Methods of treating cancer

Abstract

The present disclosure features a combination therapy useful for the treatment of solid tumors.

Description

[0001] METHODS OF TREATING CANCER

[0002] BACKGROUND OF THE INVENTION

[0003] The invention relates to methods for modulating BRG1 - or BRM-associated factors (BAF) complexes for use in the treatment of solid tumors, (e.g., melanoma, lung cancer, and prostate cancer) . In particular, the invention relates to methods for treatment of disorders associated with BAF complex function.

[0004] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is a mechanism by which such gene expression occurs. The human Switch / Sucrose Non-Fermentable (SWI / SNF) chromatin remodeling complex, also known as BAF complex, has two SWI2-like ATPases known as BRG1 (Brahma-related gene-1 ) and BRM (Brahma). The transcription activator BRG1 , also known as ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is needed for cancer cell proliferation. BRM, also known as probable global transcription activator SNF2L2 and / or ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for tumor cell growth in cells characterized by loss of BRG1 function mutations. Deactivation of BRG and / or BRM results in downstream effects in cells, including cell cycle arrest and tumor suppression.

[0005] The present disclosure relates to increasing the level of cell differentiation in solid tumors (e.g., melanoma, lung cancer, prostate cancer) by administering N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof alone or in combination with other anti-cancer therapies.

[0006] SUMMARY

[0007] In some embodiments, the subject has a solid tumor. In some embodiments, the solid tumor expresses BRG1 and / or BRM protein and / or the cell or subject has been identified as expressing BRG1 and / or BRM. In some embodiments, the solid tumor expresses BRG1 protein and / or the cell or subject has been identified as expressing BRG1 . In some embodiments, the solid tumor expresses BRM protein and / or the cell or subject has been identified as expressing BRM. In some embodiments, the solid tumor is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the solid tumor is lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC)). In some embodiments, the solid tumor is prostate cancer (e.g., neuroendocrine prostate cancer (NEPC)). In some embodiments, the solid tumor is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the solid tumor is a bone cancer (e.g., Ewing’s sarcoma). In some embodiments, the solid tumor is a neuroblastoma. In some embodiments, the solid tumor is a cutaneous melanoma. In some embodiments, the solid tumor is a rhabdoid tumor. In some embodiments, the solid tumor is an upper aerodigestive cancer. In particular embodiments, the solid tumor is an esophageal cancer (e.g., esophageal adenocarcinoma or esophageal squamous-cell carcinoma). In some embodiments, the solid tumor is a renal cell carcinoma (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma). In some embodiments, the solid tumor is metastatic (e.g., the solid tumor has spread to the liver). The metastatic cancer can include cells exhibiting migration and / or invasion of migrating cells and / or include cells exhibiting endothelial recruitment and / or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. Alternatively, the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously. In some embodiments, the effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM is an amount effective to inhibit metastatic colonization of the solid tumor to the liver.

[0008] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the effective amount is an amount sufficient to increase levels of SOX10, tyrosinase, GP100, MelanA, or a combination thereof.

[0010] In some embodiments, the effective amount is an amount sufficient to increase the level of melanocyte cells.

[0011] In some embodiments, the effective amount is an amount sufficient to decrease the level of primitive ectoderm cells.

[0012] In some embodiments, the effective amount is an amount sufficient to decrease levels of PRAME, CD44, KIT, BRG1 , or a combination thereof.

[0013] In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PRAME, CD44, KIT, BRG1 , or a combination thereof compared to a reference.

[0014] In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PRAME, CD44, KIT, BRG1 , or a combination thereof compared to a subject that does not have melanoma.

[0015] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing SOX10, tyrosinase, GP100, MelanA, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0016] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of melanocyte cells compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof. In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the melanoma expresses PRAME, CD44, KIT, BRG1 , or a combination thereof.

[0017] In some embodiments, the effective amount is an amount sufficient to increase levels of IFNy, MHCI, CD8, or a combination thereof.

[0018] In some embodiments, the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof.

[0019] In some embodiments, the effective amount is an amount sufficient to decrease the level of Treg cells, M2cp cells, tumor associated macrophages (TAM), or a combination thereof.

[0020] In some embodiments, the effective amount is an amount sufficient to decrease levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

[0021] In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a reference.

[0022] In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a subject that does not have melanoma.

[0023] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino3yridinen-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing IFNy, MHCI, CD8, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0024] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino3yridinen-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0025] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino3yridinen-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the melanoma expresses PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

[0026] In some embodiments, the levels are measured in a tissue sample of the subject. In some embodiments, the levels are measured in a blood sample of the subject.

[0027] In some embodiments, the subject is further administered at least one additional anti-cancer therapy.

[0028] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) tebentafusp-tebn.

[0029] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) bivatuzumab, RG7356, or a combination thereof.

[0030] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) IMA203 / IMA203CD8.

[0031] In some embodiments, the method further comprising administration of a PD-1 / PD-L1 inhibitor.

[0032] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

[0033] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) imatinib, dasatinib, avapritinib, nilotinib, KTN0182A, or a combination thereof.

[0034] In some embodiments, the melanoma is mucosal melanoma, uveal melanoma, or cutaneous melanoma.

[0035] In some embodiments, the melanoma is uveal melanoma.

[0036] In some embodiments, the melanoma is cutaneous melanoma.

[0037] In some embodiments, the melanoma is metastatic.

[0038] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the effective amount is an amount sufficient to decrease levels of CD44.

[0040] In some embodiments, the effective amount is an amount sufficient to increase the level of club cells and / or alveolar cells.

[0041] In some embodiments, the effective amount is an amount sufficient to decrease the level of basal cells. In some embodiments, the effective amount is an amount sufficient to decrease levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , or a combination thereof.

[0042] In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , CD44, or a combination thereof compared to a reference.

[0043] In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , CD44, or a combination thereof compared to a subject that does not have lung cancer.

[0044] In one aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to decrease the level of CD44 compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0045] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is n amount sufficient to increase the level of club cells and / or alveolar cells compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof..

[0046] In one aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the lung cancer expresses TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , high level of CD44, or a combination thereof.

[0047] In some embodiments, the AP-1 transcription factors are Jun (eJun, JunB, JunD), Fos (cFos, FosB, FosL1 / Fra1 , FosL2 / Fra2), Maf (musculoaponeurotic fibrosarcoma) (c-Maf, MafB, MafA. Mafg / f / k, Nrl), ATF-activating transcription factor (ATF2, LRF1 / ATF3, BATF, JDP1 , JDP2), or a combination thereof.

[0048] In some embodiments, the AP-1 transcription factors are eJun, cFos, FosL2, and JunB.

[0049] In some embodiments, the effective amount is an amount sufficient to increase levels of IFNy, MHCI, CD8, or a combination thereof.

[0050] In some embodiments, the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof.

[0051] In some embodiments, the effective amount is an amount sufficient to decrease the level of Treg cells, M2cp cells, tumor associated macrophages (TAM), or a combination thereof.

[0052] In some embodiments, the effective amount is an amount sufficient to decrease levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof. In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a reference.

[0053] In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a subject that does not have lung cancer.

[0054] In one aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing IFNy, MHCI, CD8, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0055] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the present disclosure provides methods of increasing the level of cell differentiation in a subject, the method comprising administering to the subject, (i) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and, following step (i), administering to the subject (ii) maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the differentiation dose regimen and the maintenance dose regimen together are effective to treat the cancer, and wherein the average daily dose during the differentiation dose regimen is at least 1 .25- fold higher than the average daily dose during the maintenance dose regimen.

[0057] In some embodiments, the present disclosure provides methods of increasing the level of cell differentiation in a subject, the method comprising administering to the subject, wherein the differentiation dose regimen (a) increases the appearance of a marker of differentiation in one or more dedifferentiated cells of the cancer, (b) decreases the appearance of a marker of dedifferentiation in one or more dedifferentiated cells of the cancer, (c) induces cell arrest in one or more dedifferentiated cells of the cancer, or (d) induces apoptosis in in one or more dedifferentiated cells of the cancer.

[0058] In some embodiments, the present disclosure provides methods of increasing the level of cell differentiation in a subject, the method comprising administering to the subject, following the administration of the differentiation dose regimen, the maintenance dose regimen inhibits the proliferation of dedifferentiated cells of the cancer.

[0059] In some embodiments, the present disclosure provides methods of increasing the level of cell differentiation in a subject, the method comprising administering to the subject, wherein the differentiation dose regimen is sufficient to produce a Caverage plasma concentration level of at least 250 ng / mL in the subject, and the maintenance dose regimen is sufficient to produce a Caverage plasma concentration level of between about 80 ng / mL and about 225 ng / mL in the subject.

[0060] In some embodiments, the present disclosure provides methods of increasing the level of cell differentiation in a subject, the method comprising administering to the subject, wherein the differentiation dose regimen comprises administering daily to the subject from greater than 7.5 mg to 22.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof, and the maintenance dose regimen comprises administering daily to the subject from 1 .5 mg to 7.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof.

[0061] In one aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the lung cancer expresses PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

[0062] In some embodiments, the levels are measured in a tissue sample of the subject.

[0063] In some embodiments, the levels are measured in a blood sample of the subject.

[0064] In some embodiments, the subject is further administered at least one additional anti-cancer therapy.

[0065] In one aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) bivatuzumab, RG7356, or a combination thereof.

[0066] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

[0067] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0068] In some embodiments, the lung cancer is small cell lung cancer (SCLC).

[0069] In some embodiments, the lung cancer is metastatic.

[0070] In one aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the effective amount is an amount sufficient to reduce the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0072] In one aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the effective amount is an amount sufficient to reduce the level of neuroendocrine prostate cancer cells compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the prostate cancer has been determined to have or predicted to have lower expression levels of AR, KLK2, KLK3, CDH1 , CYLD, NKX3-1 , SLC45A3, TARP, PTEN, SPDEF, TP53, or RB1 , or combinations thereof compared to a subject that does not have prostate cancer.

[0076] In some embodiments, the prostate cancer has been determined to have or predicted to have lower expression levels of AR, KLK2, KLK3, CDH1 , CYLD, NKX3-1 , SLC45A3, TARP, PTEN, SPDEF, TP53, or RB1 , or combinations thereof compared to reference levels for prostate cancer.

[0077] In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of CHGB, CHGA, SYP, ENO2, PEG10, SNAP25, SRRM4, VGF, VIM, SCGN, PAPPA2, WNT11 , BRG1 , or combinations thereof compared to a subject that does not have prostate cancer.

[0078] In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of CHGB, CHGA, SYP, ENO2, PEG10, SNAP25, SRRM4, VGF, VIM, SCGN, PAPPA2, WNT11 , BRG1 , or combinations thereof compared to reference levels for prostate cancer.

[0079] In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of ASCL1 , EZH2, DLX5, DLX6, SOX2, NKX2-2, HES6, SOX9, KDM3A, FOXA2, AURKA, MYCN, MYC, AKT, POU3F2 / BRN2, NANOG, ONECUT2, NKX2-1 , BRG1 , or combinations thereof compared to a subject that does not have prostate cancer.

[0080] In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of ASCL1 , EZH2, DLX5, DLX6, SOX2, NKX2-2, HES6, SOX9, KDM3A, FOXA2, AURKA, MYCN, MYC, AKT, POU3F2 / BRN2, NANOG, ONECUT2, NKX2-1 , BRG1 , or combinations thereof compared to reference levels for prostate cancer.

[0081] In some embodiments, the prostate cancer has been determined to have or predicted to have lower expression levels of RE1 silencing transcription factor (REST).

[0082] In some embodiments, the prostate cancer has been determined to have or predicted to have expression of AR and KLK3 (PSA).

[0083] In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of CHGA and SYP.

[0084] In some embodiments, the prostate cancer has been determined to have or predicted to have expression of AR, KLK3 (PSA), CHGA and SYP.

[0085] In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of AR and KLK3 (PSA). In some embodiments, the prostate cancer has been determined to have or predicted to have expression of CHGA and SYP.

[0086] In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of AR, KLK3 (PSA), CHGA and SYP.

[0087] In some embodiments, the prostate cancer has been determined to have or predicted to have a high level of TMPRSS2-ERG fusions.

[0088] In some embodiments, the prostate cancer is metastatic.

[0089] In some embodiments, the expression of BRD9, GLTSCR1 , CXXC5 TET2, or BRG1 is increased in the prostate cancer compared to a subject that does not have prostate cancer.

[0090] In some embodiments, the expression of GLTSCR1 is increased in the prostate cancer compared to a subject that does not have prostate cancer.

[0091] In some embodiments, the expression of TET2, CXXC5, H3K27ac, ID1 , PFN2, ID3, or BRG1 in the subject is increased in the prostate cancer determined to or predicted to be resistant to enzalutamide compared to a prostate cancer that responds to treatment with enzalutamide.

[0092] In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of PTEN.

[0093] In some emodiments, the prostate cancer has been determined or predicted to be AR positive.

[0094] In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0095] In some embodiments, the prostate cancer has been determined or predicted to be ERG positive.

[0096] In some embodiments, the subject is further administered an inhibitor or degrader of ERG.

[0097] In some embodiments, the ERG inhibitor or degrader is ERGi-USU (1 -[2-Thiazolylazo]-2- naphthol).

[0098] In some embodiments, the subject is further administered an anti-cancer therapy.

[0099] In some embodiments, the subject is further administered a degrader of AR.

[0100] In some embodiments, the AR degrader is bavdegalutamide (ARV-110), ARV-766, or AR-V7.

[0101] In some embodiments, the subject is further administered an inhibitor of the JAK-STAT pathway.

[0102] In some embodiments, the JAK-STAT inhibitor is AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, or WP1066.

[0103] In some embodiments, the subject is further administered an inhibitor of the MAPK pathway.

[0104] In some embodiments, the MAPK pathway inhibitor is a Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, or Teriflunomide.

[0105] In some embodiments, the subject is further administered an inhibitor of the PI3K-AKT-mTOR pathway.

[0106] In some embodiments, the PIK3-AKT-mTOR inhibitor is everolimus, alpelisib, idelalisib or copanlisib.

[0107] In one aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) bavdegalutamide (ARV- 110), ARV-766, AR-V7, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0108] In one aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0109] In one aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, Teriflunomide, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0110] In one aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) everolimus, alpelisib, idelalisib, copanlisib or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0111] In one aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) enzalutamide, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof. In one aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0112] In one aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) bavdegalutamide (ARV-110), ARV-766, AR-V7, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0113] In one aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0114] In one aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, Teriflunomide, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof. In one aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) everolimus, alpelisib, idelalisib, copanlisib or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0115] In one aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) enzalutamide, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0116] In one aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0117] In one aspect, the present disclosure provides methods of treating a homologous recombination deficient (HRD) cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) and DNA damaging agent.

[0118] In some embodiments, the cancer is ovarian cancer, fallopian tube cancer, peritoneal cancer, breast cancer, prostate cancer, or pancreatic cancer.

[0119] In some embodiments, the DNA damaging agent is cisplatin, carboplatin, oxaliplatin, methotrexate, doxorubicin, daunorubicin, cyclophosphamide, chlorambucil, temozolomide, or a combination thereof.

[0120] In some embodiments, the method further comprises administration of a PARP inhibitor. In some embodiments, the PARP inhibitor is olaparib, niraparib, rucaparib, talazoparib, or a combination thereof.

[0121] In some embodiments, the anti-cancer therapy is active surveillance, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), cryotherapy, hormone therapy, chemotherapy, immunotherapy, vaccine treatment, immune checkpoint inhibitors, targeted therapy drugs, or bone-directed treatment.

[0122] In some embodiments, the anti-cancer therapy is immunotherapy.

[0123] In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor.

[0124] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

[0125] In some embodiments, the additional anti-cancer therapy is administered prior to the administering of the compound or pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the additional anti-cancer therapy is administered in addition to the administering of the compound or pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the additional anti-cancer therapy is administered subsequent to the administering of the compound or pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered prior to surgical intervention, radiation therapy, or chemotherapy to treat the cancer in the subject.

[0129] In some embodiments, the administering step is performed as a neoadjuvant therapy.

[0130] In some embodiments, the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered subsequent to surgical intervention, radiation therapy, or chemotherapy to treat the cancer in the subject.

[0131] In some embodiments, the administering step is performed as an adjuvant therapy.

[0132] In some embodiments, the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is between 1 .5 mg and 10 mg per day.

[0133] In one aspect, the present disclosure provides methods of treating a solid tumor that failed to respond and / or progressed on a prior therapy in a patient in need thereof that, the method comprising administering to the subject N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof in an amount sufficient to increase the level of cell differentiation of the solid tumor.

[0134] In some embodiments, the amount sufficient to increase the level of cell differentiation of the solid tumor is at least 5 mg daily.

[0135] In some embodiments, the amount sufficient to increase the level of cell differentiation of the solid tumor is 5 to 7.5 mg daily.

[0136] In some embodiments, the solid tumor is melanoma, lung cancer, or prostate cancer. In some embodiments, the solid tumor is melanoma.

[0137] In some embodiments, the solid tumor failed to respond and / or progressed on prior treatment with aldesleukin, binimetinib, cobimetinib fumarate, dabrafenib mesylate, dacarbazine, encorafenib, ipilimumab, melphalan hydrochloride, nivolumab, nivolumab and relatlimab-rmbw, pembrolizumab, recombinant interferon alfa-2b, talimogene laherparepvec, tebentafusp-tebn, trametinib dimethyl sulfoxide, vemurafenib, or a combination thereof.

[0138] In some embodiments, the solid tumor is lung cancer.

[0139] In some embodiments, the solid tumor failed to respond and / or progressed on prior treatment with adagrasib, afatinib, dimaleate, alectinib, amivantamab-vmjw, atezolizumab, bevacizumab, brigatinib, capmatinib hydrochloride, cemiplimab-rwlc, ceritinib, crizotinib, dabrafenib mesylate, dacomitinib, docetaxel, doxorubicin hydrochloride, durvalumab, entrectinib, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, fam-trastuzumab, deruxtecan-nxki, gefitinib, gemcitabine hydrochloride, ipilimumab, lorlatinib, lurbinectedin, methotrexate sodium, mobocertinib succinate, necitumumab, nivolumab, osimertinib mesylate, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pembrolizumab, pemetrexed disodium, pralsetinib, ramucirumab, selpercatinib, sotorasib, taxol, tepotinib hydrochloride, topotecan hydrochloride, trametinib dimethyl sulfoxide, tremelimumab-actl, vinorelbine tartrate, or a combination thereof.

[0140] In some embodiments, the solid tumor has progressed from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) after administration of atezolizumab, doxorubicin hydrochloride, durvalumab, etoposide, etoposide phosphate, everolimus, lurbinectedin, methotrexate sodium, nivolumab, topotecan hydrochloride, or a combination thereof.

[0141] In some embodiments, the solid tumor is prostate cancer.

[0142] In some embodiments, the solid tumor failed to respond and / or progressed on prior treatment with abiraterone acetate, apalutamide, bavdegalutamide (ARV-110), ARV-766, AR-V7, AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, farnesyltransferase inhibitor (FTI), sorafenib, vemurafenib, PLX8394, dabrafenib, ulixertinib, simvastatin, alisertib, everolimus, alpelisib, idelalisib, copanlisib, teriflunomide bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof.

[0143] In some embodiments, the solid tumor has progressed from luminal prostate cancer to neuroendocrine prostate cancer.

[0144] In some embodiments, the solid tumor has progressed from adenocarcinoma to neuroendocrine prostate cancer.

[0145] In some embodiments, the solid tumor is sensitive to enzalutamide after the administration of N- (1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. Definitions

[0146] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.

[0147] As used herein, “N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide” refers to the compound having the structure:

[0148] As used herein, the term “decitabine’ refers to 5-aza-2'-deoxycytidine. As used herein, decitabine has the structure:

[0149] As used herein, cytarabine refers to cytosine arabinoside. As used herein, cytarabine has the structure:

[0150] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

[0151] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.

[0152] As used herein, the term “BAF complex” refers to the BRG1 - or HBRM-associated factors complex in a human cell.

[0153] As used herein, the term “BAF complex-related disorder” refers to a disorder that is caused or affected by the level of activity of a BAF complex.

[0154] As used herein, the term “BRG1 loss of function mutation” refers to a mutation in BRG1 that leads to the protein having diminished activity (e.g., at least 1% reduction in BRG1 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity). Exemplary BRG1 loss of function mutations include, but are not limited to, a homozygous BRG1 mutation and a deletion at the C-terminus of BRG1.

[0155] As used herein, the term “BRG1 loss of function disorder” refers to a disorder (e.g., cancer) that exhibits a reduction in BRG1 activity (e.g., at least 1 % reduction in BRG1 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity).

[0156] The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, and lymphomas.

[0157] As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while an anti-cancer therapy of the combination may be administered orally.

[0158] By “determining the level” of a protein or RNA is meant the detection of a protein or an RNA, by methods known in the art, either directly or indirectly. “Directly determining” means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analyses.

[0159] By a “decreased level” or an “increased level” of a protein or RNA is meant a decrease or increase, respectively, in a protein or RNA level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, 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%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01 -fold, about 0.02-fold, about 0.1 -fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1 .2-fold, about 1 .4-fold, about 1 .5-fold, about 1 .8-fold, about 2.0- fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20- fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass / vol (e.g., g / dL, mg / mL, pg / mL, ng / mL) or percentage relative to total protein in a sample.

[0160] By “decreasing the activity of a BAF complex” is meant decreasing the level of an activity related to a BAF complex, or a related downstream effect. A non-limiting example of decreasing an activity of a BAF complex is Sox2 activation. The activity level of a BAF complex may be measured using any method known in the art, e.g., the methods described in Kadoch et al. Cell, 2013, 153, 71 -85, the methods of which are herein incorporated by reference.

[0161] As used herein, the term “derivative” refers to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material.

[0162] A cancer “determined to be drug resistant,” as used herein, refers to a cancer that is drug resistant, based on unresponsiveness or decreased responsiveness to a chemotherapeutic agent, or is predicted to be drug resistant based on a prognostic assay (e.g., a gene expression assay).

[0163] By “drug resistant” is meant a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents (e.g., any agent described herein).

[0164] As used herein, the term “inhibiting BRM” and / or “inhibiting BRG1 ” refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or the bromodomain of the protein. BRM and / or BRG1 inhibition may be determined using methods known in the art, e.g., a BRM and / or BRG1 ATPase assay, a Nano DSF assay, or a BRM and / or BRG1 Luciferase cell assay.

[0165] As used herein, “metastatic cancer” refers to a tumor or cancer in which the cancer cells forming the tumor have a high potential to or have begun to, metastasize, or spread from one location to another location or locations within a subject, via the lymphatic system or via haematogenous spread, for example, creating secondary tumors within the subject. Such metastatic behavior may be indicative of malignant tumors. In some cases, metastatic behavior may be associated with an increase in cell migration and / or invasion behavior of the tumor cells.

[0166] Examples of cancers that can be defined as metastatic include but are not limited to lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, colorectal cancer, biliary tract cancer, bladder cancer, brain cancer including glioblastomas and medullablastomas, cervical cancer, choriocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms, liver cancer, lymphomas, neuroblastomas, oral cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer including melanoma, basocellular cancer, squamous cell cancer, testicular cancer, stromal tumors, germ cell tumors, thyroid cancer, and renal cancer. The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0167] A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.

[0168] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound described herein. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benef it / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting a free base group with a suitable organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be, e.g., acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.

[0169] As used herein, the term “progression-free survival” as used herein, refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse. The combination therapies of the invention can increase the likelihood of progression-free survival in a subject.

[0170] As used herein, the term “proliferation” as used in this application involves reproduction or multiplication of similar forms (cells) due to constituting (cellular) elements. The combination therapies of the invention can decrease proliferation of cancer cells. As used herein, the term “subject” refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[0171] By a “reference” is meant any useful reference used to compare protein or RNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference.

[0172] As used herein, the term “relapsed” means that a cancer has returned after prior treatment.

[0173] As used herein, the term “refractory” means that a cancer has stopped responding to prior treatment that it previously responded to.

[0174] As used herein, the term “resistant” means that a cancer does not respond to a treatment.

[0175] As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. In the context of treating cancer, treatment may include slowing the spread of metastasis and / or extending progression-free survival in a population of treated subjects as compared to a population of untreated subjects. Compounds of the disclosure may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.

[0176] As used herein, the term "intensive chemotherapy" refers to the so-called ”7 + 3” method, which comprises inducible chemotherapy and is characterized by high dose or standard dose cytarabine for 7 days followed by 3 days of an anthracycline or an anthracenedione, most often daunorubicin (can be substituted for doxorubicin or idarubicin or mitoxantrone).

[0177] As used herein, the term “anti-cancer therapy” refers to a therapy that is known to be useful for treatment of solid tumors (i.e. , melanoma, lung cancer, prostate cancer). Solid tumors include, but are not limited to, uveal melanoma, cutaneous melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and neuroendocrine prostate cancer. Examples of anti-cancer therapies include, but are not limited to, active surveillance, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), cryotherapy, hormone therapy, chemotherapy, immunotherapy, vaccine treatment, immune checkpoint inhibitors, targeted therapy drugs, or bone-directed treatment. Anti-cancer therapy and anti-cancer agent are used interchangeably herein.

[0178] As used herein, the term “failed to respond to a prior therapy” or “refractory to a prior therapy,” refers to a cancer that progressed despite treatment with the therapy.

[0179] 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 to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0180] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0181] BRIEF DESCRIPTION OF THE DRAWINGS

[0182] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0183] FIG. 1 A shows stem markers (CD44 and KIT) expression changes (mean Log2FC) from screening.

[0184] FIG. 1 B shows maturation markers (Sox10, melanocyte markers - Tyrosinase, GP100, and MelanA) expression changes (mean Log2FC) from screening.

[0185] FIG. 2 shows example images of a melanocyte multiplex IF panel on a tumor biopsy pair at screening and at C3D1 on treatment.

[0186] FIGS. 3A and 3B show differential gene expression in the RECIST and mixed responders (FIG. 3A) vs. RECIST non-responders (FIG. 3B). FIG. 4 shows percentage of necrotic tumor in screening vs on treatment samples.

[0187] FIG. 5 shows example H&E images from two tumor biopsy pairs at screening vs. C3D1 on treatment. Cells were observed to be less densely packed in the on-treatment samples than in the screening samples.

[0188] FIG. 6A depicts example images of SOX10 IF staining in a tumor biopsy pair at screening vs. C3D1 on treatment.

[0189] FIG. 6B depicts tumor cell density, defined as the number of tumor cells (SOX10+) per area of total tissue in mm2.

[0190] FIG. 7 depicts the % change from the minimum and maximum ctDNA levels for each subject.

[0191] FIG. 8 depicts the % change in ctDNA from Cycle 1 for individual subjects in the 5mg, 7.5mg, and 10mg QD cohorts who were on Compound A for at least one cycle (n=17).

[0192] FIG. 9 depicts the ctDNA reduction from Cycle 1 and apparent survival benefit.

[0193] FIG. 10A depicts a scheme outlining the daily and intermittent dosing schedule of Compound A and when blood was collected and analyzed for gene expression changes by RNA-seq.

[0194] FIG. 10B depicts the average log2FC from pre-dose for a selected panel of genes for each cohort. The signature was monitored in a time course through steady-state, C1 D15 onwards.

[0195] FIG. 11 A depicts GI50 for 25 NSCLC cell lines treated with a serial dilution of Compound A for 14 days.

[0196] FIG. 11 B depicts GI50 specifically for BRG1 + and BRG1 - groupings of 25 NSCLC cell lines treated with a serial dilution of Compound A for 14 days.

[0197] FIG. 12A depicts% tumor growth inhibition of NSCLC cell line-derived xenograft (CDX) models treated with 15 or 25 mg / kg of a dual BAF ATPase inhibitor.

[0198] FIG. 12B depicts % tumor growth inhibition specifically for BRG1 + and BRG1 - groupings of NSCLC cell line-derived xenograft (CDX) models treated with 15 or 25 mg / kg of a dual BAF ATPase inhibitor.

[0199] FIG. 13A depicts a western blot for AP-1 family transcription factors (eJun, cFos, Fosl2, and JunB) in NSCLC lines at baseline.

[0200] FIGS. 13B-13D show homer analysis of ATAC peaks in NSCLC cell lines NCIH23 (FIG. 13B), A549 (FIG. 13C), and NCIH1693 (FIG. 13D) treated with Compound A for 8 hours.

[0201] FIG. 14A shows a western blot of CD44 levels in four NSCLC cell lines treated with DMSO or 11 , 33, or 100 nM Compound A for 48 hours.

[0202] FIG. 14B shows quantitative real-time PCT results of CD44 levels in eight NSCLC cell lines treated with DMSO or 11 , 33, or 100 nM Compound A for 48 hours.

[0203] FIGS. 15A-15C depict a treatment scheme for a CD44 flow cytometry study in A549 and NCIH358 cell lines and the resulting histograms (FIG 15A) and mean fluorescence intensity (MFI) quantification in NCIH358 (FIG. 15B) and A549 (FIG. 15C).

[0204] FIG. 16A depicts tumor volume measurements for NCIH358 CDX tumors treated with 0.15 mg / kg BID, 0.375 mg / kg BID, and 1 mg / kg BID of Compound A.

[0205] FIG. 16B depicts immunohistochemistry (IHC) for CD44 in NCIH358 tumor sections treated with Compound A for 7 days at 0.15 mg / kg BID, 0.375 mg / kg BID, and 1 mg / kg BID of Compound A. FIGS. 16C-16D depicts RNA-seq analysis of CD44 and other basal cell identity genes in NCIH358 (FIG. 16C) and A549 (FIG. 16D) and NCIH358 treated for 21 days with Compound A at 1 mg / kg, BID.

[0206] FIG. 16E depicts the lung basal cell gene expression signature in both NSCLC CDX tumor models A549 and H358 in response to Compound A.

[0207] FIGS. 17A-17B depict viability curves used to select Compound A doses (EC20, FIG. 17A; EC30, FIG. 17B) to use for CRISPR screening in A549 and NCIH358 lines over 8-10 cell doublings.

[0208] FIGS. 17C-17D show genes ranked by beta score (p) differences between Compound A- and vehicle (vhc)-treated conditions. Biologically significant hits were defined as genes with > 4 sgRNAs, pdiff > 0.3, and pFHD-286 > 0 for positive hits, and < 0 for negative hits. MiRNAs were excluded. Positive and negative beta scores for genes reveal molecular determinants of resistance and sensitivity, respectively, to dual BRM / BRG1 inhibition. Yellow stars indicate genes involved in regulation of AP-1 activity, CD44, or sternness.

[0209] FIGS. 18A-18D show quantitation of immunosuppressive cell type changes grouped by patients with observed ctDNA decrease at C1 and colored by response (RESCIST Responder=SD or better; Mixed Responded PD with shrinkage in 1 or more targe lesions; RECIST Non-responder= PD) following treatment with Compound A.

[0210] FIG. 18E shows representative multiplex IF images of paired biopsies for each cell type of interest from FIGS 18A-18D.

[0211] FIG. 19A depicts a representative mIF image (patient 8) showing abundance of M2 macrophages “inside” tumor and close M2->Tumor cell distance following treatment with Compound A.

[0212] FIG. 19B shows neogenomics analysis of M2 macrophages that shifted from “inside” the tumor area to “outside” the tumor.

[0213] FIG. 19C shows neogenomics nearest neighbor analysis, with an increase in the M2 macrophage to tumor cell distance.

[0214] FIGS. 20A-20B depicts changes in ratio of inflammatory to repressive T cells: CD8 / CD4 (FIG. 20A) and CD8 GrnzB+ / Treg (FIG. 20B).

[0215] FIGS. 21 A-21 C shows RNA seq obtained from the peripheral blood mononuclear cells (PBMCs) of patients in Compound A dose escalation (5 mg QD, 7.5mg QD, 10 mg QD) for FOXP3 (FIG. 21 A), GZMB (FIG. 21 B), and ELANE (FIG. 21 C).

[0216] FIGS. 22A-22B shows RNA seq isolated from FFPE slides obtained from paired biopsies of 9 patients. Changes in transcripts associated with neutrophil degranulation that was differential between Responder (both RECIST and Mixed Responder) (FIG. 22A) and Non-Responder (RECIST NonResponder) (FIG. 22B) was observed.

[0217] FIG. 23 is a summary of starting cell type and genes of interest, and mature cell type and genes of interest after treatment with Compound A for uveal melanoma, AML, non-small cell lung cancer (NSCLC), and immune-oncological cancers.

[0218] DETAILED DESCRIPTION OF THE INVENTION

[0219] The present disclosure provides methods of increasing the level of cell differentiation in a subject with a solid tumor (e.g., melanoma, lung cancer, prostate cancer). Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

[0220] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

[0221] N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1 -(methylsu lfonyl)-1 H-pyrrole-3-carboxam ide

[0222] Methods for synthesizing N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide are described in International Application No. PCT / US2021 / 015876, the content of which is incorporated herein by reference in its entirety. Methods of treatment of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide are described in International Application No. PCT / US2021 / 015876, the content of which is incorporated herein by reference in its entirety. Methods of treating cancer by N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide are described in International Application No. PCT / US23 / 17829, the content of which is incorporated herein by reference in its entirety.

[0223] The present disclosure features compounds useful for the inhibition of BRG1 and / or BRM. These compounds may be used to modulate the activity of a BAF complex, for example, for the treatment of a BAF-related disorder, such as cancer. Exemplary compounds, or pharmaceutically acceptable salts thereof, described herein include compounds having the structure:

[0224]

[0225] In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 22.5 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 15 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 10 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 7.5 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 22.5 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 15 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 10 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 22.5 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 15 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 15 mg and about 22.5 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 5.0 mg per day. In some embodiments, N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 7.5 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol- 2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 10 mg per day. In some embodiments, N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 15 mg per day. In some embodiments, N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 22.5 mg per day.

[0226] Additional details are provided in the Examples.

[0227] Cell Differentiation in Solid Tumors

[0228] The present disclosure provides methods of decreasing the amount of cancer stem cells in a subject with a solid tumor; the method comprising administering to the subject an effective amount of N- (1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer stem cells are primitive ectoderm cells, basal cells, Tregs, M26 cells, Teff cells, NK cells, APC / M1 cp cells, or a combination thereof. In some embodiments, methods further include administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of cancer stem cells in the subject.

[0229] In another aspect, the present disclosure provides methods of increasing the level of differentiation in a subject with a solid tumor; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the method further includes administering an anti- cancer therapy in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the level of differentiation in the subject. In some embodiments, the solid tumor is melanoma, lung cancer, prostate cancer, breast cancer, bone cancer, neuroblastoma, esophageal cancer, renal cancer, or a combination thereof. In some embodiments, the solid tumor is uveal melanoma, cutaneous melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or neuroendocrine prostate cancer. In another aspect, the present disclosure provides methods of treating a solid tumor that failed to respond and / or progressed on a prior therapy in a patient in need thereof that, the method comprising administering to the subject N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof in an amount sufficient to increase the level of cell differentiation of the solid tumor.

[0230] In some embodiments, the amount sufficient to increase the level of cell differentiation of the solid tumor is at least 5 mg daily. In some embodiments, the amount sufficient to increase the level of cell differentiation of the solid tumor is 5 to 7.5 mg daily.

[0231] In some embodiments, the solid tumor is melanoma, lung cancer, or prostate cancer.

[0232] In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor failed to respond and / or progressed on prior treatment with aldesleukin, binimetinib, cobimetinib fumarate, dabrafenib mesylate, dacarbazine, encorafenib, ipilimumab, melphalan hydrochloride, nivolumab, nivolumab and relatlimab-rmbw, pembrolizumab, recombinant interferon alfa-2b, talimogene laherparepvec, tebentafusp-tebn, trametinib dimethyl sulfoxide, vemurafenib, or a combination thereof.

[0233] In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor failed to respond and / or progressed on prior treatment with adagrasib, afatinib, dimaleate, alectinib, amivantamab-vmjw, atezolizumab, bevacizumab, brigatinib, capmatinib hydrochloride, cemiplimab-rwlc, ceritinib, crizotinib, dabrafenib mesylate, dacomitinib, docetaxel, doxorubicin hydrochloride, durvalumab, entrectinib, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, fam-trastuzumab, deruxtecan-nxki, gefitinib, gemcitabine hydrochloride, ipilimumab, lorlatinib, lurbinectedin, methotrexate sodium, mobocertinib succinate, necitumumab, nivolumab, osimertinib mesylate, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pembrolizumab, pemetrexed disodium, pralsetinib, ramucirumab, selpercatinib, sotorasib, taxol, tepotinib hydrochloride, topotecan hydrochloride, trametinib dimethyl sulfoxide, tremelimumab-actl, vinorelbine tartrate, or a combination thereof.

[0234] In some embodiments, the solid tumor has progressed from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) after administration of atezolizumab, doxorubicin hydrochloride, durvalumab, etoposide, etoposide phosphate, everolimus, lurbinectedin, methotrexate sodium, nivolumab, topotecan hydrochloride, or a combination thereof. In some embodiments, the solid tumor is sensitive to osimertinib after the administration of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol- 2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the solid tumor is prostate cancer. In some embodiments, the solid tumor failed to respond and / or progressed on prior treatment with abiraterone acetate, apalutamide, bavdegalutamide (ARV-110), ARV-766, AR-V7, AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, farnesyltransferase inhibitor (FTI), sorafenib, vemurafenib, PLX8394, dabrafenib, ulixertinib, simvastatin, alisertib, everolimus, alpelisib, idelalisib, copanlisib, teriflunomide bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof.

[0236] In some embodiments, the solid tumor has progressed from luminal prostate cancer to neuroendocrine prostate cancer. In some embodiments, the solid tumor has progressed from adenocarcinoma to neuroendocrine prostate cancer. In some embodiments, the solid tumor is sensitive to enzalutamide after the administration of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the solid tumor has progressed on prior therapy due to a decrease in tumor cell differentiation.

[0238] In some embodiments, the solid tumor has not progressed on prior therapy due to an upregulation of transporters and / or pumps. In some embodiments, the transporter and / or pump is P-gp, MRP1 , MRP, GST, Topoisomerase II, PKC, or a combination thereof.

[0239] In some embodiments, the solid tumor has not progressed on prior therapy due to a single point mutation in the tumor that can disengage an anti-cancer therapy from a target. In some embodiments, the single point mutation is in the FLT3 gene, WT1 gene, RAS family genes, or a combination thereof.

[0240] Circulating tumor DNA (ctDNA) is single- or double-stranded DNA released by the tumor cells into the blood. ctDNA harbors mutations of the original tumor. A reduction in circulating tumor DNA after treatment with an anti-cancer therapy can indicate a survival benefit.

[0241] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with a solid tumor; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the effective amount is an amount sufficient to decrease levels of ctDNA in the subject.

[0243] Melanoma - Uveal Melanoma and Cutaneous Melanoma

[0244] Melanoma is a type of cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye (i.e., uveal melanoma). About 25% of melanomas develop from moles. Changes in a mole that can indicate melanoma include an increase in size, irregular edges, change in color, itchiness, or skin breakdown. Melanomas are usually caused by DNA damage resulting from exposure to UV light from the sun, but may also arise from genetic causes.

[0245] Uveal melanoma is a cancer of the eye involving the iris, ciliary body, or choroid (collectively referred to as the uvea). Tumors arise from the pigment cells (melanocytes) that reside within uvea giving color to the eye. It is the most common primary intraocular malignancy in adults and represents approximately 5 percent of all melanomas recorded in the United States, with approximately 5-6 cases per million people in the United States and Europe. Although 97-98 percent of patients with uveal melanoma have no evidence of metastatic disease at the time of diagnosis and the success rate for local 1 treatment surpasses 90 percent, half of all patients ultimately develop metastatic disease. The 5-year survival rate is about 80% for patients with uveal melanoma confined to the eye and about 15% for patients with metastatic uveal melanoma. Uveal melanoma can be classified into Class 1 or Class 2 tumors based on the DecisionDx®-UM GEP test, a widely used prognostic test to predict individual risk of metastasis in patients with uveal melanoma. Class 1 and 2 tumors are associated with low and high risk of metastasis, respectively. It has been shown that Class 2 tumors are less differentiated due to being stuck in a more stem-like state.

[0246] Cutaneous melanoma, or melanoma of the skin, is the most common type of melanoma worldwide, with the incidence increasing annually at a more rapid rate compared to any other type of cancer. Cutaneous melanoma is typically caused by too much exposure to ultraviolet rays from the sun. There are several subtypes of cutaneous melanoma, including superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and amelanotic melanoma.

[0247] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the effective amount is an amount sufficient to increase levels of SOX10, tyrosinase, GP100, MelanA, or a combination thereof. In some embodiments, the effective amount is an amount sufficient to increase the level of melanocyte cells. In some embodiments, the effective amount is an amount sufficient to decrease the level of primitive ectoderm cells. In some embodiments, the effective amount is an amount sufficient to decrease levels of PRAME, CD44, KIT, BRG1 , or a combination thereof. In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PRAME, CD44, KIT, BRG1 , or a combination thereof compared to a reference. In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PRAME, CD44, KIT, BRG1 , or a combination thereof compared to a subject that does not have melanoma.

[0249] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing SOX10, tyrosinase, GP100, MelanA, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0250] In another aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of melanocyte cells compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the melanoma expresses PRAME, CD44, KIT, BRG1 , or a combination thereof.

[0251] In some embodiments, the effective amount is an amount sufficient to increase levels of IFNy, MHCI, CD8, or a combination thereof. In some embodiments, the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof. In some embodiments, the effective amount is an amount sufficient to decrease the level of Treg cells, M2cp cells, tumor associated macrophages (TAM), or a combination thereof. In some embodiments, the effective amount is an amount sufficient to decrease levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof. In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a reference. In some embodiments, the melanoma has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a subject that does not have melanoma.

[0252] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing IFNy, MHCI, CD8, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0253] In another aspect, the present disclosure provides methods of of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0254] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the melanoma expresses PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

[0255] In some embodiments, the levels are measured in a tissue sample of the subject. In some embodiments, the levels are measured in a blood sample of the subject. In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) tebentafusp-tebn.

[0256] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) bivatuzumab, RG7356, or a combination thereof.

[0257] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) IMA203 / IMA203CD8.

[0258] In some embodiments, the method further comprises administration of a PD-1 / PD-L1 inhibitor. In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

[0259] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) imatinib, dasatinib, avapritinib, nilotinib, KTN0182A, or a combination thereof.

[0260] In some embodiments, the melanoma is mucosal melanoma, uveal melanoma, or cutaneous melanoma. In some embodiments, the melanoma is uveal melanoma. In some embodiments, the melanoma is cutaneous melanoma. In some embodiments, the melanoma is metastatic.

[0261] In another aspect, the present disclosure provides methods of decreasing the amount of primitive ectoderm cells in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0262] In another aspect, the present disclosure provides methods of decreasing the amount of primitive ectoderm cells in a subject with uveal melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0263] In another aspect, the present disclosure provides methods of decreasing the amount of primitive ectoderm cells in a subject with cutaneous melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of primitive ectoderm cells in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of primitive ectoderm cells in the subject.

[0264] In another aspect, the present disclosure provides methods of increasing the amount of melanocyte cells in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0265] In another aspect, the present disclosure provides methods of increasing the amount of melanocyte cells in a subject with uveal melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0266] In another aspect, the present disclosure provides methods of increasing the amount of melanocyte cells in a subject with cutaneous melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the amount of melanocyte cells in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of melanocyte cells in the subject.

[0268] In another aspect, the present disclosure provides methods of increasing the level of differentiation in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0269] In another aspect, the present disclosure provides methods of increasing the level of differentiation in a subject with uveal melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0270] In another aspect, the present disclosure provides methods of increasing the level of differentiation in a subject with cutaneous melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the amount of differentiation in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the level of differentiation in the subject.

[0272] In another aspect, the present disclosure provides methods of differentiating primitive ectoderm cells in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0273] In another aspect, the present disclosure provides methods of differentiating primitive ectoderm cells in a subject with uveal melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2- yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0274] In another aspect, the present disclosure provides methods of differentiating primitive ectoderm cells in a subject with cutaneous melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, at least 50% of the primitive ectoderm cells in the subject are differentiated. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective differentiate primitive ectoderm cells in the subject.

[0276] In another aspect, the present disclosure provides methods of increasing the level of cells expressing Sox10, tyrosinase, GP100, MelanA, or a combination thereof in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0277] In another aspect, the present disclosure provides methods of increasing the level of cells expressing Sox10, tyrosinase, GP100, MelanA, or a combination thereof in a subject with uveal melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0278] In another aspect, the present disclosure provides methods of increasing the level of cells expressing Sox10, tyrosinase, GP100, MelanA, or a combination thereof in a subject with cutaneous melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of cells expressing Sox10, tyrosinase, GP100, MelanA, or a combination thereof in the subject is increased by at least 50%.

[0279] In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of cells expressing Sox10, tyrosinase, GP100, MelanA, or a combination thereof in the subject.

[0280] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing PRAME, CD44, KIT, or a combination thereof in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0281] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing PRAME, CD44, KIT, or a combination thereof in a subject with uveal melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0282] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing PRAME, CD44, KIT, or a combination thereof in a subject with cutaneous melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the level of cells expressing PRAME, CD44, KIT, or a combination thereof in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of cells expressing PRAME, CD44, KIT, or a combination thereof in the subject.

[0284] Lung Cancer - Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC)

[0285] Lung cancer refers to tumors originating in the lung parenchyma or within the bronchi. Lung cancer is one of the leading causes of cancer-related deaths in the United States, and it is estimated that there are 225,000 new cases of lung cancer in the United States annually. The dramatic rise of lung cancer cases is attributable primarily to the increase in smoking nicotine.

[0286] At diagnosis, lung cancer is classified based on the type of cells the tumor is derived from. There are two main types of lung cancer, categorized by the size and appearance of the malignant cells: small cell lung cancer (SCLC; about 15% of cases) and non-small-cell lung cancer (NSCLC; about 85% of cases). SCLC tumors are often found near the center of the lungs, in the major airways. NSCLCs, named because the cells are large, with excess cytoplasm, large nuclei, and conspicuous nucleoli, comprise a group of three cancer types: adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma. The BRG / BRM-associated factor (BAF) complex plays critical roles in chromatin regulation. Within this complex, the two mutually exclusive ATPases BRM and BRG1 (SMARCA2 and SMARCA4, respectively) drive chromatin remodeling activity. Genetic alterations in the SMARCA4 gene, encoding BRG1 , are found in approximately 10% of patients with non-small cell lung cancer (NSCLC), leaving this subset of BRG1 -deficient tumors highly susceptible to BRM inhibition. In addition, BRG1 has oncogenic activity in NSCLC, rationalizing the use of a dual BRM / BRG1 ATPase inhibitor such as the compounds described herein, regardless of SMARCA4 status.

[0287] In one aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the effective amount is an amount sufficient to decrease levels of CD44. In some embodiments, the effective amount is an amount sufficient to increase the level of club cells and / or alveolar cells. In some embodiments, the effective amount is an amount sufficient to decrease the level of basal cells. In some embodiments, the effective amount is an amount sufficient to decrease levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , or a combination thereof. In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of TP63, KRT5, KRT 14, AP-1 transcription factors, BRG1 , CD44, or a combination thereof compared to a reference. In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , CD44, or a combination thereof compared to a subject that does not have lung cancer.

[0289] In another aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to decrease the level of CD44 compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0290] In another aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is n amount sufficient to increase the level of club cells and / or alveolar cells compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof..

[0291] In another aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the lung cancer expresses TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , high level of CD44, or a combination thereof. In some embodiments, the AP-1 transcription factors are Jun (eJun, JunB, JunD), Fos (cFos, FosB, FosL1 / Fra1 , FosL2 / Fra2), Mat (musculoaponeurotic fibrosarcoma) (c-Maf, MafB, MafA. Mafg / f / k, Nrl), ATF-activating transcription factor (ATF2, LRF1 / ATF3, BATF, JDP1 , JDP2), or a combination thereof. In some embodiments, the AP-1 transcription factors are eJun, cFos, FosL2, and JunB. In some embodiments, the effective amount is an amount sufficient to increase levels of IFNy, MHCI, CD8, or a combination thereof. In some embodiments, the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof. In some embodiments, the effective amount is an amount sufficient to decrease the level of Treg cells, M2cp cells, tumor associated macrophages (TAM), or a combination thereof. In some embodiments, the effective amount is an amount sufficient to decrease levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof. In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , or a combination thereof compared to a reference. In some embodiments, the lung cancer has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a subject that does not have lung cancer.

[0292] In another aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing IFNy, MHCI, CD8, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0293] In another aspect, the present disclosure provides methods of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

[0294] In another aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the lung cancer expresses PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

[0295] In some embodiments, the levels are measured in a tissue sample of the subject. In some embodiments, the levels are measured in a blood sample of the subject. In some embodiments, the subject is further administered at least one additional anti-cancer therapy.

[0296] In another aspect, the present disclosure provides methods of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) bivatuzumab, RG7356, or a combination thereof.

[0297] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is metastatic.

[0298] In another aspect, the present disclosure provides methods of decreasing the amount of basal cells in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2- yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0299] In another aspect, the present disclosure provides methods of decreasing the amount of basal cells in a subject with non-small cell lung cancer (NSCLC); the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0300] In another aspect, the present disclosure provides methods of decreasing the amount of basal cells in a subject with small cell lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the amount of basal cells in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of basal cells in the subject.

[0302] In another aspect, the present disclosure provides methods of increasing the amount of club and / or alveolar cells in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0303] In another aspect, the present disclosure provides methods of increasing the amount of club and / or alveolar cells in a subject with non-small cell lung cancer (NSCLC); the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0304] In another aspect, the present disclosure provides methods of increasing the amount of club and / or alveolar cells in a subject with small cell lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of club and / or alveolar cells in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of club and / or alveolar cells in the subject.

[0305] In another aspect, the present disclosure provides methods of increasing the level of differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0306] In another aspect, the present disclosure provides methods of increasing the level of differentiation in a subject with non-small cell lung cancer (NSCLC); the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)- 3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0307] In another aspect, the present disclosure provides methods of increasing the level of differentiation in a subject with small cell lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the amount of differentiation in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the level of differentiation in the subject.

[0309] In another aspect, the present disclosure provides methods of differentiating basal cells in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 - ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0310] In another aspect, the present disclosure provides methods of differentiating basal cells in a subject with non-small cell lung cancer (NSCLC); the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0311] In another aspect, the present disclosure provides methods of differentiating basal cells in a subject with small cell lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2- yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, at least 50% of the basal cells in the subject are differentiated. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective differentiate basal cells in the subject.

[0313] In another aspect, the present disclosure provides methods of increasing the level of cells expressing lower levels of CD44 in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0314] In another aspect, the present disclosure provides methods of increasing the level of cells expressing lower levels of CD44 in a subject with non-small cell lung cancer (NSCLC); the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0315] In another aspect, the present disclosure provides methods of increasing the level of cells expressing lower levels of CD44 in a subject with small cell lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the level of cells expressing lower levels of CD44 in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anticancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of cells expressing lower levels of CD44 in the subject.

[0317] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing TP63, KRT5, KRT14, AP-1 transcription factors, higher levels of CD44, or a combination thereof in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2- yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0318] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing TP63, KRT5, KRT14, AP-1 transcription factors, higher levels of CD44, or a combination thereof in a subject with uveal melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2- yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0319] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing TP63, KRT5, KRT14, AP-1 transcription factors, higher levels of CD44, or a combination thereof in a subject with cutaneous melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of cells expressing TP63, KRT5, KRT 14, AP-1 transcription factors, higher levels of CD44, or a combination thereof in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of cells expressing TP63, KRT5, KRT14, AP-1 transcription factors, higher levels of CD44, in the subject. In some embodiments, the AP-1 transcription factors are Jun (Jun, JunB, JunD), Fos (Fos, FosL1 , FosL2, FosB), BATF (BATF, BATF2, BATF3), ATF (ATF2, ATF3, ATF4, ATF7), or Jdp2.

[0320] Prostate Cancer

[0321] The androgen receptor is a transcription factor that effectuates changes in DNA expression upon binding to androgenic ligands such as testosterone and dihydroxytestosterone. Subtypes of prostate cancer may grow and spread independently of gene expression mediated by the androgen receptor. Androgen-independent prostate cancer is prostate cancer that grows and spreads in the absence of a functional androgen receptor. Androgen receptor-independent prostate cancer cannot be successfully treated with androgen starvation therapy or with androgen receptor signaling inhibitors (ARSi).

[0322] Castration-resistant prostate cancer (CRPC) is a form of prostate cancer that continues to grow even when the amount of testosterone in a subject is reduced to a very low level, e.g., even after surgical or medical castration. The estimated mean survival of a subject diagnosed with castrate-resistant prostate cancer is approximately 9 to 36 months, and the quality of life for subjects diagnosed with castrate-resistant prostate cancer and receiving the standard of care is poor.

[0323] Small cell prostate cancer is an aggressive subtype of prostate cancer that is characterized by cancer cells that are smaller in size than other forms of prostate cancer, e.g., cells that are smaller than 4 lymphocytes in diameter. Small cell prostate cancer cells possess unique and strict morphological features, scant cytoplasm, ill-defined borders, finely granular “salt and pepper” chromatic, absent or inconspicuous nucleoli, frequent nuclear molding, and a high mitotic count.

[0324] Neuroendocrine prostate cancer is a subtype of prostate cancer that develops in the neuroendocrine cells of the prostate. Neuroendocrine prostate cancer rarely arises de novo and often develops from the trans-differentiation of adenocarcinomas. Neuroendocrine prostate cancers are typically not responsive to treatments that target androgen receptor signaling.

[0325] In another aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the effective amount is an amount sufficient to reduce the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof. In some embodiments, the effective amount is an amount sufficient to reduce the level of neuroendocrine prostate cancer cells compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof. In some embodiments, the prostate cancer has been determined to have or predicted to have lower expression levels of AR, KLK2, KLK3, CDH1 , CYLD, NKX3-1 , SLC45A3, TARP, PTEN, SPDEF, TP53, or RB1 , or combinations thereof compared to a subject that does not have prostate cancer. In some embodiments, the prostate cancer has been determined to have or predicted to have lower expression levels of AR, KLK2, KLK3, CDH1 , CYLD, NKX3-1 , SLC45A3, TARP, PTEN, SPDEF, TP53, or RB1 , or combinations thereof compared to reference levels for prostate cancer. In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of CHGB, CHGA, SYP, ENO2, PEG10, SNAP25, SRRM4, VGF, VIM, SCGN, PAPPA2, WNT11 , BRG1 , or combinations thereof compared to a subject that does not have prostate cancer. In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of CHGB, CHGA, SYP, ENO2, PEG10, SNAP25, SRRM4, VGF, VIM, SCGN, PAPPA2, WNT11 , BRG1 , or combinations thereof compared to reference levels for prostate cancer. In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of ASCL1 , EZH2, DLX5, DLX6, SOX2, NKX2-2, HES6, SOX9, KDM3A, FOXA2, AURKA, MYCN, MYC, AKT, POU3F2 / BRN2, NANOG, ONECUT2, NKX2-1 , BRG1 , or combinations thereof compared to a subject that does not have prostate cancer. In some embodiments, the prostate cancer has been determined to have or predicted to have higher expression levels of ASCL1 , EZH2, DLX5, DLX6, SOX2, NKX2-2, HES6, SOX9, KDM3A, FOXA2, AURKA, MYCN, MYC, AKT, POU3F2 / BRN2, NANOG, ONECUT2, NKX2-1 , BRG1 , or combinations thereof compared to reference levels for prostate cancer. In some embodiments, the prostate cancer has been determined to have or predicted to have lower expression levels of RE1 silencing transcription factor (REST). In some embodiments, the prostate cancer has been determined to have or predicted to have expression of AR and KLK3 (PSA). In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of CHGA and SYP. In some embodiments, the prostate cancer has been determined to have or predicted to have expression of AR, KLK3 (PSA), CHGA and SYP. In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of AR and KLK3 (PSA). In some embodiments, the prostate cancer has been determined to have or predicted to have expression of CHGA and SYP. In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of AR, KLK3 (PSA), CHGA and SYP. In some embodiments, the prostate cancer has been determined to have or predicted to have a high level of TMPRSS2-ERG fusions. In some embodiments, the prostate cancer is metastatic. In some embodiments, the expression of BRD9, GLTSCR1 , CXXC5 TET2, or BRG1 is increased in the prostate cancer compared to a subject that does not have prostate cancer. In some embodiments, the expression of GLTSCR1 is increased in the prostate cancer compared to a subject that does not have prostate cancer. In some embodiments, the expression of TET2, CXXC5, H3K27ac, ID1 , PFN2, ID3, or BRG1 in the subject is increased in the prostate cancer determined to or predicted to be resistant to enzalutamide compared to a prostate cancer that responds to treatment with enzalutamide. In some embodiments, the prostate cancer has been determined to have or predicted to have undetectable expression of PTEN. In some embodiments, the prostate cancer has been determined or predicted to be ERG positive. In some embodiments, the subject is further administered an inhibitor or degrader of ERG. In some embodiments, the ERG inhibitor or degrader is ERGi-USU (1 -[2-Thiazolylazo]-2-naphthol). In some embodiments, the subject is further administered an anti-cancer therapy. In some embodiments, the subject is further administered a degrader of AR. In some embodiments, the AR degrader is bavdegalutamide (ARV-110), ARV-766, or AR-V7. In some embodiments, the subject is further administered an inhibitor of the JAK- STAT pathway. In some embodiments, the JAK-STAT inhibitor is AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, or WP1066. In some embodiments, the subject is further administered an inhibitor of the MAPK pathway. In some embodiments, the MAPK pathway inhibitor is a Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, or Teriflunomide. In some embodiments, the subject is further administered an inhibitor of the PI3K-AKT-mTOR pathway. In some embodiments, the PIK3-AKT-mTOR inhibitor is everolimus, alpelisib, idelalisib or copanlisib.

[0328] In another aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) bavdegalutamide (ARV-110), ARV-766, AR-V7, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0329] In another aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, Teriflunomide, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0330] In another aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) everolimus, alpelisib, idelalisib, copanlisib or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0331] In another aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) enzalutamide, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0332] In another aspect, the present disclosure provides methods of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) bavdegalutamide (ARV-110), ARV-766, AR-V7, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0333] In another aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0334] In another aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, Teriflunomide, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0335] In another aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) everolimus, alpelisib, idelalisib, copanlisib or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0336] In another aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) enzalutamide, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine transdifferentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0337] In another aspect, the present disclosure provides methods of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

[0338] Immuno-oncologic Cancers

[0339] In one aspect, the present disclosure provides methods of decreasing the amount of Treg cells in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, the amount of Treg cells in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of Treg cells in the subject.

[0341] In another aspect, the present disclosure provides methods of increasing the amount of APC / M1 <p, Teff, and / or NK cells in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the amount of APC / M1 <p, Teff, and / or NK cells in the subject is increased by at least 50%.

[0343] In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of APC / M1 cp, Teff, and / or NK cells in the subject. In another aspect, the present disclosure provides methods of differentiating Treg cells in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0344] In some embodiments, at least 50% of the Treg cells in the subject are differentiated. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to differentiate Treg cells in the subject.

[0345] In another aspect, the present disclosure provides methods of increasing the level of cells expressing IFNy, CD8, MHC1 , neoantigens, or a combination thereof in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the level of cells expressing IFNy, CD8, MHC1 , neoantigens or a combination thereof in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 - ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of cells expressing IFNy, CD8, MHC1 , neoantigens, or a combination thereof in the subject.

[0347] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing PROS1 , pMERTK, FOXP3, PD1 , or a combination thereof in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the level of cells expressing PROS1 , pMERTK, FOXP3, PD1 , or a combination thereof in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 - ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of cells expressing PROS1 , pMERTK, FOXP3, PD1 , or a combination thereof in the subject.

[0349] In another aspect, the present disclosure provides methods of decreasing the amount of APC / M1 <p, Teff, and / or NK cells in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the amount of APC / M1 <p, Teff, and / or NK cells in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of APC / M1 cp, Teff, and / or NK cells in the subject.

[0351] In another aspect, the present disclosure provides methods of increasing the amount of Treg cells in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 - ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the amount of Treg cells in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of Treg cells in the subject.

[0353] In another aspect, the present disclosure provides methods of differentiating APC / M1 <p, Teff, and / or NK cells in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2- yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, at least 50% of the APC / M1 <p, Teff, and / or NK cells in the subject are differentiated. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to differentiate APC / M1 cp, Teff, and / or NK cells in the subject.

[0355] In another aspect, the present disclosure provides methods of increasing the level of cells expressing PROS1 , pMERTK, FOXP3, PD1 , or a combination thereof in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0356] In some embodiments, the level of cells expressing PROS1 , pMERTK, FOXP3, PD1 , or a combination thereof in the subject is increased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 - ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of cells expressing PROS1 , pMERTK, FOXP3, PD1 , or a combination thereof in the subject.

[0357] In another aspect, the present disclosure provides methods of decreasing the level of cells expressing IFNy, CD8, MHC1 , neoantigens, or a combination thereof in a subject with cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the level of cells expressing IFNy, CD8, MHC1 , neoantigens, or a combination thereof in the subject is decreased by at least 50%. In some embodiments, the method further includes administering an anti-cancer therapy in an amount that together, with the amount of N-(1 - ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of cells expressing IFNy, CD8, MHC1 , neoantigens, or a combination thereof in the subject.

[0359] In some embodiments, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, nonHodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small bowel cancer, penile cancer, or bone cancer.

[0360] In some embodiments, the cancer is esophageal cancer.

[0361] In some embodiments, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, penile cancer, bone cancer, renal cell carcinoma, or prostate cancer.

[0362] In some embodiments, the cancer is non-small cell lung cancer.

[0363] In some embodiments, the cancer is melanoma, prostate cancer, breast cancer, bone cancer, or renal cell carcinoma.

[0364] In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is uveal melanoma, mucosal melanoma, or cutaneous melanoma. In some embodiments, the melanoma is uveal melanoma.

[0365] In some embodiments, the cancer is prostate cancer.

[0366] In some embodiments, the cancer is breast cancer.

[0367] In some embodiments, the breast cancer is an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer.

[0368] In some embodiments, the cancer is a bone cancer. In some embodiments, the bone cancer is Ewing’s sarcoma.

[0369] In some embodiments, the cancer is a renal cell carcinoma. In some embodiments, the renal cell carcinoma is a microphthalmia transcription factor family translocation renal cell carcinoma.

[0370] Homologous Recombination Deficient (HRD) Cancers

[0371] Homologous recombination (HR) is a highly conserved DNA repair mechanism that protects cells from exogenous and endogenous DNA damage. Alterations in genes involved in HR can lead to homologous recombination deficiency (HRD), in which HR proteins cannot repair double-stranded DNA breaks, and other repair pathways such as poly-ADP-ribose-polymerase (PARP) or non-homologous end joining (NHEJ) cannot compensate, resulting in genome-wide errors and tumorigenesis.

[0372] In one aspect, the present disclosure provides methods of treating a homologous recombination deficient (HRD) cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) and DNA damaging agent.

[0373] In some embodiments, the cancer is ovarian cancer, fallopian tube cancer, peritoneal cancer, breast cancer, prostate cancer, or pancreatic cancer.

[0374] In some embodiments, the DNA damaging agent is cisplatin, carboplatin, oxaliplatin, methotrexate, doxorubicin, daunorubicin, cyclophosphamide, chlorambucil, temozolomide, or a combination thereof.

[0375] In some embodiments, the method further comprises administration of a PARP inhibitor.

[0376] In some embodiments, the PARP inhibitor is olaparib, niraparib, rucaparib, talazoparib, or a combination thereof.

[0377] In some embodiments, the anti-cancer therapy is active surveillance, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), cryotherapy, hormone therapy, chemotherapy, immunotherapy, vaccine treatment, immune checkpoint inhibitors, targeted therapy drugs, or bone-directed treatment.

[0378] In some embodiments, the anti-cancer therapy is immunotherapy.

[0379] In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor.

[0380] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

[0381] Combination Treatments

[0382] The compounds of the invention can be combined with one or more anti-cancer therapies or anticancer agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any cancer described herein.

[0383] A compound of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of treatment to treat cancer (e.g., anti-cancer therapy). In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.

[0384] In some embodiments, the anti-cancer therapy is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1 -TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, Adriamycin® (doxorubicin, including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABraxane®, cremophor- free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, III.), and Taxotere® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041 -7.

[0385] In some embodiments, the anti-cancer therapy is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (Avastin®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include Rituxan (Rituximab); Zenapax (Daclizumab); Simulect (Basiliximab); Synagis (Palivizumab); Remicade (Infliximab); Herceptin (Trastuzumab); Mylotarg (Gemtuzumab ozogamicin); Campath (Alemtuzumab); Zevalin (Ibritumomab tiuxetan); Humira (Adalimumab); Xolair (Omalizumab); Bexxar (Tositumomab-l-131); Raptiva (Efalizumab); Erbitux (Cetuximab); Avastin (Bevacizumab); Tysabri (Natalizumab); Actemra (Tocilizumab); Vectibix (Panitumumab); Lucentis (Ranibizumab); Soliris (Eculizumab); Cimzia (Certolizumab pegol); Simponi (Golimumab); Haris (Canakinumab); Stelara (Ustekinumab); Arzerra (Ofatumumab); Prolia (Denosumab); Numax (Motavizumab); ABThrax (Raxibacumab); Benlysta (Belimumab); Yervoy (Ipilimumab); Adcetris (Brentuximab Vedotin); Perjeta (Pertuzumab); Kadcyla (Ado-trastuzumab emtansine); and Gazyva (Obinutuzumab). Also included are antibody-drug conjugates.

[0386] The anti-cancer therapy may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and / or surgical excision of tumor tissue.

[0387] The anti-cancer therapy may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / Opdivo®; pembrolizumab / Keytruda®; pidilizumab / CT-011 ). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / lg fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1 , CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the compound of the invention is used in combination with another anticancer therapy used for the treatment of uveal melanoma such as surgery, a MEK inhibitor, and / or a PKC inhibitor, or a combination thereof. For example, in some embodiments, the method further comprises performing surgery prior to, subsequent to, or at the same time as administration of the compound of the invention. In some embodiments, the method further comprises administration of a MEK inhibitor (e.g., selumetinib, binimetinib, or tametinib) and / or a PKC inhibitor (e.g., sotrastaurin or IDE196) prior to, subsequent to, or at the same time as administration of the compound of the invention.

[0388] In any of the combination embodiments described herein, the first and second the anti-cancer therapies are administered simultaneously or sequentially, in either order. The first the anti-cancer therapy may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1 -7, 1 -14, 1 -21 or 1 -30 days before or after the second the anti-cancer therapy.

[0389] In one aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) a BRAF / MEK inhibitor combination. In some embodiments, the BRAF / MEK inhibitor combination is dabrafenib / trametinib, vemurafenib / cobimetinib, encorafenib / binimetinib, or a combination thereof.

[0390] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) a PD-1 / PD-L1 inhibitor.

[0391] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

[0392] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-PD1 / anti-CTLA4 combination therapy.

[0393] In some embodiments, the anti-PD-1 / anti-CTLA4 combination therapy is nivolumab / ipilimumab.

[0394] In another aspect, the present disclosure provides methods of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) aldesleukin, binimetinib, cobimetinib fumarate, dabrafenib mesylate, dacarbazine, encorafenib, ipilimumab, melphalan hydrochloride, nivolumab, nivolumab and relatlimab-rmbw, pembrolizumab, recombinant interferon alfa- 2b, talimogene laherparepvec, tebentafusp-tebn, trametinib dimethyl sulfoxide, vemurafenib, or a combination thereof.

[0395] In another aspect, the present disclosure provides methods of treating non-small cell lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) adagrasib, afatinib, dimaleate, alectinib, amivantamab-vmjw, atezolizumab, bevacizumab, brigatinib, capmatinib hydrochloride, cemiplimab-rwlc, ceritinib, crizotinib, dabrafenib mesylate, dacomitinib, docetaxel, doxorubicin hydrochloride, durvalumab, entrectinib, erlotinib hydrochloride, everolimus, famtrastuzumab, deruxtecan-nxki, gefitinib, gemcitabine hydrochloride, ipilimumab, lorlatinib, methotrexate sodium, mobocertinib succinate, necitumumab, nivolumab, osimertinib mesylate, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pembrolizumab, pemetrexed disodium, pralsetinib, ramucirumab, selpercatinib, sotorasib, taxol, tepotinib hydrochloride, trametinib dimethyl sulfoxide, tremelimumab-actl, vinorelbine tartrate, or a combination thereof.

[0396] In another aspect, the present disclosure provides methods of treating small cell lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N- (1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) atezolizumab, doxorubicin hydrochloride, durvalumab, etoposide, etoposide phosphate, everolimus, lurbinectedin, methotrexate sodium, nivolumab, topotecan hydrochloride, or a combination thereof.

[0397] In another aspect, the present disclosure provides methods of treating melanoma and / or lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan- 2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) abemaciclib, celecoxib, AZD8701 , or a combination thereof..

[0398] In another aspect, the present disclosure provides methods of treating melanoma and / or lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan- 2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) a PD-1 / PD-L1 inhibitor.

[0399] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

[0400] In another aspect, the present disclosure provides methods of treating melanoma and / or lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan- 2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-PD1 / anti-CTLA4 combination therapy.

[0401] In some embodiments, the anti-PD-1 / anti-CTLA4 combination therapy is nivolumab / ipilimumab.

[0402] In some embodiments, the anti-cancer therapy is enzalutamide. In some embodiments of any of the foregoing methods, the cancer is drug resistant (e.g., the cancer has been determined to be resistant, or likely to be resistant, to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent) and / or has failed to respond to a prior therapy (e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof).

[0403] In some embodiments, the cancer is resistant to and / or has failed to respond to vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, doxorubicin, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, brilanestrant, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demcizumab, fosbretabulin, or a PD-L1 inhibitor, or combinations thereof.

[0404] In some embodiments of any of the foregoing methods, the cancer is resistant to and / or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgpl OO, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0405] In some embodiments of any of the foregoing methods, the cancer is resistant to and / or failed to respond to a previously administered therapeutic used for the treatment of uveal melanoma, e.g., a MEK inhibitor or PKC inhibitor. For example, in some embodiments, the cancer is resistant to and / or failed to respond to a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0406] In some embodiments, the method further includes administering to the subject or contacting the cell with an anti-cancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or combinations thereof. In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine-specific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA- Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor, or combinations thereof.

[0407] In some embodiments, the compound of the invention is used in combination with another anticancer therapy used for the treatment of uveal melanoma such as surgery, a MEK inhibitor, and / or a PKC inhibitor, or combinations thereof. For example, in some embodiments, the method further comprises performing surgery prior to, subsequent to, or at the same time as administration of the compound of the invention. In some embodiments, the method further comprises administration of a MEK inhibitor (e.g., selumetinib, binimetinib, or tametinib) and / or a PKC inhibitor (e.g., sotrastaurin or IDE196) prior to, subsequent to, or at the same time as administration of the compound of the invention.

[0408] In some embodiments, the additional anti-cancer therapy is administered prior to the administering of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the additional anti-cancer therapy is administered in addition to the administering of the compound or pharmaceutically acceptable salt thereof.

[0409] In some embodiments, the additional anti-cancer therapy is administered subsequent to the administering of the compound or pharmaceutically acceptable salt thereof.

[0410] In some embodiments, the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered prior to surgical intervention, radiation therapy, or chemotherapy to treat the cancer in the subject.

[0411] In some embodiments, the administering step is performed as a neoadjuvant therapy.

[0412] In some embodiments, the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered subsequent to surgical intervention, radiation therapy, or chemotherapy to treat the cancer in the subject.

[0413] In some embodiments, the administering step is performed as an adjuvant therapy.

[0414] PD-1 / PD-L1 Inhibitors

[0415] PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anti-cancer drugs. PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 (PD-L1 ) with its receptor, programmed cell death protein 1 (PD-1 ). This interaction is involved in the suppression of the immune system, and occurs following an infection in an effort to limit the killing of bystander host cells, and prevent autoimmune disease. Several PD-1 and PD-L1 inhibitors are being developed for use in advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other cancer types. In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP- 224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

[0416] FLT3 Inhibitors

[0417] In one embodiment, the invention features a combination therapy including (i) , N-(1 -((4-(6-(2,6- dimethylmorpholino)54yridine-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of, and (ii) a FLT3 inhibitor. The term “FLT3 pathway inhibitor” or “FLT3 targeting compound” or “FLT3 inhibitor” refers to a compound that specifically binds to and inhibits FLT3, which interferes with the activation of FLT3 -mediated signal transduction pathways and reduces cell proliferation in cancer cells that overexpress FLT3. In certain embodiments, a FLT3 inhibitor is a compound that specifically binds to and inhibits wild type FLT3. In certain embodiments, a FLT3 inhibitor is a compound that specifically binds to and inhibits mutant FLT3, for example, FLT3-ITD (an internal tandem duplication mutation in the JM domain-coding sequence of the FLT3 gene) and / or FLT3-KDM (a missense point mutation at the D835 residue and point mutations, deletions and insertions in the codons surrounding D835 within a TK domain of FLT3). Exemplary FLT3 inhibitors for use herein include, but are not limited to quizartinib (AC220), sunitinib (SU11248), sorafenib (BAY 43-9006), midostaurin (PKC412), lestaurtinib (CEP-701 ), crenolanib (CP- 868596), PLX3397, E6201 , AKN-028, ponatinib (AP24534), ASP2215, KW- 2449, famitinib and DCC- 2036.

[0418] ERG Inhibitors

[0419] The ETS-related gene (ERG) encodes a transcription factor with oncogenic properties that plays a role in the development of prostate cancer. In prostate cancers, the ETS gene commonly fuses with the promoter region of the TMPRRSS2 gene, which leads to overexpression of the ETS transcription factor. In some embodiments, the present invention provides methods for treating androgen receptorindependent prostate cancer that include further administering an inhibitor or degrader of ERG to a subject with androgen receptor-independent prostate cancer. A nonlimiting example of an ERG inhibitor that may be administered to a subject in accordance with the methods of the present disclosure is ERGi- USU (1 -[2-Thiazolylazo]-2-naphthol).

[0420] Androgen Receptor (AR) degraders

[0421] In some embodiments, the present invention provides methods for treating androgen receptorindependent prostate cancer that include further administering a degrader of the androgen receptor to the subject. Nonlimiting examples of AR degraders that may be administered to a subject in accordance with the methods of the present disclosure include bavdegalutamide (ARV-110), ARV-766, and AR-V7.

[0422] JAK-STAT pathway inhibitors

[0423] Aberrant activation of the Janus kinase / signal transducer and activator of transcription (JAK- STAT) pathway is related to tumor growth and disease progression in prostate cancer. Accordingly, in some embodiments, the methods of the present invention include further administering to the subject an inhibitor of the JAK-STAT pathway. Nonlimiting examples of JAK-STAT pathway inhibitors that may be administered to a subject in accordance with the methods of the present invention include AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, or WP1066.

[0424] MAPK pathway inhibitors

[0425] The mitogen activated protein kinase (MAPK) pathway includes the proteins p38, JNK, and ERK, and is implicated in the progression of prostate cancer. Accordingly, in some embodiments, the methods of the present invention include further administering to the subject an inhibitor of the MAPK pathway. Nonlimiting examples of MAPK pathway inhibitors that may be administered to a subject in accordance with the methods of the present invention include a Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, or Teriflunomide.

[0426] Pharmaceutical Compositions

[0427] The compounds of the present disclosure may be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include an active agent as described herein and a physiologically acceptable excipient (e.g., a pharmaceutically acceptable excipient). Formulation principles for the compounds disclosed herein may be those described, e.g., in W02020 / 160180, the disclosure of which is incorporated by reference herein in its entirety.

[0428] The compounds of the disclosure may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Preferably, the compound is administered orally.

[0429] Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21stEd., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary).

[0430] In one embodiment, N-(1 -((4-(6-(2,6-dimethylmorpholino)56yridine-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide may be formulated into a unit dosage form for oral administration (e.g., a capsule) as described in Table 1 .

[0431] Table 1 . Formulation of N-(1 -((4-(6-(2,6-dimethylmorpholino)56yridine-2-yl)thiazol-2-yl)amino)-3-methoxy-

[0432] 1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide

[0433] In some embodiments, the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is between 1 .5 mg and 10 mg per day. Examples

[0434] Example 1. Treatment of Metastatic Uveal Melanoma with Compound A has a Favorable Impact on Stem Maturation Markers in Subjects with Tumor Response

[0435] Seventy-three subjects were enrolled in a clinical study of treating metastatic uveal melanoma with Compound A (NCT04879017) on a daily dosing regimen ranging from 2.5 to 10 mg of Compound A, or with Compound A on an intermittent regimen of 1 -week on / 1 -week-off ranging from 10 to 22.5 mg of Compound A. Tumor biopsies were collected at either Cycle 3, or at end of treatment. Paired tumor biopsies from up to 13 subjects were analyzed. Biomarker changes in the tumor were observed by histological assessment, IHC / IF biomarker assays, and RNA sequencing. Compound A

[0436] Observations suggested a differentiation effect by Compound A on tumor cells, including a decrease in sternness genes (FIG. 1A) and an increase in mature melanocytic markers (FIG. 1 B). Mean Log2FC from screening is annotated. Melanocyte Markers H-score is a composite score from 3 melanocyte markers - Tyrosinase, GP100, and MelanA. Subjects were classified as a mixed responder if they had a stable disease (SD) target lesion response but not an overall RECIST response. Example images of the melanocyte multiplex IF panel on a tumor biopsy pair are shown in FIG. 2. The baseline expression of each melanocyte marker varied across subjects, and H-scores for individual markers were quantified using image analysis. The average Log2FC from screening is plotted in FIGS. 1 A and 1 B. Differential gene expression in the RECIST and mixed responders vs. RECIST non-responders is shown in FIGS. 3A and 3B, respectively. Markers associated with metastatic uveal melanoma (green) and general markers associated with pluripotency or sternness (cyan) are annotated.

[0437] Changes we observed suggest Compound A may lead to loss of stem-like properties and a broader impact on the tumor cellular architecture that may be not captured by RECIST criteria.

[0438] Example 2. Treatment of Metastatic Uveal Melanoma with Compound A Results in Necrosis and Lower Tumor Cell Density

[0439] In the same study described in Example 1 , evidence of necrosis and a trend of decreasing tumor cell density were also seen.

[0440] Viable and necrotic tumor areas were annotated in H&E images on paired tumor biopsies from 22 subjects. Percentage of necrotic tumor was estimated based on these areas (FIG. 4). 1 of 22 subjects had necrosis in the screening and on-treatment sample (mean with SD is annotated). Example H&E images from two tumor biopsy pairs are shown in FIG. 5. Cells were observed to be less densely packed in the on-treatment samples than in the screening samples. Example images of SOX10 IF staining in a tumor biopsy pair are shown in FIG. 6A. Tumor cell density, defined as the number of tumor cells (SOX10+) per area of total tissue in mm2, was quantified using image analysis (FIG. 6B). The median density across ROIs per sample was calculated and normalized to screening (mean Log2FC from screening is annotated). Example 3. Treatment of Metastatic Uveal Melanoma with Compound A Results in Reduction of ctDNA

[0441] In the same study described in Example 1 , treatment with Compound A also demonstrated reduction in circulating tumor DNA (ctDNA), which correlated with a survival benefit. ctDNA was measured in serial plasma samples using a targeted NGS panel. A reduction in ctDNA was shown in approximately 50% of subjects, which correlated with an increased overall survival benefit. A summary of the ctDNA anlaysis is shown in Table 2. ctDNA was measured by a targeted NGS panel in serial blood samples. ctDNA levels were quantified as mutant molecules per mL of plasma.

[0442] Table 2. ctDNA Analysis Summary

[0443] The percent change from the minimum and maximum ctDNA levels was calculated for each subject, and the median of each cohort is shown in FIG. 7. Change in ctDNA from Cycle 1 for individual subjects in the 5mg, 7.5mg, and 10mg QD cohorts who were on Compound A for at least one cycle (n=17) is shown in FIG. 8. FIG. 9 shows a comparison between the apparent survival benefit between subjects in FIG. 8 where a reduction in ctDNA from Cycle 1 was seen, vs. those where it was not. Apparent survival benefit in FIG. 9 is in the context of subjects going on additional therapies after coming off study for Compound A. Survival is based on the known date of death or last survival follow-up, with a data cut-off of July 24, 2023. We have shown that reduction in ctDNA can be used as surrogate for improved patient survival benefit when treated with Compound A.

[0444] Example 4. Treatment of Metastatic Uveal Melanoma with Compound A Results in a Robust Blood PD Signature

[0445] In the same study described in Example 1 , serial blood samples collected in Paxgene RNA tubes were analyzed by RNA sequencing. A robust dose-dependent gene signature was identified as a peripheral readout of target engagement at steady-state in both dosing regimens and across dose cohorts.

[0446] A schematic outlining the daily and intermittent dosing schedule of Compound A and when blood samples were collected and analyzed for gene expression changes by RNA-seq is shown in FIG. 10A. A gene signature score was quantified for each dose cohort using the average log2FC from pre-dose for a selected panel of genes, shown in FIG. 10B. The signature was monitored in a time course through steady-state, C1 D15 onwards.

[0447] Given the limitations and challenges to obtain tumor biopsies from every subject and at a frequent rate, the identified PD gene signature in the blood is a valuable tool to measure target engagement metastatic uveal melanoma, and other potential solid tumor indications. We have identified a blood gene signature that can be used to monitor target engagement of Compound A in potential future clinical studies. Target engagement was not sustained during the off-week in the intermittent dose cohorts.

[0448] Example 5. Non-Small Cell Lung Cancer (NSCLC) Cell Lines are Sensitive to Treatment with Compound A, Regardless of BRG1 Status

[0449] Twenty-five NSCLC cell lines were treated with a serial dilution of Compound A for 14 days, and GI50 was calculated (FIG. 11 A). No statistically significant difference in response to Compound A was observed between BRG1 -proficient and -deficient lines in vitro (FIG. 11 B).

[0450] NSCLC cell line-derived xenograft (CDX) models were treated with 15 or 25 mg / kg of a dual BAF ATPase inhibitor and tool compound. Final tumor growth inhibition relative to vehicle was determined (FIG. 12A). BRG1 -proficient and -deficient CDX tumor models demonstrated similar responses to dual BAF ATPase inhibition in vivo (FIG. 12D).

[0451] Here, we have demonstrated that a panel of NSCLC cell lines respond to dual BAF ATPase inhibition in both in vitro and in vivo settings, irrespective of SMARCA4 mutation status.

[0452] Example 6. Treatment with Compound A Decreases Expression of AP-1 Family Transcription Factors and AP-1 Transcription Factor Motifs are Enriched at Chromatin Sites that Lose Accessibility in NSCLC

[0453] NSCLC cell lines were treated for 48 hours with vehicle or 11 nM, 33 nM, or 100 nM Compound A. Western blotting for AP-1 family transcription factors revealed that NSCLC lines express varying levels of AP-1 components eJun, cFos, Fosl2, and JunB at baseline (FIG. 13A). Three out of four lines demonstrate downregulation of AP-1 transcription factors, including Fos and Jun proteins, upon Compound A treatment in a dose-dependent manner (FIG. 13A).

[0454] Homer analysis of ATAC peaks in NSCLC cell lines treated with Compound A for 8 hours reveals reduced chromatin accessibility at AP-1 motifs. A549, NCIH1693, and NCIH23 NSCLC cell lines were treated with vehicle or 100 nM Compound A for 8 hours. ATAC-seq analysis reveals that AP-1 transcription factor motifs are enriched within chromatin sites that lose accessibility upon Compound A treatment (FIGS. 13B-13D). This trend is consistent among three cell lines, suggesting that loss of AP-1 chromatin binding may be a shared molecular response to Compound A treatment in NSCLC.

[0455] Taken together, we have found that dual BRM / BRG1 inhibition in NSCLC cell lines by treatment with Compound A reduces chromatin accessibility at motifs normally bound by AP-1 transcription factors, which are known to play tumorigenic roles in NSCLC.

[0456] Example 7. Treatment with Compound A Downregulates Stem Cell Marker CD44 in NSCLC Cell Lines

[0457] Four NSCLC cell lines (two BRG-proficient (blue) and two BRG-deficient (green)) were treated with DMSO or 11 nM, 33 nM, or 100 nM of Compound A for 48 hours. A CD44 western blot demonstrated that CD44 downregulation in BRG1 -deficient cell lines (green) is dose-dependent while protein is detectable in the vehicle-treated control (FIG. 14A).

[0458] Eight NSCLC cell lines were treated with DMSO or 100 nM Compound A for 48 hours. Quantitative real-time PCR indicates that CD44 transcripts are downregulated in most NSCLC lines (FIG. 14B), apart from Calul , which is notably insensitive to Compound A in in vitro proliferation assays (see FIG. 11 A). Errors bars indicate SEM.

[0459] We have found that expression of the sternness-associated glycoprotein CD44 is decreased by treatment with Compound A, suggesting that dual BRM / BRG1 inhibition impacts the differentiation state of NSCLC.

[0460] Example 8. CD44 Expression Decreases Over Time in Response to Compound A Treatment and Recovers Following Washout in NSCLC Cell Lines

[0461] The treatment scheme for a CD44 flow cytometry study in A549 and NCIH358 NSCLC cell lines is shown in FIG. 15A. Histograms (FIG. 15A) and mean fluorescence intensity (MFI) quantification (FIGS. 15B-15C) indicate that CD44 is downregulated by treatment with 20 nM Compound A over time, and rapidly returns upon washout after D7. Error bars indicate SEM.

[0462] Example 9. Treatment with Compound A in NSCLC CDX Models Downregulates CD44 and Lung Basal Cell Genes

[0463] Tumor volume measurements for NCIH358 CDX tumors treated with Compound A are shown in FIG. 16A. Immunohistochemistry (IHC) for CD44 in NCIH358 tumor sections treated with Compound A for 7 days at doses described in Example 8 (FIG. 15A) demonstrates CD44 downregulation at higher doses (FIG. 16B).

[0464] RNA-seq on A549 and NCIH358 CDX revealed that CD44 as well as lung basal cell identity genes are downregulated by 21 -day treatment with Compound A (1 mg / kg, BID) (FIGS 16C-16D). The lung basal cell gene expression signature decreased over time in response to Compound A in both NSCLC CDX tumor models (FIG. 16E).

[0465] In summary, Compound A treatment in NSCLC xenograft tumor models induces downregulation of sternness-associated markers, including CD44 and lung basal cell genes.

[0466] Example 10. Genome-wide CRISPR Knockout Screening Establishes Molecular Vulnerabilities Induced by Compound A in NSCLC, Including JunB Loss

[0467] Genome-wide CRISPR screening indicates molecular determinants of sensitivity and resistance to Compound A in NSCLC. Viability curves used to select Compound A doses (EC20-EC30) to use for CRISPR screening in A549 and NCIH358 over 8-10 cell doublings are shown in FIGS. 17A-17B. Genes were ranked by beta score (p) differences between Compound A- and vehicle (vhc)-treated conditions for each cell line (FIGS 17C-17D). Biologically significant hits were defined as genes with > 4 sgRNAs, pdiff > 0.3, and pFHD-286 > 0 for positive hits, and < 0 for negative hits. MiRNAs were excluded. Positive and negative beta scores for genes reveal molecular determinants of resistance and sensitivity, respectively, to dual BRM / BRG1 inhibition. Yellow stars indicate genes involved in regulation of AP-1 activity, CD44, or sternness.

[0468] Transcriptional analyses of NSCLC xenograft models reveal that a basal cell gene expression signature, which is associated with a less differentiated cell state, is downregulated by Compound A treatment. Example 11. Treatment with Compound A Induces a Decrease in T egs (markers of T cell exhaustion) and PDL1+ Tumor Associated Macrophages (TAM), Consistent with Reduction of Immunosuppressive Effects on Tumor Microenvironment (TME)

[0469] From the same study described in Examples 1 -4, RNA sequencing was performed in 46 patient blood samples collected in Paxgene tubes during dose escalation (2.5 mg- 15mg, C1 D1 , C1 D15, C3D1 and other intermediate timepoints) and analyzed for transcriptional changes associated with shifts in immune polarization and activation. In addition, ctDNA was measured in serial plasma samples using a targeted NGS panel.

[0470] Optional tumor biopsies were collected at screening and either Cycle 3 or end of treatment. Biopsies were collected from 16 patients, 13 of which had samples from both screening and on-treatment. Biomarker changes in the tumor were quantified using multiplex IF (mIF) panel (Neogenomics-TIL and Myeloid Panel #2-19 markers, Table 3) and analyzed by Neogenomics to identify 8 cell types of interest via co-localization of 20 different immune related markers (Table 4). Of note, not all markers were expressed in patient samples, thus we focused our analysis on the immune cell types with highest abundance and strongest differential expression from screening and on treatment samples. Further analysis to determine the spatial orientation of cell types via nearest neighbor analysis as well as location of cells inside or outside of the tumor. Additionally, variation or absence of specific immune cell presence in baseline and / or post treatment biopsies precluded normalization output for cell types in certain patients. Transcriptional changes were assessed using RNA sequencing of paired biopsies in 9 patients.

[0471] A reduction in immunosuppressive cell types was observed following treatment with Compound A. Shown in FIGS. 18A-18D is the quantitation of changes grouped by patients with observed ctDNA decrease at C1 and colored by response (RESCIST Responder=SD or better; Mixed Responded PD with shrinkage in 1 or more targe lesions; RECIST Non-responder= PD) Additionally, representative multiplex IF images of paired biopsies are shown for each cell type of interest (FIG. 19E).

[0472] Patient samples at screening showed abundance of Tregs which decreased following treatment with Compound A. Representative paired biopsy from patient 3 showed Tregs (CD4+, FOXP3+), Teffector (CD8+ Granzyme B+), Tumor (SOX10+).

[0473] Reduction in immunosuppressive tumor associated macrophages (TAMs) were observed. Representative paired biopsy from patient 12 showed PDL1 + TAM (CD68+, PDL1 +), Tumor (SOX10+).

[0474] Observed reduction in PD1 + expression in CD4 and CD8 T cells was observed.

[0475] These results are supportive of reversion of T cell exhaustion in our patient samples after treatment with Compound A. Representative paired biopsy from patient 6 showed PD1 + Thelper (PD1 +, CD4+, CD3+) and PD1 + Tcytotoxic (PD1 +, CD8+, CD3+), Tumor (SOX10+) cells. Table 3. Neogenomics / TIL / Myeloid mIF Panel of Genes

[0476] ★markers in italic were not shown in data

[0477] Table 4. Identified Gene Signatures of Cells of Interest

[0478] Given the previously reported connection between UM biology and M2 macrophages, we quantitated the presence / location of M2 macrophages in the paired biopsies. Representative mIF image (patient 8) showed an abundance of M2 macrophages “inside” the tumor, and M2 to Tumor cell distance, which is altered following treatment with Compound A (FIG. 19A). M2 macrophages shifted from “inside” the tumor area to “outside” the tumor, as defined by Neogenomics analysis (FIG. 19B). Nearest neighbor analysis showed an increase in the M2 macrophage to tumor cell distance (FIG. 19C). We determined that treatment with Compound A shifts the tumor microenvironment (TME) of uveal melanoma patients. Table 5 shows the per patient changes summarizing cell type increase, decrease, or unknown status due to lack of quantifiable number of the cells. Boxes that are marked “Y” indicate a reduction in immunosuppressive cells, boxes that are marked “N” indicate no change or increase in immunosuppressive cells, and boxes that are marked “UNK” indicate if change is unable to be determined. Patients with unknown change had no evidence of that cell type in screening or treatment sample. Changes in the ratio of inflammatory to repressive T cells supports a shift in the tumor microenvironment towards a more tumor killing state. 7 / 13 patients showed an increase in overall CD8 / CD4 ratio (FIG. 20A), and 4 / 13 patients showed an increase in CD8+GrznB+ / Treg ratio (FIG. 20B). Table 5. Per Patient Changes in Cell Type With Compound A treatment, we observed a dose-dependent downregulation of FOXP3 (a gene signature for Tregs), and an increase in inflammatory transcripts (ELANE) in patient peripheral blood mononuclear cells (PBMCs). RNA seq obtained from the PBMCs of patients in a Compound A dose escalation (5 mg QD, 7.5mg QD, 10 mg QD) study showed changes in transcripts associated with reduction in immunosuppressive effects. A dose-dependent decrease in FOXP3 mRNA expression from baseline on C1 D2 following treatment with Compound A was observed, which deepens at steady state on C1 D15 (FIG. 21 A). A dose dependent increase in Granzyme B mRNA expression from baseline on C1 D2 following treatment with Compound A was observed, which appears to increase and plateau at steady state, showing less evidence of dose dependent effect than with FOXP3 (FIG. 21 B). A non- dose dependent increase in expression of ELANE (a marker of neutrophil activation) was observed at C1 D2 which increases at steady state on C1 D15 (FIG. 21 C). RNA seq isolated from FFPE slides obtained from paired biopsies of 9 patients identified changes in transcripts associated with neutrophil degranulation that was differential between Responder (both RECIST and Mixed Responder) (FIG. 22A) and NonResponder (RECIST Non-Responder) (FIG. 22B) patients.

[0479] In summary, we observed changes in TME post Compound A treatment that are consistent with reduction of immunosuppressive impact including a reduction in number of Tregs, a reduction in markers of T cell exhaustion (PD-1 ), a reduction in immune suppressive PDL1 + TAMS, and shifting of repressive M2 macrophages away from tumor cells. Patients showed transcriptional changes in PBMCs consistent with reduced immunosuppressive transcripts and increased inflammatory transcripts, including a dosedependent down regulation FOXP3 transcript (Treg), an increase in Granzyme B (Teff) transcript, and an increase in transcripts associated with active neutrophil degranulation (e.g. ELANE). Transcriptional changes from paired biopsies showed an increase in neutrophil degranulation genes following Compound A treatment in responder and putative responder patients. Taken together these results suggest that Compound A may reduce the immunosuppressive “blockade”, priming metastatic uveal melanoma patients to respond favorably, possibly in combination with an immune checkpoint inhibitor.

[0480] Other Embodiments

[0481] While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0482] Other embodiments are in the claims.

Claims

What is claimed is:CLAIMS1 . A method of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the effective amount is an amount sufficient to increase levels of SOX10, tyrosinase, GP100, MelanA, or a combination thereof.

3. The method of any one of claims 1 -2, wherein the effective amount is an amount sufficient to increase the level of melanocyte cells.

4. The method of any one of claims 1 -3, wherein the effective amount is an amount sufficient to decrease the level of primitive ectoderm cells.

5. The method of any one of claims 1 -4, wherein the effective amount is an amount sufficient to decrease levels of PRAME, CD44, KIT, BRG1 , or a combination thereof.

6. The method of any one of claims 1 -5, wherein the melanoma has been determined to have or predicted to have higher expression levels of PRAME, CD44, KIT, BRG1 , or a combination thereof compared to a reference.

7. The method of any one of claims 1 -5, wherein the melanoma has been determined to have or predicted to have higher expression levels of PRAME, CD44, KIT, BRG1 , or a combination thereof compared to a subject that does not have melanoma.

8. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing SOX10, tyrosinase, GP100, MelanA, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

9. A method of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of melanocyte cells compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

10. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the melanoma expresses PRAME, CD44, KIT, BRG1 , or a combination thereof.11 . The method of any one of claims 1 -10, wherein the effective amount is an amount sufficient to increase levels of IFNy, MHCI, CD8, or a combination thereof.

12. The method of any one of claims 1 -11 , wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof.

13. The method of any one of claims 1 -12, wherein the effective amount is an amount sufficient to decrease the level of Treg cells, M2cp cells, tumor associated macrophages (TAM), or a combination thereof.

14. The method of any one of claims 1 -13, wherein the effective amount is an amount sufficient to decrease levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

15. The method of any one of claims 1 -14, wherein the melanoma has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a reference.

16. The method of any one of claims 1 -15, wherein the melanoma has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a subject that does not have melanoma.

17. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing IFNy, MHCI, CD8, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

18. A method of increasing the level of cell differentiation in a subject with melanoma; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

19. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the melanoma expresses PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

20. The method of any one of claims 1 -19, wherein the levels are measured in a tissue sample of the subject.21 . The method of any one of claims 1 -19, wherein the levels are measured in a blood sample of the subject.

22. The method of any one of claims 1 -21 , wherein the subject is further administered at least one additional anti-cancer therapy.

23. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) tebentafusp-tebn.

24. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) bivatuzumab, RG7356, or a combination thereof.

25. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) IMA203 / IMA203CD8.

26. The method of claim 25, the method further comprising administration of a PD-1 / PD-L1 inhibitor.

27. The method of claim 26, wherein the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab,spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

28. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) imatinib, dasatinib, avapritinib, nilotinib, KTN0182A, or a combination thereof.

29. The method of any one of claims 1 -28, wherein the melanoma is mucosal melanoma, uveal melanoma, or cutaneous melanoma.

30. The method of claim 29, wherein the melanoma is uveal melanoma.31 . The method of claim 29, wherein the melanoma is cutaneous melanoma.

32. The method of any one of claims 1 -31 , wherein the melanoma is metastatic.

33. A method of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the effective amount is an amount sufficient to decrease levels of CD44.

35. The method of claim 33 or 34, wherein the effective amount is an amount sufficient to increase the level of club cells and / or alveolar cells.

36. The method of any one of claims 33-35, wherein the effective amount is an amount sufficient to decrease the level of basal cells.

37. The method of any one of claims 33-36, wherein the effective amount is an amount sufficient to decrease levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , or a combination thereof.

38. The method of any one of claims 33-37, wherein the lung cancer has been determined to have or predicted to have higher expression levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , CD44, or a combination thereof compared to a reference.

39. The method of any one of claims 33-37, wherein the lung cancer has been determined to have or predicted to have higher expression levels of TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , CD44, or a combination thereof compared to a subject that does not have lung cancer.

40. A method of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to decrease the level of CD44 compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.41 . A method of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is n amount sufficient to increase the level of club cells and / or alveolar cells compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof..

42. A method of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the lung cancer expresses TP63, KRT5, KRT14, AP-1 transcription factors, BRG1 , high level of CD44, or a combination thereof.

43. The method of any one of claims 37, 38, 39, or 42, wherein the AP-1 transcription factors are Jun (eJun, JunB, JunD), Fos (cFos, FosB, FosL1 / Fra1 , FosL2 / Fra2), Maf (musculoaponeurotic fibrosarcoma) (c-Maf, MafB, MafA. Mafg / f / k, Nrl), ATF-activating transcription factor (ATF2, LRF1 / ATF3, BATF, JDP1 , JDP2), or a combination thereof.

44. The method of claim 43, wherein the AP-1 transcription factors are eJun, cFos, FosL2, and JunB.

45. The method of any one of claims 33-44, wherein the effective amount is an amount sufficient to increase levels of IFNy, MHCI, CD8, or a combination thereof.

46. The method of any one of claims 33-45, wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof.

47. The method of any one of claims 33-46, wherein the effective amount is an amount sufficient to decrease the level of Treg cells, M2cp cells, tumor associated macrophages (TAM), or a combination thereof.

48. The method of any one of claims 33-47, wherein the effective amount is an amount sufficient to decrease levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

49. The method of any one of claims 33-48, wherein the lung cancer has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a reference.

50. The method of any one of claims 33-49, wherein the lung cancer has been determined to have or predicted to have higher expression levels of PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof compared to a subject that does not have lung cancer.51 . A method of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of cells expressing IFNy, MHCI, CD8, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

52. A method of increasing the level of cell differentiation in a subject with lung cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to increase the level of APC / M1 cp cells, Teff cells, NK cells, or a combination thereof, compared to a subject that is not administered the compound or a pharmaceutically acceptable salt thereof.

53. A method of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, wherein the lung cancer expresses PROS1 , GDF15, FOXP3, PD1 , CD4, CD3, CD68, GzmB, CD163, HLADR, SOX10, BRG1 , ELANE, or a combination thereof.

54. The method of any one of claims 33-53, wherein the levels are measured in a tissue sample of the subject.

55. The method of any one of claims 33-53, wherein the levels are measured in a blood sample of the subject.

56. The method of any one of claims 33-55, wherein the subject is further administered at least one additional anti-cancer therapy.

57. A method of treating lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) bivatuzumab, RG7356, or a combination thereof.

58. The method of any one of claims 33-57, wherein the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

59. The method of claim 58, wherein the lung cancer is non-small cell lung cancer (NSCLC).

60. The method of claim 58, wherein the lung cancer is small cell lung cancer (SCLC).61 . The method of any one of claims 33-60, wherein the lung cancer is metastatic.

62. A method of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

63. The method of claim 62, wherein the effective amount is an amount sufficient to reduce the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

64. A method of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

65. The method of claim 64, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levelsof CHGA, SYP, EN02, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

66. The method of any one of claims 62-65, wherein the effective amount is an amount sufficient to reduce the level of neuroendocrine prostate cancer cells compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

67. The method of any one of claims 62-66, wherein the prostate cancer has been determined to have or predicted to have lower expression levels of AR, KLK2, KLK3, CDH1 , CYLD, NKX3-1 , SLC45A3, TARP, PTEN, SPDEF, TP53, or RB1 , or combinations thereof compared to a subject that does not have prostate cancer.

68. The method of any one of claims 62-66, wherein the prostate cancer has been determined to have or predicted to have lower expression levels of AR, KLK2, KLK3, CDH1 , CYLD, NKX3-1 , SLC45A3, TARP, PTEN, SPDEF, TP53, or RB1 , or combinations thereof compared to reference levels for prostate cancer.

69. The method of any one of claims 62-68, wherein the prostate cancer has been determined to have or predicted to have higher expression levels of CHGB, CHGA, SYP, ENO2, PEG10, SNAP25, SRRM4, VGF, VIM, SCGN, PAPPA2, WNT11 , BRG1 , or combinations thereof compared to a subject that does not have prostate cancer.

70. The method of any one of claims 62-68, wherein the prostate cancer has been determined to have or predicted to have higher expression levels of CHGB, CHGA, SYP, ENO2, PEG10, SNAP25, SRRM4, VGF, VIM, SCGN, PAPPA2, WNT11 , BRG1 , or combinations thereof compared to reference levels for prostate cancer.71 . The method of any one of claims 62-70, wherein the prostate cancer has been determined to have or predicted to have higher expression levels of ASCL1 , EZH2, DLX5, DLX6, SOX2, NKX2-2, HES6, SOX9, KDM3A, FOXA2, AURKA, MYCN, MYC, AKT, POU3F2 / BRN2, NANOG, ONECUT2, NKX2-1 , BRG1 , or combinations thereof compared to a subject that does not have prostate cancer.

72. The method of any one of claims 62-70, wherein the prostate cancer has been determined to have or predicted to have higher expression levels of ASCL1 , EZH2, DLX5, DLX6, SOX2, NKX2-2, HES6, SOX9, KDM3A, FOXA2, AURKA, MYCN, MYC, AKT, POU3F2 / BRN2, NANOG, ONECUT2, NKX2-1 , BRG1 , or combinations thereof compared to reference levels for prostate cancer.

73. The method of any one of claims 62-72, wherein the prostate cancer has been determined to have or predicted to have lower expression levels of RE1 silencing transcription factor (REST).

74. The method of any one of claims 62-73, wherein the prostate cancer has been determined to have or predicted to have expression of AR and KLK3 (PSA).

75. The method of any one of claims 62-73, wherein the prostate cancer has been determined to have or predicted to have undetectable expression of CHGA and SYP.

76. The method of any one of claims 62-73, wherein the prostate cancer has been determined to have or predicted to have expression of AR, KLK3 (PSA), CHGA and SYP.

77. The method of any one of claims 62-73, wherein the prostate cancer has been determined to have or predicted to have undetectable expression of AR and KLK3 (PSA).

78. The method of any one of claims 62-73, wherein the prostate cancer has been determined to have or predicted to have expression of CHGA and SYP.

79. The method of any one of claims 62-73, wherein the prostate cancer has been determined to have or predicted to have undetectable expression of AR, KLK3 (PSA), CHGA and SYP.

80. The method of any one of claims 62-73, wherein the prostate cancer has been determined to have or predicted to have a high level of TMPRSS2-ERG fusions.81 . The method of any one of claims 62-80, wherein the prostate cancer is metastatic.

82. The method of any one of claims 62-81 , wherein expression of BRD9, GLTSCR1 , CXXC5 TET2, or BRG1 is increased in the prostate cancer compared to a subject that does not have prostate cancer.

83. The method of claim 82, wherein expression of GLTSCR1 is increased in the prostate cancer compared to a subject that does not have prostate cancer.

84. The method of any one of claims 62-83, wherein expression of TET2, CXXC5, H3K27ac, ID1 , PFN2, ID3, or BRG1 in the subject is increased in the prostate cancer determined to or predicted to be resistant to enzalutamide compared to a prostate cancer that responds to treatment with enzalutamide.

85. The method of any one of claims 62-84, wherein the prostate cancer has been determined to have or predicted to have undetectable expression of PTEN.

86. The method of any one of claims 62-85, wherein the prostate cancer has been determined or predicted to be ERG positive.

87. The method of any one of claims 62-86, wherein the subject is further administered an inhibitor or degrader of ERG.

88. The method of claim 87, wherein the ERG inhibitor or degrader is ERGi-USU (1 -[2- Thiazolylazo]-2-naphthol).

89. The method of any one of claims 62-88, wherein the subject is further administered an anti-cancer therapy.

90. The method of any one of claims 62-88, wherein the subject is further administered a degrader of AR.91 . The method of claim 90, wherein the AR degrader is bavdegalutamide (ARV-110), ARV- 766, or AR-V7.

92. The method of any one of claims 62-91 , wherein the subject is further administered an inhibitor of the JAK-STAT pathway.

93. The method of claim 92, wherein the JAK-STAT inhibitor is AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, or WP1066.

94. The method of any one of claims 62-93, wherein the subject is further administered an inhibitor of the MAPK pathway.

95. The method of claim 94, wherein the MAPK pathway inhibitor is a Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, or Teriflunomide.

96. The method of any one of claims 62-95, wherein the subject is further administered an inhibitor of the PI3K-AKT-mTOR pathway.

97. The method of claim 96, wherein the PIK3-AKT-mTOR inhibitor is everolimus, alpelisib, idelalisib or copanlisib.

98. A method of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) bavdegalutamide (ARV-110), ARV-766, AR-V7, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

99. A method of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

100. A method of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, Teriflunomide, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

101. A method of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) everolimus, alpelisib, idelalisib, copanlisib or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA,SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

102. A method of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) enzalutamide, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

103. A method of reducing the level of luminal prostate cancer cell to neuroendocrine prostate cancer cell trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

104. A method of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) bavdegalutamide (ARV-110), ARV-766, AR-V7, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

105. A method of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, ora combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

106. A method of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) Farnesyltransferase inhibitor (FTI), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, Teriflunomide, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

107. A method of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) everolimus, alpelisib, idelalisib, copanlisib or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans- differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

108. A method of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) enzalutamide, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

109. A method of reducing the level of adenocarcinoma to neuroendocrine trans-differentiation in a subject with neuroendocrine prostate cancer; the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1 -(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abirateroneacetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof, wherein the effective amount is an amount sufficient to reduce the level of adenocarcinoma to neuroendocrine trans-differentiation measured by lower expression levels of CHGA, SYP, ENO2, and / or BRG1 compared to a subject that is not administered the compound or pharmaceutically acceptable salt thereof.

110. A method of treating a homologous recombination deficient (HRD) cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and (ii) and DNA damaging agent.

111. The method of claim 110, wherein the cancer is ovarian cancer, fallopian tube cancer, peritoneal cancer, breast cancer, prostate cancer, or pancreatic cancer.

112. The method of claim 110 or 111 , wherein the DNA damaging agent is cisplatin, carboplatin, oxaliplatin, methotrexate, doxorubicin, daunorubicin, cyclophosphamide, chlorambucil, temozolomide, or a combination thereof.

113. The method of any one of claims 110-112, wherein the method further comprises administration of a PARP inhibitor.

114. The method of claim 113, wherein the PARP inhibitor is olaparib, niraparib, rucaparib, talazoparib, or a combination thereof.

115. The method of any one of claims 22, 56, or 89, wherein the anti-cancer therapy is active surveillance, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), cryotherapy, hormone therapy, chemotherapy, immunotherapy, vaccine treatment, immune checkpoint inhibitors, targeted therapy drugs, or bone-directed treatment.

116. The method of claim 115, wherein the anti-cancer therapy is immunotherapy.

117. The method of claim 116, wherein the immunotherapy is a PD-1 / PD-L1 inhibitor.

118. The method of claim 117, wherein the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, atezolizumab, avelumab, durvalumab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP- 224, AMP-514, and acrixolimab, KN035, cosibelimab, AUNP12, CA-170, BMS-986189 or a combination thereof.

119. The method of any one of claims 115-118, wherein the additional anti-cancer therapy is administered prior to the administering of the compound or pharmaceutically acceptable salt thereof.

120. The method of any one of claims 115-118, wherein the additional anti-cancer therapy is administered in addition to the administering of the compound or pharmaceutically acceptable salt thereof.121 . The method of any one of claims 115-118, wherein the additional anti-cancer therapy is administered subsequent to the administering of the compound or pharmaceutically acceptable salt thereof.

122. The method of any of claims 1 -121 , wherein N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered prior to surgical intervention, radiation therapy, or chemotherapy to treat the cancer in the subject.

123. The method of claim 122, wherein the administering step is performed as a neoadjuvant therapy.

124. The method of any one of claims 1 -121 , wherein N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered subsequent to surgical intervention, radiation therapy, or chemotherapy to treat the cancer in the subject.

125. The method of claim 124, wherein the administering step is performed as an adjuvant therapy.

126. The method of any one of claims 1 -125, wherein the amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is between 1 .5 mg and 22.5 mg per day.

127. The method of any one of claims 1 -126, the method comprising administering to the subject (i) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and, following step (i), administering to the subject (ii) maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the differentiation dose regimen and the maintenance dose regimen together are effective to treat the cancer, and wherein the average daily dose during the differentiation dose regimen is at least 1 .25-fold higher than the average daily dose during the maintenance dose regimen.

128. The method of claim 127, wherein the differentiation dose regimen (a) increases the appearance of a marker of differentiation in one or more dedifferentiated cells of the cancer, (b) decreases the appearance of a marker of dedifferentiation in one or more dedifferentiated cells of the cancer, (c) induces cell arrest in one or more dedifferentiated cells of the cancer, or (d) induces apoptosis in in one or more dedifferentiated cells of the cancer.

129. The method of claim 127 or 128, following the administration of the differentiation dose regimen, the maintenance dose regimen inhibits the proliferation of dedifferentiated cells of the cancer.

130. The method of any one of claims 127-129, wherein the differentiation dose regimen is sufficient to produce a Caverage plasma concentration level of at least 250 ng / mL in the subject, and the maintenance dose regimen is sufficient to produce a Caverage plasma concentration level of between about 80 ng / mL and about 225 ng / mL in the subject.131 . The method of any one of claims 127-130, wherein the differentiation dose regimen comprises administering daily to the subject from greater than 7.5 mg to 22.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof, and the maintenance dose regimen comprises administering daily to the subject from 1 .5 mg to 7.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof.

132. A method of treating a solid tumor that failed to respond and / or progressed on a prior therapy in a patient in need thereof that, the method comprising administering to the subject N-(1 -((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof in an amount sufficient to increase the level of cell differentiation of the solid tumor.

133. The method of claim 132, wherein the amount sufficient to increase the level of cell differentiation of the solid tumor is at least 5 mg daily.

134. The method of claim 132 or 133, wherein the amount sufficient to increase the level of cell differentiation of the solid tumor is 5 to 7.5 mg daily.

135. The method of any one of claims 132 to 134, wherein the solid tumor is melanoma, lung cancer, or prostate cancer.

136. The method of claim 135, wherein the solid tumor is melanoma.

137. The method of any one of claims 132 to 136, wherein the solid tumor failed to respond and / or progressed on prior treatment with aldesleukin, binimetinib, cobimetinib fumarate, dabrafenib mesylate, dacarbazine, encorafenib, ipilimumab, melphalan hydrochloride, nivolumab, nivolumab and relatlimab-rmbw, pembrolizumab, recombinant interferon alfa-2b, talimogene laherparepvec, tebentafusp- tebn, trametinib dimethyl sulfoxide, vemurafenib, or a combination thereof.

138. The method of claim 135, wherein the solid tumor is lung cancer.

139. The method of any one of claims 132 to 135 or 138, wherein the solid tumor failed to respond and / or progressed on prior treatment with adagrasib, afatinib, dimaleate, alectinib, amivantamab- vmjw, atezolizumab, bevacizumab, brigatinib, capmatinib hydrochloride, cemiplimab-rwlc, ceritinib, crizotinib, dabrafenib mesylate, dacomitinib, docetaxel, doxorubicin hydrochloride, durvalumab, entrectinib, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, fam-trastuzumab, deruxtecan-nxki, gefitinib, gemcitabine hydrochloride, ipilimumab, lorlatinib, lurbinectedin, methotrexate sodium, mobocertinib succinate, necitumumab, nivolumab, osimertinib mesylate, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pembrolizumab, pemetrexed disodium, pralsetinib, ramucirumab, selpercatinib, sotorasib, taxol, tepotinib hydrochloride, topotecan hydrochloride, trametinib dimethyl sulfoxide, tremelimumab-actl, vinorelbine tartrate, or a combination thereof.

140. The method of any one of claims 132-135 or 138-139, wherein the solid tumor has progressed from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) after administration of atezolizumab, doxorubicin hydrochloride, durvalumab, etoposide, etoposide phosphate, everolimus, lurbinectedin, methotrexate sodium, nivolumab, topotecan hydrochloride, or a combination thereof.141 . The method of claim 135, wherein the solid tumor is prostate cancer.

142. The method of any one of claims 132-135 or 141 , wherein the solid tumor failed to respond and / or progressed on prior treatment with abiraterone acetate, apalutamide, bavdegalutamide (ARV-110), ARV-766, AR-V7, AG490, AZD1480, AZD4205, baricitinib, dasatinib, fedratinib, filgotinib, itacitnib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, siltuximab, tofacitinib, upadacitinib, WP1066, farnesyltransferase inhibitor (FTI), sorafenib, vemurafenib, PLX8394, dabrafenib, ulixertinib, simvastatin, alisertib, everolimus, alpelisib, idelalisib, copanlisib, teriflunomide bicalutamide, cabazitaxel, darolutamide, degarelix, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, lutetium Lu 177 vipivotide tetraxetan, mitoxantrone hydrochloride, nilutamide, niraparib tosylate monohydrate and abiraterone acetate, olaparib, radium 223 dichloride, relugolix, rucaparib camsylate, sipuleucel-T, talazoparib tosylate, or a combination thereof.

143. The method of any one of claims 132-135 or 141 -142, wherein the solid tumor has progressed from luminal prostate cancer to neuroendocrine prostate cancer.

144. The method of any one of claims 132-135 or 141 -142, wherein the solid tumor has progressed from adenocarcinoma to neuroendocrine prostate cancer.

145. The method of any one of claims 132-135 or 141 -144, wherein the solid tumor is sensitive to enzalutamide after the administration of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

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