherein the ring is optionally substituted with one to three halogens and further optionally substituted with one to three R 6 replace;

[0278] R 6 It is halogen, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -N(R b )(R b ), -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 1-6Alkyl, -OC(=O)OC 1-6 Alkyl or -OR c ;and

[0279] m is 0, 1, 2, 3, or 4;

[0280] And where R 2a and R 2b As described in this article.

[0281] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-c):

[0282]

[0283] or a pharmaceutically acceptable salt thereof,

[0284] in

[0285] Each R 5 are independently halogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-N(R d )(R d ),-OR c 、-N(R b )(R b ), -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)OC 1-6 Alkyl or -C 1-6 Haloalkyl, or two R 5 The moieties are joined together to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring, wherein the ring is optionally substituted with one to three halogens and further optionally substituted with one to three R 6 replace;

[0286] R 6 It is halogen, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -N(R b )(R b ), -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)OC 1-6 Alkyl or -OR c ;and

[0287] m is 0, 1, 2, 3, or 4;

[0288] And where R 2a and R 2b As described in this article.

[0289] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-d):

[0290]

[0291] or a pharmaceutically acceptable salt thereof, wherein R 7a , R 7b , R 7c , R 7d , R 2a and R 2b As described in this article.

[0292] In some embodiments, the compound of the present disclosure is a compound having the structure of Formula (III-d):

[0293]

[0294] or a pharmaceutically acceptable salt thereof,

[0295] Where R 7a , R 7b , R 7c and R 7d are independently halogen, -C 1-6 Alkyl or -C 1-6 A haloalkyl group, or R 7a , R 7b , R 7c or R 7d Two of the moieties are joined together to form a 3- to 6-membered cycloalkyl ring, wherein the ring is optionally substituted with one to three halogens,

[0296] And where R 2a and R 2b As described in this article.

[0297] In some embodiments, the compounds of the present disclosure are compounds having the structure of Formula (II-f), (II-g), (III-a) or (III-b), or pharmaceutically acceptable salts thereof, wherein R 1 is phenyl or heteroaryl, each of which is optionally substituted with one to three halogens. In some embodiments, the compounds of the present disclosure are compounds having the structure of Formula (II-f), (II-g), (III-a) or (III-b), or pharmaceutically acceptable salts thereof, wherein R 1 is phenyl or heteroaryl, each of which is optionally substituted by one or two R3 In some embodiments, the compounds of the present disclosure are compounds having the structure of Formula (II-f), (II-g), (III-a) or (III-b), wherein R 1 Is one or two R 3 Substituted phenyl or heteroaryl.

[0298] In some embodiments, the compound of the present disclosure is a compound having a structure of Formula (II-h) or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 3-7 cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one to three halogens. In some embodiments, the compound of the present disclosure is a compound having a structure of formula (II-h) or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 3-7 Cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one or two R 3 In some embodiments, the compounds of the present disclosure are compounds having the structure of Formula (II-h), wherein R 1 Is one or two R 3 Substituted C 3-7 Cycloalkyl or heterocycloalkyl.

[0299] In some embodiments, the compound of the present disclosure is a compound having a structure of Formula (III-c) or a pharmaceutically acceptable salt thereof, wherein R 5 are independently halogen, -CN, -C 1-6 Alkyl, -C 3-7 Cycloalkyl, -C 1-6 Alkyl-N(R d )(R d ),-OR c 、-N(R b )(R b ), -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)N(H)C 1-6 Alkyl, -OC(=O)OC 1-6 Alkyl, -OC 6-12 Aryl, -O-heteroaryl or -C 1-6 In some embodiments, the compound of the present disclosure is a compound having a structure of formula (III-c) or a pharmaceutically acceptable salt thereof, wherein R 5 are independently halogen, -C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl or -OC(=O)N(H)C 1-6In some embodiments, the compound of the present disclosure is a compound having a structure of formula (III-c) or a pharmaceutically acceptable salt thereof, wherein two R 5 The moieties are joined together to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring, wherein the ring is optionally substituted with one to three halogens and further optionally substituted with one to three R 6 In some embodiments, the compounds of the present disclosure are compounds having a structure of formula (III-c), wherein two R 5 The moieties are linked together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring.

[0300] In some embodiments, the compound of the present disclosure is a compound having a structure of Formula (III-d) or a pharmaceutically acceptable salt thereof, wherein R 7a , R 7b , R 7c and R 7d are independently halogen, -C 1-6 Alkyl or -C 1-6 In some embodiments, the compound of the present disclosure is a compound having a structure of formula (III-d) or a pharmaceutically acceptable salt thereof, wherein R 7a , R 7b , R 7c and R 7d are independently halogen, -C 1-6 Alkyl or -C 1-6 haloalkyl, and R 7a , R 7b , R 7c or R 7d Two of the moieties are connected together to form a 3- to 6-membered cycloalkyl ring, wherein the ring is optionally substituted with one to three halogens. In some embodiments, the compound of the present disclosure is a compound having a structure of formula (III-d) or a pharmaceutically acceptable salt thereof, wherein R 7a , R 7b , R 7c or R 7d Two of the moieties are linked together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring.

[0301] In some embodiments, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) is a compound described in Table 2 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c) or (III-d) is a compound described in Table 2.

[0302] In some embodiments, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) is a compound having the following structure:

[0303]

[0304] or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) is a compound having the following structure:

[0306]

[0307]

[0308]

[0309]

[0310] or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) is a compound having the following structure:

[0312] In some embodiments, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) is a compound having the following structure:

[0313]

[0314]

[0315] or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) is a compound having the following structure:

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355] or a pharmaceutically acceptable salt thereof.

[0356] Also within the scope of the present invention are in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious relative to the prior art. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, novel and unobvious compounds are produced by methods comprising contacting the compound with a mammal for a period of time sufficient to produce its metabolic products. Such products are typically identified by the following process: preparing a radioactive label (e.g. 14 C or 3 H) compounds are administered parenterally to animals (such as rats, mice, guinea pigs, monkeys or humans) at detectable doses (e.g., greater than about 0.5 mg / kg), sufficient time is allowed for metabolism (usually about 30 seconds to about 30 hours), and their conversion products are isolated from urine, blood or other biological samples. These products are easily isolated because they are labeled (other products are isolated by using antibodies that can bind to epitopes that survive in the metabolites). The metabolite structures are determined in a conventional manner (e.g., by MS or NMR analysis). In general, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art.

[0357] III. Preparation Method

[0358] The compounds of the present disclosure can be prepared by a variety of methods. For example, Schemes 1-4 show representative syntheses of the compounds of the present disclosure.

[0359] Solution 1.

[0360]

[0361] 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, in a suitable solvent system (e.g., water + dihydrogen sulfoxide) alkane, THF, DME, toluene, etc.), in the presence of a palladium catalyst (e.g. Pd(dppf)Cl 2 、Pd(PPh 3 ) 4 etc.) and bases (such as Cs 2 CO 3 , K 2 CO 3 , K 3 PO 4In the case of a 2,4-dimethoxypyrimidine having a chloroimidazopyridazine (or a corresponding bromine or iodine compound) and a 2,4-dimethoxypyrimidine having a chloroimidazopyridazine (or a corresponding bromine or iodine compound) are combined with (2,4-dimethoxypyrimidin-5-yl)boronic acid at elevated temperatures (e.g., in the range of about 80°C-120°C), which can be carried out, for example, in a microwave reactor or under conventional heating. Subsequently, the resulting appropriately substituted 2,4-dimethoxypyrimidine can be treated with an acid (e.g., hydrochloric acid) in a suitable solvent system (e.g., water + methanol, ethanol, etc.) at elevated temperatures (e.g., in the range of about 50°C-80°C).

[0362] Solution 2.

[0363]

[0364] Representative Synthesis Scheme 2 shows the general synthesis of compounds of the embodiment. This method is compatible with a variety of functions. In Representative Synthesis Scheme 2, in a suitable solvent system (e.g., water + dihydrogen sulfoxide) alkane, THF, DME, toluene, etc.), in the presence of a palladium catalyst (e.g. Pd(dppf)Cl 2 , cataCXium-A-Pd G3, etc.) and bases (such as Cs 2 CO 3 , K 2 CO 3 , K 3 PO 4 In the case of a bromoimidazopyridazine (or the corresponding chloro or iodo compound) substituted with an alkylboronic acid or boronic acid derivative (e.g., a borate ester or trifluoroborate) at elevated temperature (e.g., in the range of about 90°C to 150°C), this can be carried out in a microwave reactor or under conventional heating.

[0365] Solution 3.

[0366]

[0367] Representative Synthesis Scheme 3 shows the general synthesis of compounds of the embodiment. This method is compatible with a variety of functions. In Representative Synthesis Scheme 3, in a suitable solvent system (e.g., acetonitrile, EtOH, THF, NMP, etc.), in the presence of a base (e.g., Cs 2 CO 3 , K 2 CO 3 , triethylamine, DIPEA, NaH, etc.), an appropriately substituted bromoimidazopyridazine (or the corresponding chloro or fluoro compound) is combined with a nucleophile (e.g., amine, alcohol, heterocycle, etc.) at ambient or elevated temperature (e.g., in the range of about 20°C-90°C).

[0368] Solution 4.

[0369]

[0370] 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 a suitable solvent system (e.g., DMSO / H 2 O.DCE / H 2 O, etc.), in the presence of an oxidant (e.g., TBHP), at ambient or elevated temperature (e.g., in the range of about 20°C-60°C), an appropriately substituted chloroimidazopyridazine is combined with a free radical precursor (such as sodium or zinc alkylsulfinate). A variety of free radical precursors and reaction conditions can be used to generate suitable alkyl radical intermediates, including Minisci conditions (i.e., alkyl carboxylic acids, (NH 4 ) 2 S 2 O 9 AgNO 3 , TFA).

[0371] Solution 5.

[0372]

[0373] Representative Synthesis Scheme 5 shows the general synthesis of compounds of the embodiment. This method is compatible with a variety of functions. In Representative Synthesis Scheme 5, in a suitable solvent system (e.g., water + THF, dihydrogen fluoride, pyrrolidone ... alkane, DME, toluene, etc.), in the presence of a palladium catalyst (e.g. Pd(dppf)Cl 2 、Pd(PPh 3 ) 4 etc.) and bases (such as K 2 CO 3 , Cs 2 CO 3 , K 3 PO 4 In the case of a substituted aryl or heteroaryl halide, a suitable substituted aryl or heteroaryl halide is reacted with potassium vinyl trifluoroborate (or similar -Bpin, -BMIDA or -B(OH) 2 The reaction mixture is combined with tetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2- The appropriately substituted olefin is treated with [N]oxazolyl-(N-phenyl)ruthenium(II) hexafluorophosphate (or another suitable transition metal catalyst) and 1,3-dioxoisoindolin-2-yl 2-diazoacetate. 3 Ph, etc.), the resulting appropriately substituted N-hydroxyphthalimide ester is combined with methyl isonicotinate (or another suitable isonicotinate derivative, such as tert-butyl isonicotinate, etc.) and bis(pinacol)diboron at elevated temperature (in the range of 60°C-100°C). Alternatively, the borylation reaction can be carried out by mixing the appropriately substituted N-hydroxyphthalimide ester with bis(catechol)diboron in a suitable solvent system (such as DMF) under blue LED light and combining the resulting boronate with pinacol and triethylamine.

[0374] Alternatively, the reaction sequence can provide a racemic mixture of the compound by combining an appropriately substituted olefin with ethyl diazoacetate in a suitable solvent system (i.e., toluene) at elevated temperature (e.g., in the range of about 80° C.-120° C.). Subsequently, the ethyl ester can be hydrolyzed under basic aqueous conditions (e.g., LiOH or NaOMe), and the resulting acid can be combined with N-hydroxyphthalimide and a suitable coupling agent (e.g., DIC, EDC). The final borylation step can be performed as above.

[0375] Pharmaceutical preparations

[0376] In some embodiments, the present disclosure provides a pharmaceutical preparation comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein is a pharmaceutical preparation comprising a pharmaceutically effective amount of a compound of formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0377] In some embodiments, the pharmaceutical composition is used to treat cancer.

[0378] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. Any suitable additional therapeutic agent or combination therapy can be used with a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof (such as the agents and therapies described herein).

[0379] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) and an additional therapeutic agent, wherein the additional therapeutic agent is an anticancer agent. In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent is independently an anti-tumor agent, chemotherapy, radiotherapy or resection therapy. In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent is independently rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, nivolumab, pembrolizumab, atezolizumab or ipilimumab. In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent is a PD-1 / PD-L1 inhibitor.

[0380] In some embodiments, the pharmaceutical composition is one in which the additional therapeutic agent comprises one or more immune cell populations, such as natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor infiltrating lymphocytes (TIL), and dendritic cells (DC).

[0381] In some embodiments, the pharmaceutical composition is one in which the additional therapeutic agent comprises one or more chimeric antigen receptors (CARs).

[0382] In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the additional therapeutic agent comprises immunotherapy, immunostimulatory therapy, cytokine therapy, chemokine therapy, cell therapy, gene therapy, or a combination thereof. In some embodiments, immunotherapy comprises co-administering one or more antibodies or their antigen-binding antibody fragments or their antibody-drug conjugates, multispecific molecules targeting CD3, multispecific molecules targeting CD16, or non-immunoglobulin antigen binding domains or antibody mimic proteins against one or more targets or tumor-associated antigens (TAAs).

[0383] In some embodiments, the compounds disclosed herein are formulated with conventional carriers and excipients, which are selected according to conventional practice. Tablets may contain excipients, glidants, fillers, binders, etc. Aqueous preparations can be prepared in sterile form and may be isotonic, for example when intended for delivery by non-oral administration. In some embodiments, the preparation may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients may include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH range of the preparation is from about 3 to about 11, for example, from about 7 to about 10.

[0384] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered in pharmaceutical formulations. In some embodiments, the formulations for veterinary and / or human use comprise at least one compound of formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, together with one or more acceptable carriers and optional other therapeutic ingredients, such as those additional therapeutic ingredients discussed herein. In some embodiments, the carrier is "acceptable", i.e., compatible with the other ingredients of the formulation and physiologically harmless to its recipient.

[0385] In some embodiments, the preparations of the present disclosure include those suitable for the aforementioned routes of administration. In some embodiments, the preparations are present in unit dosage form. The preparations can be prepared by methods known in the pharmaceutical field. Technology and preparations can be found in, for example, "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods include, for example, the step of associating the active ingredient with a carrier comprising one or more auxiliary ingredients. In some embodiments, the preparations are prepared by associating the active ingredient with a liquid carrier or a finely dispersed solid carrier or both and then shaping the product in some embodiments.

[0386] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient, such as a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or (III-d), or a pharmaceutically acceptable salt thereof; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is administered as a bolus, electuary, or paste.

[0387] Tablets can be prepared, for example, by compression or molding optionally with one or more auxiliary ingredients. Compressed tablets can be prepared, for example, by the following manner: compressing the active ingredient in a free-flowing form (such as powdered or granular) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be prepared, for example, by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or indented. In some embodiments, tablets are formulated to provide a slow or controlled release of active ingredients therefrom.

[0388] For infections of the eye or other external tissues (e.g., mouth and skin), the formulations can be applied as a topical ointment or cream containing, for example, a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) in an amount ranging from about 0.075% w / w to about 20% w / w (including increments of about 0.1% w / w of active ingredient in a range between about 0.1% and about 20% (such as about 0.6% w / w, about 0.7% w / w, etc.), such as from about 0.2% w / w to about 15% w / w and such as from about 0.5% w / w to about 10% w / w. When formulated into an ointment, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) or a pharmaceutically acceptable salt thereof can be used with a paraffin or water miscible ointment base. Alternatively, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) or a pharmaceutically acceptable salt thereof can be formulated into a cream with an oil-in-water cream base.

[0389] If desired, the aqueous phase of the cream base may include, for example, at least about 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400) and mixtures thereof. Topical formulations may include, in some embodiments, compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0390] The oil phase of the emulsion can be composed of known ingredients in a known manner. Although this phase can only include emulsifiers (or called emulsifiers), it can include, for example, a mixture of at least one emulsifier with fat or oil or with both fat and oil. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. In some embodiments, the emulsion includes both oil and fat. Emulsifiers with or without stabilizers together constitute so-called emulsifying waxes, and waxes together with oils and fats constitute so-called emulsifying ointment bases, which form the oily dispersed phase of the cream formulation.

[0391] Emulsifiers and emulsion stabilizers suitable for the formulation include, for example, 60. 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0392] The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.The present invention relates to the preparation of the present invention.

[0393] In some embodiments, the pharmaceutical preparations herein include a combination with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical preparation containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions can include one or more medicaments, including sweeteners, flavoring agents, colorants and preservatives, so as to provide a palatable preparation. Tablets containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; binders, such as starch, gelatin or gum arabic; and lubricants, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0394] Formulations for oral use may also be provided as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0395] Aqueous suspensions contain active substances mixed with excipients suitable for making aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic; and dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0396] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those described above and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

[0397] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

[0398] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin) or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and tragacanth; naturally occurring phospholipids such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents. Syrups and elixirs can be formulated with sweeteners such as glycerol, sorbitol or sucrose. Such preparations can also contain a demulcent, a preservative, a flavoring agent or a coloring agent.

[0399] The pharmaceutical composition can be in the form of a sterile injectable preparation or intravenous preparation, such as a sterile injectable aqueous or oily suspension. Such suspensions can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injectable or intravenous preparations can also include sterile injectable solutions or suspensions (such as solutions in 1,3-butanediol) in nontoxic parenteral acceptable diluents or solvents, or be prepared as lyophilized powders. Acceptable solvents and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils can be used as solvents or suspension media in general. For this reason, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0400] The amount of active ingredient that can be combined with carrier material to produce a single dosage form can vary according to the treated host and a specific mode of administration. For example, a sustained-release preparation intended for oral administration to a human being can contain about 1 mg to about 1000 mg of active material, which is compounded with a suitable and convenient amount of carrier material, which can vary between about 5% to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide an application amount that is easy to measure. For example, an aqueous solution intended for intravenous infusion can contain about 3 to about 500 μg of active ingredient per milliliter of solution, so as to infuse a suitable volume at a rate of about 30 mL / hr.

[0401] Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient may be present in such formulations at a concentration of about 0.5% to about 20%, such as about 0.5% to about 10%, for example about 1.5% w / w.

[0402] Formulations suitable for topical administration in the mouth include, for example, lozenges containing the active ingredient in a flavored form, such as sucrose and acacia or tragacanth; lozenges containing inert active ingredients, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0403] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0404] Preparations suitable for intrapulmonary or intranasal administration have, for example, a particle size in the range of about 0.1 micron to about 500 microns (such as about 0.5 micron, about 1 micron, about 30 microns or about 35 microns, etc.), which are administered by rapid inhalation of the nasal passage or by inhalation into the oral cavity to reach the alveolar sacs. Suitable preparations include aqueous or oily solutions of the active ingredient. Preparations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents (such as compounds used to treat cancers as described below).

[0405] Another embodiment provides an inhalable composition comprising a compound of formula (I), (II-a), (II-b), (II-c), (IIIa) or (IIIb) or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable composition is suitable for treating cancer. In some embodiments, the pharmaceutically acceptable salt is an inorganic acid salt, including hydrochloride, hydrobromide, sulfate or phosphate. For example, relative to other salts, such salts may cause less lung irritation. In some embodiments, the inhalable composition is delivered to the endobronchial space as an aerosol, and the aerosol comprises particles having a mass median aerodynamic diameter (MMAD) between about 1 μm and about 5 μm. In some embodiments, the compound of formula (I), (II-a), (II-b), (II-c), (IIIa) or (IIIb) or a pharmaceutically acceptable salt thereof is formulated for aerosol delivery using a nebulizer, a pressurized metered dose inhaler (pMDI) or a dry powder inhaler (DPI).

[0406] Non-limiting examples of nebulizers include atomizing, jetting, ultrasonic, pressurizing, vibrating porous plate or equivalent nebulizers, including those utilizing adaptive aerosol delivery technology (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supplement 1, S1-S10). Jet nebulizers utilize air pressure to break up liquid solutions into aerosol droplets. Ultrasonic nebulizers work by piezoelectric crystals that shear liquids into small aerosol droplets. Pressurized spray systems force solutions through small holes under pressure to generate aerosol droplets. Vibrating porous plate devices utilize rapid vibrations to shear liquid streams into appropriate droplet sizes.

[0407] In another embodiment, the formulation for nebulization is delivered to the endobronchial space in the form of an aerosol containing particles having an MMAD predominantly between about 1 μm and 5 μm using a nebulizer capable of aerosolizing a formulation of a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, into particles of the desired MMAD. For optimal therapeutic effectiveness and to avoid upper respiratory tract and systemic side effects, the MMAD of the majority of the nebulized particles should not be greater than about 5 μm. If the aerosol contains a large number of particles having an MMAD greater than about 5 μm, the particles are deposited in the upper airways, thereby reducing the amount of drug delivered to sites of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is less than about 1 μm, the particles can in some cases remain suspended in the inspired air and can subsequently be exhaled during exhalation.

[0408] When formulated and delivered according to the methods herein, the aerosol formulations for atomization deliver a therapeutically effective dose of a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, to a therapeutic target, such as a cancer site. The amount of drug administered can be adjusted to reflect the delivery efficiency of a therapeutically effective dose of a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof. In one embodiment, the combination of an aqueous aerosol formulation and atomization, spraying, pressurization, vibrating porous plate or ultrasonic nebulizer allows for delivery of a compound of formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) or a pharmaceutically acceptable salt thereof, depending on the nebulizer, from about 20% to about 90% (such as about 70%). In one embodiment, about 30% to about 50% of the active compound is delivered. For example, about 70% to about 90% of the active compound can be delivered.

[0409] In another embodiment, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, is delivered as a dry inhalable powder. The compound is administered intrabronchially as a dry powder formulation to effectively deliver fine particles of the compound into the endobronchial space using a dry powder or metered dose inhaler. For delivery by DPI, the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, is processed into particles having an MMAD predominantly between about 1 μm and about 5 μm by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling, and spray drying apparatus and methods capable of producing particle sizes between about 1 μm and about 5 μm with an MMAD are well known in the art. In one embodiment, an excipient is added to a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or (III-d), or a pharmaceutically acceptable salt thereof, prior to processing into particles of the desired size. In another embodiment, an excipient is blended with particles of the desired size to aid in the dispersion of the drug particles, for example by using lactose as an excipient.

[0410] Particle size determination is performed using devices well known in the art, for example, a multi-stage Anderson cascade impactor or other suitable methods, such as those specifically described in Chapter 601 of the United States Pharmacopeia as a characterization device for aerosols in metered dose inhalers and dry powder inhalers.

[0411] In another embodiment, a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, can be delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion device. Non-limiting examples of dry powder inhalers and devices include those disclosed in the following: US5,458,135, US5,740,794, US5,775,320, US5,785,049, US3,906,950, US4,013,075, US4,069,819, US4,995,385, US5,522,385, US4,668,218, US4,667,668, US4,805,811 and US5,388,572. There are two main designs of dry powder inhalers. One design is a metering device, in which a reservoir for medicine is placed in the device, and a patient adds a dose of medicine to the inhalation chamber. The second design is a factory-metered device, in which each separate dose is prepared in a separate container. Both systems rely on formulating the drug into small particles with MMAD of about 1 μm to about 5 μm, and generally involve co-formulation with larger excipient particles (such as, but not limited to, lactose). The drug powder is placed in an inhalation chamber (metered by the device or by splitting the dose measured in the factory), and the patient's inspiratory airflow accelerates the powder out of the device and into the oral cavity. The non-laminar nature of the powder path causes the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes them to impact in the back of the throat, while the smaller drug particles are deeply deposited in the lungs. In some embodiments, a dry powder inhaler of any type as described herein is used to deliver a compound of formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) or a pharmaceutically acceptable salt thereof as a dry powder, wherein the MMAD of the dry powder without any excipient is mainly in the range of 1 μm to about 5 μm.

[0412] In another embodiment, a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include those disclosed in US5,261,538, US5,544,647, US5,622,163, US4,955,371, US3,565,070, US3,361306, and US6,116,234. In some embodiments, a compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using a metered dose inhaler, wherein the MMAD of the dry powder excluding any excipients is predominantly in the range of 1 μm to about 5 μm.

[0413] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0414] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes to render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0415] The preparation is present in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injections and suspensions are prepared from sterile powders, granules and tablets of the aforementioned type. Unit dose preparations include preparations containing a daily dose or unit daily subdose of the active ingredient as described above, or an appropriate portion thereof.

[0416] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0417] There is also provided a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier.

[0418] Veterinary carriers are materials useful for administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0419] The compounds herein are useful for providing controlled release pharmaceutical formulations containing one or more compounds as active ingredients ("controlled release formulations"), in which the release of the active ingredient is controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0420] The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, delivery method, and pharmaceutical formulation, and can be determined by a clinician using conventional dose escalation studies. The dose can be expected to be about 0.0001 to about 100 mg / kg body weight per day; typically, about 0.01 to about 10 mg / kg body weight per day; more typically, about 0.01 to about 5 mg / kg body weight per day; most typically, about 0.05 to about 0.5 mg / kg body weight per day. For example, the daily candidate dose range for an adult weighing about 70 kg may be about 1 mg to about 1000 mg, such as between about 5 mg and about 500 mg, and may be in the form of a single dose or multiple doses.

[0421] Some embodiments provide a method for manufacturing a drug for treating cancer in a subject in need thereof. In some embodiments, the method for manufacturing a drug for treating cancer comprises using a compound having a structure of formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for manufacturing a drug for inhibiting cancer metastasis in a subject in need thereof. In some embodiments, the method for manufacturing a drug for inhibiting cancer metastasis comprises using a compound having a structure of formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof.

[0422] In some embodiments, the present disclosure provides a compound having a structure of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof. In some embodiments, the present disclosure provides a compound having a structure of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, for use in inhibiting cancer metastasis in a subject in need thereof. In some embodiments, the present disclosure provides a compound having a structure of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0423] IV. Route of Administration

[0424] One or more of the compounds of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d) or pharmaceutically acceptable salts thereof (referred to herein as active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc. It should be understood that the route may vary, for example, depending on the condition of the recipient. In some embodiments, the compounds disclosed herein are orally bioavailable and can be administered orally.

[0425] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. It should be understood that the route can vary with, for example, the condition of the recipient. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0426] The compounds of the present disclosure can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compounds are administered on a daily or intermittent schedule during the life of the individual.

[0427] The dosage or administration frequency of the disclosed compounds may be adjusted during the course of treatment according to the judgment of the administering physician.

[0428] The compound can be administered to an individual (eg, a human) in an effective amount. In some embodiments, the compound is administered once a day.

[0429] Compound can be used by any available approach and method, such as by oral or parenteral (for example, intravenous) administration.The therapeutically effective amount of compound can include about 0.00001mg / kg body weight / day to about 10mg / kg body weight / day, such as about 0.0001mg / kg body weight / day to about 10mg / kg body weight / day, or such as about 0.001mg / kg body weight / day to about 1mg / kg body weight / day, or such as about 0.01mg / kg body weight / day to about 1mg / kg body weight / day, or such as about 0.05mg / kg body weight / day to about 0.5mg / kg body weight / day, or such as about 0.3mg / day to about 30mg / day, or such as about 30mg / day to about 300mg / day.

[0430] The compounds of the present disclosure may be combined with one or more additional therapeutic agents in any dose of the compounds of the present disclosure (e.g., about 1 mg to about 1000 mg of the compounds). The therapeutically effective amount may include about 1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg per dose. Other therapeutically effective amounts of the disclosed compounds are about 100 mg per dose, or about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, or about 500 mg per dose. Single doses can be applied hourly, daily, or weekly. For example, a single dose can be applied once every 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 16 hours, or about once every 24 hours. A single dose can also be applied once every 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about once every 7 days. A single dose can also be applied once every 1 week, about 2 weeks, about 3 weeks, or about once every 4 weeks. In some embodiments, a single dose can be applied approximately once a week. A single dose may also be administered about once a month.

[0431] Other therapeutically effective amounts of the compounds of the present disclosure are about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg per dose.

[0432] The dosage frequency of the disclosed compound can be determined by the needs of each patient, and can be, for example, once a day or twice a day or more. As long as the treatment of the disease or condition requires, the administration of the compound continues. For example, the compound can be administered to a person suffering from cancer for a period of about 20 days to about 180 days, or for example, a period of about 20 days to about 90 days, or for example, a period of about 30 days to about 60 days.

[0433] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure over a period of several or more days, followed by a period of several or more days in which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day or three times a week. Again, for example, the patient can receive a dose of the compound every day for a period of about 1 day to about 14 days, after which the patient does not receive a dose of the compound over a period of about 7 days to about 21 days, and then the patient receives a daily dose of the compound again in a subsequent period (e.g., about 1 day to about 14 days). Depending on the clinical needs of the patient, the compound can be repeatedly administered followed by an alternating period of not administering the compound.

[0434] In one embodiment, a pharmaceutical composition is provided that comprises a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents and a pharmaceutically acceptable excipient.

[0435] In one embodiment, a kit is provided comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0436] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are combined with one, two, three, four or more additional therapeutic agents. In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are combined with two additional therapeutic agents. In other embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are combined with three additional therapeutic agents. In other embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0437] In some embodiments, when the compounds of the present disclosure are combined with one or more additional therapeutic agents as described herein, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0438] In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, for example, as a solid dosage form for oral administration.

[0439] In some embodiments, compounds of the present disclosure are co-administered with one or more additional therapeutic agents.

[0440] In order to prolong the effect of the compounds of the present disclosure, it is generally desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable preparations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

[0441] V. Combination Therapy

[0442] The compounds of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c) or (III-d), their pharmaceutically acceptable salts and / or compositions provided herein can also be used in combination with other active therapeutic agents for treating cancer.

[0443] A. Combination therapy

[0444] In various embodiments, the compounds as described herein are combined with one or more additional therapeutic agents, such as inhibitory immune checkpoint blockers or inhibitors, stimulatory immune checkpoint stimulators, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapeutic agents, anti-tumor agents, anti-proliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapeutic agents, therapeutic antigen binding molecules (monospecific and multispecific antibodies and fragments thereof in any form, such as but not limited to BiKEs, TriKEs, scFv, Fab, Fab derivatives), bispecific antibodies, non-immunoglobulin antibody mimetics (e.g., including but not limited to adnectin, affibody molecules, affilin, affimer, affitin, alphabody, anticalin, peptide aptamers, armadillo repeat proteins (ARM), atrimer, avimer, designed ankyrin repeat proteins fynomers, knottins, Kunitz domain peptides, monobodies and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or 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 any combination thereof.

[0445] Exemplary Targets

[0446] In some embodiments, one or more additional therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators, or repressors of a target (e.g., a polypeptide or polynucleotide), including, but not limited to, Epstein-Barr murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (such as ACC1 / 2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine receptors (such as A2BR, A2aR, A3aR), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), aeromonas lysin, AKT1 gene, Alk-5 protein kinase, Alkaline phosphatase, α1 adrenal receptor, α2 adrenal receptor, α-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, such as ALK1), androgen receptor, angiopoietin (such as ligand-1, ligand-2), angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2, AKT3), apolipoprotein AI (APOA1) gene, apoptosis inducing factor, apoptosis protein (such as 1, 2), apoptosis signal regulating kinase (ASK, such as ASK1), arginase (I), arginine deiminase, aromatase, steroid homolog 1 (A STE1) gene, ataxia telangiectasia and Rad3-related (ATR) serine / threonine protein kinase, Aurora protein kinase (such as 1, 2), Axl tyrosine kinase receptor, 4-1BB ligand (CD137L), baculovirus IAP repeat-containing 5 (BIRC5) gene, Basigin, B cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, beta adrenal receptor, beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte adhesion molecule, B-lymphocyte stimulator ligand, bone morphogenetic protein Brutin-10 ligand, bone morphogenetic protein-9 ligand regulator, Brachyury protein, Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain- and extra-domain (BET) bromodomain-containing proteins (such as BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinase (CaMK, such as CAMKII), cancer / testis antigen 2, cancer / testis antigen NY-ESO-1, cancer / testis antigen 1B (CTAG1) gene, cannabinoid receptors (such as CB1, CB2), carbonic anhydrase, casein kinase (CK,Such as CKI, CKII), caspases (such as caspase-3, caspase-7, caspase-9), caspase 8 apoptosis-related cysteine ​​peptidase CASP8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK activated kinase (CAK), checkpoint kinases (such as CHK1, CHK2), chemokine (CC motif) receptors (such as CCR2, CCR4, CCR5, CCR8), chemokines (such as CCR2, CCR4, CCR5, CCR8), chemokine (CXC motif) receptors (such as CXCR1, CXCR2, CXCR3 and CXCR4), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD117), CISH (cytokine-inducible SH2-containing protein), occludens (such as 6, 18), clusters of differentiation (CD) (such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand), Receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, C D223, CD276 antigen); clusterin (CLU) gene, clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), complement C3, connective tissue growth factor, COP9 signaling body subunit 5, CSF-1 (colony stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CLEC9A), cyclin D1, cyclin G1, cyclin-dependent kinase (CDK,Such as CDK1, CDK12, CDK1B, CDK2-9), cyclooxygenase (such as COX1, COX2), CYP2B1 gene, cysteine ​​palmitoyltransferase porcupine, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytochrome isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T-lymphocyte protein-4, DDR2 gene, DEAD box helicase 6 (DDX6), death receptor 5 (DR5, TRAILR2), death receptor 4 (DR4, TRAILR1), delta-like protein ligand (such as 3, 4), deoxyribonuclease, deubiquitinase (DUB), Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase enzyme IV, discoidin domain receptor (DDR, such as DDR1), diacylglycerol kinase ζ (DGKZ), DNA binding protein (such as HU-β), DNA dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (such as α), DNA primase, dUTP pyrophosphatase, L-dopamate tautomerase, E3 ubiquitin-protein ligase (such as RNF128, CBL-B), echinoderm microtubule-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulum aminopeptidase (ERAP,Such as ERAP 1, ERAP2), endoplasmic reticulin, endosialin, endostatin, endothelin (such as ET-A, ET-B), enhancer of zeste homolog 2 (EZH2), ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4), ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epithelial mitogen (Epigen), epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia virus oncogene homolog 2) tyrosine kinase enzyme receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β dehydrogenase, estrogen receptor (such as α, β), estrogen-related receptor, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinase (such as 1, 2), extracellular signal-regulated kinase (ERK), hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), factor (such as Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor factors (FGF, such as FGF1, FGF2, FGF4), fibronectin, focal adhesion kinase (FAK, such as FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), folate receptor (such as α), folate, folate transporter 1, FYN tyrosine kinase, paired alkaline amino acid lyase (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoids, glucocorticoid-induced TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK, such as 3- β), tidylinositol proteoglycan 3 (GPC3), gonadotropin-releasing hormone (GNRH), granulocyte macrophage colony-stimulating factor (GM-CSF) receptor, granulocyte colony-stimulating factor (GCSF) ligand, growth factor receptor binding protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein) calcium-binding protein, molecular chaperone groEL2 gene, heme oxygenase 1 (HO1), heme oxygenase 2 (HO2), heat shock proteins (such as 27, 70, 90α, β), heat shock protein genes, heat-stable enterotoxin receptor, Hedgehog protein, heparanase, hepatocyte growth factor, HERV-H LTR-associated protein 2, hexokinase, histamine H2 receptor, histone methyltransferase (DOT1L), histone deacetylase (HDAC,Such as 1, 2, 3, 6, 10, 11), histone H1, histone H3, HLA class I antigen (A-2α), HLA class II antigen, HLA Class I antigen αG (HLA-G), non-classical HLA, Homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA), human papillomavirus (such as E6, E7) protein, hyaluronic acid, hyaluronidase, hypoxia-inducible factor-1α (HIF1α), imprinted maternally expressed transcript (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine protein kinase HCK, I-κ-B kinase (IKK, such as IKKbe), IL-1α, IL-1β, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor α subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulins (such as G, G1, G2, K, M), immunoglobulin Fc receptor, immunoglobulin γ Fc receptor (such as I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1 and IDO2), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, insulin-like growth factor (such as 1, 2), integrin α-4 / β-1, integrin α-4 / β-7, integrin α-5 / β-1, integrin α-V / β-3, integrin α-V / β-5, integrin α-V / β-6, intercellular adhesion molecule 1 (ICAM -1), interferons (such as α, α2, β, γ), interferon-induced protein melanoma missing factor 2 (AIM2), interferon type I receptor, interleukin 1 ligand, interleukin 13 receptor α2, interleukin 2 ligand, interleukin-1 receptor associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, interleukin 35 (IL-35), isocitrate dehydrogenase (such as IDH1, IDH2), Janus kinase (JAK,Such as JAK1, JAK2), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 Feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-associated protein-1, leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), leukotriene A4 hydrolase, listeriolysin, L-selectin, luteinizing hormone receptor, lysase, lymphocyte activation gene 3 protein (LAG-3), lymphocyte antigen 75, lymphocyte function antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphocyte chemokine, Lyn (Lck / Yes novel) tyrosine kinase, lysine demethylases (such as KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D), lysophosphatidic acid-1 receptor, lysosomal associated membrane protein family (LAMP) gene, lysyl oxidase homolog 2, lysyl oxidase protein (LOX), 5-lipoxygenase (5-LOX), hematopoietic progenitor kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony stimulating factor (MCSF) ligand, macrophage migration inhibitory factor, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (such as MK2), Mas-related G protein-coupled receptor, matrix metalloproteinase (MMP, such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2p53 binding protein, Mdm4 protein, melanin-A (MART-1) melanoma antigen, melanocyte protein Pmel 17. melanocyte stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma associated antigens (such as 1, 2, 3, 6), membrane copper amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (six transmembrane epithelial antigen of the prostate 1), metastasis inhibitor, methionine aminopeptidase-2, methyltransferase, mitochondrial 3 ketoacyl CoA thiolase, mitogen activated protein kinase (MAPK), mitogen activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin) serine / threonine kinase, mTOR complex (such as 1, 2), mucin (such as 1, 5A, 16), mut T homolog (MTH,Such as MTH1), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, neural cell adhesion molecule 1, neurokinin 1 (NK1) receptor, neurokinin receptor, neuropilin 2, NFκB activated protein, NIMA-associated kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2AB activated NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) regulator, norepinephrine transporter, Notch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear erythroid 2-related factor 2, nuclear factor (NF) κB, nucleolin, nucleolar phosphatidylcholine, nucleolar phosphatidylcholine-anaplastic lymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptors (such as delta), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4TNFRSF4 or CD134) receptor, P3 protein, p38 kinase, p38MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor (PPAR, such as α, δ, γ), P-glycoprotein (such as 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, such as α, δ, γ), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, such as α, β), platelet-derived growth factor (PDGF, such as α, β), multidirectional drug resistance transporter, Plexin B1, PLK1 gene, polo-like kinase (PLK), Polo-like kinase 1, poly (ADP ribose) polymerase (PARP, such as PARP1, PARP2 and PARP3, PARP7, and single PARP), melanoma preferentially expressed antigen (PRAME) gene, prenyl binding protein (PrPB), possible transcription factor PML, progesterone receptor, programmed cell death 1 (PD-1), programmed cell death ligand 1 inhibitor (PD-L1), prosaposin (PSAP) gene, prostaglandin receptor (EP4), prostaglandin E2 synthase, prostate specific antigen, prostatic acid phosphatase, proteasome, protein E7, protein farnesyl transferase, protein kinase (PK, such as A, B, C), protein tyrosine kinase, protein tyrosine phosphatase β, proto-oncogene serine / threonine protein kinase (PIM,such as PIM-1, PIM-2, PIM-3), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-α-reductase, Raf protein kinase (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptor (such as γ), retinoid X receptor, Rheb (Ras homolog abundant in brain) GTPase, Rho (Ras homolog) associated protein kinase 2, ribonuclease, ribonucleotide reductase (such as M2 subunit), ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (Recepteur d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, γ-secretase, S100 calcium-binding protein A9, Sarco endoplasmic calcium ATPase, second mitochondrial-derived activator of caspase (SMAC) protein, secreted frizzled-related protein-2, secreted phospholipase A2, axon guidance factor-4D, serine protease, serine / threonine kinase (STK), serine / threonine protein kinase (TBK, such as TBK1), signal transduction and transcription (STAT,Such as STAT-1, STAT-3, STAT-5), signaling lymphocyte activation molecule (SLAM) family member 7, six transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide co-transporter, sodium phosphate co-transporter 2B, somatostatin receptor (such as 1, 2, 3, 4, 5), sonic hedgehog protein, Son of sevenless (SOS), specificity protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (such as 1, 2), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, stabilizer-1 (STAB1), STAT3 gene, steroid sulfatase, stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, inhibitor of cytokine signaling regulator (SOC S), survivin protein, synaptophysin 3, syndecan-1, synuclein α, T cell surface glycoprotein CD28, tank binding kinase (TBK), TATA box binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein ζ chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin domain-containing-3 (TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, telomerase reverse transcriptase (TERT) gene, tenascin, three-prime repair nucleic acid exon exonuclease 1 (TREX1), three-way repair exonuclease 2 (TREX2), thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (such as α1), thyroid hormone receptor, thyroid stimulating hormone receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR1-related death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptors (TLR, such as 1-13), topoisomerase (such as I, II, III), transcription factor, transferase, transferase Ferritin (TF), transforming growth factor alpha (TGFα), transforming growth factor beta (TGFβ) and its isoforms, TGFβ2 ligand, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-associated protein, transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast cell glycoprotein (TPBG) gene, trophoblast cell glycoprotein, tropomyosin receptor kinase (Trk) receptor (such as TrkA, TrkB, TrkC), tryptophan 2,3-dioxygenase (TDO), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF,Such as α, β), tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), tumor protein 53 (TP53) gene, tumor suppressor candidate 2 (TUSC2) gene, tumor specific neoantigens, tyrosinase, tyrosine hydroxylase, tyrosine kinase (TK), tyrosine kinase receptor, tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin conjugating enzyme E2I (UBE2I, UBC9), ubiquitin-specific processing protease 7 (USP7), urease, urokinase plasminogen activator, uteroglobin, capsaicin (Vanilloid) VR1, vascular Cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig inhibitor of T-cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine receptor kinase, Mer (Mer tyrosine kinase receptor modulator), YAP (Yes-associated protein modulator), Wee-1 protein kinase, Werner syndrome RecQ-like helicase (WRN), Wilms tumor antigen 1, Wilms tumor protein, WW domain-containing transcription regulatory protein 1 (TAZ), X-linked inhibitor of apoptosis protein, zinc finger protein transcription factor, or any combination thereof.

[0447] Exemplary Mechanism of Action

[0448] In various embodiments, one or more additional therapeutic agents can be categorized according to their mechanism of action, for example, into the following groups:

[0449] antimetabolites / anticancer agents such as the pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118;

[0450] alpha 1 adrenergic receptor / alpha 2 adrenergic receptor antagonists, such as phenoxybenzamine hydrochloride (injectable, pheochromocytoma);

[0451] androgen receptor antagonists, such as nilutamide;

[0452] Anti-cadherin antibodies, such as HKT-288;

[0453] Anti-leucine-rich repeat-containing protein 15 (LRRC15) antibodies, such as ABBV-085, ARGX-110;

[0454] angiotensin receptor blockers, nitric oxide donors;

[0455] Antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx;

[0456] Anti-angiopoietin (ANG)-2 antibodies, such as MEDI3617 and LY3127804;

[0457] Anti-ANG-1 / ANG-2 antibodies, such as AMG-780;

[0458] Anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);

[0459] Anti-endoglin antibodies, such as TRC105 (carotuximab);

[0460] Anti-ERBB antibodies, such as CDX-3379, HLX-02, seribantumab;

[0461] Anti-HER2 antibodies, such as (trastuzumab), trastuzumab biosimilars, magituximab, MEDI4276, BAT-8001, pertuzumab (Perjeta), RG6264, ZW25 (a bispecific HER2-directed antibody targeting extracellular domains 2 and 4; Cancer Discov. 2019 Jan;9(1):8; PMID:30504239);

[0462] Anti-HLA-DR antibodies, such as IMMU-114;

[0463] Anti-IL-3 antibodies, such as JNJ-56022473;

[0464] Anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI Gene ID: 8784) antibodies, such as MK-4166, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and those described in, for example, International Patent Publication Nos. WO 2017 / 096179, WO 2017 / 096276, WO 2017 / 096189, and WO 2018 / 089628;

[0465] Anti-EphA3 antibodies, such as KB-004;

[0466] Anti-CD37 antibodies, such as otlertuzumab (TRU-016);

[0467] Anti-FGFR-3 antibodies, such as LY3076226, B-701;

[0468] Anti-FGFR-2 antibodies, such as GAL-F2;

[0469] Anti-C5 antibodies, such as ALXN-1210;

[0470] Anti-EpCAM antibodies, such as VB4-845;

[0471] Anti-CEA antibodies, such as RG-7813;

[0472] Antibodies against carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6, CD66C), such as BAY-1834942, NEO-201 (CEACAM 5 / 6);

[0473] Anti-GD2 antibodies, such as APN-301;

[0474] Anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

[0475] Anti-interleukin-1β antibodies, such as canakinumab (ACZ885), VPM087;

[0476] Anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, such as TX-250;

[0477] Anti-CD38 antibodies, such as isatuximab, MOR-202, TAK-079;

[0478] Anti-CD38 attenukine, such as TAK573;

[0479] Anti-mucin 1 (MUC1) antibodies, such as gatipotuzumab, Mab-AR-20.5;

[0480] Anti-CD33 antibodies, such as IMGN-779;

[0481] Anti-KMA antibodies, such as MDX-1097;

[0482] Anti-CD55 antibodies, such as PAT-SC1;

[0483] Anti-c-Met antibodies, such as ABBV-399;

[0484] Anti-PSMA antibodies, such as ATL-101;

[0485] Anti-CD100 antibodies, such as VX-15;

[0486] Anti-EPHA3 antibodies, such as fibatuzumab;

[0487] Anti-APRIL antibodies, such as BION-1301;

[0488] Anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461;

[0489] Anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386;

[0490] Anti-Fucosyl-GM1 antibodies, such as BMS-986012;

[0491] Anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

[0492] Anti-myostatin inhibitors, such as landogrozumab;

[0493] Anti-delta-like protein ligand 3 (DDL3) antibodies, such as rovalpituzumabtesirine;

[0494] Anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab;

[0495] Anti-clusterin antibodies, such as AB-16B5;

[0496] Anti-ephrin A4 (EFNA4) antibodies, such as PF-06647263;

[0497] Anti-RANKL antibodies, such as denosumab;

[0498] Anti-mesothelin antibodies, such as BMS-986148, anti-MSLN-MMAE;

[0499] Anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as lifastuzumab;

[0500] Anti-TGFb antibodies, such as SAR439459;

[0501] Anti-transforming growth factor-β (TGF-β) antibodies, such as ABBV-151, LY3022859, NIS793, XOMA 089;

[0502] Purine analogs, folate antagonists (such as pralatrexate), cladribine, pentostatin, fludarabine, and related inhibitors;

[0503] Antiproliferative / antimitotic agents, including natural products such as vinca alkaloids (vinblastine, vincristine); and microtubule disrupting agents such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine and epipodophyllotoxins (etoposide, teniposide);

[0504] DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide Dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, ifosfamide, melphalan, nitrogen mustard (merchlorethamine), mitomycin C, mitoxantrone, nitrosoureas, procarbazine, tacrolimus, taxotere, teniposide, etoposide, and triethylenethiophosphoramide;

[0505] DNA-methylating agents, such as guadecitabine (SGI-110), ASTX727;

[0506] Antibiotics, such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin);

[0507] Enzymes, such as L-asparaginase, which systemically metabolize L-asparagine and deprive cells that do not have the ability to synthesize their own asparagine;

[0508] DNAi oligonucleotides targeting Bcl-2, such as PNT2258; agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin;

[0509] Asparaginase stimulators, such as crisantaspase and GRASPA (ERY-001, ERY-ASP), calaspargase pegol, pegaspargase;

[0510] pan-Trk, ROS1, and ALK inhibitors, such as entrectinib, TPX-0005;

[0511] Anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib, ceritinib, alecensa (RG7853), (brigatinib);

[0512] antiproliferative / antimitotic alkylating agents such as the nitrogen mustard cyclophosphamide and analogs (e.g., melphalan, chlorambucil, hexamethonium, thiotepa), alkylnitrosoureas (e.g., carmustine) and analogs, streptozotocin, and triazenes (e.g., dacarbazine);

[0513] antiproliferative / antimitotic antimetabolites, such as folic acid analogs (methotrexate);

[0514] platinum coordination complexes (e.g., cisplatin, oxaliplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide;

[0515] hormones, hormone analogs (such as estrogens, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (such as letrozole and anastrozole);

[0516] Antiplatelet agents; anticoagulants such as heparin, synthetic heparin salts, and other inhibitors of thrombin;

[0517] Fibrinolytics, such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel;

[0518] Antimigratory agents; Antisecretory agents (e.g., breveldin);

[0519] Immunosuppressants, such as tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil;

[0520] growth factor inhibitors and vascular endothelial growth factor inhibitors;

[0521] Fibroblast growth factor inhibitors, such as FPA14;

[0522] AMP-activated protein kinase stimulators, such as metformin hydrochloride;

[0523] ADP-ribosyl cyclase-1 inhibitors, such as daratumumab

[0524] caspase recruitment domain protein-15 stimulators, such as mivastatin (liposomal);

[0525] CCR5 chemokine antagonists, such as MK-7690 (vicriviroc);

[0526] CDC7 protein kinase inhibitors, such as TAK-931;

[0527] Cholesterol side-chain cleavage enzyme inhibitors, such as ODM-209;

[0528] Dihydropyrimidine dehydrogenase / orotate phosphoribosyltransferase inhibitors, such as Cefesone (tegafur + gimeracil + oxazolidinone potassium);

[0529] DNA polymerase / ribonucleotide reductase inhibitors, such as clofarabine;

[0530] DNA interfering oligonucleotides, such as PNT2258, AZD-9150;

[0531] estrogen receptor modulators, such as bazedoxifene;

[0532] estrogen receptor agonist / progesterone receptor antagonist, such as TRI-CYCLEN LO (norethindrone + ethinyl estradiol);

[0533] HLA class I antigen A-2α modulators, such as FH-MCVA2TCR;

[0534] HLA class I antigen A-2α / MART-1 melanoma antigen modulators, such as MART-1F5TCR engineered PBMCs;

[0535] Human granulocyte colony-stimulating factor, such as PF-06881894;

[0536] GNRH receptor agonists, such as leuprolide acetate, leuprolide acetate extended-release depot (ATRIGEL), triptorelin pamoate, goserelin acetate;

[0537] GNRH receptor antagonists, such as elagolix, relugolix, degarelix;

[0538] Endoplasmic retinoid modulators, such as anlotinib;

[0539] H+K+ ATPase inhibitors, such as omeprazole and esomeprazole;

[0540] ICAM-1 / CD55 modulators, such as cavatak (V-937);

[0541] IL-15 / IL-12 modulators, such as SAR441000;

[0542] Interleukin-23A inhibitors, such as guselkumab;

[0543] Lysine-specific histone demethylase 1 inhibitors, such as CC-90011;

[0544] IL-12 mRNA, such as MEDI1191;

[0545] RIG-I modulators, such as RGT-100;

[0546] NOD2 modulators, such as SB-9200 and IR-103.

[0547] Progesterone receptor agonists, such as levonorgestrel;

[0548] cereblon protein modulators, such as CC-92480, CC-90009;

[0549] cereblon protein modulators / DNA binding protein Ikaros inhibitors / zinc finger binding protein Aiolos inhibitors, such as iberdomide;

[0550] Retinoid X receptor modulators, such as alitretinoin and bexarotene (oral preparations);

[0551] RIP-1 kinase inhibitors, such as GSK-3145095;

[0552] Selective estrogen receptor degraders, such as AZD9833;

[0553] SUMO inhibitors, such as TAK-981;

[0554] Thrombopoietin receptor agonists, such as eltrombopag;

[0555] Thyroid hormone receptor agonists, such as levothyroxine sodium;

[0556] TNF agonists, such as tasonamine;

[0557] Tyrosine phosphatase substrate 1 inhibitors, such as CC-95251;

[0558] HER2 inhibitors, such as neratinib, tucatinib (ONT-380);

[0559] EGFR / ErbB2 / Ephb4 inhibitors, such as tesevatinib;

[0560] EGFR / HER2 inhibitors, such as TAK-788;

[0561] EGFR family tyrosine kinase receptor inhibitors, such as DZD-9008;

[0562] EGFR / ErbB-2 inhibitors, such as varisitinib;

[0563] Mutant-selective EGFR inhibitors, such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694;

[0564] epha2 inhibitors, such as MM-310;

[0565] Polycomb (EED) inhibitors, such as MAK683;

[0566] DHFR inhibitors / folate transporter 1 modulators / folate receptor antagonists, such as pralatrexate;

[0567] DHFR / GAR transformylase / thymidylate synthase / transferase inhibitors, such as pemetrexed disodium;

[0568] p38 MAP kinase inhibitors, such as ralimetinib;

[0569] PRMT inhibitors, such as MS203, PF-06939999, GSK3368715, GSK3326595;

[0570] Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;

[0571] Erythroid 2-related factor 2 stimulators, such as omasorolone (RTA-408);

[0572] Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579;

[0573] Mucin 1 inhibitors, such as GO-203-2C;

[0574] MARCKS protein inhibitors, such as BIO-11006;

[0575] Folate antagonists, such as arfolitixorin;

[0576] Galectin-3 inhibitors, such as GR-MD-02;

[0577] Phospho-P68 inhibitors, such as RX-5902;

[0578] CD95 / TNF modulators, such as ofranergene obadenovec;

[0579] Pan-PIM kinase inhibitors, such as INCB-053914;

[0580] IL-12 gene stimulators, such as EGEN-001, tavokinogene telseplasmid;

[0581] Heat shock protein HSP90 inhibitors, such as TAS-116 and PEN-866;

[0582] VEGF / HGF antagonists, such as MP-0250;

[0583] VEGF ligand inhibitors, such as bevacizumab biosimilars;

[0584] VEGF receptor antagonists / VEGF ligand inhibitors, such as ramucirumab;

[0585] VEGF-1 / VEGF-2 / VEGF-3 receptor antagonists, such as fruquintinib;

[0586] VEGF-1 / VEGF-2 receptor modulators, such as HLA-A2402 / HLA-A0201 restricted epitope peptide vaccines;

[0587] Placental growth factor ligand inhibitors / VEGF-A ligand inhibitors, such as aflibercept;

[0588] SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002;

[0589] Trk tyrosine kinase receptor inhibitors, such as larotrectinib sulfate;

[0590] JAK3 / JAK1 / TBK1 kinase inhibitors, such as CS-12912;

[0591] IL-24 antagonists, such as AD-IL24;

[0592] NLRP3 (NACHT LRR PYD domain protein 3) modulators, such as BMS-986299;

[0593] RIG-I agonists, such as RGT-100;

[0594] Aeromonas lysin stimulators, such as topsalysin;

[0595] P-glycoprotein 1 inhibitors, such as HM-30181A;

[0596] CSF-1 antagonists, such as ARRY-382 and BLZ-945;

[0597] CCR8 inhibitors, such as I-309, SB-649701, HG-1013, RAP-310;

[0598] Anti-mesothelin antibodies, such as SEL-403;

[0599] Thymidine kinase stimulators, such as aglatimagene besadenovec;

[0600] Polo-like kinase 1 inhibitors, such as PCM-075, onvansertib;

[0601] NAE inhibitors, such as pevonedistat (MLN-4924), TAS-4464; multidirectional pathway modulators, such as avadomide (CC-122);

[0602] Amyloid binding protein-1 inhibitors / ubiquitin ligase modulators, such as pevonedistat;

[0603] FoxM1 inhibitors, such as thiostrepton;

[0604] UBA1 inhibitors, such as TAK-243;

[0605] Src tyrosine kinase inhibitors, such as VAL-201;

[0606] VDAC / HK inhibitors, such as VDA-1102;

[0607] Elf4a inhibitors, such as rohinitib, eFT226;

[0608] TP53 gene stimulators, such as ad-p53;

[0609] Retinoic acid receptor agonists, such as tretinoin;

[0610] Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;

[0611] SIRT3 inhibitors, such as YC8-02;

[0612] Stromal cell-derived factor-1 ligand inhibitors, such as olaptesed pegol (NOX-A12);

[0613] IL-4 receptor modulators, such as MDNA-55;

[0614] Arginase-I stimulators, such as pegzilarginase;

[0615] Topoisomerase I inhibitors, such as irinotecan hydrochloride, Onivyde;

[0616] Topoisomerase I inhibitors / hypoxia-inducible factor-1α inhibitors, such as PEG-SN38 (firtecan pegol);

[0617] Hypoxia-inducible factor-1α inhibitors, such as PT-2977 and PT-2385;

[0618] CD122 (IL-2 receptor) agonists, such as proleukin (aldesleukin, IL-2); PEGylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707);

[0619] TLR7 / TLR8 agonists, such as NKTR-262;

[0620] TLR7 agonists, such as DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod);

[0621] p53 tumor suppressor protein stimulators, such as kevetrin;

[0622] Mdm4 / Mdm2p53 binding protein inhibitors, such as ALRN-6924;

[0623] Kinesin (KSP) inhibitors, such as filansib (ARRY-520);

[0624] CD80-fc fusion protein inhibitors, such as FPT-155;

[0625] Menin and mixed lineage leukemia (MLL) inhibitors, such as KO-539;

[0626] Liver x receptor agonists, such as RGX-104;

[0627] IL-10 agonists, such as Pegilodecakin (AM-0010);

[0628] VEGFR / PDGFR inhibitors, such as vorolanib;

[0629] IRAK4 inhibitors, such as CA-4948;

[0630] Anti-TLR-2 antibodies, such as OPN-305;

[0631] Calmodulin modulators, such as CBP-501;

[0632] Glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);

[0633] Second mitochondrial-derived activator of caspase (SMAC) protein inhibitors, such as BI-891065;

[0634] Lactoferrin modulators, such as LTX-315;

[0635] KIT proto-oncogene receptor tyrosine kinase (KIT) inhibitors, such as PLX-9486;

[0636] Platelet-derived growth factor receptor alpha (PDGFRA) / KIT proto-oncogene receptor tyrosine kinase (KIT) mutant-specific antagonists / inhibitors, such as BLU-285 and DCC-2618;

[0637] Exportin 1 inhibitors, such as eltanexor;

[0638] CHST15 gene inhibitors, such as STNM-01;

[0639] Somatostatin receptor antagonists, such as OPS-201;

[0640] CEBPA gene stimulators, such as MTL-501;

[0641] DKK3 gene modulators, such as MTG-201;

[0642] Chemokine (CXCR1 / CXCR2) inhibitors, such as SX-682;

[0643] p70s6k inhibitors, such as MSC2363318A;

[0644] Methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891, APL-1202;

[0645] Arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;

[0646] CD71 modulators, such as CX-2029 (ABBV-2029);

[0647] ATM (ataxia telangiectasia) inhibitors, such as AZD0156, AZD1390;

[0648] CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2);

[0649] CXCR4 antagonists, such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-10, plerixafor;

[0650] EXH2 inhibitors, such as GSK2816126;

[0651] KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552;

[0652] CXCR2 antagonists, such as AZD-5069;

[0653] GM-CSF antibodies, such as lenzilumab;

[0654] DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01); protein kinase C (PKC) inhibitors, such as LXS-196, sotrastaurin;

[0655] Selective estrogen receptor downregulators (SERDs), such as fulvestrant RG6046, RG6047, RG6171, elastatin (RAD-1901), SAR439859, and AZD9496;

[0656] Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

[0657] Selective androgen receptor modulators (SARMs), such as GTX-024, darolutamide;

[0658] Transforming growth factor-β (TGF-β) kinase antagonists, such as galonitinib, LY3200882; TGF-β inhibitors described in WO 2019 / 103203;

[0659] TGFβ receptor 1 inhibitors, such as PF-06952229;

[0660] Bispecific antibodies, such as ABT-165 (DLL4 / VEGF), MM-141 (IGF-1 / ErbB3), MM-111 (Erb2 / Erb3), JNJ-64052781 (CD19 / CD3), PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), JNJ-61186372 (EGFR / cMET), AMG-211 (CEA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3) vancizumab (angiogenin / VEGF), PF-06671008 (cadherin / CD3), AF M-13 (CD16 / CD30), APVO436 (CD123 / CD3), Flutezumab (CD123 / CD3), REGN-1979 (CD20 / CD3), MCLA-117 (CD3 / CLEC12A), MCLA-128 (HER2 / HER3), JNJ-0819, JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA-4), KN-046 (PD-1 / CTLA-4), MEDI-5752 (CTLA-4 / PD-1), RO-7121661(PD-1 / TIM-3), 80(VEFG / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), AGEN1223, IMCgp100(CD3 / gp100), AGEN-1423, ATOR-1015(C TLA-4 / OX40)、LY-3415244(TIM-3 / PDL1)、INHIBRX-105(4-1BB / PDL1)、faricimab(VEGF-A / ANG-2)、FAP-4-IBBL(4-1BB / FAP)、XmAb-13676(CD3 / CD20)、TAK-252(PD-1 / OX40L)、TG-1801(CD19 / CD47)、XmAb-18087(SSTR2 / CD3)、Catumasol (CD3 / EpCAM)、SAR-156597(IL4 / IL13)、EMB-01(EGFR / cMET)、REGN-4018(MUC16 / CD3), REGN-1979(CD20 / CD3), RG-7828(CD20 / CD3), CC-93269(CD3 / BCMA), REGN-5458(CD3 / BCMA), navicixizumab(DLL4 / VEGF), GRB-1302(CD 3 / Erbb2), vanucizumab (VEGF-A / ANG-2), GRB-1342 (CD38 / CD3), GEM-333 (CD3 / CD33), IMM-0306 (CD47 / CD20), RG6076, MEDI5752 (PD-1 / CTLA-4), LY3164530 (MET / EGFR);,

[0661] α-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613;

[0662] XPO1 inhibitors, such as selinexor (KPT-330);

[0663] Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enatanib (AG-221);

[0664] IDH1 inhibitors such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032;

[0665] IDH1 gene inhibitors, such as ivosidenib;

[0666] Interleukin-3 receptor (IL-3R) modulators, such as SL-401;

[0667] Arginine deiminase stimulators, such as pegargiminase (ADI-PEG-20);

[0668] Occlin-18 inhibitors, such as claudiximab;

[0669] β-catenin inhibitors, such as CWP-291;

[0670] Chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5);

[0671] Thymidylate synthase inhibitors, such as ONX-0801;

[0672] ALK / ROS1 inhibitors, such as lorlatinib;

[0673] Tankyrase inhibitors, such as G007-LK;

[0674] Mdm2p53 binding protein inhibitors, such as CMG-097, HDM-201; c-PIM inhibitors, such as PIM447;

[0675] Sphingosine kinase-2 (SK2) inhibitors, such as (ABC294640);

[0676] DNA polymerase inhibitors, such as sapacidabine;

[0677] cell cycle / microtubule inhibitors, such as eribulin mesylate;

[0678] c-MET inhibitors such as AMG-337, savotinib, tivantinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), meritinib, HQP-8361;

[0679] c-Met / VEGFR inhibitors, such as BMS-817378, TAS-115;

[0680] c-Met / RON inhibitors, such as BMS-777607;

[0681] BCR / ABL inhibitors, such as rebasitinib, axitinib, and ponatinib

[0682] MNK1 / MNK2 inhibitors, such as eFT-508;

[0683] Cytochrome P450 11B2 / cytochrome P450 17 / AKT protein kinase inhibitors, such as LAE-201;

[0684] Cytochrome P450 3A4 stimulators, such as mitotane;

[0685] Lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

[0686] CSF1R / KIT and FLT3 inhibitors, such as pecidinib (PLX3397);

[0687] Flt3 tyrosine kinase / Kit tyrosine kinase inhibitors and PDGF receptor antagonists, such as quizartinib dihydrochloride;

[0688] Kinase inhibitors, such as vandetanib;

[0689] E-selectin antagonists, such as GMI-1271;

[0690] Differentiation-inducing agents, such as retinoic acid;

[0691] Epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291), cetuximab;

[0692] topoisomerase inhibitors such as doxorubicin, doxorubicin, daunorubicin, dactinomycin, DaunoXome, Caelyx, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pisantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosarosin and GPX-150, adoxirubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), ilofofofen (MGI-114);

[0693] Corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone;

[0694] Growth factor signaling kinase inhibitors;

[0695] Nucleoside analogs, such as DFP-10917;

[0696] Axl inhibitors such as BGB-324 (bemcentinib), SLC-0211;

[0697] Axl / Flt3 inhibitors, such as gilteritinib;

[0698] Inhibitors of bromodomain and extra-terminal motif (BET) proteins, including ABBV-744, BRD2 (NCBI gene ID: 6046), BRD3 (NCBI gene ID: 8019), BRD4 (NCBI gene ID: 23476), and bromodomain testis-specific protein (BRDT; NCBI gene ID: 676), such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90 010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, mivebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829;

[0699] PARP inhibitors such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, BGB-290, fluzoparib (SHR-3162), niraparib (JNJ-64091742), bendamustine hydrochloride;

[0700] PARP / tankyrase inhibitors, such as 2X-121 (e-7499);

[0701] IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, simmiparib;

[0702] Proteasome inhibitors, such as ixazomib Carfilzomib Marizomib, bortezomib;

[0703] Glutamine inhibitors, such as CB-839 (telaglenastat), bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES);

[0704] Mitochondrial complex I inhibitors, such as metformin and phenformin;

[0705] Vaccines, such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S, SVN53-67 / M57-KLH, IMU-131, peptide subunit vaccines (acute lymphoblastic leukemia, University Children's Hospital Tuebingen); bacterial vector vaccines, such as CRS-207 / GVAX, axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines, such as nadofaragenefiradenovec; autologous Gp96 vaccine; dendritic cell vaccines, such as CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, ADXS31-142, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal / intravenous, Universitatsklinikum Erlangen); oncolytic vaccines, such as talimogene laherparepvec, pexastimogene devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines such as CVAC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax TM ; Tumor cell vaccines, such as (IND-14205), Oncoquest-L vaccine; live attenuated recombinant serotype 1 poliovirus vaccine, such as PVS-RIPO; Adagloxad simolenin; MEDI-0457; DPV-001 tumor-derived autophagosome-enriched cancer vaccine; RNA vaccines, such as CV-9209, LV-305; DNA vaccines, such as MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara vaccine expressing p53, such as MVA-p53; DPX-Survivac; BriaVax TM ; GI-6301; GI-6207; GI-4000; IO-103; Neoantigen peptide vaccines, such as AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001, NEO-PV-01; Peptide vaccines targeting heat shock proteins, such as PhosphoSynVax TM ; Vitespen (HSPPC-96-C), NANT colorectal cancer vaccine containing aldoxorubicin, autologous tumor cell vaccine + systemic CpG-B + IFN-α (cancer), IO-120 + IO-103 (PD-L1 / PD-L2 vaccine), HB-201, HB-202, HB-301, based on vaccines;

[0706] TLR-3 agonists / interferon inducers, such as Poly-ICLC (NSC-301463);

[0707] STAT-3 inhibitors, such as nababukacin (BBI-608);

[0708] ATPase p97 inhibitors, such as CB-5083;

[0709] Smoothened (SMO) receptor inhibitors, such as (sonidegib, formerly known as LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;

[0710] Interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilars (Biogenomics), ropeg interferon alpha-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon, Ro-25-3036), interferon alpha-2a follow-up biologics (Biosidus) (Inmutag, Inter2A), interferon alpha-2b follow-up biologics (Biosidus-Bioferon, Citopheron, Ganapar, Beijing Kawin Technology–Kaferon), Alfaferone, pegylated interferon alpha-1b, pegylated interferon alpha-2b follow-on biologic (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFNα2b conjugate, Dynavax (SD-101), and interferon alpha-n1 (Humoferon, SM-10500, Sumiferon);

[0711] Interferon gamma ligand modulators, such as interferon gamma (OH-6000, Oγ100);

[0712] IL-6 receptor modulators, such as tocilizumab, AS-101 (CB-06-02, IVX-Q-101);

[0713] Heat shock protein inhibitors / IL-6 receptor antagonists, such as sildenafil;

[0714] Telomerase modulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

[0715] DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, guacitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacytidine (CC-486);

[0716] DNA gyrase inhibitors, such as pisantron and sobuzoxan;

[0717] DNA gyrase inhibitors / topoisomerase II inhibitors, such as amrubicin;

[0718] Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, RG7601, and AT-101;

[0719] Bcl-2 / Bcl-XL inhibitors such as navitoclax;

[0720] Notch inhibitors such as LY3039478 (crenigacestat), tarextumab (anti-Notch2 / 3), BMS-906024;

[0721] Hyaluronidase stimulators, such as PEGPH-20;

[0722] Erbb2 tyrosine kinase receptor inhibitors / hyaluronidase stimulators, such as Herceptin Hylecta;

[0723] Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974;

[0724] γ-secretase inhibitors, such as PF-03084014, MK-0752, RO-4929097;

[0725] Grb-2 (growth factor receptor binding protein-2) inhibitors, such as BP1001;

[0726] TRAIL pathway inducing compounds, such as ONC201, ABBV-621;

[0727] TRAIL modulators, such as SCB-313;

[0728] Focal adhesion kinase inhibitors, such as VS-4718, defatinib, GSK2256098;

[0729] Hedgehog inhibitors, such as saridegib, songib (LDE225), and glacib;

[0730] Aurora kinase inhibitors, such as alecetin (MLN-8237) and AZD-2811, AMG-900, balacetib, ENMD-2076;

[0731] HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine, apatorsen;

[0732] ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (pazosertib), and VX-970;

[0733] Hsp90 inhibitors such as AUY922, onalespib (AT13387), SNX-2112, SNX5422;

[0734] Murine double minute (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);

[0735] CD137 agonists, such as urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480;

[0736] STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, GSK3745417;

[0737] FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;

[0738] Fatty acid synthase (FASN) inhibitors, such as TVB-2640;

[0739] Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab;

[0740] CD44 binding agents, such as A6;

[0741] Protein phosphatase 2A (PP2A) inhibitors, such as LB-100;

[0742] CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

[0743] RXR agonists, such as IRX4204;

[0744] Hedgehog / Smoothened (hh / Smo) antagonists, such as taladegib, patidegib, vismodegib;

[0745] Complement C3 modulators, such as Imprime PGG;

[0746] IL-15 agonists, such as ALT-803, NKTR-255, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, and hetIL-15;

[0747] EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126, PF-06821497;

[0748] Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301,

[0749] DOT1L (histone methyltransferase) inhibitors, such as pinostat (EPZ-5676);

[0750] toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators;

[0751] DNA plasmids, such as BC-819;

[0752] PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);

[0753] WEE1 inhibitors, such as AZD-1775 (adavosertib); Rho kinase (ROCK) inhibitors, such as AT13148, KD025;

[0754] Inhibitor of apoptosis protein (IAP) inhibitors, such as ASTX660, debio-1143, birenapam, APG-1387, LCL-161;

[0755] RNA polymerase inhibitors, such as rubicin (PM-1183), CX-5461;

[0756] Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin) and OXI-4503, fluorapacin (AC-0001), plinabulin, vinflunine;

[0757] Toll-like receptor 4 (TLR-4) agonists, such as G100, GSK1795091, and PEPA-10;

[0758] elongation factor 1α2 inhibitors, such as plitidepsin;

[0759] Elongation factor 2 inhibitors / interleukin-2 ligands / NAD ADP ribosyltransferase stimulators, such as denileukin diftitox;

[0760] CD95 inhibitors, such as APG-101, APO-010, asunercept;

[0761] WT1 inhibitors, such as DSP-7888;

[0762] Splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800;

[0763] Retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716; and

[0764] Microbiome modulators, such as SER-401, EDP-1503, MRx-0518.

[0765] In some embodiments, the compounds described herein are co-administered with one or more additional therapeutic agents, including inhibitors or antagonists of: myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator (NCBI gene ID: 4170); mitogen-activated protein kinase 1 (MAP4K1) (also known as hematopoietic progenitor cell kinase 1 (HPK1), NCBI gene ID: 11184); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-α; NCBI gene ID: 1606); 5'-ectonucleotidase (NT5E or CD73; NCBI gene ID: 4907); ectonucleotide triphosphate diphosphohydrolase 1 (E NTPD1 or CD39; NCBI Gene ID: 593); transforming growth factor β1 (TGFB1 or TGFβ; NCBI Gene ID: 7040); heme oxygenase 1 (HMOX1, HO-1 or HO1; NCBI Gene ID: 3162); heme oxygenase 2 (HMOX2, HO-2 or HO2; NCBI Gene ID: 3163); vascular endothelial growth factor A (VEGFA or VEGF; NCBI Gene ID: 7422); erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2 / neu or CD340; NCBI Gene ID: 2064), epidermal growth factor receptor (EGFR, ERBB, ER BB1 or HER1; NCBI Gene ID: 1956); ALK receptor tyrosine kinase (ALK, CD246; NCBI Gene ID: 238); poly (ADP-ribose) polymerase 1 (PARP1; NCBI Gene ID: 142); poly (ADP-ribose) polymerase 2 (PARP2; NCBI Gene ID: 10038); TCDD-inducible poly (ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); cyclin-dependent kinase 4 (CDK4; NCBI Gene ID: 1019); cyclin-dependent kinase 6 (CDK6; NCBI Gene ID: 1021); TNF receptor superfamily Family member 14 (TNFRSF14, HVEM, CD270; NCBI gene ID: 8764); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3; NCBI gene ID: 331); baculovirus IAP repeat-containing 2 (BIRC2, cIAP1; NCBI gene ID: 329); baculovirus IAP repeat-containing 3 (BIRC3, cIAP2; NCBI gene ID: 330); baculovirus IAP repeat-containing 5 (BIRC5, survivin; NCBI gene ID: 332);CC motif chemokine receptor 2 (CCR2, CD192; NCBI gene ID: 729230); CC motif chemokine receptor 5 (CCR5, CD195; NCBI gene ID: 1234); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); CXC motif chemokine receptor 2 ((CXCR2, CD182; NCBI gene ID: 3579); CXC motif chemokine receptor 3 (CXCR3, CD182, CD183; NCBI gene ID: 2833); CXC motif chemokine receptor 4 ((CXCR4, CD184; NCBI gene ID: 7852) ; 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: 769), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 772), CA14 (NCBI gene ID: 773), CA15 (NCBI gene ID: 774), CA16 (NCBI gene ID: 775), CA17 (NCBI gene ID: 776), CA18 (NCBI gene ID: 777), CA19 (NCBI gene ID: 778), CA20 (NCBI gene ID: 779), CA21 (NCBI gene ID: 780), CA22 (NCBI gene ID: 781), CA23 (NCBI gene ID: 782), CA24 (NCBI gene ID: 783), CA25 (NCBI gene ID: 784), CA26 (NCBI gene ID: 785), CA27 (NCBI gene ID: 786), CA28 (NCBI gene ID: 787), CA29 (NCBI gene ID: 790), CA30 (NCBI gene ID: 791), CA31 (NCBI gene ID: 792), CA32 (NCBI gene ID: 793), CA33 (NCBI gene ID: 794), ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 5744), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5745), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 5745), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5746), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5747), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5748), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5749), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5749), prostaglandin-endoperoxide synthase 2 (PT D: 240) and / or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053); secreted phospholipase A2 (e.g., PLA2G1B (NCBI gene ID: 5319); PLA2G7 (NCBI gene ID: 7941), PLA2G3 (NCBI gene ID: 50487), PLA2G2A (NCBI gene ID: 5320); PLA2G4A (NCBI gene ID: 5321); PLA2G12A (NCBI gene ID: 81579); PLA2G12B (NCBI gene ID: 84647); PLA2G10 (NCBI gene ID: 8399);PLA2G5 (NCBI Gene ID: 5322); PLA2G2D (NCBI Gene ID: 26279); PLA2G15 (NCBI Gene ID: 23659); indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620); indoleamine 2,3-dioxygenase 2 (IDO2; NCBI Gene ID: 169355); hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091); angiopoietin 1 (ANGPT1 ; NCBI Gene ID: 284); endothelial TEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI Gene ID: 7010); Janus kinase 1 (JAK1; NCBI Gene ID: 3716); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); histone deacetylase 9 (HDAC9; NCBI Gene ID: 9734), and / or 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464). ;

[0766] TCR signaling modulators

[0767] In various embodiments, the compounds as described herein are combined with one or more agonists or antagonists of T cell receptor (TCR) signaling regulators. T cells are essential for thymocyte development and effector T cell function by TCR activation. TCR activation promotes signaling cascades, which ultimately determine the fate of cells by regulating cytokine production, cell survival, proliferation and differentiation. Examples of TCR signaling regulators include, but are not limited to: CD2 (differentiation cluster 2, LFA-2, T11, LFA-3 receptors), CD3 (differentiation cluster 3), CD4 (differentiation cluster 4), CD8 (differentiation cluster 8), CD28 (differentiation cluster 28), CD45 (PTPRC, B220, GP180), LAT (joint for activating T cells, LAT1), Lck, LFA-1 (ITGB2, CD18, LAD, LCAMB), Src, Zap-70, SLP-76, DGKα, CBL-b, CISH, HPK1.

[0768] Examples of cluster of differentiation 3 (CD3) agonists that may be co-administered include, but are not limited to, MGD015.

[0769] In various embodiments, the compounds as described herein are combined 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. The blocking or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent the immune escape of cancer cells in the tumor microenvironment. The activation or stimulation of stimulatory immune checkpoints can enhance the effect of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37: 110). In various 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).

[0770] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); 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); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); 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); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137 ), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC Class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (PDL1, PD-L1); programmed cell death 1 (PDCD1, PD-1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain 4 (TIMD4; TIM4); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9);Lymphocyte activation 3 (LAG-3, CD223); signal transducer lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor (KIR); killer cell lectin-like receptor C 1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); 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 immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1). ;

[0771] In various embodiments, the compounds as described herein are combined 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, but are not limited to, 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); T cell activation inhibitor 1 containing V-set domain (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-related immunoglobulin domain-containing (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG-3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor (KIR); 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 various embodiments, the compounds as described herein are combined 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.

[0772] In various embodiments, a compound as described herein is combined 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, but are not limited to, 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 immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the compound as described herein is combined 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 but are not limited to CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31: 64–75; Fang et al., Semin Immunol. (2017) 31: 37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18 (11): 671-688.

[0773] In various embodiments, the compounds as described herein are combined with CD47 (IAP, MER6, OA3; NCBI gene ID: 961). Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, ALX-148, TTI-621, RRx-001, DSP-107, VT-1021, TTI-621, TTI-622, IMM-02SGN-CD47M. Examples of bispecific antibodies targeting CD47 include IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217 (CD47 / DLL3), IMM-26011 (CD47 / FLT3), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), and HMBD-004A (CD47 / CD33). Examples of anti-CD47 antibodies include IBI-188, 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, and KD-015.

[0774] 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) or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

[0775] Examples of CTLA4 inhibitors that can be co-administered include, but are not limited to, ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-11 44, PBI-5D3H5, BPI-002, HBM-4003, 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).

[0776] Examples of inhibitors / antibodies of PD-L1 (CD274) or PD-1 (PDCD1) that may be co-administered include, but are not limited to, pembrolizumab, nivolumab, cemiplizumab, pidilizumab, AMG-404, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591 , BGB-A317 (tislelizumab), GEN-1046 (PD-L1 / 4-1BB), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genozumab (CBT-50 1), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (carrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (dotalizumab), MSB-2311, JTX-4014, BGB-A333, SH R-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sindilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181,As well as the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), RO-7247669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (P D-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), RG7769 (PD-1 / TIM-3) and INBRX-105 (4-1BB / PDL1), GNS-1480 (PD-L1 / EGFR), RG-7446 (Tecentriq, atezolizumab), ABBV-181, nivolumab (, BMS-936558, MDX-1106), pembrolizumab ( MK-3477, SCH-900475, lambrolizumab (CAS Reg. No. 1374853-91-4), pidilizumab, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), CS-1003, HLX-10, MGA-012, BI-754091, REGN-2810 (simiprizumab), AGEN-2034, JS-001 (toripalizumab), JNJ-63723283, Geno Monoclonal antibody (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camelizumab), Sym-021, ABBV-181, AK-105, PD1-PIK, BAT-1306, BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI-4736), avelumab, CK-301 (MSB0010718C), MEDI-0680, CX-072, CBT-502, PDR-001 (spartalizumab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, and MDX1105-01.

[0777] Examples of PVRIG inhibitors that may be co-administered include, but are not limited to, COM-701.

[0778] Examples of TIGIT inhibitors that may be co-administered include, but are not limited to, BMS-986207, RG-6058, AGEN-1307, COM-902.

[0779] Examples of TIM-3 inhibitors that can be co-administered include, but are not limited to, TSR-022, LY-3321367, MBG-453, INCAGN-2390, RO-7121661 (PD-1 / TIM-3), LY-3415244 (TIM-3 / PDL1), and RG7769 (PD-1 / TIM-3).

[0780] Examples of LAG-3 inhibitors that may be co-administered include, but are not limited to, relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, TSR-033, MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1).

[0781] Anti-killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI Gene ID: 3811) monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102.

[0782] Examples of anti-NKG2a antibodies that may be co-administered include, but are not limited to, monalizumab.

[0783] Examples of anti-VISTA antibodies that can be co-administered include, but are not limited to, HMBD-002, CA-170 (PD-L1 / VISTA).

[0784] Examples of anti-CD70 antibodies that can be co-administered include, but are not limited to, AMG-172.

[0785] Examples of anti-CD20 antibodies that may be co-administered include, but are not limited to, obinutuzumab, IGN-002, PF-05280586.

[0786] Examples of anti-ICOS antibodies that can be co-administered include, but are not limited to, JTX-2011, GSK3359609.

[0787] Examples of ICOS agonists that may be co-administered include, but are not limited to: ICOS-L.COMP (Gariepy, J. et al., 106th Annual Meeting of the American Association of Immunologists (AAI) (May 9-13, 2019, San Diego), Abstract 71.5).

[0788] TNF receptor superfamily (TNFRSF) member agonists or activators

[0789] In various embodiments, the compounds as described herein are combined 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: 355), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3 , NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 23496), TNFRSF14A (CD269, NCBI gene ID: 3647), TNFRSF15B (CD267, NCBI gene ID: 23497), TNFRSF16C (CD268, NCBI gene ID: 3647), TNFRSF17A (CD269, NCBI gene ID: 3647), TNFRSF18A (CD269, NCBI gene ID: 3647), TNFRSF19B (CD261, NCBI gene ID: 3647), TNFRSF20A (CD261, NCBI gene ID: 3647), TNFRSF21A (CD261, NCBI gene ID: 3647), TNFRSF22B (CD261, NCBI gene ID: 3647), TNFRSF23B (CD261, NCBI gene ID: 3647), TNFRSF24 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).

[0790] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavolizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0791] Examples of anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5, TRAILR2) antibodies that can be co-administered include, but are not limited to, antibodies such as DS-8273, CTB-006, INBRX-109, and GEN-1029.

[0792] Examples of anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428, ABBV-927, JNJ-64457107.

[0793] Examples of anti-TNFRSF7 (CD27) that can be co-administered include, but are not limited to, varilumab (CDX-1127).

[0794] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, usurelumab, utolumab (PF-05082566), AGEN2373, and ADG-106.

[0795] Examples of anti-TNFRSF17 (BCMA) that can be co-administered include, but are not limited to, GSK-2857916.

[0796] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0797] Examples of anti-TRAILR1 antibodies, anti-TRAILR2 antibodies, anti-TRAILR3 antibodies, anti-TRAILR4 antibodies that can be co-administered include, but are not limited to, ABBV-621.

[0798] Examples of bispecific antibodies targeting TNFRSF family members that can be co-administered include, but are not limited to, PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), REGN-1979 (CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), XmAb-13676 (CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20), AMG-424 (CD38.CD3).

[0799] Adenosine production and signaling

[0800] In various embodiments, the compounds as described herein are combined with an agonist or antagonist of A1R, A2AR, A2BR, A3R, CD73, CD39, CD26.

[0801] Examples of adenosine A3 receptor (A3R) agonists include namodenoson (CF102);

[0802] Examples of A2aR / A2bR antagonists include AB928;

[0803] Examples of anti-CD73 antibodies include MEDI-9447 (olerumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006;

[0804] Examples of CD73 inhibitors include AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708;

[0805] Examples of CD39 / CD73 inhibitors include PBF-1662;

[0806] Examples of anti-CD39 antibodies include TTX-030;

[0807] Examples of adenosine A2A receptor antagonists include CPI-444, AZD-4635, preladenant, PBF-509;

[0808] Examples of adenosine deaminase inhibitors include pentostatin, cladribine;

[0809] Examples of adenosine deaminase inhibitors include pentostatin, cladribine.

[0810] FLT3 agonists

[0811] In various embodiments, a compound as described herein is combined with an agonist of FLT3 (FLK2, STK1, CD135, FLK-2, Gene ID: 2322).

[0812] Examples of FLT3 agonists include, but are not limited to, GS-3583, Sym-027, FLT3 Agonist Antibody (Solid Tumor), RIVAL-01, CDX-301, ONCR-177.

[0813] c-kit targeting agent

[0814] In various embodiments, the compounds as described herein are combined with an inhibitor of c-kit (PBT, SCFR, CD117, MASTC; NCBI Gene ID: 3815).

[0815] Examples of c-kit inhibitors include imatinib mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229 (c-kit / PDGFR inhibitor), telatinib (c-kit / PDGF / VEGF2 inhibitor), quizartinib dihydrochloride (FLT3 / c-kit), pexidartinib hydrochloride (CSF1R / FLT3 / c-kit), avapritinib (PDGFR / c-Kit inhibitor), vorolanib (multikinase VEGF / PDGFR / c-kit inhibitor), and ripretinib (c-kit / PDGFRα inhibitor);

[0816] Examples of c-kit multikinase inhibitors include dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, cabozantinib 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, HQP-1351, cabozantinib, ponatinib, and famitinib L-malate. Examples of anti-c-kit antibodies include CDX-0158, CDX-0159, and FSI-174.

[0817] SIRPα-targeting agents

[0818] In various embodiments, the compounds as described herein are combined with SIRPα (NCBI Gene ID: 140885).

[0819] Examples of SIRPα inhibitors include AL-008, RRx-001, and CTX-5861.

[0820] Examples of anti-SIRPα antibodies include FSI-189, ES-004, BI765063, ADU1805, and CC-95251.

[0821] Bispecific T cell engagers

[0822] In various embodiments, the compounds as described herein are combined with bispecific T cell engagers (e.g., without Fc) or anti-CD3 bispecific antibodies (e.g., with Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include: AMG-160 (PSMA / CD3), AMG-212 (PSMA / CD3), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), AMG-427 (FLT3 / CD3), AMG-562 (CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-673 (CD33 / CD3), AMG-701 (BCMA / CD3), AMG-757 (DLL3 / CD3), JNJ-64052781 (CD19 / CD3), AMG-211 (CEA / CD3), (CD19 / CD3), RG7802(CEA / CD3), ERY-974(CD3 / GPC3), huGD2-BsAb(CD3 / GD2), PF-06671008(Cadherin / CD3), APVO436(CD123 / CD3), ERY974, Flutezumab(CD123 / CD3), GEM333(CD3 / CD33), GEMoab(CD3 / PSCA), REGN-1979(CD20 / CD3), REGN-5678(PSMA / CD28), MCLA-117(CD3 / CLEC12A), JNJ-0819, JNJ-7564(CD3 / Heme), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20), XmAb-18 087(SSTR2 / CD3), Catusomab (CD3 / EpCAM), REGN-4018(MUC16 / CD3), RG6026, RG6076, RG6194, RG- 7828(CD20 / CD3), CC-93269(CD3 / BCMA), REGN-5458(CD3 / BCMA), GRB-1302(CD3 / Erbb2), GRB -1342(CD38 / CD3), GEM-333(CD3 / CD33), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw123). As appropriate, the anti-CD3 binding bispecific molecule may or may not have an Fc. Exemplary bispecific T cell engagers that can be co-administered target CD3 and 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).

[0823] Bispecific and trispecific natural killer (NK) cell engagers

[0824] In various embodiments, the compounds as described herein are combined 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.

[0825] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0826] In various embodiments, the compounds as described herein are combined with MCL1 apoptosis regulators (BCL2 family members) (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO2018183418, WO2016033486, and WO2017147410.

[0827] Hematopoietic progenitor kinase 1 (HPK1) inhibitors

[0828] In various embodiments, the compounds as described herein are combined with 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-2018183956, WO-2018183964, WO-2018167147, WO-2018183964, WO-2016205942, WO-2018049214, WO-2018049200, WO-2018049191, WO-2018102366, WO-2018049152, and WO-2016090300.

[0829] Apoptosis signal-regulating kinase (ASK) inhibitors

[0830] In various embodiments, the compounds as described herein are combined with an ASK inhibitor (e.g., mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI Gene ID: 4217). Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011 / 008709 (Gilead Sciences) and WO2013 / 112741 (Gilead Sciences).

[0831] Bruton's tyrosine kinase (BTK) inhibitors

[0832] In various embodiments, the compounds as described herein are combined with Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). Examples of BTK inhibitors include, but are not limited to: (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, Imbruvica, M-2951 (evobrutinib), M7583, tadalafil ... Tirabrutinib (ONO-4059), PRN-1008, CC-292, TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, Calquence + AZD6738, and Calquence + danvatirsen.

[0833] Cyclin-dependent kinase (CDK) inhibitors

[0834] In various embodiments, the compounds as described herein are combined 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; N 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); 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, but are not limited to, abemaciclib, avosidide (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirsili, tricaspecib, PF-06873600, AZD4573 and TG-02.

[0835] Discoidin domain receptor (DDR) inhibitors

[0836] In various embodiments, the compounds as described herein are combined with an inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include, but are not limited to, dasatinib and those disclosed in WO2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO2013 / 034933 (Imperial Innovations).

[0837] Histone deacetylase (HDAC) inhibitors

[0838] In various embodiments, the compounds as described herein are combined with an inhibitor of a histone deacetylase, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, 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, entinostat, romidepsin, tucidinostat.

[0839] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0840] In various embodiments, the compounds as described herein are combined with indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icadolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0841] Janus kinase (JAK) inhibitors

[0842] In various embodiments, the compounds as described herein are combined 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, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasocitinib), INCB052793, and XL019.

[0843] Matrix metalloproteinase (MMP) inhibitors

[0844] In various embodiments, the compounds as described herein are combined 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), MMP18 (NCBI gene ID: 4327), MMP19 (NCBI gene ID: 4330), MMP20 (NCBI gene ID: 4331), MMP21 (NCBI gene ID: 4332), MMP22 (NCBI gene ID: 4333), MMP23 (NCBI gene ID: 4334), MMP24 (NCBI gene ID: 4335), MMP25 (NCBI gene ID: 4336), MMP26 (NCBI gene ID: 4337), MMP27 (NCBI gene ID: 4338), MMP28 (NCBI gene ID: 4339), MMP29 (NCBI gene ID: 4340), MMP30 (NCBI gene ID: 4341), MMP31 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, but are not limited to, marimastat (BB-2516), simaxastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012 / 027721 (Gilead Biologics).

[0845] RAS and RAS pathway inhibitors

[0846] In various embodiments, the compounds as described herein are combined 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); HRas proto-oncogene GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265);. Ras inhibitors can inhibit Ras at the polynucleotide (e.g., transcription inhibitor) or polypeptide (e.g., GTPase inhibitor) level. In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, such as inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR.

[0847] In various embodiments, the compounds as described herein are combined with inhibitors of KRAS. Examples of KRAS inhibitors include AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (RasGTP), RT11, MRTX-849 (G12C) and K-Ras (G12D)-selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH 2 )(SEQ ID NO:108) and KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH 2 )(SEQID NO:109).

[0848] In various embodiments, the compounds as described herein are combined with inhibitors of KRAS mRNA. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 aptamers, AZD-4785, siG12D-LODER TM and siG12D exosomes.

[0849] In various embodiments, the compounds as described herein are combined with an inhibitor of MEK. Exemplary MEK inhibitors that can be co-administered include bimetinib, cobimetinib, PD-0325901, pimatinib, RG-7304, selumetinib, and trametinib.

[0850] In various embodiments, the compounds as described herein are combined with inhibitors of AKT. Exemplary AKT inhibitors that can be co-administered include RG7440, MK-2206, ipatritinib, afusetinib, AZD5363, ARQ-092, capasitinib, triciribine, ABTL-0812 (PI3K / Akt / mTOR).

[0851] In various embodiments, the compounds as described herein are combined with inhibitors of Raf. Exemplary Raf inhibitors that can be co-administered include BGB-283 (Raf / EGFR), HM-95573, LXH-254, LY-3009120, RG7304, TAK-580, dabrafenib, vemurafenib, connefenib (LGX818), PLX8394, RAF-265 (Raf / VEGFR), ASN-003 (Raf / PI3K).

[0852] In various embodiments, the compounds as described herein are combined with an inhibitor of ERK. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, GDC-0994, and uritinib.

[0853] In various embodiments, the compounds described herein are combined with an inhibitor of PI3K. Exemplary PI3K inhibitors that can be co-administered include idelixib Abolicilib, buparicilib and pictilisib. Exemplary PI3K / mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795 and RG6114.

[0854] In various embodiments, the compounds as described herein are combined with inhibitors of mTOR. Illustrative mTOR inhibitors that can be co-administered include: sapacerti, vistusertib (AZD2014), ME-344, sirolimus (oral nanoamorphous formulation, cancer) and TYME-88 (mTOR / cytochrome P450 3A4).

[0855] In certain 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.

[0856] In various embodiments, the compounds as described herein are combined with an inhibitor of RAS. Examples of RAS inhibitors include NEO-100 and regoratinib.

[0857] In various embodiments, the compounds as described herein are combined with an antagonist of EGFR, such as AMG-595, nesituzumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomatuximab, ABT-806, vicaribin, motuximab, or RM-1929.

[0858] In various embodiments, the compounds as described herein are combined with 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, SAR442720, and those described in WO2018172984 and WO2017211303.

[0859] In various embodiments, the compounds as described herein are combined with mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include: antroquinol, binimetinib, CK-127, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, RG7421.

[0860] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0861] In various embodiments, the compounds as described herein are combined with an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, such as the 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); the 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, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparizib (BKM120), BYL719 (arborisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, edlisib INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, regoratinib, RP5090, RP6530, SRX3177, taselixib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and WO 2005 / 113556 (ICOS), WO 2013 / 052699 (Gilead Calistoga), WO Compounds described in WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga) and WO 2014 / 201409 (Gilead Sciences).

[0862] Mitogen-activated protein kinase (MEK) inhibitors

[0863] In various embodiments, the compounds as described herein are combined with mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib.

[0864] Spleen tyrosine kinase (SYK) inhibitors

[0865] In various embodiments, the compounds as described herein are combined with inhibitors of spleen-associated tyrosine kinase (SYK, p72-Syk, gene ID: 6850). Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205AA, R112, R343, tamatinib (R406), and those described in US 8450321 (Gilead Connecticut) and US2015 / 0175616.

[0866] Toll-like receptor (TLR) agonists

[0867] In various embodiments, the compounds as described herein are combined 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, but are not limited to, DS-0509, GS-9620, 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, and US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189(Janssen), US20140350031(Janssen), WO2014 / 023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). The TLR7 / TLR8 agonist that can be co-administered is NKTR-262.Exemplary TLR8 agonists that can be co-administered include, but are not limited to, 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 US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (ArrayBiopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). Example TLR9 agonists that can be co-administered include, but are not limited to, 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 retamod, polyICLC,. Apoxxim, IPH-33, MCT-465, MCT-475 and ND-1.1.

[0868] Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200, and VTX-763.

[0869] Examples of TLR8 agonists include, but are not limited to, MCT-465, Motomod, GS-9688, and VTX-1463.

[0870] Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, lefitolimod, MGN-1601, and PUL-042.

[0871] Examples of TLR7 / TLR8 agonists, such as NKTR-262, IMO-4200, MEDI-9197 (tiramumod), resiquimod;

[0872] Examples of TLR agonists include, but are not limited to, lefitolimod, tilsotolimod, retamod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motomod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tiramid.

[0873] Stimulator of interferon genes (STING)

[0874] In some embodiments, the therapeutic agent is a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP) and cyclic diAMP.

[0875] Tyrosine kinase inhibitors (TKIs)

[0876] In various embodiments, the compounds as described herein are combined with tyrosine kinase inhibitors (TKIs). 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: axitinib, afatinib, ARQ-087 (drazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, clenonib, dacomitinib, dasatinib, dovitinib, E-6201, erdatinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 ( Src), lapatinib, lestautinib, lenvatinib, midostaurin, nintedanib, ODM-203, omotinib, osimertinib (AZD-9291), pazopanib, ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib L-malate (MAC-4), tivolidine, TH-4000, tivolidine and MEDI-575 (anti-PDGFR antibody), TAK-659, cabozantinib.

[0877] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0878] In various embodiments, the compounds as described herein are combined with indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icadolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0879] Chemotherapeutic agents

[0880] In various embodiments, the compounds as described herein are combined with a chemotherapeutic or anti-neoplastic agent.

[0881] 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 cyclophosphamideAlkyl 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; nostoc, especially nostoc 1 and nostoc 8; caudate alkaloids; 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, phenylephrine, 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 phill), danimycins (including danimycin A), bisphosphonates (such as clodronate), espammycins, neostatin chromophores and related chromophore protein enediyne antibiotic chromophores, aclarubicin, actinomycin, authramycin, azaserine, bleomycin, actinomycin, carabicin, carrninomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detoxibacin, 6-diazo-5-oxo-L-norleucine , doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolo-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogamycin, olivemycin, peplomycin, porfiromycin, puromycin, quinamycin, rhodorubicin, streptomycin, streptozotocin, tuberculocidin, ubenimex, zoloft and zorubicin; 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 captestosterone, drostanolone propionate, cyclothiodine, melastosane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; radiotherapeutic agents such as Radium-223, 177-Lu-PSMA-617; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxanes such as paclitaxel; Albumin-bound paclitaxel (abraxane), docetaxel Cabazitaxel, BIND-014, tesetaxel; platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; acetoglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatrexate; defosfamide; colcemid; diazocone; elformthine; elliptolide; epothilone; etoglucosamine; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansine alkaloids such as maytansine and ansamitocin; mitoguanidine; mitoxantrone ; mopidarol; diamine nitrazepam; methamine nitrogen mustard; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizoran; spirogermanamine; tenuisporic acid; trabectedin, triazoquinone; 2,2',2"-trichlorotrimethylamine; carbamate; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine Noxol; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeoloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DFMO); Retinoids, such as retinoic acid; Capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) and pharmaceutically acceptable salts, acids or derivatives of any of the above substances. Such agents can be conjugated to antibodies or any targeting agent described herein to form antibody-drug conjugates (ADCs) or targeted drug conjugates.

[0882] Antihormonal agents

[0883] Also included within 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.

[0884] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, troloxifene, raloxifene hydrochloride, LY117018, onapristone, and toremifene.

[0885] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate Exemestane, formestane, fadrozole, vorozole Letrozole and anastrozole

[0886] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galactron, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.

[0887] Examples of progesterone receptor antagonists include onapristone.

[0888] Anti-angiogenic agents

[0889] In various embodiments, the compounds as described herein are combined with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include, but are not limited to, retinoic acid and its derivatives, 2-methoxyestradiol, 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 snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators (including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thioproline), α,α'-bipyridine, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridyl)-2(3h)- oxazolidinone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-serum, chicken metalloproteinase-3 inhibitor (ChIMP-3), chymostatin, β-cyclodextrin tetradesulfate, epothilone, fumarate, gold sodium thiomalate, dextran, β-1-anticollagenase-serum, α-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthrone acid disodium or "CCA", thalidomide, angiostatic steroids, carboxyaminoimidazoles, metalloproteinase inhibitors (such as BB-94), inhibitors of S100A9 (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.

[0890] Antifibrotic agents

[0891] In various embodiments, the compound as described herein is combined with an anti-fibrotic agent. Anti-fibrotic agents that can be co-administered include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), and disclosed in US 4965288, lysyl oxidase inhibitors and their use in treating diseases and conditions associated with abnormal collagen deposition, and disclosed in US 4997854, compounds related to inhibiting LOX to treat various pathological fibrotic states, these patents are incorporated herein by reference. Other exemplary inhibitors are described in US 4943593, compounds such as 2-isobutyl-3-fluoro-, chloro- or bromo-allylamine, US 5021456, US 5059714, US 5120764, US 5182297, US 5252608, and US2004-0248871, which are incorporated herein by reference.

[0892] 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.

[0893] Other anti-fibrotic agents are copper chelators that infiltrate or do not infiltrate cells. Exemplary compounds include indirect inhibitors that block the 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-acetamidoethyl) 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-acetamidoethyl-2-acetamidoethanethiol sulfate and 4-mercaptobutanesulfinate sodium trihydrate.

[0894] Anti-inflammatory agents

[0895] In various embodiments, the compounds as described herein are combined with an anti-inflammatory agent. Example 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), CA 12 (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), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053), and / or 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.

[0896] Examples of inhibitors of prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742) that may be co-administered include, but are not limited to, mofezolic acid, GLY-230, and TRK-700.

[0897] Examples of inhibitors of prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include, but are not limited to, 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 can be co-administered include, but are not limited to, HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that can be co-administered include, but are not limited to, pomacoxib and ericoxib.

[0898] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include, but are not limited to, LY3023703, GRC 27864, and WO2015158204, WO2013024898, WO2006063466, WO2007059610, WO2007124589, WO2010100249, WO2010034796, WO2010034797, WO2012022793, WO2012076673, WO2012076672, WO2010034798, WO2010034799, WO2012022792, WO2009103778, WO2011048004, WO2012087771, WO2012161965, WO2013 The compounds described in WO2013072825, WO2014167444, WO2009138376, WO2011023812, WO2012110860, WO2013153535, WO2009130242, WO2009146696, WO2013186692, WO2015059618, WO2016069376, WO2016069374, WO2009117985, WO2009064250, WO2009064251, WO2009082347, WO2009117987 and WO2008071173. Metformin has also been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. See, e.g., Tong et al., Cancer Lett. (2017) 389: 23-32; and Liu et al., Oncotarget. (2016) 7(19): 28235-46.

[0899] Examples of inhibitors of carbonic anhydrase (e.g., one or more of CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)) that can be co-administered include, but are not limited to, acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and dichlorobenzenesulfonamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0900] Examples of inhibitors of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) that may be co-administered include, but are not limited to, meclofenamic acid sodium, zileuton.

[0901] Examples of inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) that can be co-administered include, but are not limited to, compounds described in WO2015148954. Dual inhibitors of COX-2 / SEH that can be co-administered include compounds described in WO2012082647. Dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI gene ID: 2166) that can be co-administered include compounds described in WO2017160861.

[0902] Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus-2, TPL2; NCBI gene ID: 1326) that can be co-administered include, but are not limited to, GS-4875, GS-5290, BHM-078, and those described in, for example, WO2006124944, WO2006124692, WO2014064215, WO2018005435; Teli et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila et al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0903] Tumor oxygenator

[0904] In various embodiments, the compounds as described herein are combined 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 bevacizumab, IMC-3C5, GNR-011, tenibirumab, 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 2007 / 137767, WO 2007 / 139791, WO 2014 / 107171, and WO 2016 / 149562.

[0905] Immunotherapeutic agents

[0906] In various embodiments, the compounds as described herein are combined with an immunotherapeutic agent. Exemplary immunotherapeutic agents that can be co-administered include, but are not limited to, abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bevacizumab biosimilars, and the like. Bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab ratumumab, detumomab, dinutuximab, drozitumab, duligotumab, dusigitumab, ecoromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, non-cardiac ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab,Intetumumab, ipilimumab ( MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, moxetumomab pasudotox, naptumomab, narnatumab, necitumumab, nimotuzumab ), nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab Rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatuzumab momab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, trastuzumab biosimilars, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, 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.

[0907] 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.

[0908] In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Exemplary ADCs that can be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics targeting proteins or antigens listed above and herein (e.g., in Table B). Exemplary ADCs that may be co-administered include, but are not limited to, gemtuzumab ozogamicin, brentuximab, trastuzumab, inotuzumab, glenbatuzumab, anetuzumab, mirvetuximab, depatuxizumab, rovacpitumab, vadatuximab, labetuzumab, certolizumab pegol, rifatuzumab, indostatumab, potuzumab, pinatuzumab, cotuximab, indostatin, milatuzumab, rovacpitumab, ABBV-011, ABBV-2029, ABBV-321, ABBV-647, MLN0264 (anti-GCC, guanylate cyclase C), T-DM1 (enmetuzumab trastuzumab), emtansine, Kadcycla); SYD985 (anti-HER2, duocarcin), milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin DCDT2980S, belantamab mafodotin (GSK2857916), polatuzumab vedotin (RG-7596), SGN-CD70A, SGN-CD19A, inotuzumab ozogamicin (CMC-544), lorvotuzumab mertansine, SAR3419, isactuzumab govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201 (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402, 177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab ravtansine, CX-2009, SAR-566658, W-0101, ABBV-085, gemtuzumab ozogamicin, ABT-414, glembatumumab vedotin (CDX-011), labetuzumab govitecan (IMMU-130), sacituzumab govitecan)(IMMU-132), lifastuzumab vedotin(RG-7599), milatuzumab doxorubicin(IMMU-110), indatuximab ravtansine(BT-062), pinatuzumab vedotin(RG-7593), SGN-LIV1A, SGN-CD33A, SAR566658, MLN2704, SAR408701, rovalvpituzumab tesirine, ABBV-399, AGS-16C3F, ASG-22ME, AGS67E, AMG 172, AMG 595, AGS-15E, BAY1129980, BAY1187982, BAY94-934 (anetumabravtansine), GSK2857916, Humax-TF-ADC (tisotumab vedotin), IMGN289, IMGN529; IMGN853 (mirvetuximab ravtansine), soravtansine)), LOP628, PCA062, MDX-1203, MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, PF-06688992, PF-06 804103, RG7450, RG7458, RG7598, SAR566658, SGN-CD33A, DS-1602 and DS-7300, DS-6157, DS-6000, TAK-164, MEDI2228, MEDI7247, AMG575. 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.

[0909] 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 cross-linking agent 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 agents or antitumor agents described herein.

[0910] Cancer gene therapy and cell therapy

[0911] In various embodiments, the compounds as described herein are combined 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 silent mutant genes; genetic methods that directly kill cancer cells; including infusion of immune cells, the immune cells are 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.

[0912] Cell therapy

[0913] In various embodiments, the compounds as described herein are combined with one or more cell therapies. Exemplary cell therapies include, but are not limited to, co-administering natural killer (NK) cells, NK-T cells, T cells, γδT cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor infiltrating lymphocytes (TIL) and / or dendritic cells (DC) One or more of the population. In some embodiments, cell therapy requires T cell therapy, such as co-administering α / βTCRT cells, γ / δTCR T cells, regulatory T (Treg) cells and / or TRuC TM 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.

[0914] In some embodiments, cell therapy requires co-administration of cells containing chimeric antigen receptors (CARs). In such therapies, a population of immune effector cells is engineered to express CARs, wherein the CARs contain tumor antigen binding domains. In T cell therapy, T cell receptors (TCRs) are engineered to target tumor-derived peptides presented on the surface of tumor cells.

[0915] In terms of the structure of CAR, in some embodiments, CAR includes an antigen binding domain, a transmembrane domain and an intracellular signaling domain. In some embodiments, the intracellular domain includes a primary signaling domain, a costimulatory domain or a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain includes 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 (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10 and DAP12.

[0916] In some embodiments, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 1 D: 911), CD1D (NCBI gene ID: 912), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM , Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46 and NKG2D.

[0917] In some embodiments, the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: an alpha, beta, or zeta chain of a T cell receptor, CD28, CD3 epsilon, 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), CD19, IL2R beta, IL2R gamma, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18) , ITGB7, TNFR2, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(TACTILE), CEACAM1, CRTAM, Ly 9(CD229), CD160(BY55), PSGL1, CD100(SEMA4D), SLAMF6(NTB-A, Ly108), SLAM(SLAMF1, CD150 , IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and NKG2C.

[0918] In some embodiments, the TCR or CAR antigen binding domain or the immunotherapeutic agent described herein (e.g., a monospecific or multispecific antibody or antigen binding fragment thereof or an antibody mimetic) binds to 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); neuro 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); GM-CSF receptor; TNF receptor superfamily member 17 (TNFRSF17, BCMA); B-lymphocyte cell adhesion molecule; 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); HLA Class I antigen A-2α; HLA antigen; 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; folate receptor beta, GDNFα4 receptor, receptor tyrosine protein kinase, ERBB2 (Her2 / neu); cell surface-associated mucin 1 (MUC1); APRIL receptor; ADP-ribosyl cyclase-1; Ephb4 tyrosine kinase receptor, DCAMKL1 serine threonine kinase, aspartate beta-hydroxylase, epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostatic 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 cleavage cluster region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); ephrin type A receptor 3 (EphA3), fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7 related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); blocking protein CLDN6; thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRCSD); interleukin-15 receptor (IL-15); 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); breast differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenal receptor beta 3 (ADRB3); pan-nexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCR gamma 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); melanoma-associated antigen 3 (MAGE-A3); melanoma-associated antigen 4 (MAGE-A4); T cell receptor beta 2 chain C; 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 A1; 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), 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); peptidoglycan recognition protein, synovial sarcoma, breakpoint X 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; mutated heat shock protein 70-2 (muthsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of the 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); mucin-like hormone receptor-like EGF-like module 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-2 (GPC2); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen presented in MHC. ;

[0919] In some embodiments, the tumor antigen is selected from CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HLA class I antigen αG, HM1.24, K-Ras GTPase, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factor, exogenous cognate binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D1), ephrin B2, epithelial Tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate binding protein, gp100, hepatitis B surface antigen, Epstein-Barr nuclear antigen 1, latent membrane protein 1, secretory protein BARF1, P2X7 purinergic receptor, Syndecan-1, kappa chain, kappa light chain, kdr, lambda chain, live protein, 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). .

[0920] Examples of cell therapy include, but are not limited to, AMG-119, Algenpantucel-L, Sipuleucel-T, (BPX-501)rivogenlecleucel US9089520, WO2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, SNK-01, NEXI-001, CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005, LAAP T cell therapy, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), anti-MUC1CAR T cell therapy (esophageal cancer / NSCLC), anti-MUC1CAR T cell therapy + PD-1 knockout T cell therapy (esophageal cancer / NSCLC), anti-KRAS G12DmTCR PBL, anti-CD123CAR T cell therapy, anti-mutated neoantigen TCR T cell therapy, tumor lysate / MUC1 / survivin PepTivator-loaded dendritic cell vaccine, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal / intravenous), anti-LeY-scFv-CD28-ζCAR T cells, PRGN-3005, iC9-GD2-CAR-IL-15T cells, HSC-100, ATL-DC-101, MIDRIX4-LUNG, MIDRIXNEO, anti-CD20CAR T cell therapy (non-Hodgkin's lymphoma).

[0921] Additional agents for targeting tumors include, but are not limited to:

[0922] alpha-fetoprotein modulators, such as ET-1402 and AFP-TCR;

[0923] Anthrax toxin receptor 1 modulators, such as anti-TEM8 CAR T-cell therapy;

[0924] TNF receptor superfamily member 17 (TNFRSF17, BCMA), such as bb-2121 (ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), JNJ-68284528;

[0925] Anti-CLL-1 antibodies, such as KITE-796;

[0926] Anti-PD-L1-CAR targeted natural killer cell therapy, such as KD-045;

[0927] Anti-PD-L1t-haNK, such as PD-L1t-haNK;

[0928] Anti-CD45 antibodies, such as 131I-BC8 (lomab-B);

[0929] Anti-HER3 antibodies, such as LJM716 and GSK2849330;

[0930] Anti-CD52 antibodies, such as alemtuzumab;

[0931] APRIL receptor modulators, such as anti-BCMACAR T cell therapy, Descartes-011;

[0932] ADP-ribosyl cyclase-1 / APRIL receptor modulators, such as dual anti-BCMA / anti-CD38 CAR T-cell therapy; CART-ddBCMA;

[0933] B7 homolog 6, such as CAR-NKp30 and CAR-B7H6;

[0934] B lymphocyte antigen CD19, such as TBI-1501, CTL-119huCART-19T cells, liso-cel, JCAR-015US7446190, JCAR-014, JCAR-017 (WO2016196388, WO2016033570, WO2015157386), axicabtagene ciloleucel (KTE-C19, ), KTE-X19, US7741465, US6319494, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019), WO2012079000, WO2017049166, T cells expressing CD19CAR-CD28-CD3ζ-EGFRt, armored CD19 / 4-1BBL CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζT cells, PCAR-019, MatchCART, DSCAR-01, IM19CAR-T, TC-110; anti-CD19CAR T cell therapy (B-cell acute lymphoblastic leukemia, Universiti KebangsaanMalaysia); anti-CD19CAR T cell therapy (acute lymphoblastic leukemia / non-Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD19CAR T cell therapy (IL-6 expression silencing, 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-CD19cCAR (CD19 / APRIL), ICG-134, ICG-132 (CD19 / CD20), CTA-101, WZTL-002, dual anti-CD 19 / anti-CD20CART 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;

[0935] Allogeneic anti-CD19 CART cells, such as GC-007G;

[0936] APRIL receptor modulator; SLAM family member 7 modulator BCMA-CS1cCAR;

[0937] Autologous dendritic cell tumor antigen (ADCTA), such as ADCTA-SSI-G;

[0938] B-lymphocyte antigen CD20, such as ACTR707ATTCK-20, PBCAR-20A;

[0939] Allogeneic T cells expressing CD20CAR, such as LB-1905;

[0940] B-lymphocyte antigen CD19 / B-lymphocyte antigen 22, such as TC-310;

[0941] B-lymphocyte antigen 22 cell adhesion, such as UCART-22, JCAR-018WO2016090190;

[0942] NY-ESO-1 modulators, such as GSK-3377794, TBI-1301, GSK3537142;

[0943] Carbonic anhydrase, such as DC-Ad-GMCAIX;

[0944] Caspase 9 suicide genes, such as CaspaCIDe DLI, BPX-501;

[0945] CCR5, such as SB-728;

[0946] CCR5 gene inhibitor / TAT gene / TRIM5 gene stimulator, such as autologous CD34-positive hematopoietic progenitor cells transduced with lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy;

[0947] CDw123, such as MB-102, IM-23, JEZ-567, UCART-123;

[0948] CD4, such as ICG-122;

[0949] CD5 modulators, such as CD5.28z CART cells;

[0950] Anti-CD22, such as anti-CD22 CART;

[0951] Anti-CD30, such as TT-11;

[0952] CD33, such as CIK-CAR.CD33, CD33CART;

[0953] Dual anti-CD33 / anti-CLL1, such as LB-1910;

[0954] CD38, such as T-007, UCART-38;

[0955] CD40 ligands, such as BPX-201 and MEDI5083;

[0956] CD56, such as allogeneic CD56-positive CD3-negative natural killer cells (myeloid malignancies);

[0957] CD19 / CD7 modulators, such as GC-197;

[0958] T-cell antigen CD7 modulators, such as anti-CD7 CAR T-cell therapy (CD7-positive hematological malignancies);

[0959] CD123 modulators, such as UniCAR02-T-CD123;

[0960] CEACAM protein 5 modulators, such as MG7-CART;

[0961] Occludin 6, such as CSG-002;

[0962] Occludin 18.2, such as LB-1904;

[0963] Chlorotoxins, such as CLTX-CART;

[0964] Targeting EBV, such as CMD-003;

[0965] MUC16EGFR, such as autologous 4H11-28z / fIL-12 / EFGRt T cells;

[0966] Endonucleases, such as PGN-514, PGN-201;

[0967] Epstein-Barr virus-specific T lymphocytes, such as TT-10;

[0968] Epstein-Barr nuclear antigen 1 / latent membrane protein 1 / secretory protein BARF1 modulators, such as TT-10X;

[0969] Erbb2, such as CST-102, CIDeCAR;

[0970] Gangliosides (GD2), such as 4SCAR-GD2;

[0971] γδT cells, such as ICS-200;

[0972] Folate hydrolase 1 (FOLH1, glutamate carboxypeptidase II, PSMA; NCBI Gene ID: 2346), such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101;

[0973] Glypican-3 (GPC3), such as TT-16, GLYCAR;

[0974] Hemoglobin, such as PGN-236;

[0975] Hepatocyte growth factor receptor, such as anti-cMet RNA CAR T;

[0976] HLA class I antigen A-2α modulators, such as FH-MCVA2TCR;

[0977] HLA class I antigen A-2α / melanoma associated antigen 4 modulators, such as ADP-A2M4CD8;

[0978] HLA antigen modulators, such as FIT-001 and NeoTCR-P1;

[0979] Human papillomavirus E7 protein, such as KITE-439;

[0980] ICAM-1 modulators, such as AIC-100;

[0981] Immunoglobulin gamma Fc receptor III, such as ACTR087;

[0982] IL-12, such as DC-RTS-IL-12;

[0983] IL-12 agonists / mucin 16, such as JCAR-020;

[0984] IL-13α2, such as MB-101;

[0985] IL-15 receptor agonists, such as PRGN-3006;

[0986] IL-2, such as CST-101;

[0987] Interferon alpha ligands, such as autologous tumor cell vaccine + systemic CpG-B + IFN-alpha (cancer);

[0988] K-Ras GTPases, such as anti-KRAS G12V mTCR cell therapy;

[0989] Neural cell adhesion molecule L1L1CAM (CD171), such as JCAR-023;

[0990] Latent membrane protein 1 / latent membrane protein 2, such as autologous dendritic cells transduced with Ad5f35-LMPd1-2;

[0991] MART-1 melanoma antigen modulators, such as MART-1F5TCR-engineered PBMCs;

[0992] Melanoma-associated antigen 10, such as MAGE-A10C796T MAGE-A10TCR;

[0993] Melanoma-associated antigen 3 / melanoma-associated antigen 6 (MAGE A3 / A6), such as KITE-718;

[0994] Mesothelin, such as CSG-MESO, TC-210;

[0995] Mucin 1 modulators, such as ICTCAR-052, Tn MUC-1CAR-T, ICTCAR-053;

[0996] Anti-MICA / MICB, such as CYAD-02;

[0997] NKG2D, such as NKR-2;

[0998] Ntrkr1 tyrosine kinase receptor, such as JCAR-024;

[0999] PRAMET cell receptors, such as BPX-701;

[1000] Prostate stem cell antigen modulators, such as MB-105;

[1001] Circumvallate homolog 1 modulators, such as ATCG-427;

[1002] Peptidoglycan recognition protein modulators, such as Tag-7 gene-modified autologous tumor cell vaccines;

[1003] PSMA, such as PSMA-CAR T-cell therapy (lentiviral vector, castration-resistant prostate cancer);

[1004] SLAM family member 7 modulators, such as IC9-Luc90-CD828Z;

[1005] TGFβ receptor modulators, such as DNR.NPC T cells;

[1006] T-lymphocytes, such as TT-12;

[1007] T-lymphocyte stimulators, such as ATL-001;

[1008] TSH receptor modulators, such as ICTCAR-051;

[1009] Tumor-infiltrating lymphocytes, such as LN-144 and LN-145;

[1010] Wilms tumor proteins, such as JTCR-016, WT1-CTL, ASP-7517.

[1011] Gene editing

[1012] In various embodiments, the compound as described herein is combined with a gene editor. Exemplary gene editing systems that can be co-administered include, but are not limited to, CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems (e.g., ARCUS), and homing meganuclease systems.

[1013] Other targets

[1014] In various embodiments, a compound as described herein is combined with human immunoglobulin (10% liquid preparation), Cuvitru (human immunoglobulin (20% solution)), leucovorin disodium, IMSA-101, BMS-986288, IMUNO BGC Moreau RJ, R-OKY-034F, GP-2250, AR-23, leucovorin calcium, porfimer sodium, RG6160, ABBV-155, CC-99282, polyphenprosan 20 with carmustine, Veregen, gadoxetate disodium, gadobutrol, gadoteric acid meglumine, gadoteridol, 99mTc-sitabimid, pomalidomide, pacibanil, valrubicin.

[1015] Exemplary Combination Therapies

[1016] Combination therapy for lymphoma or leukemia

[1017] Some chemotherapeutic agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, avoside, amifostine trihydrate, aminocamptothecin, antineoplastic A10, antineoplastic AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, β-alethine, BMS-345541 bortezomib ( PS-341), bryostatin 1, bulsulfan, campath-1H, carboplatin, carfilzomib 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 (17AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon α-2b, ixabepilone, lenalidomide ( CC-5013), pomalidomide 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 (PD03329 91), pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tansirolimus, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine bitartrate, SAHA (suberylamine hydroxamic acid or suberoyl, aniline and hydroxamic acid), vemurafenib Venetoclax (ABT-199).

[1018] 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 therapy include, but are not limited to, iodine-131 tositumomab Yttrium-90 Ibritumomab Tiuxetan and with CHOP.

[1019] 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.

[1020] Combination therapy for non-Hodgkin lymphoma

[1021] Treatment of non-Hodgkin lymphoma (NHL), especially those of B-cell origin, includes the use of monoclonal antibodies, standard chemotherapy methods (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.

[1022] 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.

[1023] Examples of experimental antibody agents for treating NHL / B cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumizumab, apolizumab, milatuzumab, and bevacizumab.

[1024] Examples of standard regimens for chemotherapy of NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R MCP.

[1025] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab

[1026] Combination therapy for mantle cell lymphoma

[1027] Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapy such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form 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.

[1028] 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.

[1029] An improved approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles (such as iodine-131 tositumomab) and Y-90 Ibritumomab In another example, For sequential treatment with CHOP.

[1030] Other approaches to treat MCL include autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib ( or PS-341) or administration of anti-angiogenic agents such as thalidomide, especially in combination with rituximab.

[1031] 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.

[1032] Another treatment method includes the administration of mTOR inhibitors which can lead to inhibition of cell growth or even cell death. Non-limiting examples are sirolimus, temsirolimus ( CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and or temsirolimus in combination with other chemotherapeutic agents.

[1033] 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 ( CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide ( CC-5013) and geldanamycin (17AAG).

[1034] Combination therapy for Waldenstrom's macroglobulinemia

[1035] 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 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 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 Simvastatin, sirolimus, tacrolimus, tansimab, 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.

[1036] 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.

[1037] Combination therapy for diffuse large B-cell lymphoma

[1038] 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 R ICE.

[1039] Combination therapy for chronic lymphocytic leukemia

[1040] Examples of 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.

[1041] Combination therapy for myelofibrosis

[1042] Myelofibrosis inhibitors include, but are not limited to, hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors are saridegib and vismodegib. Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat. Non-limiting examples of tyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib, radotinib, and cabozantinib.

[1043] Combination Therapy for Hyperproliferative Disorders

[1044] Gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel can be used with a JAK inhibitor and / or a PI3Kδ inhibitor to treat hyperproliferative disorders.

[1045] Combination therapy for bladder cancer

[1046] Therapeutic agents used to treat bladder cancer include atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, 5-fluorouracil (5-FU), gemcitabine, idosfamide, interferon alpha-2b, methotrexate, mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.

[1047] Combination therapy for breast cancer

[1048] Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, 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.

[1049] Combination therapy for triple-negative breast cancer

[1050] Therapeutic agents used to treat triple-negative breast cancer include cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

[1051] Combination therapy for colorectal cancer

[1052] Therapeutic agents used to treat colorectal cancer include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, aflibercept, and any combination thereof.

[1053] Combination therapy for castration-resistant prostate cancer

[1054] Therapeutic agents used to treat castration-resistant prostate cancer include abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, siprucel-T, and any combination thereof.

[1055] Combination therapy for esophageal and esophagogastric junction cancer

[1056] Therapeutic agents used to treat esophageal and esophagogastric junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[1057] Gastric cancer combination therapy

[1058] 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.

[1059] Combination therapy for head and neck cancer

[1060] 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.

[1061] Combination therapy for hepatobiliary carcinoma

[1062] Therapeutic agents used to treat hepatobiliary cancer include capecitabine, cisplatin, fluoropyrimidines, 5-fluorouridine, gemcitabine, oxaliplatin, sorafenib, and any combination thereof.

[1063] Combination therapy for hepatocellular carcinoma

[1064] Therapeutic agents used to treat hepatocellular carcinoma include capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof.

[1065] Combination therapy for non-small cell lung cancer

[1066] Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab biosimilars, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof.

[1067] Combination therapy for small cell lung cancer

[1068] Therapeutic agents used to treat small cell lung cancer (SCLC) include bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof.

[1069] ...

Claims

1. A compound selected from: or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition according to claim 3, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agent is an anti-tumor agent.

5. The pharmaceutical composition of claim 3, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agents are independently rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

6. The pharmaceutical composition according to claim 3, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agent is a PD-1 or PD-L1 inhibitor.

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