PDE1 INHIBITORS FOR USE IN THE TREATMENT OF COLON CANCER

Abstract

The disclosure relates to the combination of phosphodiesterase 1 (PDE1) inhibitors, which is useful for treating certain cancers or tumors, such as colon cancer. In another form, the disclosure relates to the use of PDE1 inhibitors and an optional antitumor agent for treating certain cancers or tumors.

Description

Treatment methods Field of dissemination The field relates to phosphodiesterase 1 (PDE1) inhibitors, which are used to treat certain cancers and tumors, such as colon cancer. The field also refers to the administration of phosphodiesterase 1 (PDE1) inhibitors for the treatment of certain cancers and tumors, such as colon cancer. Background to the disclosure Colorectal cancer is the third most frequently diagnosed cancer in men and the second in women worldwide, accounting for approximately 50,000 deaths annually. Contrary to incidence trends, declining mortality rates from colorectal cancer have been observed in many countries, most likely attributable to improved colorectal cancer screening, lower prevalence of risk factors, and / or enhanced therapies. However, when widespread malignancy is present, these cases do not respond to curative treatments. Furthermore, metastases are estimated to cause 90% of cancer-related deaths worldwide. In most cases, metastatic tumor cells develop methods to evade immune responses and become resistant to therapy. Cancer treatment resistance can be intrinsic to tumor cells, but it is often conferred or augmented by non-malignant cells that make up the tumor microenvironment (TME). The TME is composed of tissue-resident cells, stromal cells, and other cells recruited by the tumor, and may include endothelial cells, pericytes, fibroblasts, mesenchymal stem cells, and a variety of immune cells, including regulatory T lymphocytes (Tregs), mast cells, neutrophils, myeloid-derived suppressor cells, and tumor-associated macrophages.These cells promote tumor angiogenesis, the invasion of neoplastic cells, and / or disrupt immune surveillance. Macrophages are among the most common type of tumor-associated cells. Researchers originally assumed that these immune cells were part of the body's response to reject tumors, and indeed, an important control in the development of cancers is the surveillance of the immune system and its reaction to the presence of cancer by cells of the innate immune system (e.g., macrophages, neutrophils), as well as cells associated with an adaptive immune response (e.g., B and T lymphocytes). However, in some cases, cancer is able to evade and co-opt the immune system, so that instead of attacking the tumor, these immune system cells become part of the tumor's support and defense system. The immune TME can be modified to support the tumor and promote its progression while suppressing immune cell-mediated cytotoxicity. Substantial clinical and experimental evidence indicates that macrophages, abundant in most tumor types, have an important regulatory role in promoting tumor evolution to malignancy. Macrophages in both primary tumors (tumor-associated macrophages or the i ηοζηη / ζζηζ / Β / γι Tumor-associated macrophages (TAMs) and metastatic tumors (metastasis-associated macrophages, or MAMs) are abundant in most solid tumors and may be associated with tumor metastases. The accumulation of TAMs, MAMs, and their progenitor cells is apparently driven by chemokine ligands released by tumor and stromal cells. For example, there is evidence that TAMs and MAMs are derived, at least in part, from CCR2-expressing monocytes recruited by CCL2-expressing tumor cells and / or CCL2-expressing stromal cells. However, the precise mechanisms are not fully defined and other CCR2 ligands such as CCL12, cytokines such as VEGF and CSF1 and other chemoattractant signals such as CCL5-CCR5, CCL20-CCR6, CXCL12-CXCR4 may provide an alternative or additional chemoattractant pathway for TAM recruitment.Therefore, efforts to have selective action towards specific chemoattractant receptors or ligands, for example, specifically blocking the CCR2-CCL2 interaction, have not been completely effective, probably because cancers are able to exploit alternative pathways. Eleven families of phosphodiesterases (PDEs) have been identified, but only the PDEs of family I, the Ca2+ / calmodulin-dependent phosphodiesterases (CaM-PDEs), which are activated by Ca2+ / calmodulin, have been shown to mediate calcium and cyclic nucleotide signaling pathways (e.g., cGMP and cAMP). The three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are expressed in central nervous system tissue. PDE1A is expressed in the brain, lungs, and heart. PDE1B is primarily expressed in the central nervous system but is also detected in monocytes and neutrophils and has been shown to be involved in inflammatory responses in these cells. PDE1C is expressed in the olfactory epithelium, cerebellar granule cells, striatum, heart, and vascular smooth muscle. PDE1C has been shown to be a major regulator of smooth muscle proliferation in human smooth muscle. Cyclic nucleotide phosphodiesterases negatively regulate intracellular cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to their respective 5'-monophosphates (5'AMP and 5'GMP), which are inactive in intracellular signaling pathways. Both cAMP and cGMP are central intracellular second messengers and play roles in regulating many cellular functions. PDE1A and PDE1B preferentially hydrolyze cGMP over cAMP, while PDE1C exhibits approximately equal hydrolysis of cGMP and cAMP. With regard to PDE1C in particular, recent evidence indicates that PDE1C is a gene associated with proliferation, since it is expressed exclusively in proliterative vascular smooth muscle cells. (Rybalkin SD, et al., “Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smoothmuscle cells of the synthetic, proliferative phenotype”. J Clin Invest 1997; 100:2611-2621.). In addition, there are sporadic reports of PDE1C expression along with other PDE subtypes in experimental tumor models, such as melanoma (Watanabe Y, et al., “Phosphodiesterase 4 regulates the migration of B16-F10 melanoma cells.” Exp Ther Med 2012; 4:205-210.), neuroblastoma (Jang IS, Juhnn YS. Adaptation of cAMP signaling system in SH-SY5Y neuroblastoma cells following expression of a constitutively active stimulatory G protein alpha, Q227L Gsalpha. Exp Mol Med 2001; 33:37). 45), y osteosarcoma (Ahlstróm M, et al., Cyclic nucleotide phosphodiesterases (PDEs) in human osteoblastic cells; the effect of PDE inhibition on cAMP accumulation. Cell Mol Biol Lett 2005; 10:305-319). Cell proliferation, migration, tissue invasion, and inflammation are considered to promote cancer development. Each of these processes is time-dependent, variable, and complex, involving a multitude of signal transduction pathways. Multi-targeted agents are thought to produce greater benefits than mono-targeted therapies, have acceptable tolerability profiles, and are active against a broader range of tumor types. The regulation of cyclic nucleotide signaling is appropriately considered a combination of multiple component pathways involved in various aspects of tumor cell function. Impaired cAMP generation has been described in several cancer pathologies. Attempts to directly regulate cyclic nucleotides in cancer cells, although antiproliferative, have not been successful due to high cytotoxicity.Safer and more selective strategies are now needed to modulate cAMP in cancer cells. Brief description of the disclosure The inventors have previously shown that inhibiting PDE1 activity using the currently disclosed compounds can safely restore cAMP function in a broad spectrum of pathological conditions, including models of neurodegeneration and neuroinflammation, heart failure, pulmonary hypertension, and peripheral inflammation, and in humans with certain diseases. More recently, the inventors have shown that PDE1 inhibitors obstruct cell migration of microglia and monocytes. Recent evidence indicates that PDE1, particularly the PDE1C isoform, is overexpressed in experimental tumor models such as melanoma, neuroblastoma, and osteosarcoma. Furthermore, focal genomic overrepresentation of PDE1C has been shown in glioblastoma multiforme (GBM) cells.The genomic gain of PDE1C is associated with an increase in its expression in GBM-derived cell cultures and is essential for managing cell proliferation, migration, and invasion in cancer cells. Many types of cancer cells overexpress PDE1 activity, which is identified by various biomarkers, such as increased RNA expression, DNA copy number, PDE1 binding (PET or radioisotope retention of PDE1 inhibitor molecules), or enzymatic activity. These cancer cells also exhibit low levels of cAMP, which can be increased by PDE1 inhibitors. These characteristics can be treated with PDE1 inhibitors alone or in combination with chemotherapeutic agents, gene therapy, or immunological strategies. PDE1 inhibition induces apoptotic cell death, prevents migration, limits metastasis, and reduces inflammation. Thus, PDE1 inhibitors are synergistic with chemotherapeutic agents and immunological strategies. Unconstrained by theory, it is believed that the inhibition of selective PDE1 isoforms, which elevates intracellular cAMP (and / or cGMP) levels, induces apoptosis and cell cycle arrest in a broad spectrum of tumor cells and regulates the tumor microenvironment by inhibiting cell migration, inflammation, and tissue invasion. Therefore, the development and clinical application of specific inhibitors for individual PDE1 and its isoforms, particularly PDE1C, can selectively restore normal intracellular signaling, providing antitumor therapy with reduced adverse effects.Beyond mere theory, it is also believed that the PDE1 inhibitors described here inhibit the recruitment of immune system cells, including macrophages and other cells, to cancer, thereby inhibiting metastasis, tumor angiogenesis, neoplastic cell invasion, and disruption of immune surveillance provided by recruited cells. PDE1 inhibits not only CCL2 but also other cytokines and chemokines believed to be involved in this recruitment and are therefore expected to be more effective than therapies such as monoclonal antibodies or other specific inhibitors of the CCR2-CCL2 interaction. This disclosure provides for the use of a PDE1 inhibitor for the treatment of cancer or tumors, including, for example, carcinomas, melanomas, and astrocytomas. Furthermore, altered cAMP (or cGMP) levels can result from the overexpression of PDE1 isoforms in various cancer pathologies. Inhibition of selective PDE1 isoforms, which elevates intracellular cAMP (or cGMP) levels, induces apoptosis and cell cycle arrest in a broad spectrum of tumor cells and regulates the tumor microenvironment, preventing cell migration, inflammation, and tissue invasion. Therefore, the development and clinical application of PDE1-specific inhibitors can selectively restore normal intracellular signaling, providing antitumor therapy with reduced adverse effects. Previous studies have shown that PDE1 (i.e., PDE1C) is significantly overexpressed in the tumor microenvironment of glioblastoma patients compared to healthy individuals (i.e., those without glioblastoma). SiRNA-mediated silencing of PDE1C has been shown to inhibit proliferation and invasion in patient-derived glioblastoma cell cultures. Without being limited by any specific theory, PDE1 inhibition may be effective in the therapeutic intervention of certain cancers or tumors, such as glioblastoma. In several embodiments, this application provides a method for treating colon cancer (e.g., colorectal cancer) comprising administering a pharmaceutically acceptable amount of a PDE1 inhibitor to a subject in need. In some embodiments, the PDE1 inhibitor is administered in combination with an antitumor agent. In various forms, this disclosure also provides pharmaceutical compositions comprising the compounds of this disclosure prepared using conventional diluents or excipients and known techniques. Therefore, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like. In various forms, this disclosure also provides PDE1 inhibitors according to the formulas I, Ia, II, III, IV, V, VI and / or VII described below in free or salt form for use in the treatment of a selected condition from a cancer or tumor, by inhibiting the proliferation, migration and / or invasion of tumor cells, or treating colon cancer, e.g., colorectal cancer. i noznn / zznz / E / yii Brief description of the figures Figure 1 shows the effect of PDE1 inhibition on murine CT26 neoplastic cells in samples subjected to treatment with Compound 1 and an untreated control. Figure 2 shows the change in the relative proportions of immune cells in murine CT26 neoplastic cells in samples subjected to treatment with Compound 1 and an untreated control. Detailed description of the disclosure Compounds for use in disclosure methods In one modality, the PDE1 inhibitors to be used in the treatment and prophylaxis methods described herein are selective PDE1 inhibitors. PDE1 inhibitors In one embodiment, the invention provides that the PDE1 inhibitors for use in the treatment and prophylaxis methods described herein are compounds of Formula I: ηοζηη / ζζηζ / Β / γι where (i) Ri is H or C1-4 alkyl (e.g., methyl); (i) R4 is H or C14 alkyl and R2 and R3 are, independently, H or C1-4 alkyl (e.g., R2 and R3 are both methyl, or R2 is H and Rs is isopropyl), aryl, heteroaryl, arylalkoxy (optionally hetero), or arylalkyl (optionally hetero); or R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge (pref. where R3 and R4 together have the cis configuration, e.g. where the carbons bearing Rs and R4 have the R and S configurations, respectively); (ii) Rs is a substituted heteroarylalkyl, for example, substituted with a haloalkyl; or Rs is attached to one of the nitrogens in the pyrazolone portion of Formula I and is a fraction of Formula A r9ηοζηη / ζζηζ / Ε / γΐΛ Formula A wherein X, Y, and Z are independently N or C, and Rs, Rg, Rn, and R12 are independently H or halogen (e.g., Cl or F), and R10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (e.g., pyrid-2-yl) optionally substituted with halogen, or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, Rs, Rg, or R10, respectively, are not present; and (iv) Re is H, alkyl, aryl, heteroaryl, arylalkyl (for example, benzyl), arylamino (for example, phenylamino), heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N(arylalkyl)amino (for example, N-phenyl-N-(1,T-blphen-4-ylmethyl)amino); and (v) n=0 or 1; (vi) when n=1, A is-C(Ri3Ri4)- where R13 and Ri4 are independently H or C1-4 alkyl, aryl, heteroaryl, arylalkoxy (optionally hetero) or arylalkyl (optionally hetero); in free form, as a salt or prodrug, including its enantiomers, diastereomers and racemates. In another embodiment, the invention provides PDE1 inhibitors for use in the methods described herein, which are of Formula 1a: wherein (i) R2 and Rs are independently H or hydroxy and Rs and R4 together form a tri- or tetramethylene bridge [pref. with the carbons bearing R3 and R4 having the R and S configurations, respectively]; or R2 and R3 are both methyl and R4 and Rs are both H; or R2, R4 and Rs are H and R3 is isopropyl [pref., the carbon bearing R3 having the R configuration]; (i) Re is phenylamino (optionally halo substituted), benzylamino (optionally halo substituted), C1-4 alkyl, or C1-4 alkyl sulfide; for example, phenyllamino or 4-fluorophenyllamino; (iii) R10 is C1-4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, phenyl (optionally halo or hydroxy substituted), pyridyl (optionally halo or hydroxy substituted) (e.g., 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl); and X and Y are independently C or N. in free form, as a pharmaceutically acceptable salt or prodrug, including its enantiomers, diastereomers and racemates. In another embodiment, the invention provides PDE1 inhibitors for use in the treatment and prophylaxis methods described herein, which are the compounds of Formula II: noz nn / zznz / E / yii Formula II (i) X is a Ci-s alkylene (e.g., methylene, ethylene, or prop-2-yn-1-ylene); (ii) And is a single bond, alkynelene (e.g., —ChC—), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); (ii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid2-yl), halo (e.g., F, Br, Cl), C1-6 haloalkyl (e.g., trifluoromethyl), —C(O)—R1, —N(R2)(R3), or C3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl); (iv) R1 is C1-6 alkyl, C1-6 haloalkyl, —OH or —O C1-6 alkyl (for example, —OCH3); (v) R2 and R3 are independently H or C1-6 alkyl; (vi) R4 and R5 are independently C1-6 H, alkyl or aryl (e.g., phenyl) optionally substituted with one or more C1-s halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) or alkoxy groups; (vii) wherein X, Y and Z are independently and optionally substituted with one or more halo groups (e.g., F, Cl or Br), C1-s alkyl (e.g., methyl), C1-6 haloalkyl (e.g., trifluoromethyl), e.g., Z is heteroaryl, e.g., pyridyl substituted with one or more halo groups (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), C1-e haloalkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C1-e alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one or more halo groups (for example, 4-fluorophenyl), in free form, as a salt or as a prodrug. In another embodiment, the invention provides PDE1 inhibitors for use in the treatment and prophylaxis methods described herein, which are of Formula III: EITHER A 7 Nor K ηοζηη / ζζηζ / Β / γυ Formula III wherein (i) Ri is H or alkyl of Ci-4 (for example, methyl or ethyl); (ii) R2 and R3 are independently H or C1-6 alkyl (e.g., methyl or ethyl); (iii) R4 is H or C1-4 alkyl (e.g., methyl or ethyl); (iv) Rs is aryl (e.g., phenyl) optionally substituted with one or more independently selected C1-6 -C(=O)-alkyl groups (e.g., -C(=O)-CH3) and C1-6 hydroxyalkyl groups (e.g., 1-hydroxyethyl); (v) Re and R7 are independently H or aryl (e.g., phenyl) optionally substituted with one or more independently selected C1-6 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl) groups, e.g., unsubstituted phenyl or phenyl substituted with one or more halogens (e.g., F) or phenyl substituted with one or more C1-6 alkyl and one or more halogens or phenyl substituted with a C1-6 alkyl and a halogen, e.g., 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and (vi) n is 1, 2, 3, or 4, in free or salt form; In another embodiment, the invention provides PDE1 inhibitors for use in the treatment and prophylaxis methods described herein, which are of Formula IV: ηαζηη / ζζηζ / Ε / γΐΛ in free or salt form, where; (i) Ri is an alkyl of Cm (e.g., methyl or ethyl), or -NH(R2), wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl; (ii) X, Y and Z are independently N or C; (ii) R3, R4 and Rs are independently H or C1-4 alkyl (e.g., methyl); or Rs is H and R4 and Rs together form a trimethylene bridge (pref. where R4 and Rs together have the cis configuration, e.g. where the carbons bearing R4 and Rs have the R and S configurations, respectively), (iv) Re, R7 and Re are independently: H, C1-4 alkyl (e.g., methyl), hydroxy-substituted pyrid-2-yl, or -S(O)2-NH2; (v) Whenever X, Y and / or Z are N, then Re, R7 and / or Re, respectively, are not present; and when X, Y and Z are all C, then at least one of Re, R7 or Ra is S(O)2-NH2 or pyrid-2-yl substituted with hydroxy. In another embodiment, the present invention establishes that the PDE1 inhibitors for use in the methods as described herein are of Formula V: where (i) R1 is -NH(R4), where R4 is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl; (i) R2 is H or C1-6 alkyl (e.g., methyl, isobutyl or neopentyl); (ii) R3es -SO2NH2 or -COOH; in free form, as a pharmaceutically acceptable salt or prodrug, including its enantiomers, diastereomers and racemates. In another modality, the above disclosure provides that the PDE1 inhibitors to be used in the methods described herein are of Formula VI: ηοζηη / ζζηζ / Β / γι where (i) R1 is -NH(R4), where R4 is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl; (ii) R2 is H or C1-6 alkyl (e.g., methyl or ethyl); (ii) R3 is H, halogen (e.g., bromine), C1-6 alkyl (e.g., methyl), optionally halogen-substituted aryl (e.g., 4-fluorophenyl), optionally halogen-substituted heteroaryl (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl) or acyl (e.g., acetyl), in free form, of pharmaceutically acceptable salt or prodrug, including its enantiomers, diastereomers and racemates. In another modality, the above disclosure provides that the PDE1 inhibitors to be used in the methods described herein are of Formula Vil: (i) R1 is -NHjRs), wherein Rs is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl; (ii) R2 and R3 are independently H or C1-6 alkyl (e.g., methyl or ethyl); (lli) R4 is optionally halogen-substituted aryl (e.g., 4-fluorophenyl) or optionally halogen-substituted heteroaryl (e.g., 6-fluoropyrid-2-yl), in free form, of pharmaceutically acceptable salt or prodrug, including its enantiomers, diastereomers and racemates. In one embodiment, the present description provides for the administration of a PDE1 inhibitor for use in the methods described herein (for example, a compound according to Formulas I, 1a, II, III, IV, V, VI and / or VII), wherein the inhibitor is a compound according to the following: i ηοζηη / 77ηζ / E / γι ι ηαζηη / ζζηζ / Ε / γΐΛ ι ηοζηη / ζζηζ / Ε / γίΛΐ i ηαζηη / ζζηζ / Ε / γΐΛ In one embodiment, the invention provides for the administration of a PDE1 inhibitor for the treatment or prophylaxis of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound according to the following: i ηαζηη / ζζηζ / Ε / γΐΛ in free or pharmaceutically acceptable salt form. In yet another embodiment, the invention provides for the administration of a PDE1 inhibitor for the treatment or prophylaxis of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound according to the following: in free form or as a pharmaceutically acceptable salt. In yet another embodiment, the invention provides for the administration of a PDE1 inhibitor for the treatment or prophylaxis of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound according to the following: in free form or as a pharmaceutically acceptable salt. In yet another embodiment, the invention provides for the administration of a PDE1 inhibitor for the treatment or prophylaxis of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound according to the following: i ηαζηη / ζζηζ / Ε / γΐΛ in free or pharmaceutically acceptable salt form. In yet another embodiment, the invention provides for the administration of a PDE1 inhibitor for the treatment or prophylaxis of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound according to the following: in free form or as a pharmaceutically acceptable salt. In one embodiment, the selective PDE1 inhibitors of any of the preceding formulas (e.g., Formula I, l1a, II, III, IV, V, VI and / or 7l) are compounds that inhibit cGMP hydrolysis mediated by phosphodiesterase (e.g., mediated by PDE1, especially PDE1B), e.g., the preferred compounds have an ICso of less than 1 μM, preferably less than 500 nM, preferably less than 50 nM, and preferably less than 5 nM in a PDE assay with immobilized metal affinity reagent, in free or salt form. In other embodiments, the invention provides the administration of a PDE1 inhibitor for the treatment of a selected condition from cancer or tumor; to inhibit the proliferation, migration and / or invasion of tumor cells; and / or to treat a glioma, wherein the inhibitor is a compound as follows: Other examples of PDE1 inhibitors suitable for use in the methods and treatments presented herein can be found in International Publication WO2006133261A2; U.S. Patent 8,273,750; U.S. Patent 9,000,001; U.S. Patent 9,624,230; International Publication WO2009075784A1; U.S. Patent 8,273,751; U.S. Patent 8,829,008; U.S. Patent 9,403,836; International Publication WO2014151409A1; U.S. Patent 9,073,936; U.S. Patent 9,598,426; and U.S. Patent 9,556,186. US Publication 2017 / 0231994A1, International Publication WO2016022893A1, and US Publication 2017 / 0226117A1, each of which is incorporated by reference in its entirety. Further examples of PDE1 inhibitors suitable for use in the methods and treatments described herein can be found in International Publication WO2018007249A1; U.S. Publication 2018 / 0000786; International Publication WO2015118097A1; U.S. Patent 9,718,832; International Publication WO2015091805A1; U.S. Patent 9,701,665; U.S. Publication 2015 / 0175584A1; U.S. Publication 2017 / 0267664A1; International Publication WO2016055618A1; U.S. Publication 2017 / 0298072A1; International Publication WO2016170064A1; US Publication 2016 / 0311831A1; International Publication WO2015150254A1; US ​​Publication 2017 / 0022186A1; International Publication WO2016174188A1; US ​​Publication 2016 / 0318939A1; US ​​Publication 2017 / 0291903A1; International Publication WO2018073251A1; International Publication WO2017178350A1; US ​​Publication 2017 / 0291901A1; International Publication WO2018 / 115067; US Publication 2018 / 0179200A; US Publication US20160318910A1; US ​​Patent 9,868,741; International Publication WO2017 / 139186A1; International Application WO2016 / 040083; US Publication 2017 / 0240532; International Publication WO 2016033776A1; US ​​Publication 2017 / 0233373; International Publication WO2015130568; International Publication WO2014159012; US Patent 9,034,864; US Patent 9,266,859; International Publication WO2009085917; US Patent 8,084,261; International Publication WO2018039052; US Publication US20180062729; and International Publication WO2019027783, each of which is incorporated herein in its entirety by these references.In any situation where the statements in any document incorporated by reference contradict or are inconsistent with any statement made in this description, the statements in this description shall be deemed to control. Additional examples of PDE1 inhibitors and suitable methods of use are described in International Application PCT / US2019 / 033941 and U.S. Provisional Application 62 / 789,499, which are incorporated herein by reference. Unless otherwise specified or unclear from the context, the following terms have the following meanings: (a) “Selective PDE1 inhibitor”, as used herein, refers to a PDE1 inhibitor with a selectivity of at least 100 times for the inhibition of PDE1 over the inhibition of any other PDE isoform. (b) “Alkyl”, as used herein, is a portion of saturated or unsaturated hydrocarbon, preferably saturated, having preferably from one to six carbon atoms, which may be linear or branched and optionally may be mono-, di- or trisubstituted, for example, with halogen (for example, chlorine or fluorine), hydroxy or carboxy. (c) “Cycloalkyl”, as used herein, is a portion of a saturated or unsaturated, preferably saturated, non-aromatic hydrocarbon, preferably comprising from three to nine carbon atoms, at least one of which forms a non-aromatic mono- or bicyclic or bridging cyclic structure, and which may optionally be substituted, for example, with a halogen (for example, chlorine or fluorine), hydroxy, or carboxyl group. Where the cycloalkyl optionally contains one or more atoms selected from N and O and / or S, said cycloalkyl may also be a heterocycloalkyl. (d) “Heterocycloalkyl”, unless otherwise specified, is a portion of saturated or unsaturated non-aromatic hydrocarbon, preferably saturated, comprising preferably three to nine carbon atoms, at least some of which form a non-aromatic mono- or bicyclic or bridging cyclic structure, wherein at least one carbon atom is replaced with N, O, or S, said heterocycloalkyl may be optionally substituted, for example, with halogen (for example, chlorine or fluorine), hydroxy, or carboxy. (e) “Aryl”, as used herein, is a mono- or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, for example, with alkyl (for example, methyl), halogen (for example, chlorine or fluorine), haloalkyl (for example, trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (for example, biphenyl or pyridylphenyl). (f) “Heteroaryl”, as used herein, is an aromatic portion in which one or more of the atoms comprising the aromatic ring is sulfur or nitrogen instead of carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy or carboxy. The compounds disclosed herein, for example, the PDE1 inhibitors described herein, may exist in free form or as salts, for example, as acid addition salts. In this specification, unless otherwise stated, language such as “disclosure compounds” is understood to encompass the compounds in any form, for example, in free form or as acid addition salts, or, where the compounds contain acidic substituents, as base addition salts. The disclosure compounds are intended for use as pharmaceutical products; therefore, pharmaceutically acceptable salts are preferred. Salts that are unsuitable for pharmaceutical use may be useful, for example, for the isolation or purification of the disclosure free compounds or their pharmaceutically acceptable salts and are therefore also included. In some cases, disclosure compounds may also exist as prodrugs. A prodrug is a compound that is converted in the body into a disclosure compound. For example, when disclosure compounds contain hydroxy or carboxy substituents, these substituents may form physiologically hydrolyzable and acceptable esters. As used here, “physiologically hydrolyzable and acceptable ester” means esters of disclosure compounds that are hydrolyzable under physiological conditions to produce acids (in the case of disclosure compounds with hydroxy substituents) or alcohols (in the case of disclosure compounds with carboxy substituents), which are themselves physiologically tolerable at the administered dose.Therefore, when the disclosure compound contains a hydroxy group, for example, compound -OH, the acyl ester prodrug of that compound, i.e., compound -OC(O)alkyl of C1-4, can be hydrolyzed in the body to form a physiologically hydrolyzable alcohol (compound -OH) on the one hand, and an acid on the other (e.g., HOC(O)alkyl of C1-4). Alternatively, where the disclosure compound contains a carboxylic acid, for example, compound -C(O)OH, the acid ester prodrug of that compound, compound -C(O)Oalkyl of. Ci-4 can be hydrolyzed to form the compound-C(O)OH and HO-alkyl of Ci-4. As will be seen, the term encompasses conventional pharmaceutical forms of prodrugs. In another embodiment, the disclosure further provides a pharmaceutical composition comprising a PDE1 inhibitor in combination with an antitumor agent, each in free form or as a pharmaceutically acceptable salt, mixed with a pharmaceutically acceptable vehicle. The term “combination,” as used herein, encompasses the simultaneous, sequential, or contemporaneous administration of the PDE1 inhibitor and the antitumor agent. In another embodiment, the disclosure provides a pharmaceutical composition containing such a compound. In some embodiments, the combination of the PDE1 inhibitor and the antitumor agent allows the antitumor agent to be administered at a lower dose than would be effective if administered as monotherapy alone. Methods of using the disclosure compounds In another embodiment, the present application provides a method (Method 1) for treating colon cancer comprising administering a pharmaceutically acceptable amount of a PDE1 inhibitor (i.e., a PDE1 inhibitor according to Formula I, I, II, III, IV, V, VI and / or VII) to a subject in need. 1.1 Method 1, where colon cancer is colorectal cancer. 1.2 Any of the above methods, which also includes the step of administering an antitumor agent to the patient. 1.3 Method 1.2, wherein the antitumor agent is administered simultaneously with the PDE1 inhibitor. 1.4 Method 1.2, wherein the antitumor agent is administered prior to the administration of the PDE1 inhibitor. 1.5 Method 1.2, wherein the antitumor agent is administered after the administration of the PDE1 inhibitor. 1.6 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered with radiotherapy or chemotherapy. 1.7 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered simultaneously with radiotherapy or chemotherapy. 1.8 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered prior to radiotherapy or chemotherapy. 1.9 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered after radiotherapy or chemotherapy. 1.10 Any of the above methods, wherein the PDE1 inhibitor is administered together with an antitumor agent, chemotherapeutic agent, gene therapy and / or immunotherapy. 1.11 Any of the above methods, wherein the administration of the inhibitor of j ηοζηη / ζζηζ / Β / γι PDE1 is effective in inducing one or more of the following aspects in colon cancer: apoptotic cell death, inhibition of migration, inhibition of metastasis and / or reduction of inflammation. 1.12 Any of the above methods, wherein the PDE1 inhibitor is administered together with an antitumor agent, chemotherapeutic agent, gene therapy, immunotherapy, corticosteroid and / or an antihistamine. 1.13 Any of the above methods, where colon cancer is mediated by PDE. 1.14 Any of the above methods, where colon cancer is mediated by PDE1. 1.15 Any of the above methods, where colon cancer is mediated by PDE1C. 1.16 Any of the above methods, wherein colon cancer is characterized by a loss of calcium / calmodulin control. 1.17 Any of the above methods, where the subject is a human. The disclosure also provides a PDE1 inhibitor for use in a method for treating colon cancer, for example, for use in any of the following methods. The disclosure also provides for the use of a PDE1 inhibitor in the preparation of a drug for use in a method of treating colon cancer, for example, a drug for use in any of the following methods. The invention further provides a pharmaceutical composition comprising a PDE1 inhibitor, for example, any of the compounds of Formula I, II, III, IV, V, VI and / or VII, for use in any of the following methods. In another embodiment, the present application provides a method (Method 2) for inhibiting the proliferation, migration and / or invasion of cancerous or tumor cells in the colon comprising the administration of a pharmaceutically acceptable amount of a PDE1 inhibitor (i.e., a PDE1 inhibitor according to Formula I, I, II, III, IV, V, VI and / or VII) to a subject in need. 2.1 Method 2, where the method is to inhibit the proliferation of cancerous or tumor cells. 2.2 Any of the above methods, where the subject suffers from colon cancer. 2.3 Any of the above methods, where the subject suffers from colorectal cancer. 2.4 Any of the above methods, which also includes the step of administering an antitumor agent to the patient. 2.5 Method 2.4, wherein the antitumor agent is administered simultaneously with the PDE1 inhibitor. 2.6 Method 2.4, wherein the antitumor agent is administered prior to the administration of the PDE1 inhibitor. 2.7 Method 2.4, wherein the antitumor agent is administered after the administration of the PDE1 inhibitor. 2.8 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered with radiotherapy or chemotherapy. 2.9 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered simultaneously with radiotherapy or chemotherapy. 2.10 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered prior to radiotherapy or chemotherapy. 2.11 Any of the above methods, wherein the PDE1 inhibitor and optionally the antitumor agent are administered after radiotherapy or chemotherapy. 2.12 Any of the above methods, wherein the PDE1 inhibitor is administered together with an antitumor agent, chemotherapeutic agent, gene therapy and / or immunotherapy. 2.13 Any of the above methods, wherein the PDE1 inhibitor is administered together with an antitumor agent, chemotherapeutic agent, gene therapy, immunotherapy, corticosteroid and / or an antihistamine. 2.14 Any of the above methods, where neoplastic or tumor cells in the colon are regulated by PDE. 2.15 Any of the above methods, where neoplastic or tumor cells in the colon are regulated by PDE1. 2.16 Any of the above methods, where neoplastic or tumor cells in the colon are regulated by PDE1C. 2.17 Any of the above methods, which also include the step of determining a subject's calcium / calmodulin sensitivity in the expressed PDE1, restoration of cyclic nucleotide levels, PDE1 RNA expression, or mutation of a PDE1 gene. 2.18 Any of the above methods, where the subject is a human. The disclosure also provides a PDE1 inhibitor for use in a method to inhibit the proliferation, migration and / or invasion of cancer or tumor cells, for example, for use in any of Methods 2 and following. The disclosure also provides for the use of a PDE1 inhibitor in the preparation of a drug for use in a method of inhibiting the proliferation, migration and / or invasion of cancer or tumor cells, for example, a drug for use in any of Methods 2 and following. The invention further provides a pharmaceutical composition comprising a PDE1 inhibitor, for example, any of the compounds of Formula I, II, III, IV, V, VI and / or VII, for use in any of the following methods 2. In another embodiment, the present application provides a method (Method 3) for treating a condition selected from cancer or tumor cancer comprising the administration of a pharmaceutically acceptable amount of a PDE1 inhibitor (i.e., a PDE1 inhibitor according to Formula I, II, III, IV, V, VI and / or VII) and a checkpoint inhibitor to a subject in need. 3.1 Method 3, where the cancer is colon cancer. 3.2 Any of the above methods, where the cancer is colorectal cancer. 3.3 Any of the above methods, wherein the PDE1 inhibitor and the checkpoint inhibitor are administered with radiotherapy or chemotherapy. 3.4 Any of the above methods, wherein the PDE1 inhibitor and the checkpoint inhibitor are administered simultaneously with radiotherapy or chemotherapy. 3.5 Any of the above methods, wherein the PDE1 inhibitor and the checkpoint inhibitor are administered prior to radiotherapy or chemotherapy. 3.6 Any of the above methods, wherein the PDE1 inhibitor and the checkpoint inhibitor are administered after radiotherapy or chemotherapy. 3.7 Any of the above methods, wherein the PDE1 inhibitor and checkpoint inhibitor are administered together with an additional antitumor, chemotherapeutic, gene therapy and / or immunotherapy agent. 3.8 Any of the above methods, wherein administration of the PDE1 inhibitor is effective in inducing one or more of the following aspects in colon cancer: apoptotic cell death, inhibition of migration, inhibition of metastasis and / or reduction of inflammation. 3.9 Any of the above methods, wherein the PDE1 inhibitor is administered together with an antitumor agent, chemotherapeutic agent, gene therapy, immunotherapy, corticosteroid and / or an antihistamine. 3.10 Any of the above methods, where colon cancer is mediated by PDE. 3.11 Any of the above methods, where colon cancer is mediated by PDE1. 3.12 Any of the above methods, where colon cancer is mediated by PDE1C. 3.13 Any of the above methods, wherein the checkpoint inhibitor is an inhibitor of CTLA-4, PD-1 and / or PD-L1. 3.14 Any of the above methods, wherein the set point inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, avelumab, durvalumab, atezolizumab, spartalizumab, or combinations thereof. 3.15 Any of the above methods, where colon cancer is characterized by a loss of calcium / calmodulin control. 3.16 Any of the above methods, where the subject is a human. 3.17 Any of the above methods, wherein the PDE1 inhibitor is administered in a sufficient quantity to reduce the infiltration of monocytes and / or macrophages into a tumor-associated microenvironment. 3.18 Any of the above methods, wherein the PDE1 inhibitor and the checkpoint inhibitor are administered in sufficient quantities to reduce the infiltration of monocytes and / or macrophages into a tumor-associated microenvironment and / or to increase the infiltration of natural killer cells and CD4+ T lymphocytes (i.e., CD4+ T lymphocytes that produce TNFα). 3.19 Any of the above methods, wherein the PDE1 inhibitor is administered in an amount of approximately 1-1000 mg / kg, for example, approximately 250-750 mg / kg, for example, approximately 400-600 mg / kg, for example, approximately 500 mg / kg. The disclosure also provides a PDE1 inhibitor for use in a method to inhibit the proliferation, migration and / or invasion of cancer or tumor cells, for example, for use in any of the following Methods 3. The disclosure also provides for the use of a PDE1 inhibitor in the preparation of a drug for use in a method of inhibiting the proliferation, migration and / or invasion of cancer or tumor cells, for example, a drug for use in any of the following Methods 3. The invention further provides a pharmaceutical composition comprising a PDE1 inhibitor, for example, any of the compounds of Formula I, II, III, IV, V, VI and / or VII, for use in any of the following methods 3. In some modalities, the pharmaceutical compositions are administered in combination with one or more antitumor drugs, for example, drugs known to have an effect on the treatment or elimination of various types of cancers or tumors. Non-limiting examples of antitumor drugs include: Ademaciclid, Adiratherone acetate, Aditrexate (Methotrexate), Adraxane (aldumin-stabilized paclitaxel nanoparticle formulation), ABVD, ABVE, ABVE-PC, AC, Acaladrutinid, ACT, Adcetris (Brentuximad Vedotin), ADE, Ado-Trastuzumad Emtansine, Adriamycin (Doxorubicin hydrochloride), Afatinib dimaleate, Afinitor (Everolimus), Aquinzeo (Netupitant and Palonosetron hydrochloride), Aldara (Imiquimod), Aldesleucin, Alecensa (Alectinib), Alectinib, Alemtuzumab, Alimta (Pemetrexed disodium), Alicopa (Copanlisib hydrochloride), and Alqueran for injection (hydrochloride of Melfalan), Alqueran tablets (Melfalan), Aloxi (Palonosetron hydrochloride), Alunbrig (Brigatinib),Amboclorin (Clorambucil), Amboclorin (Clorambucil), Amifostine, Aminolevulinic Acid, Anastrozol, Aprepitant, Aredia, Disodic Pamidronate, Arimidex (Anastrozol), Aromasina (Exemestane), Arranona (Nelarabina), Trióxido arsenico, Arzerra (Ofatumumab), Asparaginasa de Erwinia chrysanthemi, Atezolizumab, Avastin (Bevacizumab), Avelumab, Axicabtageno Ciloleucel, Axitinib, Azacitidine, Bavencio (Avelumab), BEACOPP, Becenum (Carmustine), Beleodac (Belinostat), Belinostat, Clorhidrato de Bendamustina, BEP, Besponsa (Inotuzumab Ozogamicina), Bevacizumab, Bexaroteno, Bicalutamida, BiCNU (Carmustine), Bleomycin, Blinatumomab, Bllncyto (Blinatumomab), Bortezomib, Bosulif (Bosutinib), Bosutinib, Brentuximab Vedotin, Brigatinib, BuMel, Busulfan, Busulfex (Busulfan), Cabazitaxel, Cabometix (Cabozantinib-S-Malate), j ηοζηη / ζζηζ / Ε / γι Cabozantine-Malate, CAF, Calquence (Acqualabrutinib), Campat (Aletuzumab), Camptosar (Irinotecan Hydrochloride), Capecitabine, CAPOX, Carac (Topical Fluorouracil), Carboplatin, CARBOPLATINOTAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine, Carmustine Implant, Casodex (Bicalutamide), CEM, Ceritinib, Cerubidine (Daunorubicin Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine), Cetuximab, CEV, Chlorambucil, CHLORAMBUCILO-PREDNISONA, CHOP, Cisplatin, Cladribine, Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar (Clofarabine), CMF, Cobimetinib, Cometriq (Cabozantinib-S-Malate), Clorhidrato de Copanlisib, COPDAC, COPP, COPPABV, Cosmegen (Dactinomycin), Cotélico (Cobimetinib), Crizotinib, CVP, Ciclofosfamida, Cyfos (Ifosfamida), Ciramza (Ramucirumab), Citarabine, Citarabine Liposómica, Citosar-U (Citarabine), Citoxan (Cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (Decitabine), Dactinomycin, Daratumumab, Darzalex (Daratumumab), Dasatinib,Daunorubicin Hydrochloride, Daunorubicin Hydrochloride and Liposomal Cytarabine, Decitabine, Defibrotide Sodium, Defitelio (Defibrotide Sodium), Degarelix, Denileucine Diftitox, Denosumab, DepoCyt (Liposomal Cytarabine), Dexamethasone, Dexrazoxane Hydrochloride, Dinutuximab, Docetaxel, Doxil (Liposomal Doxorubicin Hydrochloride), Doxorubicin Hydrochloride, Liposomal Doxorubicin Hydrochloride, Dox-SL (Liposomal Doxorubicin Hydrochloride), DTIC-Dome (Dacarbazine), Durvalumab, Efudex (Topical Fluorouracil), Elitek (Rasburicase), Ellence (Epirubicin Hydrochloride), Elotuzumab, Eloxatine (Oxaliplatin), Eltrombopag Olamine Emend (Aprepitant), Empliciti (Elotuzumab), Enasidenib Mesylate, Enzalutamide, Epirubicin Hydrochloride, EPOCH, Erbitux (Cetuximab), Eribulin Mesylate, Erivedge (Vismodegib), Erlotinib Hydrochloride, Erwinaza (Asparaginase Erwinia chrysanthemi), Etilol (Amifostine), Etopofos (Etoposide Phosphate), Etoposide, Etoposide PhosphateEvacet (Liposomal Doxorubicin Hydrochloride), Everolimus, Evista (Raloxifene Hydrochloride), Evomela (Melphalan Hydrochloride), Exemestane, 5-FU (Fluorouracil Injection), 5-FU (Fluorouracil-Topical), Fareston (Toremifene), Faridak (Panobinostat), Faslodex (Fulvestrant), FEC, Femara (Letrozole), Filgrastima, Fludara (Fludarabine Phosphate), Fludarabine Phosphate, Fluoroplex (Fluorouracil-Topical), Fluorouracil Injection, Fluorouracil-Topical, Flutamide, Folex (Methotrexate), Folex PFS (Methotrexate), Folfiri, Folfiri-Bevacizumab, Folfiri-Cetuximab, Folfirinox, Folfox, Folotyn (Pralatrexate), FU-LV, Fulvestrant, Gardasil (Recombinant Quadrivalent HPV Vaccine), Gardasil 9 (Recombinant Nonavalent HPV Vaccine), Gaziva (Obinutuzumab), Gefitinib, Gemcitabine Hydrochloride, Gemcitabine-Cisplatin, Gemcitabine-Oxaliplatin, Gemtuzumab-Ozogamicin, Gemzar (Gemcitabine Hydrochloride), Gilotrif (Afatinib Dimaleate), Gleevec (Imatinib Mesylate)Gliadel (Carmustine Implant), Gliadel (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaveno (Eribulin Mesylate), Hemangeol (Propronolol Hydrochloride), Herceptin (Trastuzumab), Recombinant Bivalent HPV Vaccine, Recombinant Nonavalent HPV Vaccine, Recombinant Quadrivalent HPV Vaccine, Hicamtine (Topotecan Hydrochloride), Hidrea (Hydroxyurea), Hydroxyurea, Hyper-CVAD, Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig (Ponatinib Hydrochloride), Idamycin (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idelalisib, Idhifa (Enasidenib Mesylate), Ifex (Ifosfamide) Ifosfamide, Ifosfamidum (Ifosfamide), IL-2 (Aldesleukin), Imatinib Mesylate, Imbruvica (Ibrutinib), Imfinzi (Durvalumab), Imiquimod, Imlygic (Talimogeno Laherparepvec), Inlyta (Axitinib), Inotuzumab Ozogamicin, i noznn / zznz / E / yii, Interferon Alpha-2b, Recombinant, Interleukin-2 (Aldesleukin), Intron A (Recombinant Interferon Alpha-2b), Ipilimumab, Iressa (Gefitinib), Irinotecan Hydrochloride, Liposomal Irinotecan Hydrochloride, Istodax (Romidepsin), Ixabepilone, Ixazomib Citrate, Ixempra (Ixabepilone), Jakafi (Ruxolitinib Phosphate), JEB, Jevtana (Cabazitaxel), Kadcyla (Ado-Trastuzumab Emtansine), Keoxifen (Raloxifene Hydrochloride), Kepivance (Palifermin), Keytruda (Pembrolizumab), Kisqali (Ribociclib), Kymriah (Tisagenlecleucel), Kiprolis (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate Lartruvo (Olaratumab), Lenalidomide, Lenvatine Mesylate, Lenvima (Lenvatine Mesylate), Letrozole, Leucorine, Calciov, Leukeran (Chlorambucil), Leuprolide Acetate, Leustatin (Cladribine), Levulan (Aminolevulinic Acid), Lympholizine (Chlorambucil), LipoDox (Doxorubicin Hydrochloride Liposome), Lomustine, Lonsurf (Trifluridine Hydrochloride and Tipiracil), Lupron (Leuprolide Acetate),Lupron Depot (Leuprolide Acetate), Lupron Depot-Ped (Leuprolide Acetate), Linparza (Olaparib), Marqibo (Vincristine Sulfate Liposome), Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megestrol Acetate, Mekinist (Trametinib), Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, Mesnex (Mesna), Metazolastone (Temozolomide), Methotrexate, Methotrexate LPF (Methotrexate), Methylnaltrexone Bromide, Mexato (Methotrexate), Mexato-AQ (Methotrexate), Midostaurin, Mitomycin C, Mitoxantrone Hydrochloride, Mitozitrex (Mitomycin C), MOPP, Mozobil (Plerixafor), Mustargeno (Mechlorethamine Hydrochloride), Mutamycin (Mitomycin C), Mileran (Busulfan), Milosar (Azacitidine), Milotarg (Gemtuzumab Ozogamicin), Paclitaxel Nanoparticle (Albumin-Stabilized Paclitaxel Nanoparticle Formulation), Navelbin (Vinorelbine Tartrate), Necitumumab, Nelarabine, Neosar (Cyclophosphamide), Neratinib Maleate, Nerlinx (Neratinib Maleate),Netupitant y Chlorhidrato de Palonosetron, Neulasta (Pegfilgrastim), Neupogen (Filgrastimo), Nexavar (Sorafenib Tosilato), Nilandron (Nilutamida), Nilotinib, Nilutamida, Ninlaro (Citrato de Ixazomib), Tosilato de Niraparib Monohidratado, Nivolumab, Nolvadex (Citrato de Tamoxifeno), Nplato (Romiplostim), Obinutuzumab, Odomzo (Sonidegib), OEPA, Ofatumumab, OFF, Olaparib, Olaratumab, Mepesuccinato de Omacetaxa, Oncaspar (Pegaspagasa), Chlorhidrato de Ondansetron, Onivida (Clorhidrato de Irinotecan Liposómico), Ontak (Denileucina Diftitox), Opdivo. (Nivolumab), OPPA, Osimertinib, Oxaliplatino, Paclitaxel, Formulation de Paclitaxel Estabilizadas con Albumina, PAD, Palbociclib, Palifermina, Chlorhidrato de Palonosetron, Chlorhidrato de Palonosetron y Netupitante, Pamidronato Disódico, Panitumumab, Panobinostat, Paraplat (Carboplatino), Paraplatino (Carboplatino), Chlorhidrato de Pazopanib, PCV, PEB, Megasphaera, Pegfilgrastim, Peginterferon Alfa-2b,PEG-Intron (Peginterferon Alfa-2b), Pembrolizumab, Pemetrexed Disodium, Perinatal (Epratuzumab), Epratuzumab, Platinum (Cisplatin), Platinum-AQ (Cisplatin), Plerixafor, Pomalidomide, Pomalidomide (Pomalidomide), Ponatinib Hydrochloride, Portability (Necitumumab), Pralatrexate, Prednisone, Procarbazine Hydrochloride, Proleucine (Aldesleucine), Prolia (Denosumab), Promacta (Eltrombopag Olamine), Propranolol Hydrochloride, Provenge (Sipuleucel-T), Purinetol (Mercaptopurine), Purixan (Mercaptopurine), Radium-223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, R-CHOP, R-CVP, Bivalent Vaccine Recombinant Human Papillomavirus (HPV), Nonavalent Recombinant Human Papillomavirus (HPV) Vaccine, Quadrivalent Recombinant Human Papillomavirus (HPV) Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, Relistor Methylnaltrexone), R-EPOCH, Revlimid (Lenalidomide), Reumatrex (Methotrexate), Ribociclib, R-ICE, Rituxan (Rituximab), Rituxan Hicela (Rituximab and Human Hyaluronidase), Rituximab, Rituximab and Human Hyaluronidase, Rolapitant Chlorhydrate, Romidepsin, Romiplostim, Rubidomycin (Daunorubicin Chlorhydrate), Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Ruxolitinib Phosphate, Ridapt (Midostaurin), Intrapleural Sclerosol Aerosol (Talc), Siltuximab, Sipuleucel-T, Somatulin Depósito (Lanreotide Acetate), Sonidegib, Sorafenib Tosilate, Espricel (Dasatinib), STANFORD V, Estéril Talc Powder (Talc), Esteritalc (Talc), Stivarga (Regorafenib), Sunitinib Malate, Sutent (Sunitinib Malate), Silatron (Peginterferon Alfa-2b), Silvant (Siltuximab), Sinribo (Omacetaxine Mepesuccinate), Tabloid (Thioguanine), TAC, Tafinlar (Dabrafenib), Tagrisso (Osimertinib), Talc, Laherparepvec Talimogén, Tamoxifen Citrate, Tarabina PFS (Citarabine),Tarceva (Clorhidrato de Erlotinib), Targretina (Bexaroteno), Tasigna (Nilotinib), Taxol (Paclitaxel), Taxotere (Docetaxel), Tecentriq (Atezolizumab), Temodar (Temozolomida), Temozolomida, Temsirolimus, Talidomida, Talomida (Talidomida), Tioguanine, Thiotepa, Tisagenlecleucel, Tolak (Fluorouracilo-Tópico), Clorhidrato de Topotecán, Toremifeno, Torisifeno (Temsirolimus), Totect (Clorhidrato de Dexrazoxano), TPF, Trabectedina, Trametinib, Trastuzumab, Treanda (Clorhidrato de Bendamustina), Trifluridina y Clorhidrato de Tipiracilo, Trisenox (Trióxido de Arsenic), Tikerb (Lapatinib Ditosylate), Unituxin (Dinutuximab), Uridine Triacetate, VAC, Valrubicin, Valstar (Valrubicin), Vandetanib, VAMP, Varubi (Rolapitant Chlorhydrate), Vectibix (Panitumumab), VelP, Velban (Vinblastine Sulfate), Velcade (Bortezomib), Velsar (Vinblastine Sulfate), Vemurafenib, Venclexta (Venetoclax), Venetoclax, Verzenio (Abemaciclib), Viadur (Leuprolide Acetate), Vidaza (Azacitidine),Vinblastine Sulfate, Vincasar PFS (Vincristine Sulfate), Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, VIP, Vismodegib, Vistogard (Uridine Triacetate), Voraxaze (Glucarpidase), Vorinostat, Votrient (Pazopanib Chlorhydrate), Vixeos (Daunorubicin and Liposuction Cytarabine Chlorhydrate), Wellcovorin (Calcium Leucovorin), Xalkori (Crizotinib), Xeloda (Capecitabine), XELIRI, XELOX, Xgeva (Denosumab), Xofigo (Radium 223 Dichloride), Xtandi (Enzalutamida), Yervoy (Ipilimumab), Yescarta (Axicabtageno Ciloleucel), Yondelis (Trabectedin), Zalap (Ziv-Aflibercept), Zarxio (Filgrastima), Zejula (Tosilato de Niraparib Monohidratado), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zinecard (Clorhidrato de Dexrazoxano), Ziv-Aflibercept, Zofran (Clorhidrato de Ondansetrón), Zoladex (Acetato de Goserelina), Ácido Zoledrónico, Zolinza (Vorinostat), Zometa (Ácido Zoledrónico), Zidelig (Idelalisib), Zykadia (Ceritinib),Zitiga (Abiraterone Acetate)., As used herein, the term “antitumor agent” is understood to refer to any chemical agent or drug effective in preventing or inhibiting the formation or growth of cancers or tumors. The antitumor agents described herein may include alkylating agents, antimetabolites, natural products, hormones, or antibodies. The treatment of tumors or cancer may include limiting the proliferation, migration, or invasion of cancerous or tumor cells in the body, or limiting the symptoms associated with such cancer or tumor. As used herein, antitumor agents are understood to encompass anticancer agents and are otherwise synonymous with anticancer agents. i ηαζηη / ζζηζ / Β / γι Methods of preparing the compounds of the disclosure Disclosures of PDE1 inhibitors and their pharmaceutically acceptable salts may be made using known methods, which are described and exemplified in US 8,273,750, US 2006 / 0173878, US 8,273,751, US 2010 / 0273753, US 8,697,710, US 8,664,207, US 8,633,180, US 8,536,159, US 2012 / 0136013, US 2011 / 0281832, US 2013 / 0085123, US 2013 / 0324565, US 2013 / 0338124, US 2013 / 0331363, WO 2012 / 171016, and WO 2013 / 192556, and by methods similar to these and by methods known in the chemical arts. Such methods include, but are not limited to, the methods described below. If these are not commercially available, the starting materials for these processes may be made by procedures selected from the chemical arts using techniques that are similar or analogous to the synthesis of known compounds. Several PDE1 inhibitors and starting materials for them can be prepared using the methods described in US 2008-0188492 A1, US 2010-0173878 A1, US 2010-0273754 A1, US 2010-0273753 A1, WO 2010 / 065153, WO 2010 / 065151, WO 2010 / 065151, WO 2010 / 065149, WO 2010 / 065147, WO 2010 / 065152, WO 2011 / 153129, WO 2011 / 133224, WO 2011 / 153135, WO 2011 / 153136, WO 2011 / 153138. All references cited herein are incorporated herein as references in their entirety. In addition, PDE1 inhibitors and related methods are disclosed in provisional application US 62 / 833,481, which is incorporated herein by reference in its entirety. Additional related PDE1 inhibitors and related methods are disclosed in international publication WO2018 / 049417, which is incorporated herein by reference in its entirety. The compounds covered by this disclosure include their enantiomers, diastereomers, and racemates, as well as their polymorphs, hydrates, solvates, and complexes. Some individual compounds within the scope of this disclosure may contain double bonds. Representations of double bonds in this disclosure include both the E and Z isomers of the double bond. In addition, some compounds within the scope of this disclosure may contain one or more asymmetric centers. This disclosure includes the use of any optically pure stereoisomers and any combination of stereoisomers. The disclosure also aims to cover both their stable and unstable isotopes. Stable isotopes are non-radioactive isotopes that contain one extra neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes will be retained, and such a compound would also be useful for measuring the pharmacokinetics of non-isotopic analogs. For example, the hydrogen atom at a specific position in the disclosure compounds could be replaced with deuterium (a stable, non-radioactive isotope). Some examples of known stable isotopes include deuterium, 13C, 15N, and 18O.Alternatively, unstable isotopes, which are radioactive isotopes containing extra neutrons compared to the abundant nuclides of the same species (i.e., element), for example, 123I, 131I, 125I, 11C, 18F, can replace the corresponding abundant species of I, C, and F. Another example of a useful isotope of the disclosure compound is the 11C isotope. These radioisotopes are useful for radioimaging and / or pharmacokinetic studies of the disclosure compounds. Melting points are uncorrected, and (dec) indicates decomposition. Temperature is given in degrees Celsius (°C); unless otherwise stated, operations are carried out at room or ambient temperature, i.e., within the range of 18–25 °C. Chromatography means ultrafast silica gel chromatography; thin-layer chromatography (TLC) is performed on silica gel plates. NMR data are the delta values ​​of the principal diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as the internal standard. Conventional abbreviations are used for signal shape. Coupling constants (J) are given in Hz. For mass spectra (MS), the lowest-mass principal ion is reported for molecules where isotope splitting results in multiple spectral mass peaks.Solvent mixture compositions are given as volume percentages or volume ratios. In cases where NMR spectra are complex, only diagnostic signals are reported. The words “treatment” and “treat” should consequently be understood as encompassing the treatment or mitigation of the symptoms of the disease and also the treatment of the cause of the disease. For treatment methods, the expression “effective amount” encompasses a therapeutically effective amount for treating a specific disease or disorder. The term “patient” includes both human and non-human (i.e., animal) patients. In one modality, the disclosure covers both humans and non-humans. In another modality, the disclosure covers non-humans. In yet another modality, the term covers humans. The term “comprising” used in this disclosure is open-ended and does not exclude additional elements or method steps not mentioned. The dosages used in the practice described herein will, of course, vary depending on factors such as the specific disease or condition being treated, the particular compounds described herein used, the route of administration, and the desired therapy. The compounds described herein may be administered by any suitable route, including oral, parenteral, transdermal, or inhalation, but oral administration is preferred. Generally, satisfactory results are indicated, for example, for the treatment of the diseases described above, by oral administration at doses in the range of approximately 0.01 to 2.0 mg / kg. In larger mammals, such as humans, a daily dose indicated for oral administration of the PDE1 inhibitor will consequently be in the range of approximately 0.50 to 300 mg, conveniently administered once or in divided doses 2 to 4 times daily or in sustained-release form. Unit-dose forms for oral administration, for example, may thus comprise from approximately 0.2 to 150 or 300 mg, for example, from approximately 0.2 or 2.0 to 10, 25, 50, 75, 100, 150 or 200 mg of a compound of the disclosure, together with a pharmaceutically acceptable diluent or vehicle therefor. The compounds disclosed, particularly for use or administration in either Method 1 or 2 below, may be administered at higher doses as required to treat a cancer or tumor, for example, colorectal cancer. It is envisaged that administration of a PDE1 inhibitor by such a method may be in the range of approximately 50 mg to 1000 mg daily.For example, a patient who is to be given a PDE1 inhibitor for a condition according to any of Methods 1 through 6 below, may be given a PDE1 inhibitor according to Formula I, II, III, or IV, in an amount of 50 mg to 1000 mg daily, 50 mg to 900 mg daily, 50 mg to 800 mg daily, 50 mg to 700 mg daily, 50 mg to 600 mg daily, 50 mg to 500 mg daily, 50 mg to 400 mg daily, 50 mg to 350 mg daily, 50 mg to 300 mg daily, 50 mg to 250 mg daily, 50 mg to 200 mg daily, 50 mg to 150 mg daily, or 50 mg to 100 mg daily. The compounds disclosed herein may be administered by any satisfactory route, including oral, parenteral (intravenous, intramuscular, or subcutaneous), or transdermal, but are preferably administered orally. In certain formulations, the compounds disclosed herein, for example, in depot formulations, are preferably administered parenterally, for example, by injection. The compounds and pharmaceutical compositions disclosed herein can be used in combination with one or more additional therapeutic agents, particularly at lower dosages than when the individual agents are used as monotherapy, to enhance the therapeutic activities of the combined agents without causing the undesirable side effects commonly associated with conventional monotherapy. Therefore, the compounds disclosed herein can be administered concurrently, separately, sequentially, or simultaneously with other agents used in the treatment of the disease.In another example, side effects can be reduced or minimized by administering a disclosure compound in combination with one or more additional therapeutic agents in free or salt form, where the dosages of (i) the second therapeutic agent(s) or (ii) both the disclosure compound and the second therapeutic agent are lower than if the agent / compound were administered as monotherapy. By way of non-limiting example, these additional therapeutic agents may include ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, etc. The term simultaneously, when referring to a therapeutic use, means the administration of two or more active ingredients at the same time or approximately by the same route of administration. The term "separately" when referring to a therapeutic use means the administration of two or more active ingredients at the same time or approximately by different routes of administration. The pharmaceutical compositions comprising the compounds disclosed can be prepared using conventional diluents or excipients and techniques known in pharmaceutical practice. Therefore, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like. j noznn / zznz / E / Yl· Examples EXAMPLE 1: Determination of the ability of PDE1 inhibitors to inhibit the growth of colon cancer in murine. Aliquots of neoplastic cells are injected into the subscapular space of BALB / C mice to induce colon carcinoma. Tumors are allowed to grow for 7 days, at which point tumor volume is quantified. Once a tumor has formed, drug therapy (50 mg / kg of Compound 1, once daily, i.p. in 0.5% methylcellulose vehicle) is initiated, and tumor growth is observed and recorded daily. The Compound 1s are shown below: i ηοζηη / ζζηζ / Ε / γι Compound 1 The mice were sacrificed 30 days after injection, and the tumors were isolated from the mice. As shown in Figure 1, Compound 1 significantly slowed tumor growth in CT26 cell samples after 30 days. Tumors were enzymatically dissociated into single-cell suspensions, stained with fluorophore-labeled antibodies, and analyzed by flow cytometry. Cells were sorted and analyzed for immune markers. As shown in Figure 2, treatment with Compound 1 led to significant increases in monocytes and CD8 T lymphocytes, but a significant decrease in the presence of macrophages in the tumor microenvironment was observed. Beyond theory, it is believed that PDE1 inhibitors have the ability to regulate immune function in the tumor microenvironment, one way of which includes reducing tumor invasion by macrophages. This, in turn, is thought to allow the innate immune system to more efficiently target tumor cells, which is consistent with the results observed here (i.e., increased T lymphocyte activation in the tumor microenvironment). EXAMPLE 2: Analysis of the co-administration of PDE1 inhibitors with regulatory point inhibitors to inhibit cancer growth in murine. The effects of Compound 1, alone or in combination with subeffective doses of the regulatory point inhibitor, anti-PD-1, were evaluated on the growth of CT26 xenograft tumors in BALB / c mice. Previously untreated tumor mice (i.e., isotype group) were compared with groups of mice that received Compound 1 monotherapy as defined in Example 1, mice that received a subeffective dose of a regulatory point inhibitor (anti-PD-1 antibody), and mice that received both Compound 1 and a subeffective dose of anti-PD-1 antibody. BALB / c mice were injected subcutaneously with CT26 cells on day 0 and then divided into four groups on day 7: (1) Compound 1 treatment (50 mg / kg, i.p. qd), 5 days / week; (2) isotype group, i.p. mlgG on days 7, 10, and 14; (3) anti-PD-1 group, i.p. administered on days 7, 10, and 14; and (4) combination group, treated with Compound 1 and anti-PD-1 as groups 1 and 3. Tumor volumes were quantified every 2 to 3 days. On days 17–18, tumors were excised, dissected, and used to produce single-cell suspensions. These tumor single-cell suspensions were incubated with FC blocker (eBioscience) and then stained with antibodies on ice in the dark. Samples were acquired on a FACSCalibur, LSRII or yellow LSRII (BD Biosciences), and analyzed with FlowJo (Tree Star). Zero of nine mice in the isotype-treated group showed tumor clearance (i.e., the tumor volume was less than 100 mm³), while one of five mice in the Compound 1-treated group and one of ten mice in the anti-PD-1-treated group showed tumor clearance. However, seven of fifteen mice in the group treated with the combination of Compound 1 and anti-PD-1 showed tumor clearance. At the end of the experiments, the tumors were also weighed. The results showed that the tumor weight in mice receiving combination therapy of Compound 1 and anti-PD-1 was significantly lower than in those in the control group treated with the isotype alone. Fluorescence-activated cell sorting (FACS) of tumor-infiltrating immune cells revealed that tumors in mice treated with Compound 1 monotherapy showed significantly decreased numbers of tumor-infiltrating CD45+ macrophages and monocytes, and that combination therapy with Compound 1 and anti-PD-1 enhanced antitumor immunity by eliciting increased numbers of CD45+ natural killer (NK) T cells and TNFα-producing CD4 T cells. These results suggest that Compound 1 alone is capable of reducing the tumor macrophage burden, thus enhancing the antitumor immunity of anti-PD-1. Alternative combinations and variations of the examples provided will become apparent based on disclosure. It is not possible to provide specific examples for all the many possible variations of the described modalities, but these combinations and variations may eventually be published claims.

Claims

1. A method for treating colon cancer comprising administering a pharmaceutically acceptable amount of a PDE1 inhibitor to a subject in need.

2. The method according to claim 1, wherein colon cancer is colorectal cancer.

3. A method for inhibiting the proliferation, migration and / or invasion of cancerous or tumor cells in the colon comprising the administration of a pharmaceutically acceptable amount of a PDE1 inhibitor to a subject in need.

4. The method according to claim 3, wherein the subject suffers from colon cancer.

5. The method according to claim 3 or 4, wherein the subject suffers from colorectal cancer.

6. A method according to any of the preceding claims, wherein the PDE1 inhibitor is a compound selected from: (A) Formula I: j ηοζηη / ζζηζ / E / γι wherein (i) Ri is H or C1-4 alkyl (such as methyl); (ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H or C1-4 alkyl (such as R2 and Rs are both methyl, or R2 is H and R3 is isopropyl), aryl, heteroaryl, arylalkoxy (optionally hetero), or arylalkyl (optionally hetero); or R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge (pref. where R3 and R4 together have the cis configuration, such as where the carbons bearing R3 and R4 have the R and S configurations, respectively); (iii) Rs is a substituted heteroarylalkyl, such as substituted with a haloalkyl;or Rs is attached to one of the nitrogens in the pyrazol portion of Formula I and is a fraction of Formula A Rg 1 ηαζηη / ζζηζ / E / γΐΛ Formula A wherein X, Y and Z are independently N or C, and Rs, R9, R11 and R12 are independently H or halogen (such as Cl or F), and R10 is halogen, alkyl, cycloalkyl, haloalkyl (such as trifluoromethyl), aryl (such as phenyl), heteroaryl (such as pyridyl (such as pyrid-2-yl) optionally substituted with halogen, or thiadiazolyl (such as 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (such as benzoyl), alkylsulfonyl (such as, methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, Rs, R9, or Rw, respectively, are not present;and (iv) Re is H, alkyl, aryl, heteroaryl, arylalkyl (such as benzyl), arylamino (such as phenylamino), heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino (such as N-phenyl-N-(1,1'-biphenyl-4-ylmethyl)amino); and (v) n=0 or 1; (vi) when n=1, A is-C(Ri3Ru)- where R13 and Ru. are independently H or C1-4 alkyl, aryl, heteroaryl, arylalkoxy (optionally hetero) or arylalkyl (optionally hetero); in free form, as a salt or prodrug, including its enantiomers, diastereomers and racemates; (B) Formula II: Formula II (i) X is a C1-6 alkylene (such as methylene, ethylene or prop-2-yn-1-ylene); (i) Y is a single bond, alkynylene (such as —ChC—), arylene (such as phenylene) or heteroarylene (such as pyridylene);(iii) Z is H, aryl (such as phenyl), heteroaryl (such as pyridyl, such as pyrid-2-yl), halo (such as F, Br, Cl), C1-6 haloalkyl (such as trifluoromethyl), —C(O)—R1, —N(R2)(R3), or C3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (such as cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl); (iv) R1 is C1-6 alkyl, C1-6 haloalkyl, —OH or —O C1-6 alkyl (such as —OCH3); (v) R2 and R3 are independently H or C1-6 alkyl; (vi) R4 and R5 are independently C1-6 H, alkyl or aryl (such as, phenyl) optionally substituted with one or more C1-6 halo (such as, fluorophenyl, such as, 4-fluorophenyl), hydroxy (such as, hydroxyphenyl, such as, 4-hydroxyphenyl or 2-hydroxyphenyl) or alkoxy;(vile) wherein X, Y, and Z are independently and optionally substituted with one or more halo groups (such as F, Cl, or Br), C1-6 alkyl groups (such as methyl), C1-6 haloalkyl groups (such as trifluoromethyl), Z is heteroaryl, such as pyridyl substituted with one or more halo groups (such as 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), C1-6 haloalkyl groups (such as 5-trifluoromethylpyrid-2-yl), or C1-6 alkyl groups (such as 5-methylpyrid-2-yl), or Z is aryl, such as phenyl, substituted with one or more halo groups (such as, 4-fluorophenyl), in free form, as a salt or prodrug. (C) Formula III: 1 Formula III wherein (i) R1 is H or C1-4 alkyl (such as methyl or ethyl); (ii) R2 and Rs are independently H or C1-6 alkyl (such as methyl or ethyl); (iii) R4 is H or C1-4 alkyl (such as methyl or ethyl);(iv) Rs is aryl (such as phenyl) optionally substituted with one or more independently selected C1-6 -C(=O)-alkyl groups (such as -C(=O)-CH3) and C1-6 hydroxyalkyl groups (such as 1-hydroxyethyl); (v) Re and R7 are independently H or aryl (such as phenyl) optionally substituted with one or more independently selected C1-6 alkyl groups (such as methyl or ethyl) and halogen (such as F or Cl), such as unsubstituted phenyl or phenyl substituted with one or more halogens (such as F) or phenyl substituted with one or more C1-6 alkyl and one or more halogens or phenyl substituted with a C1-6 alkyl and a halogen, such as 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and (vi) n is 1, 2, 3, or 4, in free or salt form; (D) Formula IV 1 noznn / zznz / E / yii in free or salt form, wherein;(iv) Ri is an alkyl of Oh (such as methyl or ethyl), or -NH(R2), wherein R2 is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl; (v) X, Y, and Z are independently N or C; (vi) R3, R4, and Rs are independently H or C1-4 alkyl (such as methyl); or R3 is H and R4 and Rs together form a tri-methylene bridge (pref. wherein R4 and Rs together have the cis configuration, such as wherein the carbons bearing R4 and Rs have the R and S configurations, respectively); (vii) Re, R7, and Rs are independently: H, C1-4 alkyl (such as methyl), hydroxy-substituted pyrid-2-yl, or -S(O)2-NH2; provided that when X, Y and / or Z are N, then Re, R7 and / or Rs, respectively, are not present; and when X, Y and Z are all C, then at least one of Re, R7 or Raes -S(O)2-NH2 or pyrid2-yl substituted with hydroxy, in free or salt form;and (E) Formula 1a: wherein (iv) R2 and Rs are independently H or hydroxy and R3 and R4 together form a tri- or tetramethylene bridge [pref. with the carbons bearing R3 and R4 having the R and S configurations, respectively]; or R2 and R3 are both methyl and R4 and Rs are both H; or R2, R4 and Rs are H and R3 is isopropyl [pref., the carbon bearing R3 having the R configuration]; (v) Re is phenylamino (optionally halo-substituted), benzylamino (optionally halo-substituted), C1-4 alkyl, or C1-4 alkyl sulfide; such as phenyllamino or 4-fluorophenyllamino; (vi) Rw is C14 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, phenyl (optionally halo or hydroxy substituted), pyridyl (optionally halo or hydroxy substituted) (such as 6-fluoropyrid-2-yl), or thiadiazolyl (such as, 1,2,3-thiadiazol-4-yl);and X and Y are independently C or N. in free form, as a pharmaceutically acceptable salt or as a prodrug, including its enantiomers, diastereomers and racemates; (F) Formula V 1 naznn / zznz / B / yii Formula V wherein (iv) R1 is -NH(R4), wherein R4 is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl; (v) R2 is H or C1-6 alkyl (such as methyl, isobutyl or neopentyl); (vi) R3 is -SO2NH2 or -COOH; in free form, as a pharmaceutically acceptable salt or as a prodrug, including its enantiomers, diastereomers and racemates; and / or (G) Formula VI Formula VI wherein (iv) Ri is -NH(R4), wherein R4 is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl; (v) R2 is H or C1-6 alkyl (such as methyl or ethyl);(vi) R3 is H, halogen (such as bromine), C1-6 alkyl (such as methyl), optionally halogen-substituted aryl (such as 4-fluorophenyl), optionally halogen-substituted heteroaryl (such as 6-fluoropyrid-2-yl or pyrid-2-yl) or acyl (such as acetyl), in free form, as a pharmaceutically acceptable salt or as a prodrug, including its enantiomers, diastereomers and racemates; or (H) Formula VII: 1 noznn / zznz / E / yii Formula VII (viii) R1 is -NH(Rs), wherein Rs is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl; (ix) R2 and R3 are independently H or C1-6 alkyl (such as methyl or ethyl); (x) R4 is optionally halogen-substituted aryl (such as, 4-fluorophenyl) or optionally halogen-substituted heteroaryl (such as, 6-fluoropyrid-2-yl), in free form, of pharmaceutically acceptable salt or prodrug, including its enantiomers, diastereomers and racemates.; 7. A method according to any of the preceding claims, wherein the PDE1 inhibitor is selected from any of the following: i ηαζηη / ζζηζ / E / γΐΛ in free form or as a pharmaceutically acceptable salt.

8. A method according to any of the preceding claims, wherein the PDE1 inhibitor is administered in combination with an antitumor agent.

9. A method for treating a selected condition arising from a type of cancer or tumorous cancer comprising administering a pharmaceutically acceptable amount of a PDE1 inhibitor (i.e., PDE1 inhibitor according to Formula I, l, 1a, II, III, IV, V, VI and / or 1b) and a checkpoint inhibitor to a subject in need.

10. A method according to claim 9, wherein the type of cancer is colon cancer.

11. A method according to claim 10, wherein the type of cancer is colorectal cancer.

12. A method according to any one of claims 9 to 11, wherein the PDE1 inhibitor is a compound selected from: (A) Formula I: j ηοζηη / ζζηζ / E / γΐΛ wherein (i) Ri is H or C1-4 alkyl (such as methyl); (ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H or C1-4 alkyl (such as R2 and Rs are both methyl, or R2 is H and R3 is isopropyl), aryl, heteroaryl, arylalkoxy (optionally hetero), or arylalkyl (optionally hetero); or R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge (pref. where R3 and R4 together have the cis configuration, such as where the carbons bearing R3 and R4 have the R and S configurations, respectively); (iii) Rs is a substituted heteroarylalkyl, such as substituted with a haloalkyl;or Rs is attached to one of the nitrogens in the pyrazol portion of Formula I and is a fraction of Formula A R9 Formula A wherein X, Y and Z are independently N or C, and Rs, Rs, R11 and R12 are independently H or halogen (such as Cl or F), and R10 is halogen, alkyl, cycloalkyl, haloalkyl (such as trifluoromethyl), aryl (such as phenyl), heteroaryl (such as pyridyl (such as pyrid-2-yl) optionally substituted with halogen, or thiadiazolyl (such as 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (such as benzoyl), alkylsulfonyl (such as methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, Rs, Rs, or R10, respectively, are not present;and (iv) Re is H, alkyl, aryl, heteroaryl, arylalkyl (such as benzyl), arylamino (such as phenylamino), heteroarylamino, N,Nd-alkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino (such as N-phenyl-N-(1,1'-biphenyl-4-ylmethyl)amino); and (v) n=0 or 1; (vi) when n=1, A is-C(Ri3Ri4)- where R13 and Ri4 are independently H or C1-4 alkyl, aryl, heteroaryl, arylalkoxy (optionally hetero) or arylalkyl (optionally hetero); in free form, as a salt or prodrug, including its enantiomers, diastereomers and racemates; (B) Formula II: 1 ηοζηη / ζζηζ / Β / γι Formula II (i) (ii) Y is a single bond, alkynylene (such as —ChC—), arylene (such as phenylene) or heteroarylene (such as pyridylene);(iii) Z is H, aryl (such as phenyl), heteroaryl (such as pyridyl, such as pyrid-2-yl), halo (such as F, Br, Cl), C1-6 haloalkyl (such as trifluoromethyl), —C(O)—R1, —N(R2)(R3), or C3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (such as cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl); (iv) R1 is C1-6 alkyl, C1-6 haloalkyl, —OH or —O C1-6 alkyl (such as —OCH3); (v) R2 and R3 are independently H or C1-6 alkyl; (vi) R4 and R5 are independently C1-6 H, alkyl or aryl (such as, phenyl) optionally substituted with one or more C1-6 halo (such as, fluorophenyl, such as, 4-fluorophenyl), hydroxy (such as, hydroxyphenyl, such as, 4-hydroxyphenyl or 2-hydroxyphenyl) or alkoxy;(vii) wherein X, Y and Z are independently and optionally substituted with one or more halo groups (such as F, Cl or Br), C1-6 alkyl groups (such as methyl), C1-6 haloalkyl groups (such as trifluoromethyl), Z is heteroaryl, pyridyl substituted with one or more halo groups (such as 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dlchloropyrid-2-yl), C1-6 haloalkyl groups (such as 5-trifluoromethylpyrid-2-yl) or C1-6 alkyl groups (such as 5-methylpyrid-2-yl), or Z is aryl, phenyl, substituted with one or more halo groups (such as 4-fluorophenyl), in free form, as a salt, or as a prodrug. (C) Formula III: 1 ηαζηη / ζζηζ / Β / γι Formula III wherein (i) Ri is H or C1-4 alkyl (such as methyl or ethyl); (ii) R2 and R3 are independently H or C1-6 alkyl (such as methyl or ethyl); (iii) R4 is H or C1-4 alkyl (such as methyl or ethyl);(iv) Rs is an aryl (such as phenyl) optionally substituted with one or more independently selected -C(=O)-C1 6 alkyl groups (such as -C(=O)-CH3) and C1-6 hydroxyalkyl groups (such as 1-hydroxyethyl); (v) Re and R? are independently H or aryl (such as phenyl) optionally substituted with one or more independently selected C1-6 alkyl groups (such as methyl or ethyl) and halogen (such as F or Cl), such as unsubstituted phenyl or phenyl substituted with one or more halogens (such as F) or phenyl substituted with one or more C1-6 alkyl and one or more halogens or phenyl substituted with a C1-6 alkyl and a halogen, such as 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and (vi) n is 1, 2, 3, or 4, in free or salt form; in free or salt form, wherein; (xi) R1 is C1-4 alkyl (such as methyl or ethyl), or -NH(Rz), wherein R2 is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl;(xii) X, Y and Z are independently N or C; (xiii) R3, R4 and Rs are independently H or C1-4 alkyl (such as methyl); or R3 is H and R4 and Rs together form a tri-methylene bridge (pref. where R4 and Rs together have the cis configuration, such as where the carbons bearing R4 and Rs have the R and S configurations, respectively); (xiv) Re, R7 and Rs are independently: H, C1-4 alkyl (such as methyl), hydroxy-substituted pyrid-2-yl, or -S(O)2-NH2; provided that when X, Y and / or Z are N, then Re, R7 and / or Rs, respectively, are not present; and when X, Y and Z are all C, then at least one of Re, R7 or Raes -S(O)2-NH2 or pyrid2-yl substituted with hydroxy, in free or salt form; and (E) Formula 1a: 1 ηοζηη / ζζηζ / Β / γι wherein (vii) R2 and Rs are independently H or hydroxy and R3 and R4 together form a tri- or tetramethylene bridge [preferably with the carbons bearing R3 and R4 having the R and S configuration, respectively];or R2 and R3 are both methyl and R4 and Rs are both H; or R2, R4 and Rs are H and R3 is isopropyl [preferably the carbon bearing R3 having the R configuration]; (viii) Re is phenylamino (optionally halo-substituted), benzylamino (optionally halo-substituted), C1-4 alkyl, or C1-4 alkyl sulfide; such as phenyllamino or 4-fluorophenyllamino; (ix) R10 is C1-4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, phenyl (optionally halo- or hydroxy-substituted), pyridyl (optionally halo- or hydroxy-substituted) (such as 6-fluoropyrid-2-yl), or thiadiazolyl (such as 1,2,3-thiadiazol-4-yl); and X and Y are independently C or N. in free form, of pharmaceutically acceptable salt or of the prodrug, which includes its enantiomers, diastereomers and racemates. (F) Formula V 1 naznn / zznz / B / yii wherein (vii) Ri is -NH(R4), wherein R4 is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl;(viii) R2 is H or C1-6 alkyl (such as methyl, isobutyl or neopentyl); (ix) R3 is -SO2NH2 or -COOH; in free form, as a pharmaceutically acceptable salt or as a prodrug, including its enantiomers, diastereomers and racemates; and / or (G) Formula VI r3 Formula VI wherein (vii) R1 is -NH(R4), wherein R4 is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl; (viii) R2 is H or C1-6 alkyl (such as methyl or ethyl); (ix) R3 is H, halogen (such as bromine), C1-6 alkyl (such as methyl), optionally halogen-substituted aryl (such as 4-fluorophenyl), optionally halogen-substituted heteroaryl (such as 6-fluoropyrid-2-yl or pyrid-2-yl) or acyl (such as acetyl), in free form, of a pharmaceutically acceptable salt or prodrug, including its enantiomers, diastereomers and racemates;or (H) Formula Vil: Formula Vil (xv) Ri is -NH(Rs), wherein Rs is optionally halo-substituted phenyl (such as fluoro), such as 4-fluorophenyl; (xvi) R2 and R3 are independently H or C1-6 alkyl (such as methyl or ethyl); (xvii) R4 is optionally halo-substituted aryl (such as 4-fluorophenyl) or optionally halo-substituted heteroaryl (such as 6-fluoropyrid-2-yl), in free form, of pharmaceutically acceptable salt or prodrug, including its enantiomers, diastereomers and racemates.; 13. A method according to any of claims 9 to 12, wherein the PDE1 inhibitor is selected from any of the following: i ηαζηη / ζζηζ / E / γΐΛ in free form or as a pharmaceutically acceptable salt.

14. The method according to any of claims 9 to 13, wherein the checkpoint inhibitor is an inhibitor of CTLA-4, PD-1 and / or PD-L1.

15. The method according to any of claims 9 to 14, wherein the set point inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, avelumab, durvalumab, atezolizumab, spartalizumab, or combinations thereof.

16. The method according to any of claims 9 to 15, wherein the PDE1 inhibitor is administered in a sufficient quantity to reduce the infiltration of monocytes and / or macrophages into a tumor-associated microenvironment.

17. The method according to any of claims 9 to 16, wherein the PDE1 inhibitor and the checkpoint inhibitor are administered in sufficient quantities to reduce the infiltration of monocytes and / or macrophages into a tumor-associated microenvironment and / or to increase the infiltration of natural killer cells and CD4+ T lymphocytes.

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