CD73 compound

Abstract

Provided herein are compounds of formula I: TIFF2024541979000070.tif44128 or a pharma- ceutically acceptable salt thereof, wherein the various substituents are as described herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 273,454, filed October 29, 2021, and entitled "CD73 Compounds," which is incorporated herein by reference in its entirety. [Background technology]

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

[0003] Extracellular Ado accumulates in cancer tissues and is an important mechanism for tumor immune evasion. 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 mouse Tregs (regulatory CD4+ T cells), has been shown to contribute to tumor immune suppression. CD73 can be found constitutively expressed at high levels on various types of cancer cells. It is hypothesized that adenosine generated by CD73 suppresses anti-tumor adaptive immune responses, thereby promoting tumor growth and metastasis. Furthermore, studies in animal models have shown that blocking CD73 activity suppresses tumor growth and prolongs survival by promoting anti-tumor adaptive immunity (Forte et al. (2012) J Immunol. 189(5):2226-33). Given the need for cancer treatment, novel compositions and methods for modulating CD73 activity and related therapeutics are needed. The present disclosure fulfills this and other needs. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Stagg J, Smyth MJ.Extracellular adenosine triphosphate and adenosine in cancer.Oncogene.2010;29:5346-58.doi:10.1038 / onc.2010.292 [Non-patent document 2] Forte et al. (2012) J Immunol.l89(5):2226-33 Summary of the Invention

[0005] In one embodiment, the present disclosure provides a compound of formula I:

[0006] [ka] or a pharmaceutically acceptable salt thereof, X is C or N; Y is CH or N; Z is C or N; provided that one of X, Y and Z is CH or C, and two of X, Y and Z are N; R1 is selected from H and CH2OP(O)(OH)2; R 2 But C 3~6 cycloalkyl or 3- to 8-membered heterocyclyl, and the cycloalkyl and heterocyclyl are each independently selected from one or more R 4 is replaced by R 3 is H or halo, R 4 are independently H, halo, and C 1~4 Alkyl, -OR 5 , C 6~10 aryl, or 4- to 10-membered heteroaryl; 1~4 Alkyl, C 6~10 The aryl or 4- to 10-membered heteroaryl may optionally be one or more R 6 is replaced by R 5 is C 15 Alkyl, C 1~5 Alkenyl, C 1~5 Alkynyl, C 1~5 Alkyl, C 1~5 Alkenyl, C 1~5 Alkynyl, C 6~10 The aryl or 4- to 10-membered heteroaryl may optionally be one or more R 6 and substituted by halo; R 6 is C 1~5 Alkyl, C 3~6 Cycloalkyl, C 1~5 Alkenyl, C 1~5 alkynyl, or 4-10 membered heteroaryl, C 1~5 Alkyl, C 3~6 Cycloalkyl, C 1~5 Alkenyl, or C 1~5 The alkynyl is optionally substituted with halo, and the 4-10 membered heteroaryl is optionally C 1~4 Alkyl or C 1~4 Substituted with haloalkyl.

[0007] In some embodiments, R 1 is H. In other embodiments, R 1is CH2OP(O)(OH)2.

[0008] In some embodiments, R 2 is one or more R 4 C replaced by 3~6 It is cycloalkyl.

[0009] In other embodiments, R 2 is one or more R 4 and 3- to 8-membered heterocyclyl substituted by: [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows the plasma concentration (nM) of compound Comparative Example B within 24 hours after administration of either Comparative Example B or Example 1. [Figure 2] 1 shows the plasma concentration (nM) of Comparative Example C within 24 hours after administration of either Comparative Example C or Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0011] I. Working Example Abbreviations. Certain abbreviations and acronyms are used in describing the experimental details. While most of these will be understood by those skilled in the art, Table 1 contains a list of some of these abbreviations and acronyms.

[0012] [Table 1-1]

[0013] General Step 1: Preparation of di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate.

[0014] [ka]

[0015] To a solution of 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (500 mg, 1.38 mmol, 1 equiv.) and triethylamine (0.67 mL, 4.83 mmol, 3.5 equiv.) in DMF (16 Ml) was added di-tert-butyl(chloromethyl)phosphate (1.07 g, 4.14 mmol, 3 equiv.). The reaction mixture was heated to 60° C. and stirred for 16 hours. Another aliquot of di-tert-butyl(chloromethyl)phosphate (1.07 g, 4.14 mmol, 3 equiv.) and triethylamine (0.67 mL, 4.83 mmol, 3.5 equiv.) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was then diluted with EtOAc / water and extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by silica chromatography (100% EtOAc) to give di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate.

[0016] Preparation of (5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate

[0017] [ka]

[0018] To a solution of di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate (671 mg, 1.15 mmol, 1 equiv.) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 15 min, then concentrated in vacuo and purified by HPLC (10-80% MeCN / water with TFA). LC-MS m / z: 473.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 11.79(s,1H),8.25(s,1H),8.08(d,J=1.2Hz,1H),7.59(d,J=1.2Hz,1H),6 .54(s,1H),5.53(d,J=10.7Hz,2H),4.41(s,2H),3.86(s,2H),1.21(s,6H). 19F NMR (376MHz, DMSO-d6) δ-115.33 (m, 2F). 31P NMR (162MHz, DMSO-d6) δ-2.24 (t, J=10.6Hz, 1P).

[0019] The following compound was prepared in a manner similar to (5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate using the modifications listed below.

[0020] Di-tert-butyl((2,4-dioxo-5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate was reacted with 5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate in a 5-chloro-1,2-dihydro-2-(2H-indazol-6-yl)cyclopropylmethyl group. Prepared using 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione; hydrochloride salt instead of 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.

[0021] [ka]

[0022] Instead of di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, di-tert-butyl ((2,4-dioxo-5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazole) 5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione was prepared using 5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.

[0023] [ka]

[0024] LC-MS m / z: 578.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 11.90(s,1H),8.33(s,1H),8.28(d,J=1.3Hz,1H),8.16(d,J=0.9Hz,1H),7.77-7.66(m,3H),7.49(s,1H),7.13(dd,J=8.6,1.2Hz,1H),5.56(d, 1H) 19F NMR (376MHz, DMSO-d6) δ-70.08 (t, J=9.1Hz, 3F). 31P NMR (162MHz, DMSO-d6) δ-2.22 (t, J=11.0Hz, 1P).

[0025] 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine instead of 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione Tetra-tert-butyl (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxopyrimidin-1,3(2H,4H)-diyl)bis(methylene)) bis(phosphate) was prepared using -2,4(1H,3H)-dione.

[0026] [ka]

[0027] Instead of di-tert-butyl((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, tetra-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl) (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxopyrimidin-1,3(2H,4H)-diyl)bis(methylene))bis(dihydrogen phosphate) was prepared using (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxopyrimidin-1,3(2H,4H)-diyl)bis(methylene))bis(dihydrogen phosphate).

[0028] [ka]

[0029] LC-MS m / z:706.1(M+1). 1H NMR(400MHz,DMSO-d6)δ 8.45(s,1H),8.15(d,J=0.8Hz,1H),7.73(d,J=8.2Hz,2H),7.60(d,J=7.1Hz, 1H),7.43(s,1H),7.13(dd,J=8.4,1.4Hz,1H),5.69(d,J=6.5Hz,2H),5.64(d, J=10.8Hz,2H),5.41(q,J=9.2Hz,2H),3.02(ddd,J=8.9,6.3,4.3Hz,1H),2.83 (ddd,J=8.8,5.9,4.3Hz,1H),2.21-2.09(m,1H),1.91(dt,J=8.7,5.5Hz,1H). 19F NMR(376MHz,DMSO-d6)δ-70.08(t,J=9.1Hz,3F),-155.02(d,J=7.2Hz,1F). 31P NMR (162MHz, DMSO-d6) δ-2.18(t,J=11.0Hz,1P),-3.44(t,J=6.5Hz,1P).

[0030] General Step 2: Preparation of di-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate

[0031] [ka]

[0032] To a solution of 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione; hydrochloride salt (100 mg, 0.192 mmol, 1 equiv.) in DMAc (1 mL) was added KHCO (48 mg, 0.479 mmol, 2.5 equiv.) and di-tert-butyl(chloromethyl)phosphate (59.5 mg, 0.23 mmol, 1.2 equiv.). The reaction mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was then diluted with EtOAc / water and extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by silica chromatography (100% EtOAc) to give di-tert-butyl ((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate.

[0033] Preparation of (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate

[0034] [ka]

[0035] To a solution of di-tert-butyl ((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate (90 mg, 0.127 mmol, 1 equiv.) in DCM (2.5 mL) was added TFA (0.25 mL). The reaction mixture was stirred at room temperature for 15 min, then concentrated in vacuo and purified by HPLC (10-80% MeCN / water with TFA). LC-MS m / z: 596.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 11.92(s,1H),8.36(s,1H),8.15(s,1H),7.78-7.68(m,2H),7.58(d,J= 7.0Hz,1H),7.49(s,1H),7.12(d,J=8.5Hz,1H),5.57(d,J=10.8Hz,2H), 5.40(q,J=9.1Hz,2H),3.04(ddd,J=9.3,6.3,4.4Hz,1H),2.79(dt,J=9.4,5.2Hz,1H),2.18(dt,J=8.8,5.2Hz,1H),1.90(dt,J=8.6,5.2Hz,1H). 19F NMR(376MHz,DMSO-d6)δ-70.08(t,J=9.2Hz,3F),-155.18(d,J=7.0Hz,1F).

[0036] The following compound was prepared in a manner similar to (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate using the modifications listed below.

[0037] Di-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate by 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate -indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione; prepared using 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione instead of the hydrochloride salt.

[0038] [ka]

[0039] Instead of di-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate was prepared using (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate.

[0040] [ka]

[0041] LC-MS m / z:597.1(M+1). 1H NMR(400MHz,DMSO-d6)δ 11.93(s,1H),8.36(s,1H),8.25(s,1H),8.20(d,J=8.3Hz,1H),7.58(d,J=7.1 Hz,1H),7.51(s,1H),7.38(d,J=8.3Hz,1H),5.57(d,J=10.8Hz,2H),5.34(tt,J =9.3,4.8Hz,2H),3.24(ddd,J=8.6,5.9,4.1Hz,2H),3.07(ddd,J=8.9,6.1,4. 0Hz,1H), 2.22(ddd,J=8.6,6.2,3.9Hz,1H),2.06(ddd,J=9.4,5.8,3.9Hz,1H). 19F NMR (376MHz, DMSO-d6) δ-69.89(t,J=9.1Hz,3F),-155.18(d,J=7.1Hz,1F). 31P NMR (162MHz, DMSO-d6) δ-2.18 (t, J=10.8Hz, 1P).

[0042] Di-tert-butyl((2,4-dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate and tetra-tert-butyl((2,4-dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-1,3(2H,4H)-diyl (I)bis(methylene))bis(phosphate) was prepared using 5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione; trifluoroacetic acid was used in place of 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione; hydrochloride salt.

[0043] [ka]

[0044] Instead of di-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, (2,4-Dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate was prepared using (2,4-dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate.

[0045] [ka]

[0046] LC-MS m / z: 578.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 11.91(s,1H),8.68(s,1H),8.21(d,J=2.3Hz,1H),8.17(s,1H),7.78(s,1H) ),7.75(d,J=8.4Hz,1H),7.68(s,1H),7.20(dd,J=8.4,1.3Hz,1H),6.70(d ,J=2.3Hz,1H),5.61(d,J=11.1Hz,2H),5.42(q,J=9.1Hz,2H),3.17(ddd,J =8.5,6.4,4.4Hz,1H),2.82(td,J=7.1,4.5Hz,1H),1.97(t,J=8.2Hz,2H). 19F NMR (376MHz, DMSO-d6) δ-70.06 (t, J=9.1Hz, 3F). 31P NMR (162MHz, DMSO-d6) δ-2.17 (t, J=11.1Hz, 1P).

[0047] Instead of di-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, tetra-tert-butyl((2,4-dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazole-6 (2,4-Dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-1,3(2H,4H)-diyl)bis(methylene))bis(dihydrogen phosphate) was prepared using (2,4-dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-1,3(2H,4H)-diyl)bis(methylene))bis(dihydrogen phosphate).

[0048] [ka]

[0049] LC-MS m / z: 688.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 8.77(s,1H),8.23(d,J=2.4Hz,1H),8.17(s,1H),7.79(s,1H),7.76(d,J=8 .3Hz,1H),7.63(s,1H),7.21(dd,J=8.4,1.3Hz,1H),6.73(d,J=2.4Hz,1H), 5.73(d,J=6.3Hz,2H),5.69(d,J=11.1Hz,2H),5.42(q,J=9.1Hz,2H),3.21 (td,J=7.4,4.5Hz,3H),2.83(td,J=7.8,4.5Hz,1H),2.00(t,J=7.6Hz,2H). 19F NMR (376MHz, DMSO-d6) δ-70.06 (t, J=9.1Hz, 3F). 31P NMR (162MHz, DMSO-d6) δ-2.15(t,J=11.1Hz),-3.45(t,J=6.5Hz).

[0050] II. Definition "Alkyl" refers to a straight- or branched-chain saturated monovalent hydrocarbon. For example, an alkyl group may contain 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 1~4Examples of alkyl groups include methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH(CH)CHCH), 2-methyl-2- Propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH 3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl ( Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0051] "Alkylene" refers to a straight-chain or branched saturated aliphatic radical, i.e., a divalent hydrocarbon radical, having the number of carbon atoms indicated and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n -, where 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. Alkylene groups can be substituted or unsubstituted.

[0052] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl includes, for example, C, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 Alkenyl groups can contain any number of carbons, such as C, C, and C6. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0053] "Alkynyl" refers to either a straight or branched chain hydrocarbon containing at least two carbon atoms and at least one triple bond. Alkynyl includes C, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 and C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

[0054] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. With respect to alkyl groups, alkoxy groups include C 1~6 Alkoxy groups can have any suitable number of carbon atoms, such as , ...

[0055] "Alkoxyalkyl" refers to an alkoxy group linked to an alkyl group which is linked to the remainder of the compound, such that the alkyl group is divalent. Alkoxyalkyls are those having 2 to 6 (C 2~6 alkoxyalkyl), 2 to 5 (C 2~5alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C 2~3 Alkoxy and alkyl are as defined above, where the alkyl is divalent and can include, but are not limited to, methoxymethyl (CHOCH-), methoxyethyl (CHOCHCH-), and the like.

[0056] "Alkoxy-alkoxy" refers to an alkoxy group linked to a second alkoxy group that is linked to the remainder of the compound. Alkoxy is as defined above and can include, but is not limited to, methoxy-methoxy (CH3OCH2O-), methoxy-ethoxy (CHOCH2CHO-), and the like.

[0057] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (I).

[0058] As used herein, "haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by halo substituents, which may be the same or different. For example, C 1~4 Haloalkyl is C 1~4 alkyl, 1~4 wherein one or more of the alkyl hydrogen atoms are replaced by halo substituents. 1~4 Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0059] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. 1~6The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, or more. The alkoxy group may be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is persubstituted, e.g., perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0060] "Cycloalkyl" refers to a group of 3 to 20 cyclic carbon atoms (i.e., C 3~20 Cycloalkyl) refers to a saturated or partially unsaturated all-carbon monocyclic ring, e.g., having 3 to 12 ring atoms, e.g., 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms. The term "cycloalkyl" also encompasses saturated and partially unsaturated all-carbon multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocycles, e.g., bicyclic carbocycles (e.g., bicyclic carbocycles having 6 to 12 ring carbon atoms, e.g., bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having up to 20 ring carbon atoms). The rings of multiple condensed ring systems may be connected to each other by fused, spiro, and bridged bonds, where permitted by valency requirements. Non-limiting examples of monocyclic cycloalkyls 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.

[0061] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where 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 at least divalent alkylene in order to connect the cycloalkyl component and the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can be any of 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 moiety is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0062] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or multiple ring system having at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur) in the ring, where the multiple ring system includes at least a non-aromatic ring containing at least one heteroatom. The multiple ring system may also include other aromatic and non-aromatic rings. Unless otherwise specified, a heterocyclyl group has 3 to 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term encompasses saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having 1 to 6 ring carbon atoms and 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroatoms are optionally oxidized to -N(-OH)-, ═N(-O)-, etc. -)-, -S(=O)-, or -S(=O)2-. The rings of multiple condensed ring (e.g., bicyclic heterocyclyl) systems may be connected to each other by fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thiazolinone ... -6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, pyrazolidin-3-one, piperazin-2-one, oxazolidin-2-one, and the like.

[0063] Heterocycloalkyl rings also include 9- to 15-membered fused heterocycloalkyls having two, three, or more rings, where 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]dioxine, dihydrobenzo[d]oxazole, dihydrobenzo[d]oxazole, dihydrobenzo[b ... benzo[d][1,3]dioxole, benzo[b][1,4]thiazole, dihydrobenzo[b]thiophene, dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenzo[c]isothiazole, spiro[cyclobutane-1,3'-indolin]-2'-one, spiro[cyclopropane-1,3'-indolin]-2'-one, 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole, benzo[d][1,3]dioxole, and benzo[b][1,4]thiazine.

[0064] [ka]

[0065] A fused bicyclic heterocycloalkyl has the following structure:

[0066] [ka] wherein X 1 , X 2 , X 3 , and X 4 are each independently absent, —CH—, —NH—, —O—, or —S—; X 1 , X 2 , X 3 , and X 4At least one of is -NH-, -O-, or -S-, and the dashed circle represents a saturated or partially unsaturated non-aromatic ring. A fused bicyclic heterocycloalkyl is optionally substituted.

[0067] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where 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 at least a divalent alkylene in order to connect the heterocycloalkyl component and the point of attachment. The alkyl component is selected from the group consisting of 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 The alkyl-heterocycloalkyl group may contain any number of carbons, such as . In some cases, the alkyl component may be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may be substituted or unsubstituted.

[0068] As used herein, "aryl" refers to an all-carbon aromatic monocyclic ring or an all-carbon multiple condensed ring system in which at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having 9 to 20 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbocyclic). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the multiple condensed ring system. The rings of the multiple condensed ring system may be connected to each other by fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. When an aryl having a particular range of atom members (e.g., a 6- to 10-membered aryl) is referred to, it is also understood that the atom range is for the total ring atoms of the aryl. For example, 6-membered aryl includes phenyl, and 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0069] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the aryl component and the point of attachment. The alkyl component is selected from the group consisting of C 0~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C4~5 , C 4~6 , and C 5~6 The alkyl group may contain any number of carbon atoms, such as , ...

[0070] As used herein, "heteroaryl" refers to a monocyclic aromatic ring having at least one atom other than carbon in the ring, where that atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also encompasses multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" encompasses a monocyclic aromatic ring of 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may be present in oxidized form, provided the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also encompasses multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group as defined above is fused with one or more rings selected from heteroaryl (e.g., to form 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a multiple condensed ring system. Thus, a heteroaryl (aromatic monocyclic or multiple condensed ring system) has 1 to 20 carbon atoms and 1 to 6 heteroatoms in the heteroaryl ring. Such fused polycyclic ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of a multiple condensed ring system may be connected to each other through fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. It is understood that the individual rings of a multiple condensed ring system may be connected to each other in any order. It is understood that the point of attachment of a heteroaryl or heteroaryl to a multiple condensed ring system may be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). When a heteroaryl having a particular range of atom member numbers (e.g., a 5- to 10-membered heteroaryl) is referred to, it is also understood that the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms.For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, pyridin-2(1H)-one, isoquinolin-1(2H)-one, and triazolyl.

[0071] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where 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 at least divalent alkylene in order to connect the heteroaryl component and the point of attachment. The alkyl component is selected from the group consisting of 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 be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0072] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining 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.

[0073] "Pharmaceutically effective amount" refers to the amount of a compound of the present disclosure in a formulation or combination thereof that produces the desired therapeutic or pharmaceutical result.

[0074] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0075] As used herein, "treatment" or "treating" or "treating" refers to an approach for obtaining a beneficial or desired result. For purposes of this disclosure, a beneficial or desired result includes, but is not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition); b) delaying the onset of or inhibiting one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, slowing the worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, ameliorating the pathology, slowing disease progression, improving quality of life, and / or prolonging survival.

[0076] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount that, when administered to a subject to treat a disease, is effective to elicit a desired biological or medical response, including an amount of compound sufficient to achieve such treatment of the disease. An effective amount may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. An 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 a desired therapeutic endpoint. An effective amount may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when a desired or beneficial result can be or is achieved in combination with one or more other agents. The suitable dose of any co-administered compound may, in some cases, be reduced due to the combined effects (e.g., additive or synergistic effects) of the compounds.

[0077] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, or subcutaneous administration, intrathecal administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, to a subject. Administration can be carried out according to a schedule that dictates the frequency of administration, the dosage administered, and other factors.

[0078] As used herein, "co-administration" refers to administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, e.g., administration of a compound disclosed herein within seconds, minutes, or hours of administration of the one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0079] "Subject" refers to animals such as mammals, 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.

[0080] "Disease" or "condition" refers to the physical state or health of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In embodiments, the disease is cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma). The disease can be an autoimmune disease, an inflammatory disease, a cancer disease, an infectious disease, a metabolic disease, a developmental disorder, a cardiovascular disease, a liver disease, an intestinal disease, an endocrine disease, a nervous system disease, or other disease.

[0081] "Cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma, and sarcoma.Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain 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 resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), Examples of cancers that may be present include ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung cancer, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophageal), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, and multiple myeloma.

[0082] Additional examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, or uterus, or cancer of the medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant leukemia, and malignant leukemia. thyroid cancer, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, carcinoma of the pancreatic stellate cells, carcinoma of hepatic stellate cells, or prostate cancer.

[0083] "Leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on: (1) the duration and character of the disease: acute or chronic; (2) the type of cells involved: bone marrow (myeloid), lymphocytes (lymphoid), or monocytic; and (3) whether or not there is an increase in the number of abnormal cells in the blood: leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, and leukocytic leukemia. leukemia), basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hematoblastic leukemia, hematoblast Cytic cell leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia leukemia), lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0084] "Sarcoma" generally refers to a tumor composed of a substance like embryonic connective tissue and generally composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid rhabdomyosarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, and idiopathic multiple pigmented hemorrhagic sarcoma. sarcoma), immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0085] "Melanoma" is understood to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0086] "Carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenoid carcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, comedocarcinoma, uterine carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, scirrhous carcinoma durum, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, glandular epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, childhood embryonal carcinoma, carcinoma in situ, carcinoma in situ in epidermis, carcinoma in situ, Krompecher carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucocytic carcinoma, mucoepidermoid carcinoma, mucinous carcinoma mucosum, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, cord-like carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or choriocarcinoma.

[0087] The terms "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 to another, non-adjacent organ or body part. Cancer begins at a site of origin, e.g., the breast, and that site is called a primary tumor, e.g., primary breast cancer. Some cancer cells within the primary tumor or site of origin acquire the ability to invade and infiltrate surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular system and spread through that system to other sites and tissues in the body. A second, clinically detectable tumor formed from cancer cells of the primary tumor is called a metastatic tumor or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor in the breast site will consist of abnormal lung cells, not abnormal breast cells. A secondary tumor in the breast is called metastatic lung cancer. Therefore, the term metastatic cancer refers to a disease in which a subject has or has previously had a primary tumor and has one or more secondary tumors.The term non-metastatic cancer or a subject with non-metastatic cancer refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors.For example, metastatic lung cancer refers to a disease in a subject who has or has a history of a primary lung tumor and has one or more secondary tumors at a second site or multiple sites, for example, in the breast.

[0088] In the context of a substance or the activity or function of a substance related to a disease (e.g., diabetes, cancer (e.g., prostate cancer, kidney cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma)), "related to" or "related to" means that the substance or the activity or function of the substance causes (in whole or in part) 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) or causes (in whole or in part) a symptom of the disease.

[0089] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0090] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne, hexyne-1,4-diol, hexyne-2 ... 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0091] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. +(X is C1-C4 alkyl). Base addition salts such as sodium or potassium salts are also included.

[0092] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may have enhanced resistance to metabolism and may therefore be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0093] Examples of isotopes that can be incorporated into the disclosed compounds 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 can also be mentioned. 11 C. 18 F, 15 O, and 13Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (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 processes analogous to those described in the Examples below, using appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0094] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as 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 the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0095] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0096] "Stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric forms if they have one or more asymmetric centers or double bonds with asymmetric substitution and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0097] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to both the -NH- and =N- rings, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0098] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes before or after chemical groups are for convenience; chemical groups may be designated with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn across lines in structures indicate points of attachment of groups. Dashed lines indicate optional bonds. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or their point of attachment to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and both can be linked in either direction. Similarly, for example, an "arylalkyl" group may be attached to the rest of the molecule at either the aryl or alkyl portion of the group. "C u-v " or (C u -C v) indicates that the following group has u to v carbon atoms. For example, "C 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has from 1 to 6 carbon atoms.

[0099] As used herein, "solvate" refers to the result of the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0100] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug through some chemical or enzymatic pathway.

[0101] III.Compound Pharmaceutical preparations In some embodiments, the present disclosure provides a pharmaceutical formulation 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 formulation comprising a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0102] In some embodiments, the pharmaceutical composition is for use in treating cancer.

[0103] 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) or a pharmaceutically acceptable salt thereof, such as the agents and therapies described herein.

[0104] In some embodiments, a pharmaceutical composition comprises a compound of Formula (I) and an additional therapeutic agent, wherein the additional therapeutic agent is an anti-cancer agent. In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent is independently an anti-tumor agent, chemotherapy, radiation therapy, or ablation therapy. In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent is independently Rituxan, doxorubicin, gemcitabine, 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.

[0105] 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).

[0106] In some embodiments, the pharmaceutical composition is one in which the additional therapeutic agent comprises one or more chimeric antigen receptors (CARs).

[0107] In some embodiments, the pharmaceutical composition is one 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, the immunotherapy comprises co-administration of one or more antibodies or antigen-binding antibody fragments thereof or antibody-drug conjugates thereof, CD3-targeted multispecific molecules, CD16-targeted multispecific molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins directed against one or more targets or tumor-associated antigens (TAA).

[0108] In some embodiments, the compounds disclosed herein are formulated with conventional carriers and excipients, which may be selected according to ordinary practice. Tablets may contain excipients, glidants, fillers, binders, etc. Aqueous formulations may be prepared in sterile form and may be isotonic, for example, if intended for delivery by a route other than oral administration. In some embodiments, formulations 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, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. The pH of the formulation ranges from about 3 to about 11, e.g., from about 7 to about 10.

[0109] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered in a pharmaceutical formulation. In some embodiments, formulations for veterinary and / or human use comprise at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, together with one or more acceptable carriers and optionally other therapeutic ingredients, such as additional therapeutic ingredients discussed herein. In some embodiments, the carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0110] In some embodiments, formulations of the present disclosure include those suitable for the aforementioned routes of administration. In some embodiments, the formulations are provided in unit dosage form. The formulations may be prepared by methods known in the art of pharmacy. Techniques and formulations may be found, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include, for example, the step of bringing into association the active ingredient with the carrier(s) which may include one or more accessory ingredients. In some embodiments, the formulations are prepared by bringing into association the active ingredient(s) with liquid carriers or finely divided solid carriers, or both, and then, in some embodiments, shaping the product.

[0111] Formulations suitable for oral administration may be presented as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, e.g., a compound of Formula (I) 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 or water-in-oil liquid emulsion. In some embodiments, the active ingredient is administered as a bolus, electuary, or paste.

[0112] Tablets can be made, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent, in a suitable machine. Molded tablets can be produced, for example, by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored. In some embodiments, tablets are formulated to provide sustained or controlled release of the active ingredient therefrom.

[0113] For infections of the eye or other external tissues, e.g., mouth and skin, a compound of formula (I) can be formulated as a topical ointment or cream containing, for example, about 0.075 to about 20% w / w (in increments of about 0.1% w / w, ranging from about 0.1% to about 20%, e.g., about 0.6% w / w, about 0.7% w / w, etc., of the active ingredient(s)), e.g., about 0.2 to about 15% w / w, and e.g., about 0.5 to about 10% w / w. When formulated as an ointment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used with either a paraffinic or water-miscible ointment base. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated into a cream using an oil-in-water cream base.

[0114] Optionally, the aqueous phase of the cream base may contain, for example, at least about 30% w / w of a polyhydric alcohol, 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 PEG 400), and mixtures thereof. In some embodiments, the topical formulation may include a compound that enhances 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 analogues.

[0115] The oily phase of the emulsion can be composed of known ingredients in a known manner. The phase can contain only an emulsifier (also known as an emulsifier (emulgent)), but can also contain, for example, a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that functions as a stabilizer. In some embodiments, the emulsion contains both an oil and a fat. Together, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, which, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of a cream formulation.

[0116] Suitable emulsifiers and emulsion stabilizers for use in the formulation include, for example, Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0117] The selection of suitable oils or fats for the formulation is based on achieving the desired properties. The cream can be a non-greasy, non-staining, and washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, can be used. These can be used alone or in combination depending on the required properties. Alternatively, high-melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0118] In some embodiments, the pharmaceutical formulations herein comprise one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents in combination. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; 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.

[0119] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0120] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with 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 or n-propyl p-hydroxybenzoates, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0121] Oil suspensions can be prepared by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin.Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0122] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing 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.

[0123] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may 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 acacia and gum tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, flavorings, or coloring agents.

[0124] The pharmaceutical compositions may be in the form of a sterile injectable or intravenous preparation, for example, a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable or intravenous preparations may also include sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or may be prepared as lyophilized powders. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, bland fixed oils, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0125] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form may vary depending on the subject being treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain from about 1 to about 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to about 500 μg of active ingredient per milliliter of solution, such that infusion of a suitable volume at a rate of about 30 mL / hour can occur.

[0126] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient may be present in such formulations in a concentration of about 0.5 to about 20%, e.g., about 0.5 to about 10%, e.g., about 1.5% w / w.

[0127] Formulations suitable for topical administration in the mouth include, for example, lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0128] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0129] Formulations suitable for pulmonary or nasal administration have particle sizes ranging from about 0.1 to about 500 micrometers, e.g., about 0.5, about 1, about 30, or about 35 micrometers, and are administered by rapid inhalation through the nasal passages or by inhalation through the oral cavity to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents, such as compounds previously used to treat cancer, as described below.

[0130] Another embodiment provides an inhalable composition comprising a compound of Formula (I) 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, such salts may be less likely to cause pulmonary inflammation compared to other salts. In some embodiments, the inhalable composition is delivered to the endobronchial space in an aerosol comprising particles having a mass median aerodynamic diameter (MMAD) of about 1 to about 5 μm. In some embodiments, the compound of Formula (I) 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).

[0131] Non-limiting examples of nebulizers include atomizers, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers, including nebulizers that utilize adaptive aerosol delivery technologies (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10). Jet nebulizers utilize air pressure to break up liquid solutions into aerosol droplets. Ultrasonic nebulizers work by using piezoelectric crystals to shear liquids into small aerosol droplets. Pressurized nebulizer systems create aerosol droplets by applying pressure to force a solution through small pores. Vibrating porous plate devices use rapid vibrations to shear a liquid stream into the appropriate droplet size.

[0132] In another embodiment, the nebulized formulation is delivered to the endobronchial space in an aerosol containing primarily particles having an MMAD of about 1 μm to about 5 μm using a nebulizer capable of aerosolizing a formulation of the compound of Formula (I) or a pharmaceutically acceptable salt thereof into particles of the required MMAD. To optimize therapeutic efficacy and avoid upper respiratory tract and systemic side effects, the majority of aerosolized particles should not have an MMAD greater than about 5 μm. If the aerosol contains a large number of particles with an MMAD greater than about 5 μm, the particles will be deposited in the upper respiratory tract, reducing the amount of drug delivered to sites of inflammation and bronchial narrowing in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 μm, the particles may remain suspended in the inhaled air and may then be exhaled.

[0133] When formulated and delivered by the methods herein, the aerosol formulation for nebulization delivers a therapeutically effective dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a therapeutic target, e.g., a cancer site. The amount of drug administered can be adjusted to reflect the efficiency of delivery of a therapeutically effective dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the combination of an aqueous aerosol formulation with a spray, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer allows delivery of about 20 to about 90%, e.g., 70%, of an administered dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the respiratory tract, depending on the nebulizer. 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 may be delivered.

[0134] In another embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is delivered as a dry inhalable powder. The compound is administered intrabronchially as a dry powder formulation using a dry powder inhaler or metered-dose inhaler to effectively deliver fine particles of the compound to the endobronchial space. For delivery via a DPI, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is processed by milling, spray drying, critical fluid processing, or precipitation from solution to produce particles primarily having an MMAD of about 1 μm to about 5 μm. Media milling, jet milling, and spray drying devices and procedures capable of producing particle sizes in the MMAD range of about 1 μm to about 5 μm are well known in the art. In one embodiment, an excipient is added to the compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to processing into particles of the required size. In another embodiment, an excipient is mixed with the particles of the required size to facilitate dispersion of the drug particles, for example, by using lactose as an excipient.

[0135] Particle size determination is performed using devices well known in the art, such as a multistage Anderson cascade impactor or other suitable methods, such as those specifically cited in U.S. Pharmacopeia Chapter 601 as characterization devices for aerosols in metered dose inhalers and dry powder inhalers.

[0136] In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt 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 U.S. Patent No. 5,458,135, U.S. Patent No. 5,740,794, U.S. Patent No. 5,775,320, U.S. Patent No. 5,785,049, U.S. Patent No. 3,906,950, U.S. Patent No. 4,013,075, U.S. Patent No. 4,069,819, U.S. Patent No. 4,995,385, U.S. Patent No. 5,522,385, U.S. Patent No. 4,668,218, U.S. Patent No. 4,667,668, U.S. Patent No. 4,805,811 and U.S. Patent No. 5,388,572.There are two main designs of dry powder inhalers. One design is a metered device, in which a reservoir for the drug is placed within the device and the patient adds a dose of drug to the inhalation chamber. The second design is a factory-metered device, in which each individual dose is manufactured in a separate container. Both systems rely on the formulation of the drug into small particles of approximately 1 μm to approximately 5 μm MMAD, often requiring co-formulation with larger excipient particles, such as, but not limited to, lactose. The drug powder is placed in the inhalation chamber (either by metering into the device or by dividing a factory-metered dose), and the patient's inspiratory airflow accelerates the powder as it exits the device and enters the oral cavity. The non-laminar flow characteristics of the powder path break up excipient-drug agglomerates, allowing clumps of large excipient particles to stick to the back of the throat, while smaller drug particles are deposited deep in the lungs. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is delivered as a dry powder using any type of dry powder inhaler described herein, wherein the MMAD of the dry powder, excluding any excipients, is primarily in the range of 1 μm to about 5 μm.

[0137] In other embodiments, the compound of Formula (I) 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 U.S. Patent Nos. 5,261,538, 5,544,647, 5,622,163, 4,955,371, 3,565,070, 3,361,306, and 6,116,234. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a metered dose inhaler, and the MMAD of the dry powder, excluding any excipients, is primarily in the range of about 1 to about 5 μm.

[0138] 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.

[0139] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which 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.

[0140] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Unit-dose formulations include those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0141] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents standard in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0142] There is further provided a veterinary composition comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

[0143] A veterinary carrier may be a solid, liquid, or gaseous substance that is useful for the purpose of administering the composition and is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0144] The compounds herein are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more of the compounds as active ingredients, wherein 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.

[0145] 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. This 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, and most typically about 0.05 to about 0.5 mg / kg body weight per day. For example, the candidate daily dose for an adult human weighing about 70 kg can range from about 1 mg to about 1000 mg, e.g., about 5 mg to about 500 mg, and can take the form of a single dose or multiple doses.

[0146] Some embodiments provide methods for manufacturing a medicament for treating cancer in a subject in need thereof. In some embodiments, the method for manufacturing a medicament for treating cancer comprises using a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide methods for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof. In some embodiments, the method for manufacturing a medicament for inhibiting cancer metastasis comprises using a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the disclosure provides for the use of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment of cancer in a subject in need thereof. In some embodiments, the disclosure provides for the use of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, in the inhibition of cancer metastasis in a subject in need thereof. In some embodiments, the disclosure provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0148] IV. Route of Administration The compounds of formula (I), or one or more of its pharmaceutically acceptable salts (referred to herein as the active ingredient), 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). It will be understood that the route may vary depending, for example, on the condition of the recipient. In some embodiments, the compounds disclosed herein can and will be orally administered.

[0149] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to 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). It will be understood that the route may vary depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0150] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for a desired period of time or duration, for example, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, hi some embodiments, the compounds are administered on a daily or intermittent schedule for the duration of the individual's life.

[0151] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0152] The compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0153] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compound can include about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example, about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or for example, about 0.3 mg to about 30 mg per day, or for example, about 30 mg to about 300 mg per day.

[0154] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., from about 1 mg to about 1000 mg of compound). Therapeutically effective amounts can include from about 1 mg per dose to about 1000 mg per dose, e.g., from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg per dose, or about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 mg per dose. Dose can be administered hourly, daily, or weekly. For example, a dose may be administered about once every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or about once every 24 hours. A dose may also be administered about once every 1, 2, 3, 4, 5, or 6 days, or about once every 7 days. A dose may also be administered about once every 1, 2, 3, or 4 weeks, or about once every 4 weeks. In some embodiments, a dose may be administered about once every week. A dose may also be administered about once every month.

[0155] Other therapeutically effective amounts of the compounds of the present disclosure are about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 mg per dose.

[0156] The frequency of administration of the compounds of the present disclosure can be determined by the needs of an individual patient, and can be, for example, once a day, twice a day, or more frequently. Administration of the compound continues as long as necessary to treat the disease or condition. For example, the compound can be administered to a human with cancer for a period of about 20 to about 180 days, or for example, for a period of about 20 to about 90 days, or for example, for a period of about 30 to about 60 days.

[0157] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure for a period of several days or more, followed by a period of several days or more during 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 per week. As a further example, the patient can be administered a dose of the compound daily for a period of about 1 to about 14 days, followed by a period of about 7 to about 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., about 1 to about 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of compound administration followed by non-administration of the compound can be repeated as clinically needed to treat the patient.

[0158] In one embodiment, a pharmaceutical composition is provided comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents, and a pharmaceutically acceptable excipient.

[0159] In one embodiment, a kit is provided that includes a compound of the disclosure or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents.

[0160] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents.

[0161] In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or as a sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0162] In some embodiments, compounds of the present disclosure are combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, for example, as a solid dosage form for oral administration.

[0163] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0164] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the compound depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0165] V. Combination Therapy The compounds of Formula I, pharmaceutically acceptable salts thereof, and / or compositions provided herein can further be used in combination with other active therapeutic agents for the treatment of cancer.

[0166] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more (e.g., 1, 2, 3, or 4) additional therapeutic agents. In some embodiments, the additional therapeutic agent is, for example, an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist, or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferative agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen binding molecule (e.g., monospecific and multispecific antibodies in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimic (e.g., adnectin, affibody molecule, affilin, affimer, afftin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein, protein, DARPin®), finomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifying or editing agents, cells comprising a chimeric antigen receptor (CAR), engineered T cell receptors (TCR-T), including, for example, T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics, or any combination thereof.

[0167] Exemplary Targets In some embodiments, the one or more additional therapeutic agents include, for example, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator, or suppressor of a target (e.g., a polypeptide or polynucleotide), such as: 2'-5'-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5'-nucleotidase ecto (NT5E, CD73; NCBI Gene ID: 4907); ABL gene Oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); Absent-in-melanoma 2 (AIM2; NCBI Gene ID: 9447); Acetyl-CoA acyltransferase 2 (ACAA2; NCBI Gene ID: 10499); Acid phosphatase 3 (ACP3; NCBI Gene ID: 55); Adenosine deaminase (ADA, ADA1; NCBI Gene ID: 100); Adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA 2B (A2b, A2BR), ADORA3 (A3); NCBI Gene ID: 134, 135, 136, 137); AKT serine / threonine kinase 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase, membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha-fetoprotein (AFP; NCBI Gene ID: 174); amine oxidase copper-containing (e.g., AOC1 (DAO1), AOC2, AOC 3 (VAP1); NCBI Gene ID: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietin (ANGPT1, ANGPT2; NCBI Gene ID: 284, 285); angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); apoptosis-inducing factor mitochondrial-associated 1 (AIFM1, AIF; NCBI Gene ID: 9131);Arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); asteraid homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI Gene ID: 472); ATP-binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI Gene ID: 5243); ATP-dependent Clp-protease (CLPP; NCBI Gene ID: 8192); ATR serine / threonine kinase (ATR; NCBI Gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI Gene ID: 558); B and T lymphocyte-associated (BTLA, CD272; NCBI Gene ID: 151888); baculovirus IAP repeat-containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene IDs: 329, 330, 331, 332); basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 68 2); B-cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2-binding protein 3 (BBC3, PUMA; NCBI Gene ID: 27113); Bcl2-like (e.g., Bcl2L1 (Bcl-x), Bcl2L2 (BIM); Bcl-x; NCBI Gene ID: 598, 10018); beta 3-adrenergic receptor (ADRB3; NCBI Gene ID: 155); bone gamma-carboxyglutamic acid protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein-10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI Gene IDs: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain and ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695);Cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004); cancer / testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363); carbonic anhydrases (CA1, CA2, CA3, CA4, CA5A, CA5 B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI Gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677); carcinoembryonic antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI Gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK 2); NCBI Gene ID: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene ID: 836, 840, 841, 864); catenin β1 (CTNNB1; NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); CC motif chemokine ligand 21 (CCL21; NCBI Gene ID: 6366); CC motif chemokine receptor 2 (CCR2; NCBI Gene ID: 72923 0); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI Gene ID: 1232, 1233, 1234, 1237); CCAAT enhancer-binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NCBI Gene ID: 8317); cell communication network factor 2 (CCN2; NCBI Gene ID: 1490);Cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatomammotropic hormone 1 (CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI Gene IDs: 9074, 51208); markers of cluster of differentiation - (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD3 beta (TRB), CD3 gamma (TRG), CD3 delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 ( BLAST1), CD52, CD55(DAF), CD58(LFA3), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CS F1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 (IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), CD194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2) R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902 , 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI Gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI Gene IDs: 2155, 2159); collagen type IV alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI Gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily members colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI Gene IDs: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI Gene IDs: 718, 727); COP9 signalosome subunit 5 (COPS5; NCBI Gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD3 71); CD371, NCBI Gene ID: 160364, 170482, 283420; C-X-C motif chemokine ligand 12 (CXCL12; NCBI Gene ID: 6387); C-X-C motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI Gene ID: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI Gene ID: 595);Cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI Gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (CCNG1; NCBI Gene ID: 900); cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidations; reductase (POR; NCBI Gene ID: 5447); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD-box helicases (e.g., DDX5, DDX6, DDX58; NCBI Gene IDs: 1655, 1656, 23586); delta-like canonical Notch ligands (e.g., DLL3, DLL4; NCBI Gene IDs: 10683, 54567); diabetic IAP-binding mitochondrial proteins (Diablo, SMAC; NCBI Gene ID: 56616); diacylglycerol kinase (e.g., DGKA, DGKZ; NCBI Gene ID: 1606, 8525); Dickkopf WNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI Gene ID: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); dis Koidin domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167, NCBI Gene ID: 780, 4921); DNA-dependent protein kinase (PRKDC; NCBI Gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI Gene ID: 7150, 7153, 7155, 7156, 8940); dopachrome tautomer (DCT; NCBI Gene ID: 1638); dopamine receptor D2 (DRD2; NCBI Gene ID: 1318) ; DOT1-like histone lysine methyltransferase (DOT1L; NCBI Gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI Gene ID: 5169); EMAP-like 4 (EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene IDs: 51752, 64167); enhancer of zeste2 polycomb repressive complex 2 subunit (EZH2;NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI Gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), E RBB3 (HER3), ERBB4 (HER4); NCBI Gene ID: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI Gene ID: 4072); epidermal mitogen (EPGN; NCBI Gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI Gene ID: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI Gene ID: 1973, 1984); exopolitin-1 (XPO1; NCBI Gene ID: 7514); renal cell endothelial cell line (NR1H4, FXR; NCBI Gene ID: 9971); Fa ligand (FASLG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragment of Ig receptor (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene IDs: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI Gene ID: 2209); Gene ID: 83416); fibroblast activation protein alpha (FAP; NCBI Gene ID: 2191); fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI Gene IDs: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI Gene IDs: 2246, 2247, 2249, 2250); fibronectin 1 (FN1, MSF;NCBI Gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI Gene ID: 2321, 2322, 2324); fms-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI Gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI Gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2 348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); furin (furin, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI Gene ID: 2534); galectins (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene IDs: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glucuronidase glutaminase (GLS; NCBI Gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 2950); glycogen synthase kinase 3 beta (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI Gene ID: 2796); gonadotropin-releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein NMB (GPNMB, osteoactivin; NCBI Gene ID: 10457); growth differentiation factor 2 (GDF2, BMP9; NCBI Gene ID: 2658); growth factor receptor-bound protein 2 (GRB2, ASH; NCBI Gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL; NCBI Gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI Gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK;NCBI Gene ID: 3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI Gene IDs: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene IDs: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatic growth factor (HGF; NCBI Gene ID: 3082); HERV-H LTR-associated 2 (HHLA2, B7-H7; NCBI Gene ID: 11148); histamine receptor H2 (HRH2; NCBI Gene ID: 3274); histone deacetylases (e.g., HDAC1, HDAC7, HDAC9; NCBI Gene IDs: 3065, 9734, 51564); HRas proto-oncogene, GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI Gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI Gene IDs: 3551, 3553); IKAROS family zinc finger (IKZF1 (LYF1), IKZF3; NCBI Gene IDs: 10320, 22806); immune Indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2, NCBI Gene IDs: 3620, 169355); inducible T cell costimulatory molecule (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulatory molecule ligand (ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2R; NCBI Gene IDs: 3480, 3482); insulin-like growth factor (e.g., IGF1, IGF2; NCBI Gene IDs: 3479, 3481); insulin receptor (INSR, CD220; NCBI Gene ID: 3643);Integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene ID: 3678, 3685, 3688, 3695, 3698); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene ID: 3383); interleukin-1 receptor-associated kinase 4 (IRAK4; NCBI Gene ID: 51135); interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122) ), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI Gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6 (HGF), IL7, IL8 (CXCL8), IL10 (TGIF), IL12A, IL12B, IL15, IL17A (CTLA8), IL18, IL23A, IL24, IL-29 (IFNL1); NCBI Gene IDs: 3552, 3553 , 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618); isocitrate dehydrogenase (NADP()1) (e.g., IDH1, IDH2; NCBI Gene ID: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI Gene ID: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI Gene ID: 354); killer cell immunoglobulin-like receptor, Ig domain and long cytoplasmic tails (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI Gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285);Killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene ID: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KiSS1; NCBI Gene ID: 3814); KIT proto-oncogene, receptor tyrosine kinase (KIT, c-KIT, CD117; NCBI Gene ID: 3815); KRAS proto-oncogene, GTPase (KRAS; NCBI Gene ID: 3845); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene, Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 40 35); leucine-rich repeat-containing 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NCBI Gene ID: 14040) NCBI Gene ID: 3973); LY6 / PLAUR domain containing 3 (LYPD3; NCBI Gene ID: 27076); lymphocyte activation 3 (LAG3; CD223, NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene ID: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytosolic protein 2 (LCP2; NCBI Gene ID: 3937); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase-like 2 (LOXL2; NCBI Gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 1 receptor (MST1R, CD136; NCBI Gene ID: 4486);MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI Gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); major histocompatibility complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene IDs: 3105, 313 3, 3134, 3135); major vault protein (MVP, VAULT1; NCBI Gene ID: 9961); MALT1 paracaspase (MALT1; NCBI Gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene ID: 2872, 8569); matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP1 1, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI Gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCBI NCBI Gene ID: 4170); MDM2 oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI Gene ID: 2475); melan-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene IDs: 4157, 4148); MER proto-oncogene, tyrosine kinase (MERTK; NCBI Gene ID: 10461); mesothelin (MSLN;NCBI Gene ID: 10232); MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI Gene ID: 4233); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI Gene ID: 10988); MHC class I polypeptide-related sequence (e.g., MICA, MICB; NCBI Gene IDs: 4277, 100507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI Gene IDs: 5594, 5595 , 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI Gene IDs: 4217, 1326); mitogen-activated protein kinase kinase kinase kinase 1 (HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene IDs: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (thrombopoietin receptor, MPL; NCBI Gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., MUC1 / A, C, D, X, Y, Z, and REP)), MUC5AC, MUC16 (CA125); NCBI Gene ID: 4582, 4586, 94025); MYC proto-oncogene, bHLH transcription factor (MYC; NCBI Gene ID: 4609); myostatin (MSTN, GDF8; NCBI Gene ID: 2660); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4883); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, MAGE family member (NDN; NCBI Gene ID: 4692);Nectin cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4); NCBI Gene ID: 5819, 81607); neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene ID: 8828, 8829); neurotrophin receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene ID: 4914 , 4915, 4916); NFKB-activating protein (NKAP; NCBI Gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain-containing 3 (NLRP3, NALP3; NCBI Gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI Gene ID: 4893); Nuclear factor kappa B (NFK B1, NFKB2; NCBI Gene ID: 4790, 4791); nuclear factor, erythroid 2-like 2 (NFE2L2; NRF2; NCBI Gene ID: 4780); nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI Gene ID: 3164); nucleolin (NCL; NCBI Gene ID: 4691); nucleophosmin 1 (NPM1; NCBI Gene ID: 4869); nucleotide-binding oligomerization domain-containing 2 (NOD2; NCBI Gene ID: 64127); nudix hydrolase 1 (NUDT1; NCBI Gene ID: 452 1); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI Gene ID: 4255); opioid receptor delta 1 (OPRD1; NCBI Gene ID: 4985); ornithine decarboxylase 1 (ODC1; NCBI Gene ID: 4953); oxoglutarate dehydrogenase (OGDH; NCBI Gene ID: 4967); parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); periostin (POSTN; NCBI Gene ID: 10631);Peroxisome proliferator-activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene ID: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA; PI3K a PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3CG (PI3K gamma); NCBI Gene ID: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2 G15; NCBI Gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI Gene IDs: 5292, 11040, 415116); placental growth factor (PGF); NCBI Gene ID: 5228); plasminogen activator gen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene ID: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus receptor (poliovirus receptor, PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); polo-like kinase 1 (PLK1; NCBI Gene ID: 5347); poly(ADP-ribose) polymerases (e.g., PARP1, PARP2, PARP3; NCBI Gene IDs: 142, 10038, 10039); polycomb protein EED (EED; NCBI Gene ID: 8726); porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI Gene ID: 23532); premelanosome protein (PMEL;NCBI Gene ID: 6490); progesterone receptor (progesterone receptor, PGR; NCBI Gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI Gene ID: 5133); programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2; NCBI Gene ID: 80380); Prominin1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (PML; NCBI Gene ID: 5371); proprioceptor sarcoidosis (PSAP; NCBI Gene ID: ID: 5660); prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); prostaglandin E synthase (PTGES; NCBI Gene ID: 9536); prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2); NCBI Gene ID: 5742, 5743); proteasome 20S subunit beta 9 (PSMB9; NCBI Gene ID: 5698); protein arginine methyltransferase Spherases (e.g., PRMT1, PRMT5; NCBI Gene ID: 3276, 10419); protein kinase N3 (PKN3; NCBI Gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI Gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI Gene ID: 5754); protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene ID : 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X7 (P2RX7; NCBI Gene ID: 5027); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene, serine / threonine kinase (Raf1, c-Raf; NCBI Gene ID: 589 4); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); Ras homolog family member C (RHOC); NCBI Gene ID: 389); Ras homolog, mTORC1-binding (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); receptor-interacting serine / threonine protein kinase 1 (RIPK1; NCBI Gene ID: 8737); ret proto-oncogene (RET; NCBI Gene ID: 5979); retinoic acid early transcripts (e.g., RAET1e, RAET1g, RAET1L; NCBI Gene IDs: 135250, 154064, 353091); retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene IDs: 5914, 5916);Retinoid X receptors (e.g., RXRA, RXRB, RXRG; NCBI Gene IDs: 6256, 6257, 6258); Rho-associated coiled-coil-containing protein kinases (e.g., ROCK1, ROCK2; NCBI Gene IDs: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-beta1; NCBI Gene ID: 6198); RING finger protein 128 (RNF128, GRAIL; NCBI Gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROS1; NCBI Gene ID: 6098); roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium-binding protein A9 (S100A9; NCBI Gene ID: 6280); secreted flutter-related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID: 6696); secretoglobin family 1A member 1 (SCGB1A1; NCBI Gene ID: 7356 selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene ID: 6401, 6402, 6403); semaphorin 4D (semaphorin, SEMA4D; CD100, NCBI Gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI Gene ID: 27036, 27180, 89790); signal regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); Sig Neural transducers and activators of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene IDs: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI Gene ID: 23410); signaling lymphocyte activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI Gene IDs: 56833, 57823, 89886, 114836);SLIT and NTRK-like family member 6 (SLITRK6; NCBI Gene ID: 84189); smooth, frizzled class receptor (SMO; NCBI Gene ID: 6608); soluble epoxide hydrolase 2 (EPHX2; NCBI Gene ID: 2053); solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC44A4; NCBI Gene IDs: 6520, 6528, 6530, 8273, 10 568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI Gene ID: 6751, 6752, 6753, 6754, 6755); sonic hedgehog signaling molecule (SHH; NCBI Gene ID: 6469); Sp1 transcription factor (SP1; NCBI Gene ID: 6667); sphingosine kinase (e.g., SPHK1, SPHK2; NCBI Gene ID: 8877, 56848); sphingosine-1-phosphate receptor 1 agonist (S1PR1, CD363; NCBI Gene ID: 1901); spleen-associated tyrosine kinase (SYK; NCBI Gene ID: 6850); splicing factor 3B factor 1 (SF3B1; NCBI Gene ID: 23451); SRC proto-oncogene, non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); stabilin 1 (STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family member 1 (STEAP1; NCBI Gene ID: 26872); steroid sulfatase (STS; NCBI Gene ID: 412); interleukin-1 (IL-1; NCBI Gene ID: 1901); Stimulator of feron response cGAMP interactor 1 1 (STING1; NCBI Gene ID: 340061); superoxide dismutase 1 (SOD1, ALS1; NCBI Gene ID: 6647); suppressor of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI Gene ID: 8651, 9021); synapsin 3 (SYN3; NCBI Gene ID: 8224); syndecan 1 (SDC1, CD138, syndecan; NCBI Gene ID: 6382); synuclein alpha (SNCA, PARK1;NCBI Gene ID: 6622); T-cell immunoglobulin and mucin domain-containing 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene ID: 6869, 6870); TANK-binding kinase 1 (TBK1, NCBI Gene ID: 29110); tankyrase (TNKS, NCBI Gene ID: 8658); TATA-box binding protein-associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25976); lymphocyte-specific protein tyrosine kinase (TEC); NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010); human telomerase reverse transcriptase (TERT; NCBI Gene ID: 7015); tenascin C (TNC; NCBI Gene ID: 3371); 3 prime repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); thrombomodulin (THBD, CD14 1; NCBI Gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI Gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene ID: 7606, 7608); thyrotropin receptor (TSHR; NCBI Gene ID: 7253);TNFSF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 ( GITRL); NCBI Gene IDs: 944, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995; Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); Transfection Transferrin (TF; NCBI Gene ID: 7018); Transferrin Receptor (TFRC, CD71; NCBI Gene ID: 7037); Transforming Growth Factor (e.g., TGFA, TGFB1; NCBI Gene ID: 7039, 7040); Transforming Growth Factor Receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI Gene ID: 7046, 7048, 7049); Transforming Protein E7 (E7; NCBI Gene ID: 1489079); Transglutaminase 5 (TGM5; NCBI Gene ID: 9 333); transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI Gene ID: 7442); transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptors expressed in myeloid cells (e.g., TREM1 (CD354), TREM2; NCBI Gene IDs: 54209, 54210); trophinin (TRO, MAGED3; NCBI Gene ID: 7216); trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162);tryptophan 2,3-dioxygenase (TDO2; NCBI Gene ID: 6999); tryptophan hydroxylase (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor (TNF; NCBI Gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD137, 4-1BB), TNFRS); F10A(CD261), TNFRSF10B(TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B(OPG), TNFRSF12A, TNFRSF13B, TNFR13C(, CD268, BAFF R), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI gene ID: 355, 608, 93 9, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); tumor protein p53 (TP53; NCBI Gene ID: 7157); tumor suppressor 2, mitochondrial calcium regulator (TUSC2; NCBI Gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI Gene ID: 7301); tyrosinase (TYR; NCBI Gene ID: 7302); NCBI Gene ID: 7299); tyrosine hydroxylase (TH; NCBI Gene ID: 7054); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine protein phosphatase, non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin-conjugating enzyme E2I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI Gene ID: 51377); ubiquitin-specific peptidase 7 (USP7; NCBI Gene ID: 51377) NCBI Gene ID: 7874); ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI Gene ID: 7317); UL16-binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene IDs: 79465, 80328, 80328); valosin-containing protein (VCP, CDC48; NCBI Gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI Gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI Gene IDs: 7422, 7423); vimentin (VIM;NCBI Gene ID: 7431); vitamin D receptor (VDR; NCBI Gene ID: 7421); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunoregulatory receptor (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRNRecQ-like helicase (WRN; RECQ3, NCBI Gene ID: 7486); WT1 transcription factor ( WT1; NCBI Gene ID: 7490; WW domain-containing transcription factor 1 (WWTR1; TAZ; NCBI Gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI Gene ID: 6375); XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI Gene ID: 2829); Yes1-associated transcription factor (YAP1; NCBI Gene ID: 10413); Zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535);

[0168] In some embodiments, the one or more additional therapeutic agents include, for example, 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Adenosine A receptor (ADORA2A; NCBI gene ID: 135) 2Breceptor (ADORA2B; NCBI Gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI Gene ID: 1606); Fms-like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); integrin-associated protein (IAP, CD47; NCBI Gene ID: 961); interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin-2 receptor (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (Kirsten rat sarcoma, KRAS; NCBI Gene ID: 3845; including mutations such as KRAS G12C or G12D; mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator (MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293); programmed death-ligand 1 (PD-L1, CD274; NCBI Gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 29126) Gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI Gene ID: 3815); signal-regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210); triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209);Tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, CD134, OX40; NCBI Gene ID: 7293); tumor necrosis factor receptor superfamily, member 9 (TNFRSF9, 4-1BB, CD137; NCBI Gene ID: 3604); tumor necrosis factor receptor superfamily, member 18 (TNFRSF18, CD357, GITR; NCBI Gene ID: 8784); WRNRecQ-like helicase (WRN; NCBI Gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807);

[0169] Exemplary Mechanisms of Action Immune Checkpoint Modulators In some embodiments, the compounds provided herein are administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor environment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate NK cell responses (e.g., Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition of regulatory T cells (Tregs) or Treg depletion can relieve their suppression of anti-tumor immune responses and have anti-cancer effects (reviewed, e.g., in Platas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0170] Examples of immune checkpoint proteins or receptors include CD27 (NCBI Gene ID: 939), CD70 (NCBI Gene ID: 970); CD40 (NCBI Gene ID: 958), CD40LG (NCBI Gene ID: 959); CD47 (NCBI Gene ID: 961), SIRPA (NCBI Gene ID: 140885); CD48 (SLAMF2; NCBI Gene ID: 962), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI Gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI Gene ID: 8832), CD96 (NCBI Gene ID: 10225), CD160 (NCBI Gene ID: 10226), and the like. NCBI Gene ID: 11126), MS4A1 (CD20; NCBI Gene ID: 931), CD244 (SLAMF4; NCBI Gene ID: 51744); CD276 (B7H3; NCBI Gene ID: 80381); V-set domain-containing T-cell activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-associated 2 (HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; N NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797), TNFRSF9 (CD137; NCBI Gene ID: 3604), TNFSF9 (CD137L; NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2;NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA), NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8 784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI Gene ID: 5133); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493 CD80 (B7-1; NCBI Gene ID: 941), CD28 (NCBI Gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI Gene ID: 5819); CD226 (DNAM-1; NCBI Gene ID: 10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); T cell immunoreceptor with Ig and ITIM domains (TIGIT ;NCBI Gene ID: 201633); T-cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4; NCBI Gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); Galectin 9 (LGALS9; NCBI Gene ID: 3965); Lymphocyte activation 3 (LAG3, CD223; NCBI Gene ID: 3902); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI Gene ID: 6504);Lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI gene ID: 57823); UL16 binding protein 1 (ULBP1; NCBI gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI gene ID: 79465); retinoic acid early translocation Retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI Gene ID: 154064); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1; NCBI Gene ID: 3811, e.g., lirilumab (IPH-2102, IPH-4102)); killer cell lectin-like receptor C1 ( Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI gene ID: 22914); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI gene ID: 3822); killer cell lectin-like receptor C3 (KLRC3, NKG2E; NCBI gene ID: 3823); killer cell lectin-like receptor C4 (KLRC4, NKG2F; NCBI gene ID: 8302); killer cell immunoglobulin-like receptor, two Ig domains killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3; NCBI Gene ID: 3804); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1; NCBI Gene ID: 3824);Killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI gene ID: 10219); sialic acid-binding Ig-like lectin 7 (SIGLEC7; NCBI gene ID: 27036); and sialic acid-binding Ig-like lectin 9 (SIGLEC9; NCBI gene ID: 27180).

[0171] In some embodiments, compounds provided herein are administered with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B- and T-lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PVRIG, CD1 12R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, compounds provided herein are administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0172] In some embodiments, compounds provided herein are administered with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 3 (KIR3DL3). (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94), killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-binding Ig-like lectin 7 (SIGLEC7); and sialic acid-binding Ig-like lectin 9 (SIGLEC9). In some embodiments, the compounds provided herein are administered with one or more agonists or activators of one or more NK cell-stimulatory immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0173] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., an antibody or fragment thereof, or an antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of LAG3.

[0174] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, and KN-04. 4, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0175] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, Retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimuzumab (CBT-501), LZM-009, prorugolimab (BCD-100), lodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CB T-502, dostallimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), embafolimab (KN-035), sintilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, zimbelelimab (AB122), spartalizumab ( PDR-001), and compounds disclosed in WO 2018195321, WO 2020014643, WO 2019160882, or WO 2018195321, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / CTLA3), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4),MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), TAK-252 (PD-1 / OX4) 0L), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1), FS-118(LAG-3 / PD-L1), FPT-155(CTLA4 / P PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp alfa (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor such as CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0176] Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vivostarob, domvanalimab, domvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0177] An example of an inhibitor of LAG3 that can be co-administered is leramirimab (LAG525).

[0178] Inhibition of regulatory T cell (Treg) activity or depletion of Tregs can alleviate the suppression of anti-tumor immune responses and may have anti-cancer effects. For example, see Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, the compounds provided herein are administered with one or more inhibitors of Treg activity or Treg depletion agents. Treg inhibition or depletion can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment.

[0179] In some embodiments, compounds provided herein are administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can suppress migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor can modulate cell phenotype and induce the production of proinflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI Gene ID: 1233) antagonists and Ikaros zinc finger proteins (e.g., Ikaros (IKZF1; NCBI Gene ID: 10320), Helios (IKZF2; NCBI Gene ID: 22807), Aiolos (IKZF3; NCBI Gene ID: 22806), and Eos (IKZF4; NCBI Gene ID: 64375).

[0180] Examples of Helios degraders that may be co-administered include, but are not limited to, I-57 (Novartis) and compounds disclosed in WO 2019 / 038717, WO 2020 / 012334, WO 2020 / 0117759, and WO 2021 / 101919.

[0181] In some embodiments, compounds provided herein are administered with one or more Treg-depleting agents. In some embodiments, the Treg-depleting agent is an antibody. In some embodiments, the Treg-depleting antibody has antibody-dependent cellular cytotoxicity (ADCC) activity. In some embodiments, the Treg-depleting antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg-depleting antibody is an antibody-drug conjugate (ADC). Exemplary targets of Treg depleting agents include, but are not limited to, CD25 (IL2RA; NCBI Gene ID: 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18; NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID: 3604), OX-40 (CD134; NCBI Gene ID: 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).

[0182] In some embodiments, Treg inhibitors or Treg depletors that may be co-administered include C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T cells (CCR4 ... Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin and combinations thereof.

[0183] Examples of Treg-depleting anti-CCR8 antibodies that may be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor Biomed), IO-1 (Oncurious), and antibodies disclosed in WO 2021 / 163064, WO 2020 / 138489, and WO 2021 / 152186.

[0184] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0185] Inhibition, depletion, or reprogramming of unstimulated myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5):541-550, 2010; WO 2016 / 049641). Exemplary targets for depleting or reprogramming unstimulated myeloid cells include the triggering receptors TREM-1 (CD354, NCBI gene ID: 54210) and TREM-2 (NCBI gene ID: 54209) expressed on myeloid cells. In some embodiments, the compounds provided herein are administered with one or more myeloid cell depleting or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; an antibody disclosed in WO 2019 / 032624) or an anti-TREM-2 antibody (e.g., PY314; an antibody disclosed in WO 2019 / 118513).

[0186] Cluster of differentiation agonists or activators In some embodiments, the compounds provided herein are administered with an agent that targets a cluster of differentiation (CD) marker. Exemplary agents that target CD markers that can be co-administered include: A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A2402 / HLA-A0201 restricted epitope peptide vaccine, Dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranelgene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, revastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverenvatinib dimesylate (HQP-1351), cabozantinib tinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asnercept (APG-101), APO-010, and WO 2016 / 196388, WO 2016 / 033570, WO 2015 / 157386, WO 1992 / 03459, WO 1992 / 21766, WO 2004 / 080462, International Publication No. 2005 / 020921, International Publication No. 2006 / 009755, International Publication No. 2007 / 078034, International Publication No. 2007 / 092403, International Publication No. 2007 / 127317, International Publication No. 2008 / 005877, International Publication No. 2012 / 154480, International Publication No. 2014 / 100620, International Publication No. 2014 / 039714, International Publication No. 2015 / 134536, International Publication No. 2017 / 167182, International Publication No. 2018 / 112136,International Publication No. WO 2018 / 112140, International Publication No. WO 2019 / 155067, International Publication No. WO 2020 / 076105, International Application No. PCT / US2019 / 063091, International Publication No. WO 1917 / 3692, International Publication No. WO 2016 / 179517, International Publication No. WO 2017 / 096179, International Publication No. WO 2017 / 096182, International Publication No. WO 2017 / 096281, International Publication No. WO 2017 / 096282, International Publication No. WO 2017 / 096283, International Publication No. WO 2017 / 096284, International Publication No. WO 2017 / 096285, International Publication No. WO 2017 / 096286, International Publication No. WO 2017 / 096287, International Publication No. WO 2017 / 096288, International Publication No. WO 2017 / 096289, International Publication No. WO 2017 / 096290, International Publication No. WO 2017 / 096291, International Publication No. WO 2017 / 096292, International Publication No. WO 2017 / 096293, International Publication No. WO 2017 / 096294, International Publication No. WO 2017 / 096295, International Publication No. WO 2017 / 096296, International Publication No. WO 2017 / 096297, International Publication No. WO 2017 / 096298, International Publication No. WO 2017 / 096299 8 / 089628, WO 2017 / 096179, WO 2018 / 089628, WO 2018 / 195321, WO 2020 / 014643, WO 2019 / 160882, WO 2018 / 195321, WO 2001 / 40307, ​​WO 2002 / 092784, WO 2007 / 133811, WO Publication No. 2009 / 046541, International Publication No. 2010 / 083253, International Publication No. 2011 / 076781, International Publication No. 2013 / 056352, International Publication No. 2015 / 138600, International Publication No. 2016 / 179399, International Publication No. 2016 / 205042, International Publication No. 2017 / 178653, International Publication No. 2018 / 026600, International Publication No. 2018 / 057 669, WO 2018 / 107058, WO 2018 / 190719, WO 2018 / 210793, WO 2019 / 023347, WO 2019 / 042470, WO 2019 / 175218, WO 2019 / 183266, WO 2020 / 013170, WO 2020 / 068752, Cancer Discov. 2019 Jan 9(1):8; and Gariepy J., et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).

[0187] In some embodiments, agents targeting CD markers that may be co-administered include the following: PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, lobritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, CD117 - small molecule inhibitors such as ADC, AZD3229, telatinib, borolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), Plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0188] In some embodiments, agents targeting CD markers that may be co-administered include the following: interleukin-2 receptor subunit gamma, eltrombopag, lintatolimod, poly ICLC (NSC-301463), reboxone, apoxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, levothyroxine ... Small molecule agonists such as siquimod, sergantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, ritenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0189] In some embodiments, agents targeting CD markers that may be co-administered include the following: tafasitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzalutamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX®), TTX-030, cericlerumab (R G7876), APX-005M, ABBV-428, ABBV-927, mitazarimab (JNJ-64457107), lenzilumab, alemtuzumab, emactuzumab, AMG-820, FPA-008 (caviralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulukafusp alfa alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, leratolimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enselimab (TSR-033), atipotuzumab, BrevaRex (MAB-AR-20).5), MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, rituximab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006, I Antibodies such as NBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in WO 2017 / 096179, WO 2017 / 096276, WO 2017 / 096189, and WO 2018 / 089628 are included.

[0190] In some embodiments, agents targeting CD markers that may be co-administered include the following: CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, iso-cel, lysocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), Ttisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL-armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), Anti-CD19 CAR T-cell therapy (Acute lymphoblastic leukemia / Non-Hodgkin's lymphoma, University Hospital Heidelberg), Anti-CD19 CAR T-cell therapy (Silent IL-6 expression, Cancer, Shanghai Unicar Therapeutic Biopharmaceutical Therapeutic Technology), MB-CART2019.1(CD19 / CD20), GC-197(CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR(CD19 / APRIL), ICG-134, ICG-132(CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecleucel-T, CART-19, tisagenlecleucel (CTL-019), anti-CD20 CAR T cell therapy (non-Hodgkin's lymphoma), MB-CART2019.1 (CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01(NKG2D LIGAND Modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, or cell therapies such as those disclosed in WO 2012 / 079000 or WO 2017 / 049166.

[0191] Cluster of differentiation 47 (CD47) inhibitors In some embodiments, compounds provided herein are administered with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies or CD47 blockers, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include the following: CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), retaplimab (IBI-188), lemzoparimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-1 02, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or International Publication Nos. WO 1997 / 27873, WO 1999 / 40940, WO 2002 / 092784, WO 2005 / 044857, WO 2009 / 046541, WO 2010 / 070047, WO 2011 / 143624, WO 2012 / 170250, WO Publication No. 2013 / 109752, International Publication No. 2013 / 119714, International Publication No. 2014 / 087248, International Publication No. 2015 / 191861, International Publication No. 2016 / 022971, International Publication No. 2016 / 023040, International Publication No. 2016 / 024021, International Publication No. 2016 / 081423, International Publication No. 2016 / 109415, International Publication No. 2016 / 141328, International Publication No. 2016 / 188449, International Publication No. 2017 / 027422, International Publication No. 2017 / 049251, International Publication No. 2017053423, International Publication No. 2017 / 121771, International Publication No. 2017194634, International Publication No. 2017 / 196793, International Publication No. 2017 / 215585, International Publication No. 2018 / 075857, International Publication No. 2018 / 075960, International Publication No. 2018 / 089508,International Publication No. 2018 / 095428, International Publication No. 2018 / 137705, International Publication No. 2018 / 233575, International Publication No. 2019 / 027903, International Publication No. 2019 / 034895, International Publication No. 2019 / 042119, International Publication No. 2019 / 042285, International Publication No. 2019 / 042470, International Publication No. 2019 / 086573, International Publication No. 2019 / 108733, International Publication No. 2019 / 138367, International Publication No. 2019 / 144895 , WO 2019 / 157843, WO 2019 / 179366, WO 2019 / 184912, WO 2019 / 185717, WO 2019 / 201236, WO 2019 / 238012, WO 2019 / 241732, WO 2020 / 019135, WO 2020 / 036977, WO 2020 / 043188, and WO 2020 / 009725. In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is magrolimab.

[0192] In some embodiments, the CD47 inhibitor is IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217, (CD47 / DLL3), IMM-26011 (CD47 / FLT3), IMM-0207 (CD47 / VEGF), or any combination thereof. GF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801.

[0193] Drugs targeting SIRPa In some embodiments, a compound provided herein is administered with an agent that targets SIRPa (NCBI Gene ID: 140885; UniProt P78324). Examples of agents that target SIRPa include SIRPa inhibitors (such as AL-008, RRx-001, and CTX-5861), and anti-SIRPa antibodies (FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPa / PD-L1). Additional SIRPα targeting agents of use are described in, for example, WO 2001 / 40307, ​​WO 2002 / 092784, WO 2007 / 133811, WO 2009 / 046541, WO 2010 / 083253, WO 2011 / 076781, WO 2013 / 083254, WO 2014 / 083255, WO 2015 / 083256, WO 2016 / 083257, WO 2017 / 083258, WO 2018 / 083259, WO 2019 / 083260, WO 2019 / 083261, WO 2019 / 083262, WO 2019 / 083263, WO 2019 / 083264, WO 2019 / 083265, WO 2019 / 083266, WO 2019 / 083267, WO 2019 / 083268, WO 2019 / 083269 ... 056352, WO 2015 / 138600, WO 2016 / 179399, WO 2016 / 205042, WO 2017 / 178653, WO 2018 / 026600, WO 2018 / 057669, WO 2018 / 107058, WO 2018 / 190719, WO 2018 / 210793, WO 2019 / 023347, WO 2019 / 042470, WO 2019 / 175218, WO 2019 / 183266, WO 2020 / 013170 and WO 2020 / 068752.

[0194] FLT3R agonists In some embodiments, a compound provided herein is administered with an FLT3R agonist. In some embodiments, a compound provided herein is administered with an FLT3 ligand. In some embodiments, a compound provided herein is administered with an FLT3L-Fc fusion protein, for example, as described in WO 2020 / 263830. In some embodiments, a compound provided herein is administered with GS-3583 or CDX-301. In some embodiments, a compound provided herein is administered with GS-3583.

[0195] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In some embodiments, the compounds provided herein are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNF RSF7 (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; 87 94), TNFRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 23495), TNFRSF13C (CD268, NCBI gene ID; 115650), TNFRSF and administered with one or more agonists of TNFRSF16 (NGFR, CD271, NCBI gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID; 608), TNFRSF18 (GITR, CD357, NCBI gene ID; 8784), TNFRSF19 (NCBI gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI gene ID; 27242), and TNFRSF25 (DR3, NCBI gene ID; 8718).

[0196] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tabolixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO 2016 / 179517, WO 2017 / 096179, WO 2017 / 096182, WO 2017 / 096281, and WO 2018 / 089628.

[0197] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0198] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0199] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0200] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0201] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication Nos. WO 2017 / 096179, WO 2017 / 096276, WO 2017 / 096189, and WO 2018 / 089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in International Publication Nos. WO 2017096179 and WO 2018089628.

[0202] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronectumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), pramotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20).

[0203] Bispecific T cell engager In some embodiments, the compounds provided herein are administered with a bispecific T-cell engager (e.g., Fc-less) or an anti-CD3 bispecific antibody (e.g., Fc-containing). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), odronextamab (R EGN-1979;CD20 / CD3), MCLA-117(CD3 / CLEC12A), JNJ-0819(heme / CD3), JNJ-7564(CD3 / heme), AMG-757(DLL3-CD3), AMG-330(C D33 / CD3), AMG-420(BCMA / CD3), AMG-427(FLT3 / CD3), AMG-562(CD19 / CD3), AMG-596(EGFRvIII / CD3), AMG-673(CD33 / CD3),A MG-701 (BCMA / CD3), AMG-757 (DLL3 / CD3), AMG-211 (CEA / CD3), blinatumomab (CD19 / CD3), huGD2-BsAb (CD3 / GD2), ERY974 (GPC3 / CD 3),GEMoab(CD3 / PSCA),RG6026(CD20 / CD3),RG6194(HER2 / CD3),PF-06863135(BCMA / CD3),SAR440234(CD3 / CDw123),JNJ-93 83(MGD-015), AMG-424(CD38 / CD3), tidutamab(XmAb-18087(SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33 ),MGD-009(CD3 / B7H3),IMCgp100(CD3 / gp100),XmAb-14045(CD123 / CD3),XmAb-13676(CD3 / CD20),tidutamab(XmAb-18087;Examples of suitable anti-CD3 binding bispecific molecules include SSTR2 / CD3, catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828; CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc domain. Exemplary bispecific T cell engagers that can be co-administered target CD3 and tumor-associated antigens described herein, including, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230).

[0204] Bispecific and trispecific natural killer (NK) cell engagers In some embodiments, the compounds provided herein are administered with a bispecific NK cell engager (BiKE) or tri-specific NK-cell engager (TriKE) (e.g., without an Fc domain), or a bispecific antibody (e.g., with an Fc domain) against an NK cell activating receptor, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (which mediate 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, BiKE, or TriKE that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc domain. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.

[0205] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor In some embodiments, compounds provided herein are administered with an inhibitor of the MCL1 apoptosis regulator, a BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO 2018 / 183418, WO 2016 / 033486, and WO 2017 / 147410.

[0206] SHP2 inhibitors In some embodiments, compounds provided herein are administered with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI Gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in WO 2018 / 172984 and WO 2017 / 211303.

[0207] Hematopoietic progenitor kinase 1 (HPK1) inhibitors and degraders In some embodiments, the compounds provided herein are administered with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include those described in WO 2020 / 092621, WO 2018 / 183956, WO 2018 / 183964, WO 2018 / 167147, WO 2018 / 049152, WO 2020 / 092528, WO 2016 / 205942, and WO 2016 / 205942. These include, but are not limited to, those described in WO 2016 / 090300, WO 2018 / 049214, WO 2018 / 049200, WO 2018 / 049191, WO 2018 / 102366, WO 2018 / 049152, and WO 2016 / 090300.

[0208] Apoptosis signal-regulating kinase (ASK) inhibitors In some embodiments, compounds provided herein are administered with an ASK inhibitor, such as mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO 2011 / 008709 (Gilead Sciences) and WO 2013 / 112741 (Gilead Sciences).

[0209] Bruton's tyrosine kinase (BTK) inhibitors In some embodiments, the compounds provided herein are administered with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0210] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, the compounds provided herein are selected from the group consisting of cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI Gene ID: 1018); cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID: 1019); :1019); cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID:1021); cyclin-dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID:1022), or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID:1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexol, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, simulosertib hydrate (TAK931), and TG-02.

[0211] Discoidin domain receptor (DDR) inhibitors In some embodiments, compounds provided herein are combined with inhibitors of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication Nos. 2009-0142345 (Takeda Pharmaceutical), 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0212] Targeted E3 ligase ligand conjugates In some embodiments, compounds provided herein are administered with a targeted E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and Survival) E3 ubiquitin ligase binding moiety, a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, a cereblon E3 ubiquitin ligase binding moiety, or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase degradation of the targeted protein, e.g., via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein described herein and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of, e.g., BTK and an E3 ligase ligand or binding moiety). See, e.g., WO 2018 / 098280. In some embodiments, the targeted E3 ligase ligand conjugate comprises a binding moiety that targets or binds to interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); a rapidly accelerated fibrosarcoma (RAF, such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD protein; and an E3 ligase ligand or binding moiety.See, e.g., WO 2019 / 099926, WO 2018 / 226542, WO 2018 / 119448, WO 2018 / 223909, WO 2019 / 079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, e.g., in WO 2018 / 237026, WO 2019 / 084026, WO 2019 / 084030, WO 2019 / 067733, WO 2019 / 043217, WO 2019 / 043208, and WO 2018 / 144649.

[0213] Histone deacetylase (HDAC) inhibitors In some embodiments, the compounds provided herein are administered with an inhibitor of histone deacetylase, for example, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, and entinostat.

[0214] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, compounds provided herein are administered with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0215] Janus kinase (JAK) inhibitors In some embodiments, compounds provided herein are administered with an inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restortinib, momelotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0216] Lysyl oxidase-like protein (LOXL) inhibitors In some embodiments, compounds provided herein are administered in combination with an inhibitor of a LOXL protein, e.g., LOXL1 (NCBI Gene ID: 4016), LOXL2 (NCBI Gene ID: 4017), LOXL3 (NCBI Gene ID: 84695), LOXL4 (NCBI Gene ID: 84171), and / or LOX (NCBI Gene ID: 4015). Examples of LOXL2 inhibitors include the antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences), and WO 2011 / 097513 (Gilead Biologics).

[0217] Matrix metalloproteinase (MMP) inhibitors In some embodiments, the compounds provided herein are inhibitors of matrix metallopeptidases (MMPs), such as MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP18 (NCBI Gene ID: 4327), MMP19 (NCBI Gene ID: 4330), MMP20 (NCBI Gene ID: 4331), MMP21 (NCBI Gene ID: 4332), MMP22 (NCBI Gene ID: 4333), MMP23 (NCBI Gene ID: 4334), MMP24 (NCBI Gene ID: 4335), MMP25 (NCBI Gene ID: 4336), MMP26 (NCBI Gene ID: 4337), MMP27 (NCBI Gene ID: 4338), MMP28 (NCBI Gene ID: 4339), MMP29 (NCBI Gene ID: 4340), MMP29 (NCBI Gene ID: 4341), MMP20 (NCBI Gene ID: 4342), MMP21 (NCBI Gene ID: 4343), MMP22 (NCBI Gene ID: 4344), MMP23 (NCBI Gene ID: 4 and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012 / 027721 (Gilead Biologics).

[0218] RAS and RAS pathway inhibitors In some embodiments, the compounds provided herein are directed to 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; The treatment is administered in conjunction with an inhibitor of the HRAS proto-oncogene (NRAS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or HRAS proto-oncogene, a GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). The Ras inhibitor can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that may be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1(G12C), adagrasib (MRTX-849), ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849(G12C), and K-Ras(G12D) selective inhibitory peptides (including KRpep-2 and KRpep-2d). Exemplary KRAS mRNA inhibitors include anti-KRAS U1 adaptor-, AZD-4785, siG12D-LODER™, and siG12D-exosomes.Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, rabocertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that can be co-administered include lidigosertib. Exemplary PI3K inhibitors that may be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Exemplary AKT inhibitors that may be co-administered include capivasertib and GSK2141795. Exemplary PI3K / mTOR inhibitors that may be co-administered include daptolisib, omipalisib, voxalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nano-amorphous formulation, cancer), racemetyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. K-RAS and mutant N-RAS can also be reduced by neratinib, an irreversible inhibitor of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0219] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, a compound provided herein is administered with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib.

[0220] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, the compounds provided herein are directed to phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BET A, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, bupallisib (BKM120), BYL719 (alpelisib), CH5132799, and copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7 604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication No. 2005 / 113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Sciences, Inc., New York, NY, USA) Calistoga), WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga), and WO 2014 / 201409 (Gilead Sciences).

[0221] Spleen Tyrosine Kinase (SYK) inhibitor In some embodiments, compounds provided herein are administered with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI Gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, celdulatinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 2015 / 0175616.

[0222] Toll-like receptor (TLR) agonists In some embodiments, the compounds provided herein are administered with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Examples of TLR7 agonists that may be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509, and those disclosed in U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences), and U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (VentirxPharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics). A TLR7 / TLR8 agonist that may be co-administered is NKTR-262. Examples of TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 00736 42 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (VentirxPharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics). Exemplary TLR9 agonists that may be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0223] Tyrosine kinase inhibitors (TKIs) In some embodiments, the compounds provided herein are administered with a tyrosine kinase inhibitor (TKI). The TKI may target the epidermal growth factor receptor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src ), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib, L-malic acid, (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR-targeted agents include neratinib, tucatinib (ONT-380), tecevatinib, mobocertinib (TAK-788), DZD-9008, valitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®, and Booth, et al., Cancer Biol Ther. 2018 Feb. 1;19(2):132-137. Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab sarotarocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab.

[0224] chemotherapy drugs In some embodiments, the compounds provided herein are administered in combination with a chemotherapeutic or anti-neoplastic agent.

[0225] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) are meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethyleneimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including the synthetic analogs adozelesin, carzelesin, and bizelesin; cryptoxanthin; ficins, especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi II), dynemycins, including dynemycin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin leucine, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenime antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; radiotherapeutic agents such as radium-223; trichothecenes, particularly T-2 toxin, veracrine A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Sabizablin (Veru-111); platinum analogues such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; hestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformutine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidines; folinic acid; podophyllic acid, 2-ethylhydrazide; procarbazine; polysaccharide K (PSK); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Trabectedin, Triaziquone; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZA R®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin, aminopterin, xeloda; ibandronate; CPT-11; topoisomerase inhibitors RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan);Examples include FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated to antibodies or any of the targeting agents described herein to create antibody drug conjugates (ADCs) or targeted drug conjugates.

[0226] Antihormonal drugs Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

[0227] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0228] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0229] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (apatorsen).

[0230] Examples of progesterone receptor antagonists include onapristone. Additional progesterone targeting agents include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri-Cyclen), and levonorgestrel.

[0231] Antiangiogenic agents In some embodiments, the compounds provided herein are administered with an anti-angiogenic agent. Anti-angiogenic agents that may be co-administered include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necuranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shell), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,l-3,4-dehydroproline, thiaproline, and the like. benzodiazepine, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-2 serum, chicken inhibitor of metalloproteinases-3 (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, β-1 anticollagenase serum, alpha-2 antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthonylate disodium or "CCA", thalidomide, angiogenesis-suppressing steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be co-administered include bevacizumab, vanucizumab, faricimab, zilpacimab (ABT-165; DLL4 / VEGF), or nabicikizumab (OMP-305B83; DLL4 / VEGF).

[0232] antifibrotic agents In some embodiments, the compounds provided herein are administered with an anti-fibrotic agent. Anti-fibrotic agents that may be co-administered include compounds such as beta-aminoproprionitrile (BAPN), as well as compounds disclosed in U.S. Patent No. 4,965,288, which relates to inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal collagen deposition, and U.S. Patent No. 4,997,854, which relates to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, each of which is incorporated herein by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, U.S. Pat. No. 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application No. 2004 / 0248871, which are incorporated herein by reference.

[0233] Exemplary antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that generate resonance-stabilized products after binding to the carbonyl, such as the following primary amines: ethylenamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine ​​lactone.

[0234] Other antifibrotic agents are copper chelators, which may or may not be cell-permeable. Exemplary compounds include indirect inhibitors that inhibit the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0235] anti-inflammatory agents In some embodiments, the compounds provided herein are administered with an anti-inflammatory agent. Exemplary anti-inflammatory agents include arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA1 4 (NCBI Gene ID: 23632), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX dual inhibitor.

[0236] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) that can be co-administered include mofezolac, GLY-230, and TRK-700.

[0237] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maceoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that may be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that may be co-administered include pormacoxib and imrecoxib.

[0238] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include LY3023703, GRC27864, and the compounds disclosed in WO 2015 / 158204, WO 2013 / 024898, WO 2006 / 063466, WO 2007 / 059610, WO 2007 / 124589, WO 2010 / 100 249, WO 2010 / 034796, WO 2010 / 034797, WO 2012 / 022793, WO 2012 / 076673, WO 2012 / 076672, WO 2010 / 034798, WO 2010 / 034799, WO 2012 / 022792, WO 2009 / 103778, WO 2011 / 048004, WO 201 2 / 087771, WO 2012 / 161965, WO 2013 / 118071, WO 2013 / 072825, WO 2014 / 167444, WO 2009 / 138376, WO 2011 / 023812, WO 2012 / 110860, WO 2013 / 153535, WO 2009 / 130242, WO 2009 / 146696, WO Examples of compounds that can be co-administered include those described in International Publication Nos. 2013 / 186692, 2015 / 059618, 2016 / 069376, 2016 / 069374, 2009 / 117985, 2009 / 064250, 2009 / 064251, 2009 / 082347, 2009 / 117987, and 2008 / 071173. Additionally, metformin has been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. For example, as described in Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0239] Carbonic anhydrases that may be co-administered (e.g., CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA Examples of inhibitors of one or more of CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632) include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and diclophenamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0240] Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) that may be co-administered include meclofenamate sodium and zileuton.

[0241] Soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that may be co-administered include compounds described in WO 2015 / 148954. Dual COX-2 / SEH inhibitors that may be co-administered include compounds described in WO 2012 / 082647. Dual SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) inhibitors that may be co-administered include compounds described in WO 2017 / 160861.

[0242] Mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI gene ID: 1326) compounds that can be co-administered include GS-4875, GS-5290, BHM-078, and compounds described in, for example, WO 2006 / 124944, WO 2006 / 124692, WO 2014 / 064215, WO 2018 / 005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila, et al. al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0243] Tumor oxygenators In some embodiments, the compounds provided herein are administered with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Exemplary agents that can be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors, such as PT-2977 and PT-2385; VEGF inhibitors, such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding protein (HNOX)), such as OMX-302 and HNOX proteins, as described in WO 2007 / 137767, WO 2007 / 139791, WO 2014 / 107171, and WO 2016 / 149562.

[0244] immunotherapy agents In some embodiments, the compounds provided herein are administered in combination with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody.Examples of immunotherapeutic agents that may be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutumumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumumab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratuzumab, detumomab, diazepam, and zitaxel. Nutuximab, dombanalimab, drozitumab, durigotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituzumab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, framvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734) 016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minletuzumab, mitumomab, mogamulitumab, moxetumomab, naptumomab, narutuzumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatuzumab, pasudotox, patritumab, pemtumomab mab, pertuzumab, pintumomab, pritumumab, racotumomab, radletuzumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubirituximab, veltuzumab, borsetuzumab, votumumab, zalutumumab, zimberelimab, and 3F8.Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0245] The exemplified therapeutic antibodies may be further labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0246] In some embodiments, the immunotherapeutic agent is an antibody drug conjugate (ADC). Exemplary ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein.Examples of ADCs that may be co-administered include gemtuzumab, brentuximab, brentuximab (e.g., belantamab mafodotin), camidanlumab (e.g., camidanlumab tesirin), trastuzumab (e.g., trastuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuximab (e.g., mirvetuximab sovatansine), depatuximab, vadasotuximab, labetuzumab, and radlatuzumab (e.g., radlatuzumab vedotin). , roncatuximab (e.g., roncatuximab tesulin), sacituzumab (e.g., sacituzumab govitecan), datopotomab (e.g., datopotomab deruxtecan; DS-1062; Dato-DXd), patritumab (e.g., patritumab deruxtecan), rifazutuzumab, indusatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, iupifitamab (e.g., iupifitamab rilsodutin), indatuximab, milatuzumab, rovalpituzumab (e.g., rovalpituzumab lupituzumab tesirine), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamavutansine), dicitamab (e.g., dicitamab vedotin), telisotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, I Examples include MGN529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130, and IMMU-140.ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0247] Exemplary therapeutic agents (e.g., anti-cancer or anti-tumor agents) that can be conjugated to a drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, maytansine or analogs thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinker SC-DR002 (D6.5), duocarmycins, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or dimers thereof, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), and other anti-cancer or anti-neoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to the drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anti-cancer or anti-neoplastic agent) that can be conjugated to the drug-conjugated antibody, fragment thereof, or antibody mimetic comprises an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 comprises BPI-002.

[0248] In some embodiments, ADCs that can be co-administered include antibodies targeting tumor-associated calcium signaling factor 2 (TROP-2; TACSTD2; EGP-1; NCBI gene ID: 4070). Exemplary anti-TROP-2 antibodies include TROP-2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Shanghai DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP-2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius) BioTech), LIV-2008b (Shanghai / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University ofWisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), as well as patents disclosed in WO 2020 / 016662 (Abmart), WO 2020 / 249063 (Bio-Thera Solutions), U.S. Patent Application Publication No. 2019 / 0048095 (Bio-Thera Solutions), U.S. Patent Application Publication No. 2013 / 077458 (LivTech / Chiome), European Patent Application Publication No. 2011 / 0783675 (Chiome), WO 2015 / 098099 (Daiichi Sankyo), WO 2017 / 002776 (Daiichi Sankyo), WO 2020 / 130125 (Daiichi Sankyo), International Publication No. 2020 / 240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021 / 093730 (Daiichi Sankyo), U.S. Patent Application Publication No. 9850312 (DaiichiSankyo), Chinese Patent No. 112321715 (Biosion), US Patent Application Publication No. 2006 / 193865 (Immunomedics / Gilead), US Patent Application Publication No. 2011 / 068845 (Immunomedics / Gilead), US Patent Application Publication No. 2016 / 296633 (Immunomedics / Gilead), US Patent Application Publication No. 2017 / 021017 (Immunomedics / Gilead), US Patent Application Publication No. 2017 / 209 594 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017 / 274093 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 110772 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 185351 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 271992 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 217227 (Immunomedics / Gilead) Immunomedics / Gilead), U.S. Patent Application Publication No. 2019 / 248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021 / 093730 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021 / 069343 (Immunomedics / Gilead), U.S. Patent No. 8435539 (Immunomedics / Gilead), U.S. Patent Xu No. 8435529 (Immunomedics / Gilead), U.S. Patent No. 9492566 (Immunomedics / Gilead), WO 2003 / 074566 (Gilead), WO 2020 / 257648 (Gilead), WO 2013 / 039861 (Gilead), WO 2014 / 163684 (Gilead), U.S. Patent No. 9427464 (LivTech / Chiome), U.S. Patent No. 10501555 (Abruzzo Theranostic / Oncoxx), WO 2018 / 036428 (Sichuan KelunExamples of antibodies include, but are not limited to, those described in Pharma, WO 2013 / 068946 (Pfizer), WO 2007 / 095749 (Roche), and WO 2020 / 094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Pat. Nos. 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anti-cancer agent joined by a linker. In some embodiments, the linker includes a linker disclosed in U.S. Pat. No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug moiety of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doxorubicin (DOX), epirubicin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lutotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxanes, geldanmycin, ansamycins, and epothilones. In some embodiments, the chemotherapeutic moiety is SN-38. In some embodiments, a compound provided herein is administered with sacituzumab govitecan.

[0249] In some embodiments, ADCs that may be co-administered include antibodies targeting carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a; NCBI gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (e.g., as described in WO 1996011013). In some embodiments, the CEACAM1-ADC is as described in WO 2010 / 093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, compounds provided herein are administered with CEACAM1-ADC IMMU-130.

[0250] In some embodiments, the ADC that may be co-administered comprises an MHC class II cell surface receptor (HLA-DR) encoded by an antibody-targeting human leukocyte antigen complex. In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO 2006 / 094192). In some embodiments, the HLA-DR-ADC is as described in WO 2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the compounds provided herein are administered with HLA-DR-ADC IMMU-140.

[0251] Cancer Gene Therapy and Cell Therapy In some embodiments, provided herein is a compound administered together with cancer gene therapy and cell therapy.Cancer gene therapy and cell therapy include: inserting normal gene into cancer cell to replace mutated or altered gene; gene modification to silence mutated gene; genetic approach to directly kill cancer cell; for example, injecting immune cells designed to enhance the immune response to cancer cell, or activate the patient's own immune system (T cell or natural killer cell) to kill cancer cell or to replace most of the patient's own immune system to detect and kill cancer cell; genetic approach to modify cell activity to further change the endogenous immune response to cancer.

[0252] cell therapy In some embodiments, a compound provided herein is administered with one or more cell therapies. Exemplary cell therapies include, but are not limited to, the co-administration of one or more populations of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor-infiltrating lymphocytes (TIL), and / or dendritic cells (DC). In some embodiments, the cell therapy involves the co-administration of a T cell therapy, e.g., a population of α / β TCR T cells, γ / δ TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, the cell therapy involves the co-administration of an NK cell therapy, e.g., NK-92 cells. Optionally, the cell therapy can involve the co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0253] In some embodiments, cell therapy involves co-administering cells comprising a chimeric antigen receptor (CAR). In such therapy, a population of immune effector cells is engineered to express a CAR, where the CAR comprises a tumor antigen-binding domain. In T cell therapy, T cell receptors (TCRs) are engineered to target tumor-derived peptides displayed on the surface of tumor cells.

[0254] Regarding the structure of the CAR, in some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain comprises a signaling functional domain of one or more proteins selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0255] In some embodiments, the costimulatory domain is 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), CD160, CD19, CD 4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 912), and CD1E (NCBI gene ID: 913). 12), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL 1. It comprises a functional domain of one or more proteins selected from the group consisting of CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0256] In some embodiments, the transmembrane domain is selected from the group consisting of the α, β, or ζ chain of the T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rβ, IL2Rγ, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E , ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0257] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapeutic agent (e.g., a monospecific or multispecific antibody or antigen-binding fragment thereof or antibody mimetic) described herein binds to a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is one of the following: CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also referred to as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testisin or PR SS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine protein kinase, ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP);Insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropein) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of the breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl-GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); prostate I 6 Single transmembrane epithelial antigen (STEAP1); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRCSD); X chromosome open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-la); melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase;Prostate cancer tumor antigen-1 (PCTA-1 or galectin-8), melanoma antigen 1 recognized by T cells (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-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myeloma 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 (sibling of BORIS or regulator of imprinted sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5);and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of an MHC-presented tumor-associated antigen;

[0258] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD4 6, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factors, 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 receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, 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-microglobulin, and Fc receptor-like 5 (FcRL5).

[0259] In some embodiments, the antigen binding domain binds to an epitope of a target antigen or tumor-associated antigen (TAA) that is presented on a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer-testis antigen. In some embodiments, the cancer testis antigen is acrosin binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI Gene ID: 84519), alpha-fetoprotein (AFP; AFPD, FETA, HPAFP; NCBI Gene ID: 174); A-kinase anchor protein 4 (AKAP4; AKAP82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI Gene ID: 8852), ATPase family AAA domain containing 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI Gene ID: 29028), kinetochore scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI Gene ID: 174); Gene ID: 57082), centrosomal protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI Gene ID: 55165), cancer / testis antigen 1A (CTAG1A; ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1; NCBI Gene ID: 246100), cancer / testis antigen 1B (CTAG1B; CT6.1, CTAG, CTAG1, E SO1, LAGE-2, LAGE2B, NY-ESO-1; NCBI gene ID: 1485), cancer / testis antigen 2 (CTAG2; CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B; NCBI gene ID: 30848), CCCTC-binding factor-like (CTCFL; BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20.2; NCBI Gene ID: 140690), catenin alpha 2 (CTNNA2; CAP-R, CAPR, CDCBM9, CT114, CTNR; NCBI Gene ID: 1496), cancer / testis antigen 83 (CT83; CXorf61, KK-LC-1, KKLC1; NCBI Gene ID: 203413), cyclin A1 (CCNA1; CT146; NCBI Gene ID: 8900), and DEAD-box helicase 43 (DDX43; CT13, HAGE; NCBI Gene ID: 55510). , developmental pluripotency associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI Gene ID: 151871), fetal and adult testicular expressed 1 (FATE1; CT43, FATE; NCBI Gene ID: 89885), FMR1 adjacent (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI Gene ID: 158521), HORMA domain containing 1 (HORMAD1; CT46, NOHMA; NCBI Gene ID: 84072), insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3; CT98, IMP-3, IMP3, KOC, KOC1, VICKZ3; NCBI gene ID: 10643), leucine zipper protein 4 (LUZP4; CT-28, CT-8, CT28, HOM-TES-85; NCBI gene ID: 51213), lymphocyte antigen 6 family member K (LY6K; CT97, HSJ001348, URLC10, ly-6K; NCBI gene ID: 54742), maelstrom spermatogenesis transposon silencer (MAEL; CT128, SPATA35 ; NCBI Gene ID: 84944), MAGE family member A1 (MAGEA1; CT1.1, MAGE1; NCBI Gene ID: 4100); MAGE family member A3 (MAGEA3; CT1.3, HIP8, HYPD, MAGE3, MAGEA6; NCBI Gene ID: 4102); MAGE family member A4 (MAGEA4; CT1.4, MAGE-41, MAGE-X2, MAGE4, ​​MAGE4A, MAGE4B; NCBI Gene ID: 4103); MAGE family member A11 (MAGEA11; CT1.11, MAGE-11, MAGE11, MAGEA-11; NCBI Gene ID: 4110); MAGE family member C1 (MAGEC1; CT7, CT7.1; NCBI Gene ID: 9947); MAGE family member C2 (MAGEC2; CT10, HCA587, MAGEE1; NCBI Gene ID: 51438); MAGE family member D1 (MAGED1; DLXIN-1, NRAGE; NCBI Gene ID: 9500); MAGE family member D2 (MAGED2; 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2; NCBI Gene ID: 10916), kinesin family member 20B (KIF20B; CT90, KRMP1, MPHOSPH1, MPP-1, MPP1; NCBI Gene ID: 9585), NUF2 component of the NDC80 kinetochore complex (NUF2; CDCA1, CT106, NUF2R; NCBI Gene ID: 83540), nuclear RNA export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI Gene ID: 5600 1), PAS domain-containing repressor 1 (PASD1; CT63, CT64, OXTES1; NCBI Gene ID: 139135), PDZ-binding kinase (PBK; CT84, HEL164, Nori-3, SPK, TOPK; NCBI Gene ID: 55872), piwi-like RNA-mediated gene silencing 2 (PIWIL2; CT80, HILI, PIWIL1L, mili; NCBI Gene ID: 55124), melanoma preferentially expressed antigen (PRAME; CT130, MAPE, OIP-4, OIP4; NCBI Gene ID: 55124). Gene ID: 23532), sperm-associated antigen 9 (SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI Gene ID: 9043), nuclear X-linked family member A1-related sperm protein (SPANXA1; CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A; NCBI Gene ID: 30014), SPANX family member A2 (SPANXA2; CT11.1, CT11.3).3, SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC; NCBI Gene ID: 728712), SPANX family member C (SPANXC; CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE; NCBI Gene ID: 64663), SPANX family member D (SPANXD; CT11.3, CT11.4, SPANX-C, SPANX-D, SPANX-E, SPANXC, SPANXE, dJ171K16.1; NCBI Gene ID: 64648), SSX family member 1 (SSX1; CT5.1, SSRC; NCBI Gene ID: 6756), SSX family member 2 (SSX2; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI Gene ID: 6757). , synaptonemal structural protein 3 (SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI Gene ID: 50511), testis-expressed 14 intercellular bridge forming factor (TEX14; CT113, SPGF23; NCBI Gene ID: 56155), transcription factor Dp family member 3 (TFDP3; CT30, DP4, HCA661; NCBI Gene ID: 51270), serine protease 50 (PRSS50; CT20, TSP50; NCBI Gene ID: 29122), TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI Gene ID: 7272), and zinc finger protein 165 (ZNF165; CT53, LD65, ZSCAN7; NCBI Gene ID: 7718). T cell receptors (TCRs) and TCR-like antibodies that bind to epitopes of cancer-testis antigens presented on major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer-testis antigens associated with neoplasia are summarized, for example, in Gibbs, et al., Trends Cancer 2018 Oct;4(10):701-712, and in the CT database website at cta.lncc.br / index.php. Exemplary TCRs and TCR-like antibodies that bind to epitopes of NY-ESO-1 presented on MHC are described, for example, in Stewart-Jones, et al.,Proc Natl Acad Sci USA.2009 Apr 7;106(14):5784-8; WO 2005 / 113595, WO 2006 / 031221, WO 2010 / 106431, WO 2016 / 177339, WO 2016 / 210365, WO 2017 / 044661, WO 2017 / 076308, WO 2017 / 109496, WO 2018 / 132739, WO 2019 / 084538, WO 2019 / 162043, WO 2020 / 086158, and WO 2020 / 086647. Exemplary TCRs and TCR-like antibodies that bind to MHC-presented epitopes of PRAME are described, for example, in WO 2011 / 062634, WO 2016 / 142783, WO 2016 / 191246, WO 2018 / 172533, WO 2018 / 234319, and WO 2019 / 109821. Exemplary TCRs and TCR-like antibodies that bind to MHC-presented epitopes of MAGE variants are described, for example, in WO 2007 / 032255, WO 2012 / 054825, WO 2013 / 039889, WO 2013 / 041865, WO 2014 / 118236, WO 2016 / 055785 Exemplary TCRs and TCR-like antibodies that bind to an epitope of MHC-presented alpha-fetoprotein (AFP) are described, for example, in WO 2015 / 011450. Exemplary TCRs and TCR-like antibodies that bind to an epitope of MHC-presented SSX2 are described, for example, in WO 2020 / 063488. Exemplary TCRs and TCR-like antibodies that bind to an epitope of MHC-presented KK-LC-1 (CT83) are described, for example, in WO 2017189254.

[0260] Examples of cell therapy include Algenpantucel-L, Sipuleucel-T, (BPX-501) Ribogenreclucel, U.S. Pat. No. 9,089,520, WO 2016 / 100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Immunoglobulins. Leclucel-T, valtalucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL These include CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

[0261] In some embodiments, the one or more additional co-administered therapeutic agents can be categorized by their mechanism of action, e.g., into the following groups: Drugs that target adenosine deaminase, such as pentostatin or cladribine; · Drugs that target ATM, such as AZD1390; Agents that target MET, such as servotinib, capmatinib, tetponitinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; Drugs targeting mitogen-activated protein kinases, such as antroquinol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mirdametinib (PD-0325901), pimasertib, and refametinib, or drugs described in WO 2011 / 008709, WO 2013 / 112741, WO 2006 / 124944, WO 2006 / 124692, WO 2014 / 064215, and WO 2018 / 005435; Zhou, et al., Cancer Lett. 2017 Nov 1, 408:130-137; Teli, et al., J Enzyme Inhib Med Chem.(2012)27(4):558-70;Gangwall,et al.,Curr Top Med Chem.(2013)13(9):1015-35;Wu,et al.,Bioorg Med Chem Lett.(2009)19(13):3485-8;Kaila,et al.,Bioorg Med Chem.(2007)15(19):6425-42, or Hu, et al., Bioorg Med Chem Lett.(2011)21(16):4758-61; Drugs that target thymidine kinase, such as agratimadine besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk); · Targeted agents that target the interleukin pathway, such as pegilodecaquin (AM-0010) (PEGylated IL10) and CA-4948 (IRAK4 inhibitor); Drugs that target members of the cytochrome P450 family, such as letrozole, anastrozole, aminoglutethimide, medistrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); Drugs that target CD73, such as CD73 inhibitors (e.g., quemliculstat (AB680)) or anti-CD73 antibodies (e.g., oleculab); ·Drugs that target DKK3, such as MTG-201; · Drugs that target EEF1A2, such as platydysine; Drugs that target EIF4A1, such as rohitinib; · Drugs that target endoglin, such as TRC105 (inflotuximab); · Drugs that target exopolitin-1, such as Eltanexa; Agents that target fatty acid amide hydrolases, such as the compounds disclosed in WO 2017 / 160861; · Drugs that target heat shock protein 90 beta family member 1, such as anlotinib; · Drugs that target lactoferrin, such as ruxotemitide (LTX-315); agents that target lysyl oxidase, such as the compounds disclosed in U.S. Pat. No. 4,965,288, U.S. Pat. No. 4,997,854, U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, or U.S. Patent Application Publication No. 2004 / 0248871; · Drugs that target MAGE family members, such as KITE-718, MAGE-A10C796T, or MAGE-A10TCR; · Agents that target MDM2, such as ALRN-6924, CMG-097, milademethane monotosylate monohydrate (DS-3032b), or AMG-232; · Drugs that target MDM4, such as ALRN-6924; · Agents targeting Melan-A, such as MART-1 F5 TCR-engineered PBMCs; Drugs that target mesothelin, such as CSG-MESO or TC-210; Drugs that target METAP2, such as M8891 or APL-1202; · Drugs that target NLRP3, such as BMS-986299; · Drugs that target oxoglutarate dehydrogenase, such as devimistat (CPI-613); · Drugs that target placental growth factor, such as aflibercept; agents that target SLC10A3, such as the compounds disclosed in WO 2015 / 148954, WO 2012 / 082647, or WO 2017 / 160861; · Agents targeting transforming growth factor alpha (TGFa), such as the compounds disclosed in WO 2019 / 103203; · Drugs that target the tumor protein p53, such as kebetrin (stimulator); ·Medications that target vascular endothelial growth factor A, such as aflibercept; · Drugs that target vascular endothelial growth factor receptors, such as fluquinotinib or MP0250; · Drugs that target VISTA, such as CA-170 or HMBD-002; · Drugs that target WEE1, such as adavosertib (AZD-1775); · Small molecule inhibitors targeting ABL1, such as imatinib, rebastinib, asciminib, and ponatinib (ICLUSIG®); · Small molecule antagonists targeting adenosine receptors, such as CPI-444, AZD-4635, preladenant, etrumadenant (AB928), or PBF-509; · Small molecule inhibitors that target arachidonate 5-lipoxygenase, such as meclofenamate sodium or zileuton; · Small molecule inhibitors targeting the ATR serine / threonine kinase, such as BAY-937, selalasertib (AZD6738), AZD6783, VX-803, or VX-970 (berzosertib); · Small molecule inhibitors targeting the AXL receptor tyrosine kinase, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); ·(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posertinib (HM71224), ibrutinib (Imbruvica), M-2951 ( small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebrutinib (CC-292), becabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; · Small molecule inhibitors targeting neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or ceritrectinib (LOXO-195); · Small molecule inhibitors targeting the ROS proto-oncogene 1 receptor tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; · Small molecule inhibitors targeting the SRC proto-oncogene non-receptor tyrosine kinase, such as VAL-201, tirbanibulin (KX2-391), or irginatinib maleate (NS-018); · Small molecule inhibitors targeting B-cell lymphoma 2, such as navitoclax (ABT-263), venetoclax (ABT-199, RG-7601), and AT-101 (gossypol); small molecule inhibitors targeting bromodomain and ectodomain (BET) bromodomain-containing proteins, such as ABBV-744, INCB-054329, INCB057643, AZD-5153, ABT-767, BMS-986158, CC-90010, NHWD-870, ODM-207, ZBC246, ZEN3694, CC-95775 (FT-1101), mibebresisb, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829; ·Small molecule inhibitors targeting carbohydrate sulfotransferase 15, such as STNM-01; Small molecule inhibitors that target carbonic anhydrase, such as polmacoxib, acetazolamide, or methazolamide; · Small molecule inhibitors targeting catenin beta 1, such as CWP-291 or PRI-724; · Small molecule antagonists targeting CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Vicriviroc); · Vilixafortide, a small molecule antagonist targeting C-X-C motif chemokine receptors (e.g., CXCR4); Small molecule inhibitors that target cereblon, such as avadomide (CC-122), CC-92480, CC-90009, or iberdomide; · Small molecule inhibitors targeting checkpoint kinase 1, such as SRA737; ·Small molecule inhibitors that target complement components, such as Imprime PGG (Biothera Pharmaceuticals); · Small molecule inhibitors targeting C-X-C motif chemokine ligands (e.g., CXCL12), such as oraptecedopegol (NOX-A12); · Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; · Small molecule inhibitors targeting DEAD-box helicase 5, such as spinoxin (RX-5902); small molecule inhibitors targeting DGKa, such as those described in WO 2021 / 130638; · Small molecule inhibitors targeting Diablo IAP-binding mitochondrial proteins, such as BI-891065; · Small molecule inhibitors that target dihydrofolate reductase, such as pralatrexed or pemetrexed disodium; · Small molecule inhibitors targeting DNA-dependent protein kinases, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastaurin; · Small molecule inhibitors targeting MARCKS, such as BIO-11006; · Small molecule inhibitors targeting RIPK1, such as GSK-3145094; · Small molecule inhibitors targeting Rho-associated coiled-coil-containing protein kinases, such as AT13148 or KD025; Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, filtecampegol, or amrubicin; ·Small molecule inhibitors targeting the dopamine receptor D2, such as ONC-201; · Small molecule inhibitors targeting histone lysine methyltransferases such as DOT1, such as pinometostat (EPZ-5676); Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497; · Small molecule inhibitors targeting fatty acid synthase, such as TVB-2640 (Sagimet Biosciences); · Small molecule inhibitors targeting fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144); · Small molecule inhibitors targeting focal adhesion kinase (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098; · Small molecule inhibitors targeting folate receptor 1, such as pralatrexate; · Small molecule inhibitors targeting FOXM1, such as thiostrepton; · Small molecule inhibitors targeting galectin-3, such as berapectin (GR-MD-02); · Small molecule antagonists that target the glucocorticoid receptor, such as relacorilant (CORT-125134); · Small molecule inhibitors targeting glutaminase, including but not limited to CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); Small molecule inhibitors that target the GNRHR, such as elagolix, relugolix, or degarelix; · Small molecule inhibitors targeting EPAS1, such as velzutifan (PT-2977 (Merck & Co.)); · Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)), such as restrictive ivosidenib (AG-120), vorasidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221); · Small molecule inhibitors targeting lysine demethylase 1A, such as CC-90011; · Small molecule inhibitors targeting MAPK-interacting serine / threonine kinases, such as tomivosertib (eFT-508); · Small molecule inhibitors targeting Notch receptors, such as AL-101 (BMS-906024); · Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as volasertib or onvansertib; small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazoleparib (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121(e-7499)), simiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP 9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102; · Small molecule inhibitors targeting the polycomb protein EED, such as MAK683; ·Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974; Small molecule inhibitors targeting prostaglandin-endoperoxide synthase, such as HP-5000, rofecoxib, ketorolac tromethamine, bromfenac sodium, otenaproxyl (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, reformulated celecoxib (DRGT-46), AAT-076, Macuoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumizole, firocoxib, rofecoxib, rutaecarpine, tilmacoxib, zaltoprofen, or imrecoxib; Small molecule inhibitors targeting protein arginine N-methyltransferase, such as MS203, PF-06939999, GSK3368715, or GSK3326595; small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720), or compounds disclosed in WO 2018 / 172984 or WO 2017 / 211303; · Small molecule antagonists that target retinoic acid receptors, such as tamibarotene (SY-1425); · Small molecule inhibitors targeting ribosomal protein S6 kinase B1, such as MSC2363318A; · Small molecule inhibitors targeting the S100 calcium-binding protein A9, such as tasquinimod; · Small molecule inhibitors targeting selectin E, such as uproleseran sodium (GMI-1271); · Small molecule inhibitors targeting SF3B1, such as H3B-8800; YC8 ~ small molecule inhibitors targeting sirtuin-3, such as 02; Small molecule inhibitors targeting SMO, such as sonidegib (Odomzo®, formerly LDE-225), vismodegib (GDC-0449), glasdegib (PF-04449913), itraconazole, or pachidegib and taladegib; ·Small molecule antagonists that target somatostatin receptors, such as OPS-201; · Small molecule inhibitors targeting sphingosine kinase 2, such as opaganib (Yeliva®, ABC294640); · Small molecule inhibitors targeting STAT3, such as napabucasin (BBI-608); · Small molecule inhibitors targeting tankyrase, such as G007-LK or stenoparib (2X-121(e-7499)); · Small molecule inhibitors targeting TFGBR1, such as galunisertib and PF-06952229; · Small molecule inhibitors targeting thymidylate synthase, such as idetrexed (ONX-0801); · Small molecule inhibitors that target the tumor protein p53, such as CMG-097; · Small molecule inhibitors that target valosin-containing proteins, such as CB-5083; · Small molecule inhibitors targeting WT1, such as Ombipepimto-S (DSP-7888); · Small molecule agonists that target adenosine receptors, such as namodenoson (CF102); small molecule agonists targeting asparaginase, such as crisantaspase (Erwinase®), GRASPA (ERY-001, ERY-ASP), calaspargase pegol, or pegaspargase; · Small molecule agonists targeting CCAAT enhancer binding protein alpha, such as MTL-501; · Small molecule agonists that target the cytochrome P450 family, such as mitotane; ·Small molecule agonists targeting DExD / H-box helicase 58, such as RGT-100; · Small molecule agonists that target the GNRHR, such as leuprorelin acetate, leuprorelin acetate extended-release depot (ATRIGEL), triptorelin pamoate, or goserelin acetate; · Small molecule agonists targeting GRB2, such as plexigeneversen (BP1001); · Small molecule agonists targeting NFE2L2, such as omaveloxolone (RTA-408); · Small molecule agonists targeting NOD2, such as mifamurtide (liposomal); · Small molecule agonists targeting the RAR-related orphan receptor gamma, such as syntirolgon (LYC-55716); Small molecule agonists that target the retinoic acid receptor (RAR), such as tretinoin; · Small molecule agonists targeting STING1, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, cyclic GAMP (cGAMP), or cyclic di-AMP; · Small molecule agonists that target thyroid hormone receptor beta, such as levothyroxine sodium; · Small molecule agonists that target tumor necrosis factor, such as tasonermin; ·Antisense agents targeting baculovirus IAP repeats containing 5, such as EZN-3042; · Antisense agents targeting GRB2, such as plexigeneversen; ·Antisense agents targeting heat shock protein 27, such as apatrusen; ·Antisense agents targeting STAT3, such as danvatilsen (IONIS-STAT3-2.5Rx); · Gene therapies targeting CC motif chemokine receptors, such as SB-728-T; · Interleukin-targeted gene therapies, such as EGENE-001, tavoquinogenterce plasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55; ·Antibodies targeting claudin-18, such as claudiximab; ·Antibodies targeting clusterin, such as AB-16B5; ·Antibodies that target complement components, such as ravulizumab (ALXN-1210); ·Antibodies targeting C-X-C motif chemokine ligands, such as BMS-986253 (HuMax-Inflam); · Antibodies targeting Delta-like canonical Notch ligand 4 (DLL4) (DLL4 / VEGF), such as demcizumab and nabicixizumab; ·Antibodies targeting the EPH receptor A3, such as fivatuzumab (KB-004); ·Antibodies targeting epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845); ·Antibodies targeting fibroblast growth factors, such as GAL-F2 and B-701 (bofatamab); ·Antibodies targeting hepatocyte growth factor, such as MP-0250; · Interleukin-targeting antibodies, such as canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talaxanthus (JNJ-56022473), siltuximab, or tocilizumab; ·Antibodies targeting LRRC15, such as ABBV-085 or cusatuzumab (ARGX-110); ·Antibodies targeting mesothelin, such as BMS-986148, SEL-403, or anti-MSLN-MMAE; ·Antibodies that target myostatin, such as landgrozumab; ·Antibodies targeting Notch receptors, such as tarectumab; antibodies targeting TGFB1 (TGFb1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA 089, or the compounds disclosed in WO 2019 / 103203; · Vaccines targeting fms-related receptor tyrosine kinases, such as HLA-A2402 / HLA-A0201-restricted epitope peptide vaccines; · Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax); Vaccines targeting PD-L1, such as IO-120+IO-103 (PD-L1 / PD-L2 vaccine) or IO-103; · Vaccines targeting the tumor protein p53, such as MVA-p53; Vaccines targeting WT1, such as WT-1 analog peptide vaccines (WT1-CTL); · Baculovirus IAP repeat-containing 5-targeted cell therapy, such as tumor lysate / MUC1 / survivin PepTivator-loaded dendritic cell vaccine; · Carbonic anhydrase-targeted cell therapies, such as DC-Ad-GMCAIX; · Cellular therapies targeting CC motif chemokine receptors, such as CCR5-SBC-728-HSPC; · Cellular therapies targeting folate hydrolase 1, such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN; · GSTP1-targeted cell therapies, such as CPG3-CAR (GLYCAR); HLA-A targeted cell therapy, such as FH-MCVA2TCR or NeoTCR-P1; · Interleukin-targeted cell therapies, such as CST-101; · KRAS-targeted cell therapy, such as anti-KRAS G12D mTCR PBL; · MET-targeted cell therapies, such as anti-cMet RNA CAR T; · MUC16-targeted cell therapies, such as JCAR-020; · Cellular therapies targeting PD-1, such as PD-1 knockout T-cell therapy (esophageal cancer / NSCLC); · Cellular therapies targeting PRAME, such as BPX-701; · Cell therapies targeting the transforming protein E7, such as KITE-439; Cellular therapies targeting WT1, such as WT1-CTL, ASP-7517, or JTCR-016.

[0262] Exemplary Combination Therapies Lymphoma or leukemia combination therapy Certain chemotherapeutic agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, tin antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta-arretin, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, brusulfan, Campath-1H, carboplatin, carfilzomib (Kyprom), and others. is®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cycloporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone), thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine), fluticasone, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafine gadolinium, mycophenolate mofetil,Nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab) and FCM), R-ICE (rituximab and ICE), R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine tartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

[0263] One improved approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® in combination with CHOP.

[0264] The above-mentioned therapies may be supplemented or combined with stem cell transplantation or therapy, including peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablative with stem cell support, transplantation of in vitro treated peripheral blood stem cells, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0265] Combination therapy for non-Hodgkin's lymphoma Treatment of non-Hodgkin's lymphoma (NHL), particularly lymphomas of B-cell origin, includes the use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, prednisolone), all optionally including rituximab®), radioimmunotherapy, and combinations thereof, particularly the integration of antibody therapy with chemotherapy.

[0266] Examples of unconjugated monoclonal antibodies for the treatment of 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.

[0267] Examples of experimental antibody drugs used to treat NHL / B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

[0268] Examples of standard chemotherapy regimens for NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

[0269] Examples of radioimmunotherapy for NHL / B-cell cancer include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

[0270] Combination therapy for mantle cell lymphoma Curative treatments for mantle cell lymphoma (MCL) include combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above-mentioned therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0271] 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, that are based on the genetic makeup of an individual patient's tumor.

[0272] An improved approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential treatment with CHOP.

[0273] Other approaches to treating MCL include the combination of autologous stem cell transplantation and high-dose chemotherapy, the administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or the administration of antiangiogenic agents such as thalidomide, particularly in combination with rituximab.

[0274] Another treatment approach is to administer drugs that cause the degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapy drugs.

[0275] Further therapeutic approaches include the administration of mTOR inhibitors, which can cause inhibition of cell proliferation and even cell death. Non-limiting examples are sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and combinations of temsirolimus with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0276] Other recent treatments for MCL have been disclosed, including flavopiridol, palbociclib (PD0332991), R-roscovitine (seliciclib, CYC202), styryl sulfones, obatoclax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CC1-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG).

[0277] Combination therapy for Waldenström macroglobulinemia Waldenstrom's macroglobulinemiaTherapeutic agents used to treat macroglobulinemia (WM) include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta-arretin, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H, carboplatin, and carmustine. , caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 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 toxin Momab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody to CD19 (e.g., tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody to CD20, motexafine gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, pentobarbital Statins, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, urocuprumab, veltuzumab, vincristine sulfate, vinorelbine tartrate, vorinostat, WT1126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0278] Examples of therapeutic approaches used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biologic therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablative with stem cell support, transplantation of in vitro processed peripheral blood stem cells, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0279] Combination therapy for diffuse large B-cell lymphoma (DLBCL) Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and RICE. In some embodiments, therapeutic agents used to treat DLBCL include liximab (Rituxan®), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin®), prednisone, bendamustine, ifosfamide, carboplatin, etoposide, ibrutinib, polatuzumab vedotin piiq, bendamustine, copanlisib, lenalidomide (Revlimid®), dexamethasone, cytarabine, cisplatin, Yescarta®, Kymriah®, Polivy® (polatuzumab vedotin), BR (bendamustine (Treanda®)), gemcitabine, oxiplatin, oxaliplatin, tafasitamab, polatuzumab, cyclophosphamide, or a combination thereof.In some embodiments, therapeutic agents used to treat DLBCL include R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone), rituximab + bendamustine, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), rituximab + lenalomide, R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara C) + cisplatin), Polivy® (polatuzumab vedotin) + BR (bendamustine (Treanda®) and rituximab (Rituxan®), R-GeMOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafasitamab + lenalidomide), tafasitamab + Revlimid®, polatuzumab + bendamustine, gemcitabine + oxaliplatin, R-EPOCH (rituximab + etoposide phosphate + prednisone + vincristine sulfate (Oncovin®) + cyclophosphamide + doxorubicin hydrochloride (hydroxydopamine), or CHOP (cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone). In some embodiments, therapeutic agents used to treat DLBCL include tafasitamab, glofitamab, epocolitamab, Lonca-T (loncatuximab tesirin), Debio-1562, polatuzumab, Yescarta, JCAR017, ADCT-402, brentuximab vedotin, MT-3724, odronectumab, Auto-03, Allo-501A, or TAK-007.

[0280] Combination therapy for chronic lymphocytic leukemia Therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include combination chemotherapy and chemoimmunotherapy, including chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and the common combination regimens CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0281] High Risk Myelodysplastic Syndrome (HR MDS) Combination Therapy Therapeutic agents used to treat HR MDS include azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, daunorubicin, and combinations thereof. In some embodiments, combinations include cytarabine plus daunorubicin and cytarabine plus idarubicin. In some embodiments, therapeutic agents used to treat HR MDS include pevonedistat, venetoclax, sabatolimab, guadecitabine, rigosertib, ivosidenib, enazidenib, selinexor, BGB324, DSP-7888, or SNS-301.

[0282] Combination therapy for Low Risk Myelodysplastic Syndrome (LR MDS) Therapeutic agents used to treat LR MDS include lenalidomide, azacitidine, and combinations thereof. In some embodiments, therapeutic agents used to treat LR MDS include roxadustat, raspatercept, imetelstat, LB-100, or rigosertib.

[0283] Acute myeloid leukemia (AML) combination therapy Therapeutic agents used to treat AML include cytarabine, idarubicin, daunorubicin, midostaurin (Rydapt®), venetoclax, azacitidine, ivasidenib, gilteritinib, enadidenib, low-dose cytarabine (LoDAC), mitoxantrone, fludarabine, granulocyte colony-stimulating factor, idarubicin, gilteritinib (Xospata®), enadidenib (Idhifa®), ivosidenib (Tibsovo®), decitabine (Dacogen®), mitoxantrone, etoposide, gemtuzumab ozogamicin (Mylotarg®), glasdegib (Daurismo®), and combinations thereof. In some embodiments, therapeutic agents used to treat AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte-colony stimulating factor (G-CSF), and idarubicin), cytarabine + idarubicin, cytarabine + daunorubicin + midostaurin, venetoclax + azacitidine, cytarabine + daunorubicin, or MEC (mitoxantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents used to treat AML include pevonedistat, venetoclax, sabatolimab, eprenetapopt, or renzoparlimab.

[0284] Multiple myeloma (MM) combination therapy Therapeutic agents used to treat MM include lenalidomide, bortezomib, dexamethasone, daratumumab (Darzalex®), pomalidomide, cyclophosphamide, carfilzomib (Kyprolis®), elotuzumab (Empliciti), and combinations thereof. In some embodiments, therapeutic agents used to treat MM include RVS (lenalidomide + bortezomib + dexamethasone), RevDex (lenalidomide + dexamethasone), CYBORD (cyclophosphamide + bortezomib + dexamethasone), Vel / Dex (bortezomib + dexamethasone), or PomDex (pomalidomide + low-dose dexamethasone). In some embodiments, therapeutic agents used to treat MM include JCARH125, TAK-573, belantamab-m, ide-cel (CAR-T).

[0285] Breast cancer combination therapy Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, atezolizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat breast cancer (e.g., HR+ / - / HER2+ / -) include trastuzumab (Herceptin®), pertuzumab (Perjeta®), docetaxel, carboplatin, palbociclib (Ibrance®), letrozole, trastuzumab emtansine (Kadcyla®), fulvestrant (Faslodex®), olaparib (Lynparza®), eribulin, tucatinib, capecitabine, lapatinib, everolimus (Afinitor®), exemestane, eribulin mesylate (Halaven®), and combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab + pertuzumab + docetaxel, trastuzumab + pertuzumab + docetaxel + carboplatin, palbociclib + letrozole, tucatinib + capecitabine, lapatinib + capecitabine, palbociclib + fulvestrant, or everolimus + exemestane. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab deruxtecan (Enhertu®), datopotamab deruxtecan, DS-1062, enfortumumab vedotin (Padcev®), balixafortide, elacestrant, or combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer include balixafortide + eribulin.

[0286] Triple Negative Breast Cancer (TNBC) Combination Therapy Therapeutic agents used to treat TNBC include atezolizumab, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, therapeutic agents used to treat TNBC include olaparib (Lynparza®), atezolizumab (Tecentriq®), paclitaxel (Abraxane®), eribulin, bevacizumab (Avastin®), carboplatin, gemcitabine, eribulin mesylate (Halaven®), sacituzumab govitecan (Trodelvy®), pembrolizumab (Keytruda®), cisplatin, doxorubicin, epirubicin, or combinations thereof. In some embodiments, therapeutic agents for treating TNBC include atezolizumab and paclitaxel, bevacizumab and paclitaxel, carboplatin and paclitaxel, carboplatin and gemcitabine, or paclitaxel and gemcitabine. In some embodiments, therapeutic agents used to treat TNBC include eliyaspase, capivasertib, alpelisib, rucaparib and nivolumab, atezolumab, paclitaxel, gemcitabine, capecitabine, and carboplatin, ipatasertib and paclitaxel, radilatuzumab vedotin and pembrolimab, durvalumab and DS-8201a, and trilaciclib, gemcitabine, and carboplatin. In some embodiments, therapeutic agents used to treat TNBC include trastuzumab deruxtecan (Enhertu®, datopotamab deruxtecan (DS-1062), enfortumab vedotin (Padcev®), balixafortide, adaggloxad simolenin, neripepimet (NeuVax®), nivolumab (Opdivo®), rucaparib, toripalimab (Tuoyi®), camrelizumab, capivasertib, durvalumab (Imfinzi®), and combinations thereof.In some embodiments, therapeutic agents used to treat TNBC include nivolumab plus rucaparib, bevacizumab (Avastin®) plus chemotherapy, toripalimab plus paclitaxel, toripalimab plus albumin-bound paclitaxel, camrelizumab plus chemotherapy, pembrolizumab plus chemotherapy, balixafortide plus eribulin, durvalumab plus trastuzumab deruxtecan, durvalumab plus paclitaxel, or capivasertib plus paclitaxel.

[0287] Bladder cancer combination therapy Therapeutic agents used to treat bladder cancer include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), erdafitinib, eganelisib, lenvatinib, bempegaldesleukin (NKTR-214), or combinations thereof. In some embodiments, therapeutic agents used to treat bladder cancer include eganelisib plus nivolumab, pembrolizumab (Keytruda®) plus enfortumumab vedotin (Padcev®), nivolumab plus ipilimumab, duravalumab plus tremelimumab, lenvatinib plus pembrolizumab, enfortumumab vedotin (Padcev®) plus pembrolizumab, and bempegaldesleukin plus nivolumab.

[0288] Colorectal cancer (CRC) combination therapy Therapeutic agents used to treat CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab (Avastin®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda®), FOLFIRI, regorafenib (Stivarga®), aflibercept (Zaltrap®), cetuximab (Erbitux®), Lonsurf (Orcantas®), XELOX, FOLFOXIRI, or a combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, therapeutic agents used to treat CRC include binimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabucasin + FOLFIRI + bevacizumab, and nivolumab + ipilimumab.

[0289] Combination therapy for esophageal and gastroesophageal junction cancer Therapeutic agents used to treat esophageal and gastroesophageal junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. In some embodiments, therapeutic agents used to treat gastroesophageal junction cancer (GEJ) include Herceptin, cisplatin, 5-FU, ramicurimab, or paclitaxel. In some embodiments, therapeutic agents used to treat GEJ cancer include ALX-148, AO-176, or IBI-188.

[0290] Gastric cancer combination therapy Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0291] Head and neck cancer combination therapy 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.

[0292] Therapeutic agents used to treat head and neck squamous cell carcinoma (HNSCC) include pembrolizumab, carboplatin, 5-FU, docetaxel, cetuximab (Erbitux®), cisplatin, nivolumab (Opdivo®), and combinations thereof. In some embodiments, therapeutic agents used to treat HNSCC include pembrolizumab + carboplatin + 5-FU, cetuximab + cisplatin + 5-FU, cetuximab + carboplatin + 5-FU, cisplatin + 5-FU, and carboplatin + 5-FU. In some embodiments, therapeutic agents used to treat HNSCC include durvalumab, durvalumab plus tremelimumab, nivolumab plus ipilimumab, robaleucel, pembrolizumab, pembrolizumab plus epacadostat, GSK3359609 plus pembrolizumab, lenvatinib plus pembrolizumab, retifanlimab, retifanlimab plus enobituzumab, ADU-S100 plus pembrolizumab, epacadostat plus nivolumab plus ipilimumab / lirilumab.

[0293] Combination therapy for non-small cell lung cancer Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat NSCLC include alectinib (Alecensa®), dabrafenib (Tafinlar®), trametinib (Mekinist®), osimertinib (Tagrisso®), entrectinib (Tarceva®), crizotinib (Xalkori®), pembrolizumab (Keytruda®), carboplatin, pemetrexed (Alimta®), nab-paclitaxel (Abraxane®), ramucirumab (Cyramza®), docetaxel, bevacizumab (Avastin®), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif®), nivolumab, tetanus ... In some embodiments, therapeutic agents used to treat NSCLC include dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + nab-paclitaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed + carboplatin, cisplatin + pemetrexed, bevacizumab + carboplatin + nab-paclitaxel, cisplatin + Gemzar, nivolumab + docetaxel, carboplatin + pemetrexed, carboplatin + nab-paclitaxel, or pemetrexed + cisplatin + carboplatin.In some embodiments, therapeutic agents used for NSCLC include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), enfortumab vedotin (Padcev®), durvalumab, canakinumab, cemiplimab, nogapendekin alfa, avelumab, tiragolumab, donbanalimab, vibostolimab, osipellimab, or combinations thereof. In some embodiments, the therapeutic agents used to treat NSCLC include datopotamab deruxtecan plus pembrolizumab, datopotamab deruxtecan plus durvalumab, durvalumab plus tremelimumab, pembrolizumab plus lenvatinib plus pemetrexed, pembrolizumab plus olaparib, nogapendequin alfa (N-803) plus pembrolizumab, tiragolumab plus atezolizumab, vibostolimab plus pembrolizumab, or osipellimab plus tislelizumab.

[0294] Small cell lung cancer combination therapy Therapeutic agents used to treat small cell lung cancer (SCLC) include atezolizumab, bendamustimeth, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivolumab, durvalumab, trilaciclib, or a combination thereof. In some embodiments, the therapeutic agents used to treat SCLC include atezolizumab plus carboplatin plus etoposide, atezolizumab plus carboplatin, atezolizumab plus etoposide, or carboplatin plus paclitaxel.

[0295] Ovarian cancer combination therapy Therapeutic agents used to treat ovarian cancer include 5-fluorouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[0296] Pancreatic cancer combination therapy Therapeutic agents used to treat pancreatic cancer include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel (Abraxane®), FOLFIRINOX, and combinations thereof. In some embodiments, therapeutic agents used to treat pancreatic cancer include 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, leucovorin + nanoliposomal irinotecan, and gemcitabine + nab-paclitaxel.

[0297] Prostate Cancer Combination Therapy Therapeutic agents used to treat prostate cancer include enzalutamide (Xtandi®), leuprolide, trifluridine, tipiracil (Lonsurf®), cabazitaxel, prednisone, abiraterone (Zytiga®), docetaxel, mitoxantrone, bicalutamide, LHRH, flutamide, ADT, sabizablin (Veru-111), and combinations thereof. In some embodiments, therapeutic agents used to treat prostate cancer include enzalutamide + leuprolide, trifluridine + tipiracil (Lonsurf®), cabazitaxel + prednisone, abiraterone + prednisone, docetaxel + prednisone, mitoxantrone + prednisone, bicalutamide + LHRH, flutamide + LHRH, leuprolide + flutamide, and abiraterone + prednisone + ADT.

[0298] Additional Illustrated Combination Therapies In some embodiments, a compound provided herein is administered with one or more therapeutic agents selected from a PI3K inhibitor, a Trop-2 binding agent, a CD47 antagonist, a SIRPα antagonist, a FLT3R agonist, a PD-1 antagonist, a PD-L1 antagonist, an MCL1 inhibitor, a CCR8 binding agent, an HPK1 antagonist, a DGKa inhibitor, a CISH inhibitor, a PARP-7 inhibitor, a Cbl-b inhibitor, a KRAS inhibitor (e.g., a KRAS G12C or G12D inhibitor), a KRAS degrader, a beta-catenin degrader, a Helios degrader, a CD73 inhibitor, an adenosine receptor antagonist, a TIGIT antagonist, a TREM1 binding agent, a TREM2 binding agent, a CD137 agonist, a GITR binding agent, an OX40 binding agent, and a CAR-T cell therapy.

[0299] In some embodiments, the compounds provided herein are selected from the group consisting of PI3Kd inhibitors (e.g., idealisib, anti-Trop-2 antibody conjugates (e.g., sacituzumab govitecan, datopotamab deruxtecan (DS-1062)), anti-CD47 antibodies or CD47 blockers (e.g., magrolimab, DSP-107, AO-176, ALX-148, retaplimab (IBI-188), lemzoparlimab, TTI-621, TTI-622), anti-SIRPα antibodies (e.g., GS-0189), FLT3L-Fc fusion proteins (e.g., GS-3583), anti-PD-1 antibodies (pembrolizumab, nivolumab, dimvelelimab), small molecule PD-L1 inhibitors (e.g., GS-4224), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab), small molecule MCL1 inhibitors (e.g., GS-9716), small molecule HPK1 inhibitors (e.g., GS-6451), HPK1 degraders (PROTACs; e.g., ARV-766), small molecule DGKa inhibitors, small molecule CD73 inhibitors (e.g., quemliculstat (AB680)), anti-CD73 antibodies (e.g., oleculab), dual A 2a / A 2b The patient is administered in combination with one or more therapeutic agents selected from an adenosine receptor antagonist (e.g., etormadenant (AB928)), an anti-TIGIT antibody (e.g., tiragolumab, vibostolimab, domvanalimab, AB308), an anti-TREM1 antibody (e.g., PY159), an anti-TREM2 antibody (e.g., PY314), a CD137 agonist (e.g., AGEN-2373), a GITR / OX40 binder (e.g., AGEN-1223), and a CAR-T cell therapy (e.g., axicabtadine ciloleucel, brexcabtadine autoleucel, tisagenlecleucel).

[0300] In some embodiments, a compound provided herein is administered with one or more therapeutic agents selected from idealisib, sacituzumab govitecan, magrolimab, GS-0189, GS-3583, dimverelimab, GS-4224, GS-9716, GS-6451, quemliculstat (AB680), etrumadenant (AB928), domvanalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicabtadine ciloleucel, and brexcabtadine autoleucel.

[0301] VI. Working Examples Abbreviation Certain abbreviations and acronyms are used in describing the experimental details. While most of these will be understood by those skilled in the art, Table 1 contains a list of some of these abbreviations and acronyms.

[0302] [Table 1-2]

[0303] [Table 2-1]

[0304] [Table 2-2]

[0305] General Step 1: Preparation of di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate:

[0306] [ka]

[0307] To a solution of 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (500 mg, 1.38 mmol, 1 equiv.) and triethylamine (0.67 mL, 4.83 mmol, 3.5 equiv.) in DMF (16 mL) was added di-tert-butyl(chloromethyl)phosphate (1.07 g, 4.14 mmol, 3 equiv.). The reaction mixture was heated to 60° C. and stirred for 16 hours. Another aliquot of di-tert-butyl(chloromethyl)phosphate (1.07 g, 4.14 mmol, 3 equiv.) and triethylamine (0.67 mL, 4.83 mmol, 3.5 equiv.) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was then diluted with EtOAc / water and extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by silica chromatography (100% EtOAc) to give di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate. [Example]

[0308] Example 1 Preparation of (5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate

[0309] [ka]

[0310] To a solution of di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate (671 mg, 1.15 mmol, 1 equiv.) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 15 min, then concentrated in vacuo and purified by HPLC (10-80% MeCN / water with TFA). LC-MS m / z: 473.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 11.79(s,1H),8.25(s,1H),8.08(d,J=1.2Hz,1H),7.59(d,J=1.2Hz,1H),6 .54(s,1H),5.53(d,J=10.7Hz,2H),4.41(s,2H),3.86(s,2H),1.21(s,6H). 19F NMR (376MHz, DMSO-d6) δ-115.33 (m, 2F). 31P NMR (162MHz, DMSO-d6) δ-2.24 (t, J=10.6Hz, 1P).

[0311] The following compound was prepared in a manner similar to (5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate using the modifications listed below.

[0312] Example 2 Di-tert-butyl((2,4-dioxo-5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate was reacted with 5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate in a 5-chloro-1,2-dihydro-2-(2H-indazol-6-yl)cyclopropylmethyl group. Prepared using 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione; hydrochloride salt instead of 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.

[0313] [ka]

[0314] Instead of di-tert-butyl ((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, di-tert-butyl ((2,4-dioxo-5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazole) 5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione was prepared using 5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.

[0315] [ka]

[0316] LC-MS m / z: 578.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 11.90(s,1H),8.33(s,1H),8.28(d,J=1.3Hz,1H),8.16(d,J=0.9Hz,1H),7.77-7.66(m,3H),7.49(s,1H),7.13(dd,J=8.6,1.2Hz,1H),5.56(d, 1H) 19F NMR (376MHz, DMSO-d6) δ-70.08 (t, J=9.1Hz, 3F). 31P NMR (162MHz, DMSO-d6) δ-2.22 (t, J=11.0Hz, 1P).

[0317] Example 3 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine instead of 5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione Tetra-tert-butyl (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxopyrimidin-1,3(2H,4H)-diyl)bis(methylene)) bis(phosphate) was prepared using -2,4(1H,3H)-dione.

[0318] [ka]

[0319] Instead of di-tert-butyl((5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, tetra-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl) (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxopyrimidin-1,3(2H,4H)-diyl)bis(methylene))bis(dihydrogen phosphate) was prepared using (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxopyrimidin-1,3(2H,4H)-diyl)bis(methylene))bis(dihydrogen phosphate).

[0320] [ka]

[0321] LC-MS m / z:706.1(M+1). 1H NMR(400MHz,DMSO-d6)δ 8.45(s,1H),8.15(d,J=0.8Hz,1H),7.73(d,J=8.2Hz,2H),7.60(d,J=7.1Hz, 1H),7.43(s,1H),7.13(dd,J=8.4,1.4Hz,1H),5.69(d,J=6.5Hz,2H),5.64(d, J=10.8Hz,2H),5.41(q,J=9.2Hz,2H),3.02(ddd,J=8.9,6.3,4.3Hz,1H),2.83 (ddd,J=8.8,5.9,4.3Hz,1H),2.21-2.09(m,1H),1.91(dt,J=8.7,5.5Hz,1H). 19F NMR(376MHz,DMSO-d6)δ-70.08(t,J=9.1Hz,3F),-155.02(d,J=7.2Hz,1F). 31P NMR (162MHz, DMSO-d6) δ-2.18(t,J=11.0Hz,1P),-3.44(t,J=6.5Hz,1P).

[0322] General Step 2: Preparation of 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate

[0323] [ka]

[0324] To a solution of 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione; hydrochloride salt (100 mg, 0.192 mmol, 1 equiv.) in DMAc (1 mL) was added KHCO (48 mg, 0.479 mmol, 2.5 equiv.) and di-tert-butyl(chloromethyl)phosphate (59.5 mg, 0.23 mmol, 1.2 equiv.). The reaction mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was then diluted with EtOAc / water and extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by silica chromatography (100% EtOAc) to give di-tert-butyl ((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate.

[0325] Example 4 Preparation of (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate.

[0326] [ka]

[0327] 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate To a solution of (90 mg, 0.127 mmol, 1 equiv) in DCM (2.5 mL) was added TFA (0.25 mL). The reaction mixture was stirred at room temperature for 15 min, then concentrated in vacuo and purified by HPLC (10-80% MeCN / water with TFA). LC-MS m / z: 596.1 (M+1). 1H NMR(400MHz,DMSO-d6)δ 11.92(s,1H),8.36(s,1H),8.15(s,1H),7.78-7.68(m,2H),7.58(d,J= 7.0Hz,1H),7.49(s,1H),7.12(d,J=8.5Hz,1H),5.57(d,J=10.8Hz,2H), 5.40(q,J=9.1Hz,2H),3.04(ddd,J=9.3,6.3,4.4Hz,1H),2.79(dt,J=9.4,5.2Hz,1H),2.18(dt,J=8.8,5.2Hz,1H),1.90(dt,J=8.6,5.2Hz,1H). 19F NMR(376MHz,DMSO-d6)δ-70.08(t,J=9.2Hz,3F),-155.18(d,J=7.0Hz,1F).

[0328] The following compound was prepared in a manner similar to (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate using the modifications listed below.

[0329] Example 5 Di-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate by 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate Prepared using 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione; hydrochloride instead of 5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione;

[0330] [ka]

[0331] Instead of di-tert-butyl((5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate, (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate was prepared using (5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate.

[0332] [ka]

[0333] LC-MS m / z: 597.1(M+1). 1H NMR(400MHz,DMSO-d6)δ 11.93(s,1H),8.36(s,1H),8.25(s,1H),8.20(d,J=8.3Hz,1H),7.58(d,J=7.1 Hz,1H),7.51(s,1H),7.38(d,J=8.3Hz,1H),5.57(d,J=10.8Hz,2H),5.34(tt,J =9.3,4.8Hz,2H),3.24(ddd,J=8.6,5.9,4.1Hz,2H),3.07(ddd,J=8.9,6.1,4. 0Hz,1H),2.22(ddd,J=8.6,6.2,3.9Hz,1H),2.06(ddd,J=9.4,5.8,3.9Hz,1H). 19F NMR (376MHz, DMSO-d6) δ-69.89(t,J=9.1Hz,3F),-155.18(d,J=7.1Hz,1F). 31P NMR (162MHz, DMSO-d6) δ-2.18 (t, J=10.8Hz, 1P).

[0334] Example 6 and Example 7 Di-tert-butyl((2,4-dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phosphate and tetra-tert-butyl((2,4-dioxo-5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-1,3(2H,4H)-diyl (I)bis(methylene))bis(phosphate) was prepared using 5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione; trifluoroacetic acid was used in place of 5-(3-fluoro-8-((1S,...

Claims

1. Formula I: 【Chemistry 58】 (In the ceremony X is C or N; Y is N; Z is C or N; provided that one of X and Z is C and two of X, Y and Z are N; R １ is H and CH ２ OP(O)(OH) ２ is selected from R ２ But C ３～６ cycloalkyl or 3- to 8-membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are each independently one or more of R ４ is replaced by R ３ is H or halo; R ４ are independently H, halo, C １～４ Alkyl, -OR ５ , C ６～１０ aryl, or 4- to 10-membered heteroaryl, １～４ Alkyl, C ６～１０ The aryl or 4- to 10-membered heteroaryl may optionally be one or more R ６ is replaced by R ５ is C １～５ Alkyl, C １～５ Alkenyl, C １～５ Alkynyl, C ６～１０ aryl, or 4- to 10-membered heteroaryl, １～５ alkyl, the C １～５ Alkenyl, the C １～５ Alkynyl, the C ６～１０ The aryl, or the 4- to 10-membered heteroaryl, may optionally be one or more R ６ and substituted by halo; R ６ is C １～５ Alkyl, C ３～６ Cycloalkyl, C １～５ Alkenyl, C １～５ alkynyl, or 4- to 10-membered heteroaryl, １～５ alkyl, the C ３～６ cycloalkyl, the C １～５ alkenyl, or the C １～５ The alkynyl is optionally substituted by halo, and said 4-10 membered heteroaryl is optionally C １～４ Alkyl, or C １～４ substituted by haloalkyl), or a pharmaceutically acceptable salt thereof.

2. R １ or a pharmaceutically acceptable salt thereof.

3. R １ is CH ２ OP(O)(OH) ２ 2. The compound of claim 1, wherein:

4. R ２ is one or more R ４ C substituted by ３～６ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

5. R ２ is one or more R ４ 3. The compound according to claim 1 or 2, wherein the heterocyclyl is a 3- to 8-membered heterocyclyl substituted by:

6. R ２ is one or more R ４ 3. The compound of claim 1, wherein R is cyclopropyl substituted with R, or a pharmaceutically acceptable salt thereof.

7. R ４ optionally one or more R ６ The compound according to any one of claims 1 to 3, wherein R is a 4- to 10-membered heteroaryl substituted by: or a pharmaceutically acceptable salt thereof.

8. R ４ is one or more R ６ 8. The compound of claim 7, wherein the heteroaryl is a 4- to 10-membered heteroaryl substituted by: or a pharmaceutically acceptable salt thereof.

9. R ４ is one or more C １～５ 4-10 membered heteroaryl substituted with alkyl, １～５ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with halo.

10. R ４ is one or more C １～５ 4-10 membered heteroaryl substituted with alkyl, １～５ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the alkyl is substituted with one or more halo.

11. R ４ is one or more C １～５ 4-10 membered heteroaryl substituted with alkyl, １～５ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the alkyl is substituted with one or more fluoro.

12. R ４ is one or more C １～５ is an indazole substituted with alkyl, １～５ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the alkyl is substituted with one or more fluoro.

13. R ４ is one C １～５ is an indazole substituted with alkyl, １～５ 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the alkyl is substituted with one or more fluoro.

14. R ４ 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein: is an indazole substituted by trifluoroethyl.

15. R ３ is H, or a pharmaceutically acceptable salt thereof.

16. R ３ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein: is halo.

17. R ３ or a pharmaceutically acceptable salt thereof.

18. below: 【Chemistry 59】 14. The compound of claim 13, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. R ２ is a 3- to 8-membered heterocyclyl, said heterocyclyl being selected from one or more R ４ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, substituted by:

20. R ２ is one or more R ４ 20. The compound of claim 19, which is pyrrolidinyl substituted by: or a pharmaceutically acceptable salt thereof.

21. The pyrrolidinyl has two fluoro groups and -OR ５ or a pharmaceutically acceptable salt thereof.

22. R ５ is a 4- to 10-membered heteroaryl, optionally containing one or more R ６ and halo, or a pharmaceutically acceptable salt thereof.

23. The pyrrolidinyl may independently be selected from four R ４ or a pharmaceutically acceptable salt thereof.

24. 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein said pyrrolidinyl is substituted with two methyl groups and two fluoro groups.

25. 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein said pyrrolidinyl is substituted with gem dimethyl.

26. below: 【Transformation 60】 21. The compound of claim 20, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

28. 10. A composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for treating cancer in a patient in need thereof.

29. 10. A pharmaceutical composition for treating cancer in a patient in need thereof, comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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