Organic compounds

Abstract

The disclosure relates to the use of phosphodiesterase 1 (PDE1) inhibitors for treatment or prophylaxis for a metabolic disorder (e.g., obesity, fatty liver disease, type 2 diabetes, pre-diabetic conditions, and conditions associated with fat-induced inflammation), reducing high blood glucose levels (e.g. as reflected in high fasting glucose or Hb-A1C levels), and / or promoting or maintaining body weight loss or suppressing body weight gain.

Description

ORGANIC COMPOUNDSFIELD OF DISCLOSURE

[0001] The field relates to the use of phosphodiesterase 1 (PDE1) inhibitors for promoting or maintaining body weight loss or suppressing body weight gain, including for the treatment of obesity.BACKGROUND OF THE DISCLOSURE

[0002] Eleven families of phosphodiesterases (PDEs) have been identified but only PDEs in Family I, the Ca2+ / calmodulin-dependent phosphodiesterases (CaM-PDEs), which are activated by Ca2+ / calmodulin, have been shown to mediate the calcium dependent cyclic nucleotide (e.g., cGMP and cAMP) signaling pathways. The three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in central nervous system tissue. PDE1A is expressed in the brain, lung and heart. PDE1B is primarily expressed in the central nervous system, but it is also detected in monocytes and neutrophils and has been shown to be involved in inflammatory responses of these cells. PDE1C is expressed in olfactory epithelium, cerebellar granule cells, striatum, heart, vascular smooth muscle and tumor cells. PDE1C has been demonstrated to be a major regulator of smooth muscle proliferation in human smooth muscle. Cyclic nucleotide phosphodiesterases down-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 terms of intra-cellular signaling pathways. Both cAMP and cGMP are central intracellular second messengers and they play roles in regulating numerous cellular functions. PDE1A and PDE1B preferentially hydrolyze cGMP over cAMP, while PDE1C shows approximately equal cGMP and cAMP hydrolysis.

[0003] Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. A body mass index (BMI) over 25 is considered overweight, and over 30 is obese. Obesity has significant adverse effects on quality of life and psychological well-being. In addition, obesity is known to increase the risk of developing various diseases such as cardiovascular disease, stroke, insulin resistance, type 2 diabetes, fatty liver disease, neurodegenerative disease, and respiratory diseases. The increasing prevalence of obesity is aworldwide health problem, with over 4 million people dying each year as a result of being overweight or obese in 2017 according to the global burden of disease.

[0004] Weight gain and obesity are caused by energy imbalance between calories consumed and calories expended, although many factors such as eating patterns, physical activity levels, and sleep routines can contribute to excess weight gain. Energy intake that exceeds energy expenditure leads to a net storage of excess calories in the form of fat in adipose tissue. Obesity is metabolically linked with type 2 diabetes and hepatosteatosis. Hepatosteatosis is the buildup of lipids within hepatocytes and is the simplest stage in nonalcoholic fatty liver disease (NAFLD). It can lead to steatohepatitis, hepatocarcinogenesis and liver failure. Pharmaceutical treatments that suppress appetite, block dietary fat absorption, induce fat mobilization, or increase metabolism would be ideal for the treatment of obesity and related metabolic disorders. However, currently available weight loss drugs are not effective in all subjects or are of limited efficacy and may cause various side effects. For example, GLP-1 receptor agonists such as semaglutide can often cause stomach side effects like diarrhea, upset stomach (nausea or vomiting), heartbum, and gas or constipation. Stimulant-type drugs such as phentermine can lead to insomnia, increased blood pressure, fast heart rate, restlessness, drug dependence, abuse, and withdrawal symptoms. Drugs that interfere with fat absorption, such as orlistat, can lead to oily spotting, gas, and soft stools. People often regain their weight after stopping taking weight loss drugs.

[0005] There is a need for the development of safe and efficacious pharmaceutical treatments for obesity.SUMMARY OF THE DISCLOSURE

[0006] It is surprisingly found that PDE1 inhibitors have profound effect in maintaining a healthy metabolism, and so are useful in treatment or prophylaxis of obesity, metabolic disorders, fatty liver disease (c.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and steatohepatitis), type 2 diabetes, pre-diabetic conditions, and conditions associated with fat- induced inflammation. For example, a PDE1 inhibitor is found (i) to significantly inhibit weight gain in high-fat diet (HFD) fed but not in normal fat diet (NFD) fed mice, without inhibiting food intake; (ii) to decrease fasting glucose levels in HFD mice, and reduce the potential for obesityinduced development of Type 2 diabetes; (iii) to inhibit and reverse HFD-induced weight, including reducing perigonadal white fat, subcutaneous white fat, and fat in liver; and (iv) to reduce Ml -type macrophage populations in perigonadal white fat samples, consistent with reduction in inflammation in white fat.

[0007] While GLP-1 agonists act by suppressing feeding and reducing cravings and have received great attention for their impact in treating obesity, PDE1 inhibitors work by a different mechanism and appear to have no impact on food cravings. Accordingly, it is believed that GLP- 1 agonists and PDE-1 inhibitors can be combined to exert beneficial effects on body weight; that PDE1 inhibitors can help maintain healthy body weight and ease the transition to a normal diet after weight loss, for example from GLP-1 agonists therapy; and that PDE1 inhibitors can be effective to treat fatty liver diseases, as the liver appears to be an important site of action for these drugs.

[0008] In an aspect, the disclosure provides methods of treating obesity, promoting or maintaining body weight loss or suppressing body weight gain, and / or treating metabolic disorders, including fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and steatohepatitis), type 2 diabetes, pre-diabetic conditions, and conditions associated with fat-induced inflammation, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof. In some embodiments, the subject is overweight or obese, i.e., body mass index (BMI) of the subject is over 25. In some embodiments, the subject is obese, i.e., body mass index (BMI) of the subject is over 30. In some embodiments, the subject has consumed and / or consumes a high fat diet. In some embodiments, the subject suffers from metabolic syndrome. In some embodiments, the subject suffers from at least a disease or condition associated with overweight or obesity, e.g., cardiovascular disease, stroke, insulin resistance, type 2 diabetes, liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and steatohepatitis), neurodegenerative disease, or respiratory diseases.

[0009] The PDE1 inhibitor may be administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject. In some embodiments, the PDE1 inhibitor is administered in combination with a therapeutic agent suppressing appetite to thesubject. In certain embodiments, the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide). In some embodiments, the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, e.g., tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.

[0010] The PDE1 inhibitor may be administered alone without an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain to the subject. In some embodiments, any active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) is not administered to the subject. In some embodiments, any therapeutic agent suppressing appetite is not administered to the subject. In some embodiments, any therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain other than the PDE1 inhibitor is not administered to the subject.

[0011] The PDE1 inhibitor may be used as a sole adjunct to a reduced-calorie diet and increased physical activity for chronic weight management. In some embodiments, the PDE1 inhibitor may be administered to the subject after a therapeutic agent promoting or maintaining body weight loss or suppressing body weight gain that has been administered to the subject has ceased. In some embodiments, the therapeutic agent that has ceased is a therapeutic agent suppressing appetite. In some embodiments, the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide). In some embodiments, the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, e.g., tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.

[0012] In certain embodiments, the PDE1 is administered to maintain weight loss, for example following weight loss induced by treatment with a therapeutic agent suppressingappetite to the subject. In certain embodiments, the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon-like peptide, glucagon receptor agonist, GLP-1 receptor agonist (e.g., semaglutide), SGLT2 inhibitor, or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide). In some embodiments, the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, e.g., tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.

[0013] The PDE1 inhibitor can be used in combination with additional weight loss drugs and also as monotherapy to maintain body weight loss or suppress body weight gain. Therefore, in some embodiments, the PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject but the treatment with the PDE1 inhibitor is continued as monotherapy once the administration of the additional therapeutic agent is stopped, e.g., because of intolerance. In certain embodiments, the PDE1 inhibitor is administered in combination with semaglutide to the subject but the PDE1 inhibitor continues to be administered as monotherapy once the administration of semaglutide is stopped.

[0014] In some embodiments, the PDE1 inhibitor is a PDE1 inhibitor of Formulas I, la, II, III, IV, V, VI, and / or VII described hereinbelow in free or pharmaceutically acceptable salt form.

[0015] In another aspect, the disclosure provides a method of reducing the accumulation of fat in adipose tissue and / or liver, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor, e.g., any of PDE1 inhibitors described in this disclosure, to a subject in need thereof. In some embodiments, the adipose tissue is white adipose tissue. In some embodiment, the adipose tissue comprises perigonadal and subcutaneous adipose tissue. In some embodiments, the subject is overweight or obese, i.e., body mass index (BMI) of the subject is over 25. In some embodiments, the subject is obese, i.e., body mass index (BMI) of the subject is over 30. In some embodiments, the subject has consumed and / or consumes a high fat diet. In some embodiments, the subject suffers from metabolic syndrome. In some embodiments, the subject suffers from at least a disease or condition associated with overweight or obesity, e.g., cardiovascular disease, stroke, insulin resistance, type 2 diabetes, liver disease (e.g., nonalcoholicfatty liver disease (NAFLD), hepatosteatosis, and steatohepatitis), neurodegenerative disease, or respiratory diseases. In certain embodiment, the subject suffers from nonalcoholic fatty liver disease (NAFLD).

[0016] The PDE1 inhibitor may be administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain to the subject. In some embodiments, the PDE1 is administered in combination with a therapeutic agent suppressing appetite to the subject. In certain embodiments, the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon-like peptide, glucagon receptor agonist, GLP-1 receptor agonist (e.g., semaglutide), SGLT2 inhibitor, or other agents that may directly or indirectly increase plasma glucagon).

[0017] In some embodiments, the PDE1 is administered to maintain weight loss, for example following weight loss induced by treatment with a therapeutic agent suppressing appetite to the subject. In certain embodiments, the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon-like peptide, glucagon receptor agonist, GLP-1 receptor agonist (e.g., semaglutide), SGLT2 inhibitor, or other agents that may directly or indirectly increase plasma glucagon).

[0018] The PDE1 inhibitor may be administered alone without any additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain to the subject. In some embodiments, any active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon-like peptide, glucagon receptor agonist, GLP-1 receptor agonist (e.g., semaglutide), SGLT2 inhibitor, or other agents that may directly or indirectly increase plasma glucagon) is not administered to the subject. In some embodiments, any therapeutic agent suppressing appetite is not administered to the subject. In some embodiments, any therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain other than the PDE1 inhibitor is not administered to the subject.

[0019] In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of a PDE1 inhibitor, e.g., any of PDE1 inhibitors described in this disclosure, for use in any of methods described in the disclosure, e.g.,a method of promoting or maintaining body weight loss or suppressing body weight gain, reducing the accumulation of fat in adipose tissue and / or liver, or preventing or treating obesity.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows body weight of high fat diet (HFD)-fed or Chow diet-fed mice treated or not treated with 900 ppm Compound 1 over time. Date of GTT (glucose tolerance test) is indicated by an arrow. n=8 / group. **** Pc0.0001.

[0021] FIG. 2 shows food intake per day of high fat diet (HFD)-fed or Chow diet-fed mice treated or not treated with 900 ppm Compound 1. Date of GTT (glucose tolerance test) is indicated by an arrow. n=8 / group.

[0022] FIG. 3A shows fasting glucose level of high fat diet (HFD)-fed or Chow diet- fed mice treated or not treated with 900 ppm Compound 1 at Weeks 0, 8, 14, and 16. FIG. 3B shows GTT (glucose tolerance test) -AUC levels of Chow diet-fed mice or high fat diet (HFD)-fed mice treated or not treated with 900 ppm Compound 1 at week 12. n=8 / group. * P<0.05, *** Pc0.001, **** Pc0.0001.

[0023] FIG. 4A, B, and C show plasma insulin levels (FIG. 4A), plasma cholestreol levels (FIG. 4B) and liver triglyceride (TG) levels (FIG. 4C) of high fat diet (HFD)-fed mice treated or not treated with 900 ppm Compound 1. n=8 / group. * P<0.05, ** P<0.01, *** Pc0.001.

[0024] FIG. 5 shows the weights of perigonadal white adipose tissue fat (pWAT), subcutaneous white adipose tissue fat (scWAT), brown adipose tissue fat (BAT) and fat in liver of high fat diet (HFD)-fed or Chow diet-fed mice treated or not treated with 900 ppm Compound 1. n=8 / group. * P<0.05, **** Pc0.0001.

[0025] FIG. 6 shows fat mass, fat (%), lean mass, bone mineral density (BMD), bone mineral content (BMC), and bone area of high fat diet (HFD)-fed mice treated or not treated with 900 ppm Compound 1. n=8 / group. * P<0.05, ** P<0.01, ns: not significant.

[0026] FIG. 7A and B show distance travelled (light and dark) (FIG. 7A) and energy expenditure (light and dark) (FIG. 7B) of high fat diet (HFD)-fed mice treated or not treated with 900 ppm Compound 1. n=8 / group. *** Pc0.001.

[0027] FIG. 8A shows relative proportion of CD45+ cells in perigonadal white adipose tissue of high fat diet (HFD)-fed or Chow diet-fed mice treated or not treated with 900 ppmCompound 1. FIG. 8B shows relative proportions of M1 macrophages and M2 macrophages in perigonadal while adipose tissue of high fat diet (HFD)-fed or Chow diet-fed mice treated or not treated with 900 ppm Compound 1. FIG. 8C shows the M1 / M2 ratio of macrophages in perigonadal white adipose tissue of high fat diet (HFD)-fed or Chow diet-fed mice treated or not treated with 900 ppm Compound 1. n=8 / group. * P<0.05, ** P<0.01, **** P<0.0001.DETAILED DESCRIPTION OF THE DISCLOSURE

[0028] It was previously shown that inhibition of PDE1 activity using the presently disclosed compounds can safely restore cAMP function in a wide spectrum of pathological conditions, including models of neurodegeneration and neuroinflammation, heart failure, cancers, pulmonary hypertension and peripheral inflammation and in humans with certain diseases.

[0029] In the present invention, the inventors have discovered that PDE-1 inhibitors, e.g., Compound 1, suppress weight gain in a mouse model of diet induced obesity. It has been found that Compound 1 suppresses weight gain when mice are exposed to a high fat diet but does not alter weight gain when mice are exposed to a normal diet. Compound 1 does not suppress food intake in both normal diet-fed mice and high fat diet-fed mice, indicating that PDE-1 inhibitors do not suppress appetite. It has been further found that Compound 1 reduces the accumulation of fat in adipose tissue and liver when mice are exposed to a high fat diet. In addition, it has been found that Compound 1 decreases fasting glucose levels in HFD mice and reduces M1 -type macrophage populations in perigonadal white fat samples. Without being bound by any theory, it is believed that PDE1 inhibitors suppress body weight gain and fat accumulation in adipose tissue by affecting metabolism (e.g., lipid metabolism) in the body but not by suppressing appetite. These findings provide a mean to promote or maintain body weight loss or suppress body weight gain by using PDE1 inhibitors in combination with additional weight loss drugs, e.g., appetite suppressors, or as monotherapy. PDE1 inhibitors may be used as a sole adjunct to a reduced-calorie diet and increased physical activity for chronic weight management. For example, PDE1 inhibitors may be used as monotherapy for weight maintenance after the use of weight loss drugs is stopped. In addition, PDE1 inhibitors may be used to maintain a healthy metabolism, e.g., for the treatment or prophylaxis of metabolic disorders (e.g., obesity, fatty liverdisease, type 2 diabetes, pre-diabetic conditions, and conditions associated with fat-induced inflammation).Compounds for use in the methods of the disclosure

[0030] In one embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are selective PDE1 inhibitors.PDE1 Inhibitors

[0031] In one embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula I:wherein(i) R1is H or C1-4alkyl (e.g., methyl);(ii) R4is H or C1-4alkyl and R2and R3are, independently, H, C1-4alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl (e.g., R2and R3are both methyl, or R2is H and R3is isopropyl); or R2is H and R3and R4together form a di-, tri- or tetramethylene bridge(pref, wherein the R3and R4together have the cis configuration, e.g., where the carbons carrying R3and R4have the R and S configurations, respectively);(iii) R5is a substituted heteroarylalkyl, e.g., substituted with haloalkyl; or R5is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula Awherein X, Y, and Z are, independently, N or C, and R8, R9, R11and R12are independently H or halogen (e.g., Cl or F), and R10is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl) optionally substituted with halogen, 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, R8, R9, or R10, respectively, is not present;(iv) R6is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino (e.g., N- phenyl-N-( 1 , 1 ’-biphen-4-ylmethyl)amino);(v) n=0 or 1;(vi) provided that when n=l, A is -C(R13R14)- wherein R13and R14, are, independently, H, C1-4alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

[0032] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula la:wherein(i) R2and R5are independently H or hydroxy and R3and R4together form a tri- or tetramethylene bridge [pref, with the carbons carrying R3and R4having the R and S configuration respectively]; or R2and R3are each methyl and R4and R5are each H; or R2, R4and R5are H and R3is isopropyl [pref, the carbon carrying R3having the R configuration];(ii) R6is (optionally halo-substituted or hydroxy-substituted) phenylamino, (optionally halo- substituted or hydroxy-substituted) benzylamino, C1-4alkyl, or C1-4alkyl sulfide, for example, phenylamino or 4-fluorophenylamino;(iii) R10is C1-4alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl (for example 6-lluoropyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl), or R10is -CH(CH3)-O- C(O)- R11, wherein R11is C1-6alkyl (e.g., methyl, ethyl, or propyl), or R10is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g., saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl), or R10is -C(=O)-X1, wherein X1is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g., saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl); and(iv) X and Y are independently CH or N, in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers and racemates, thereof.

[0033] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula II;wherein(i) X is C1-6alkylene (e.g., methylene, ethylene or prop-2-yn-l-ylene);(ii) Y is a single bond, alkynylene (e.g., — C≡C — ), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene);(iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloC1-6alkyl (e.g., trifluoromethyl), — C(O) — R1, — N(R2)(R3), or C3-7cycloalkyl 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) R1is C1-6alkyl, haloC1-6alkyl, — OH or — OC1-6alkyl (e.g., — OCH3);(v) R2and R3are independently H or C1-6alkyl;(vi) R4and R5are independently H, C1-6alkyl, or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4- hydroxyphenyl or 2-hydroxyphenyl), or C1-6alkoxy; and(vii) wherein X, Y and Z are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), C1-6alkyl (e.g., methyl), or haloC1-6alkyl (e.g., trifluoromethyl), for example, Z is heteroaryl, e.g., pyridyl substituted with one or more halo (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), haloC1-6alkyl (e.g., 5-trifluoromethylpyrid-2-yl), or C1-6-alkyl (e.g., 5-methylpyrid-2-yl), or Zis aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl), in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

[0034] In yet another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula III:wherein(i) R1is H or C1-4alkyl (e.g., methyl or ethyl);(ii) R2and R3are independently H or C1-6alkyl (e.g., methyl or ethyl);(iii) R4is H or C1-4alkyl (e.g., methyl or ethyl);(iv) R5is aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from -C(=O)-C1-6alkyl (e.g., -C(=O)-CH3) and C1-6-hydroxyalkyl (e.g., 1- hydroxy ethyl);(v) R6and R7are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example, unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F), or phenyl substituted with one or more C1-6alkyl and one or more halogen, or phenyl substituted with one C1-6alkyl and one halogen, for example, 4-fluorophenyl or 3,4-difluorophenyl or 4- fluoro-3-methylphenyl; and(vi) n is 1, 2, 3, or 4,in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

[0035] In yet another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula IV:in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof, wherein:(i) R1is C1-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) X, Y and Z arc, independently, N or C;(iii) R3, R4and R5are independently H or C1-4alkyl (e.g., methyl); or R3is H and R4and R5together form a tri-methylene bridge (pref, wherein the R4and R5together have the cis configuration, e.g., where the carbons carrying R4and R5have the R and S configurations, respectively),(iv) R6, R7and R8are independently H, C1-4alkyl (e.g., methyl), pyrid-2-yl substituted with hydroxy, or -S(O)2-NH2;(v) provided that when X, Y and / or Z are N, then R6, R7and / or R8, respectively, are not present; and when X, Y and Z are all C, then at least one of R6, R7or R8is -S(O)2-NH2or pyrid- 2-yl substituted with hydroxy.

[0036] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula V:wherein(i) R1is -NH(R4), wherein R4is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) R2is H or C1-6alkyl (e.g., methyl, isobutyl or neopentyl); and(iii) R3is -SO2NH2or COOH; in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, or racemates, thereof.

[0037] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula VI:wherein(i) R1is -NH(R4), wherein R4is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) R2is H or C1-6alkyl (e.g., methyl or ethyl); and(iii) R3is H, halogen (e.g., bromo), C1-6alkyl (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl); in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

[0038] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula VII:wherein(i) R1is H or C1-4alkyl (e.g., methyl or ethyl);(ii) R2and R3are independently H or C1-6alkyl (e.g., methyl or ethyl);(iii) R4is H or C1-4alkyl (e.g., methyl or ethyl);(iv) R5is aryl (e.g., phenyl) substituted with -C(=O)-CD3, wherein D is deuterium(2H);(v) R6and R7are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F) or phenyl substituted with one or more C1-6alkyl and one or more halogen or phenyl substituted with one C1-6alkyl and one halogen, for example 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3- methylphenyl; and(vi) n is 1, 2, 3, or 4,in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

[0039] In another embodiment, the PDE1 inhibitor for use in the methods, compositions, and combination therapies, described herein (e.g., the compound according to Formulas I, la, II, III, IV, V, VI, and / or VII), is a compound according to one or more of the following:, or D each in free or salt form, e.g., pharmaceutically acceptable salt form.

[0040] In one embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.

[0041] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0042] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0043] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0044] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0045] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0046] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0047] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0048] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0049] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0050] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0051] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0052] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0053] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0054] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0055] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0056] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0057] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0058] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0059] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0060] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0061] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0062] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0063] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0064] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0065] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0066] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0067] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0068] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0069] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0070] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0071] In still another embodiment, the invention provides administration of a PDE1 inhibitor for methods described herein, wherein the inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.

[0072] In some embodiments, the PDE1 inhibitors of the any of the preceding formulae (e.g., Formulas I, la, II, III, IV, V, VI, and / or VII) inhibit phosphodiesterase-mediated (e.g., PDE1 -mediated, especially PDE IB -mediated) hydrolysis of cGMP, e.g., with an IC50of less than 1μM, preferably less than 500 nM, preferably less than 50 nM, and preferably less than 5nM, such as in an immobilized-metal affinity particle reagent PDE assay.

[0073] In another embodiment, the PDE1 inhibitor for use in the methods, compositions, and combination therapies, described herein, is a compound according to one or more of the following:each in free or salt form, e.g., pharmaceutically acceptable salt form.

[0074] Further examples of PDE1 inhibitors suitable for use in the methods and treatments discussed 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 PublicationW02009075784A1; U.S. Patent 8,273,751; U.S. Patent 8,829,008; U.S. Patent 9,403,836;International Publication W02014151409A1, U.S. Patent 9,073,936; U.S. Patent 9,598,426; U.S.Patent 9,556,186; U.S. Publication 2017 / 0231994A1, International PublicationWO2016022893A1, and U.S. Publication 2017 / 0226117A1, each of which are incorporated by reference in their entirety.

[0075] Still further examples of PDE1 inhibitors suitable for use in the methods and treatments discussed herein can be found in International Publication W02018007249A1; U.S.Publication 2018 / 0000786; International Publication W02015118097A1; U.S. Patent 9,718,832;International Publication W02015091805A1; U.S. Patent 9,701,665; U.S. Publication2015 / 0175584A1; U.S. Publication 2017 / 0267664A1; International PublicationWO2016055618A1; U.S. Publication 2017 / 0298072A1; International PublicationW02016170064A1; U.S. Publication 2016 / 0311831A1; International PublicationWO2015150254A1; U.S. Publication 2017 / 0022186A1; International PublicationWO2016174188A1; U.S. Publication 2016 / 0318939A1; U.S. Publication 2017 / 0291903A1;International Publication WO2018073251A1; International Publication WO2017178350A1; U.S.Publication 2017 / 0291901 Al; International Publication WO2018 / 115067; U.S. Publication2018 / 0179200A; U.S. Publication US20160318910A1; U.S. Patent 9,868,741; InternationalPublication WO2017 / 139186A1; International Application W02016 / 040083; U.S. Publication 2017 / 0240532; International Publication WO 2016033776A1; U.S. Publication 2017 / 0233373;International Publication WO2015130568; International Publication W02014159012; U.S.Patent 9,034,864; U.S. Patent 9,266,859; International Publication W02009085917; U.S. Patent8,084,261; International Publication W02018039052; U.S. Publication US20180062729; andInternational Publication WO2019027783 each of which are incorporated by reference in their entirety. In any situation in which the statements of any documents incorporated by reference contradict or arc incompatible with any statements made in the present disclosure, the statements of the present disclosure shall be understood as controlling.

[0076] If not otherwise specified or clear from context, the following terms herein have the following meanings:a. “Selective PDE1 inhibitor” as used herein refers to a PDE1 inhibitor with at least100-fold selectivity for PDE1 inhibition over inhibition of any other PDE isoform; b. “Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having one to six carbon atoms, which may be linear or branched, and may be optionally mono-, di- or tri- substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy; c. “Cycloalkyl” as used herein is a saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. When 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” is, unless otherwise indicated, saturated or unsaturated nonaromatic moiety, preferably saturated, preferably comprising three to nine atoms, or three to six atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, wherein at least one ring atom is N, O or S, for example tetrahydrofuryl, dihydrofuryl, or aziridyl, which heterocycloalkyl may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy; e. “Aryl” as used herein is a mono or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, e.g., with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); f. “Hctcroaryl” as used herein is an aromatic moiety wherein one or more of the atoms making up the aromatic ring is sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy or carboxy.

[0077] Compounds of the Disclosure, e.g., PDE1 inhibitors as described herein, may exist in free or salt form, e.g., as acid addition salts. In this specification unless otherwise indicated, language such as “Compounds of the Disclosure” is to be understood as embracing the compounds in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. The Compounds of the Disclosure are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Disclosure or their pharmaceutically acceptable salts, are therefore also included.

[0078] Compounds of the Disclosure may in some cases also exist in prodrug form. A prodrug form is compound which converts in the body to a Compound of the Disclosure. For example, when the Compounds of the Disclosure contain hydroxy or carboxy substituents, these substituents may form physiologically hydrolysable and acceptable esters. As used herein, “physiologically hydrolysable and acceptable ester” means esters of Compounds of the Disclosure which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Disclosure which have hydroxy substituents) or alcohols (in the case of Compounds of the Disclosure which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. Therefore, wherein the Compound of the Disclosure contains a hydroxy group, for example, Compound-OH, the acyl ester prodrug of such compound, i.e., Compound-O-C(O)-C1-4alkyl, can hydrolyze in the body to form physiologically hydrolysable alcohol (Compound-OH) on the one hand and acid on the other (e.g., HOC(O)-C1-4alkyl). Alternatively, wherein the Compound of the Disclosure contains a carboxylic acid, for example, Compound-C(O)OH, the acid ester prodrug of such compound, Compound-C(O)O-C1-4alkyl can hydrolyze to form Compound-C(O)OH and HO-C1-4alkyl. As will be appreciated the term thus embraces conventional pharmaceutical prodrug forms.Methods of Using Compounds of the Disclosure

[0079] In one embodiment, the present invention provides a method (Method 1.0) of treatment or prophylaxis for a metabolic disorder (e.g., obesity, fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), bepatosteatosis, and steatohepatitis), type 2 diabetes,pre-diabetic conditions, and conditions associated with fat-induced inflammation), reducing high blood glucose levels (e.g., as reflected in high fasting glucose or Hb-AlC levels), and / or promoting or maintaining body weight loss or suppressing body weight gain, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (e.g., PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII) to a subject in need thereof.1.1 Method 1.0, wherein the subject is overweight or obese, optionally wherein body mass index (BMI) of the subject is over 25, further optionally wherein body mass index (BMI) of the subject is over 25 and below 30.1.2 Any preceding method, wherein the subject is obese, i.e., a body mass index(BMI) of the subject is over 30.1.3 Any preceding method, wherein the subject has consumed and / or consumes a high fat diet, optionally wherein the high fat diet is defined as a diet in which at least 35% of total calories is consumed from fat.1.4 Any preceding method, wherein the subject suffers from metabolic syndrome.1.5 Any preceding method, wherein the subject suffers from at least a disease or condition associated with overweight or obesity.1.6 Method 1.5, wherein the disease or condition associated with overweight or obesity is selected from cardiovascular disease, stroke, insulin resistance, type 2 diabetes, fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and steatohepatitis), neurodegenerative disease, and respiratory diseases, optionally wherein the administration of the PDE1 inhibitor ameliorates or treats the disease or condition associated with overweight or obesity.1.7 Any preceding method, wherein administering the pharmaceutically acceptable amount of the PDE1 inhibitor to the subject reduces the accumulation of fat in adipose tissue and / or liver, optionally wherein the adipose tissue comprises perigonadal and subcutaneous adipose tissue.1.8 Method 1.7, wherein the adipose tissue is white adipose tissue (WAT).1.9 Any preceding method, wherein The PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to thesubject, optionally wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.1.10 Any preceding method, wherein the PDE1 inhibitor is administered in combination with a therapeutic agent suppressing appetite to the subject.1.11 Method 1.10, wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).1.12 Method 1.11, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.1.13 Method 1.11, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).1.14 Method 1.11, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.1.15 Method 1.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).1.16 Method 1.15, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.1.17 Method 1.15, wherein the activin type 2 receptor agonist is bimagrumab.1.18 Method 1.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.1.19 Method 1.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.1.20 Any of Method 1.0 to 1.8, wherein any active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide) is not administered to the subject.1.21 Any of Method 1.0 to 1.8, wherein any therapeutic agent suppressing appetite is not administered to the subject.1.22 Any of Method 1.0 to 1.8, wherein any therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain other than the PDE1 inhibitor is not administered to the subject.1.23 Any of Method 1.0 to 1.8, wherein the PDE1 inhibitor is used as a sole adjunct to a reduced-calorie diet and increased physical activity for chronic weight management.1.24 Any of Method 1.0 to 1.8, wherein the PDE1 inhibitor is administered to the subject after a therapeutic agent promoting or maintaining body weight loss or suppressing body weight gain that has been administered to the subject has ceased, optionally wherein the therapeutic agent that has ceased is selected from bupropionnaltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab..1.25 Method 1.24, wherein the therapeutic agent that has ceased is a therapeutic agent suppressing appetite, optionally wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).1.26 Method 1.25, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.1.27 Method 1.25, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).1.28 Method 1.25, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.1.29 Method 1.24, wherein the therapeutic agent that has ceased is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).1.30 Method 1.29, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.1.31 Method 1.29, wherein the activin type 2 receptor agonist is bimagrumab.1.32 Method 1.24, wherein the therapeutic agent that has ceased is a melanocortin-4 receptor agonist, e.g., setmelanotide.1.33 Method 1.24, wherein the therapeutic agent that has ceased is a lipase inhibitor, e.g., orlistat.1.34 Any of Method 1.0 to 1.8, wherein the PDE1 inhibitor is administered to the subject following weight loss induced by treatment with a therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agentsuppressing appetite) to the subject, optionally wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.1.35 Method 1.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a therapeutic agent suppressing appetite, optionally wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide)).1.36 Method 1.35, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.1.37 Method 1.35, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).1.38 Method 1.35, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.1.39 Method 1.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).1.40 Method 1.39, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab. 1.41 Method 1.39, wherein the activin type 2 receptor agonist is bimagrumab.1.42 Method 1.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.1.43 Method 1.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.1.44 Any of Method 1.0 to 1.8, wherein the PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject but the PDE1 inhibitor continues to be administered to the subject as monotherapy once the administration of the additional therapeutic agent is stopped, optionally wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.1.45 Method 1.44, wherein the administration of the additional therapeutic agent is stopped because of intolerance, e.g., the subject experiences a side effect of the additional therapeutic agent.1.46 Method 1.44 or 1.45, wherein the additional therapeutic agent is a therapeutic agent suppressing appetite to the subject.1.47 Method 1.46, wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2inhibitor or other agents that may directly or indirectly increase plasma glucagon), or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., Lirzepatide).1.48 Method 1.47, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and lirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.1.49 Method 1.47, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).1.50 Method 1.47, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.1.51 Method 1.44 or 1.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).1.52 Method 1.51, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.1.53 Method 1.51, wherein the activin type 2 receptor agonist is bimagrumab.1.54 Method 1.44 or 1.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.1.55 Method 1.44 or 1.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.1.56 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, in, IV, V, VI, and / or VII.1.57 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.1.58 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.1.59 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.1.60 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.61 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.62 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.63 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.64 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.65 Any of Methods 1.0- 1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.66 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.67 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.68 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.69 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.70 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.71 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.72 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.73 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.74 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.75 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.76 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.77 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.78 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.79 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.80 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.81 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.82 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.83 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.84 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.85 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.86 Any of Methods 1.0- 1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.87 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.88 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.89 Any of Methods 1.0-1.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.90 Any of Methods 1.0- 1.55 , wherein the PDE 1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.91 Any preceding methods, wherein the subject is human.1.92 Any preceding method, wherein the PDE1 inhibitor is administered orally, optionally wherein the PDE1 inhibitor is administered as a tablet or capsule.1.93 Any of Methods 1.0-1.91, wherein the PDE1 inhibitor is administered by inhalation, optionally wherein the PDE1 inhibitor is administered as a nasal spray or inhaler.1.94 Any of Methods 1.0-1.91, wherein the PDE1 inhibitor is administered as an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection), optionally wherein the PDE1 inhibitor is administered as a form of a long-acting depot for administration by injection to provide sustained release.1.95 Any preceding methods, wherein the subject has taken or takes an antipsychotic agent, e.g., selected from benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazinc, chlorprothixcnc, clopcnthixol, flupcntixol, thiothixene, zuclopcnthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, molindone, amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin,pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.1.96 Method of 1.95, wherein the antipsychotic agent is an atypical antipsychotic agent, e.g., selected from amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.

[0080] In another embodiment, the present invention provides a method (Method 2.0) of reducing the accumulation of fat in adipose tissue and / or liver, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (e.g., PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII) to a subject in need thereof.2.1 Method 2.0, wherein the subject is overweight or obese, optionally wherein body mass index (BMI) of the subject is over 25, further optionally wherein body mass index (BMI) of the subject is over 25 and below 30.2.2 Any preceding method, wherein the subject is obese, i.e., a body mass index(BMI) of the subject is over 30.2.3 Any preceding method, wherein the subject has consumed and / or consumes a high fat diet, optionally wherein the high fat diet is defined as a diet in which at least 35% of total calories is consumed from fat.2.4 Any preceding method, wherein the subject suffers from metabolic syndrome.2.5 Any preceding method, wherein the subject suffers from at least a disease or condition associated with overweight or obesity.2.6 Method 2.5, wherein the disease or condition associated with overweight or obesity is selected from cardiovascular disease, stroke, insulin resistance, type 2 diabetes, fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and steatohepatitis), neurodegenerative disease, and respiratory diseases, optionally wherein the administration of the PDE1 inhibitor ameliorates or treats the disease or condition associated with overweight or obesity.2.7 Any preceding method, wherein the adipose tissue comprises perigonadal and subcutaneous adipose tissue.2.8 Any preceding method, wherein the adipose tissue is white adipose tissue (WAT).2.9 Any preceding method, wherein The PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject, optionally wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.2.10 Any preceding method, wherein the PDE1 inhibitor is administered in combination with a therapeutic agent suppressing appetite to the subject.2.11 Method 2.10, wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).2.12 Method 2.11 wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.2.13 Method 2.11, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).2.14 Method 2.11, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-D1-70, and SAR438335.2.15 Method 2.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).2.16 Method 2.15, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.2.17 Method 2.15, wherein the activin type 2 receptor agonist is bimagrumab.2.18 Method 2.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.2.19 Method 2.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.2.20 Any of Method 2.0 to 2.8, wherein any active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide) is not administered to the subject.2.21 Any of Method 2.0 to 2.8, wherein any therapeutic agent suppressing appetite is not administered to the subject.2.22 Any of Method 2.0 to 2.8, wherein any therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain other than the PDE1 inhibitor is not administered to the subject.2.23 Any of Method 2.0 to 2.8, wherein the PDE1 inhibitor is used as a sole adjunct to a reduced-caloric diet and increased physical activity for chronic weight management.2.24 Any of Method 2.0 to 2.8, wherein the PDE1 inhibitor is administered to the subject after a therapeutic agent promoting or maintaining body weight loss or suppressing body weight gain that has been administered to the subject has ceased, optionally wherein the therapeutic agent that has ceased is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagiiflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab..2.25 Method 2.24, wherein the therapeutic agent that has ceased is a therapeutic agent suppressing appetite, optionally wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).2.26 Method 2.25, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, further optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.2.27 Method 2.25, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).2.28 Method 2.25, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.2.29 Method 2.24, wherein the therapeutic agent that has ceased is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).2.30 Method 2.29, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.2.31 Method 2.29, wherein the activin type 2 receptor agonist is bimagrumab.2.32 Method 2.24, wherein the therapeutic agent that has ceased is a melanocortin-4 receptor agonist, e.g., setmelanotide.2.33 Method 2.24, wherein the therapeutic agent that has ceased is a lipase inhibitor, e.g., orlistat.2.34 Any of Method 2.0 to 2.8, wherein the PDE1 inhibitor is administered to the subject following weight loss induced by treatment with a therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject, optionally wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-1-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.2.35 Method 2.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a therapeutic agent suppressing appetite, optionally wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide)).2.36 Method 2.35, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, further optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.2.37 Method 2.35, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).2.38 Method 2.35, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-D1-70, and SAR438335.2.39 Method 2.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).2.40 Method 2.39, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.2.41 Method 2.39, wherein the activin type 2 receptor agonist is bimagrumab.2.42 Method 2.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.2.43 Method 2.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.2.44 Any of Method 2.0 to 2.8, wherein the PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject but the PDE1 inhibitor continues to be administered to the subject as monotherapy once the administration of the additional therapeutic agent is stopped, optionally wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin ctabonatc), scrgliflozin (e.g., scrgliflozin ctabonatc), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.2.45 Method 2.44, wherein the administration of the additional therapeutic agent is stopped because of intolerance, e.g., the subject experiences a side effect of the additional therapeutic agent.2.46 Method 2.44 or 2.45, wherein the additional therapeutic agent is a therapeutic agent suppressing appetite to the subject.2.47 Method 2.46, wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon), or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).2.48 Method 2.47, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, further optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.2.49 Method 2.47, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).2.50 Method 2.47, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.2.51 Method 2.44 or 2.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).2.52 Method 2.51, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.2.53 Method 2.51, wherein the activin type 2 receptor agonist is bimagrumab.2.54 Method 2.44 or 2.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.2.55 Method 2.44 or 2.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.2.56 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, in, IV, V, VI, and / or VII.2.57 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.2.58 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form.2.59 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.2.60 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.61 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.62 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.63 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.64 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.65 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.66 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.67 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.68 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.69 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.70 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.71 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.72 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.73 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.74 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.75 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.76 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.77 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.78 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.79 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.80 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.81 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.82 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.83 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.84 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.85 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.86 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.87 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.88 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.89 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.90 Any of Methods 2.0-2.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.91 Any preceding methods, wherein the subject is human.2.92 Any preceding method, wherein the PDE1 inhibitor is administered orally, optionally wherein the PDE1 inhibitor is administered as a tablet or capsule.2.93 Any of Methods 2.0-2.91, wherein the PDE1 inhibitor is administered by inhalation, optionally wherein the PDE1 inhibitor is administered as a nasal spray or inhaler.2.94 Any of Methods 2.0-2.91, wherein the PDE1 inhibitor is administered as an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection), optionally wherein the PDE1 inhibitor is administered as a form of a long-acting depot for administration by injection to provide sustained release.2.95 Any preceding methods, wherein the subject has taken or takes an antipsychotic agent, e.g., selected from benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazinc, chlorprothixcnc, clopcnthixol, flupcntixol, thiothixene, zuclopcnthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, molindone, amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin,pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.2.96 Method of 2.95, wherein the antipsychotic agent is an atypical antipsychotic agent, e.g., selected from amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.

[0081] In one embodiment, the present invention provides a method (Method 3.0) of preventing or treating obesity, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (e.g., PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII) to a subject in need thereof.3.1 Method 3.0, wherein the subject is overweight or obese, optionally wherein body mass index (BMI) of the subject is over 25, further optionally wherein body mass index (BMI) of the subject is over 25 and below 30.3.2 Any preceding method, wherein the subject is obese, i.e., a body mass index(BMI) of the subject is over 30.3.3 Any preceding method, wherein the subject has consumed and / or consumes a high fat diet, optionally wherein the high fat diet is defined as a diet in which at least 35% of total calories is consumed from fat.3.4 Any preceding method, wherein the subject suffers from metabolic syndrome.3.5 Any preceding method, wherein the subject suffers from at least a disease or condition associated with overweight or obesity.3.6 Method 3.5, wherein the disease or condition associated with overweight or obesity is selected from cardiovascular disease, stroke, insulin resistance, type 2 diabetes, fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hcpatostcatosis, and steatohepaiitis), neurodegenerative disease, and respiratory diseases, optionally wherein the administration of the PDE1 inhibitor ameliorates or treats the disease or condition associated with overweight or obesity.3.7 Any preceding method, wherein administering the pharmaceutically acceptable amount of the PDE1 inhibitor to the subject reduces the accumulation of fat in adipose tissue and / or liver, optionally wherein the adipose tissue comprises perigonadal and subcutaneous adipose tissue.3.8 Method 3.7, wherein the adipose tissue is white adipose tissue (WAT).3.9 Any preceding method, wherein The PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject, optionally wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.3.10 Any preceding method, wherein the PDE1 inhibitor is administered in combination with a therapeutic agent suppressing appetite to the subject.3.11 Method 3.10, wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).3.12 Method 3.11, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, further optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.3.13 Method 3.11, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).3.14 Method 3.11, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-D1-70, and SAR438335.3.15 Method 3.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).3.16 Method 3.15, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.3.17 Method 3.15, wherein the activin type 2 receptor agonist is bimagrumab.3.18 Method 3.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.3.19 Method 3.9, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.3.20 Any of Method 3.0 to 3.8, wherein any active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide) is not administered to the subject.3.21 Any of Method 3.0 to 3.8, wherein any therapeutic agent suppressing appetite is not administered to the subject.3.22 Any of Method 3.0 to 3.8, wherein any therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain other than the PDE1 inhibitor is not administered to the subject.3.23 Any of Method 3.0 to 3.8, wherein the PDE1 inhibitor is used as a sole adjunct to a reduced-caloric diet and increased physical activity for chronic weight management.3.24 Any of Method 3.0 to 3.8, wherein the PDE1 inhibitor is administered to the subject after a therapeutic agent promoting or maintaining body weight loss or suppressing body weight gain that has been administered to the subject has ceased, optionally wherein the therapeutic agent that has ceased is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagiiflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab..3.25 Method 3.24, wherein the therapeutic agent that has ceased is a therapeutic agent suppressing appetite, optionally wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).3.26 Method 3.25, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, further optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.3.27 Method 3.25, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).3.28 Method 3.25, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.3.29 Method 3.24, wherein the therapeutic agent that has ceased is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).3.30 Method 3.29, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.3.31 Method 3.29, wherein the activin type 2 receptor agonist is bimagrumab.3.32 Method 3.24, wherein the therapeutic agent that has ceased is a melanocortin-4 receptor agonist, e.g., setmelanotide.3.33 Method 3.24, wherein the therapeutic agent that has ceased is a lipase inhibitor, e.g., orlistat.3.34 Any of Method 3.0 to 3.8, wherein the PDE1 inhibitor is administered to the subject following weight loss induced by treatment with a therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject, optionally wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-1-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.3.35 Method 3.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a therapeutic agent suppressing appetite, optionally wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon agonist (e.g., GLP-1 agonist), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide)).3.36 Method 3.35, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, further optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.3.37 Method 3.35, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).3.38 Method 3.35, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-D1-70, and SAR438335.3.39 Method 3.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).3.40 Method 3.39, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.3.41 Method 3.39, wherein the activin type 2 receptor agonist is bimagrumab.3.42 Method 3.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.3.43 Method 3.34, wherein the therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.3.44 Any of Method 3.0 to 3.8, wherein the PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject but the PDE1 inhibitor continues to be administered to the subject as monotherapy once the administration of the additional therapeutic agent is stopped, optionally wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin ctabonatc), scrgliflozin (e.g., scrgliflozin ctabonatc), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.3.45 Method 3.44, wherein the administration of the additional therapeutic agent is stopped because of intolerance, e.g., the subject experiences a side effect of the additional therapeutic agent.3.46 Method 3.44 or 3.45, wherein the additional therapeutic agent is a therapeutic agent suppressing appetite to the subject.3.47 Method 3.46, wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon), or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).3.48 Method 3.47, wherein the active agent that increases circulating glucagon or increases glucagon receptor activity is GLP-1 receptor agonist or SGLT2 inhibitor, further optionally wherein the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide, further optionally wherein the therapeutic agent suppressing appetite is semaglutide.3.49 Method 3.47, wherein the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).3.50 Method 3.47, wherein the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist, optionally wherein the dual GLP-1 receptor / GIPR agonist is selected from tirzepatide, NNCOO90-2746, ZP-I-98, ZP-DI-70, and SAR438335.3.51 Method 3.44 or 3.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).3.52 Method 3.51, wherein the myostatin inhibitor is an anti-myostatin antibody, e.g., a monoclonal anti-myostatin antibody, optionally wherein the myostatin inhibitor is selected from apitegromab, domagrozumab, landogrozumab, and stamulumab.3.53 Method 3.51, wherein the activin type 2 receptor agonist is bimagrumab.3.54 Method 3.44 or 3.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.3.55 Method 3.44 or 3.45, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.3.56 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, in, IV, V, VI, and / or VII.3.57 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.3.58 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound according to the following:, or , in free or pharmaceutically acceptable salt form.3.59 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.3.60 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.61 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.62 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.63 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.64 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.65 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.66 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.67 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.68 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.69 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.70 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.71 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.72 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.73 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.74 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.75 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:F o HN / / NN N.0 in free or pharmaceutically acceptable salt form.3.76 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.77 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.78 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.79 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.80 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.81 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.82 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.83 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.84 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.85 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.86 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.87 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.88 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.89 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.90 Any of Methods 3.0-3.55, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.91 Any preceding methods, wherein the subject is human.3.92 Any preceding method, wherein the PDE1 inhibitor is administered orally, optionally wherein the PDE1 inhibitor is administered as a tablet or capsule.3.93 Any of Methods 2.0-2.91, wherein the PDE1 inhibitor is administered by inhalation, optionally wherein the PDE1 inhibitor is administered as a nasal spray or inhaler.3.94 Any of Methods 2.0-2.91, wherein the PDE1 inhibitor is administered as an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection), optionally wherein the PDE1 inhibitor is administered as a form of a long-acting depot for administration by injection to provide sustained release.3.95 Any preceding methods, wherein the subject has taken or takes an antipsychotic agent, e.g., selected from benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazinc, chlorprothixcnc, clopcnthixol, flupcntixol, thiothixene, zuclopcnthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, molindone, amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin,pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.3.96 Method of 3.95, wherein the antipsychotic agent is an atypical antipsychotic agent, e.g., selected from amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.

[0082] In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII) for use in any of methods 1, 2, or 3, et seq.

[0083] The PDE1 inhibitor may be administered to a subject who is overweight or obese for promoting or maintaining body weight loss or suppressing body weight gain. Weight that is higher than what is considered healthy for a given height is considered as overweight or obesity.In some embodiments, a body mass index (BMI) over 25 is considered overweight, and over 30 is obese.

[0084] In some embodiments, the subject has consumed and / or consumes a high fat diet. High fat diet is a diet containing a high portion of fat. In some embodiments, the high fat diet is defined as a diet in which at least 35% of total calories is consumed from fat.

[0085] In some embodiments, the subject suffers from metabolic syndrome. Metabolic syndrome is a group of conditions that together raise the rise of coronary heart disease, diabetes, stroke, and other serious health problems. In some embodiment, the subject is considered to have metabolic syndrome if the subject has three or more of the following conditions: a large waist line, high blood pressure, high blood sugar level, high blood triglycerides, and low HDL cholesterol.

[0086] Weigh gain and / or obesity may be caused by antipsychotic agents. In some embodiments, the subject has taken or takes an antipsychotic agent. Non-limiting examples of antipsychotic agents include benperidol, bromperidol, droperidol, haloperidol, moperone,pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, molindone, amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine. In some embodiments, the antipsychotic agent is an atypical antipsychotic agent. The term “atypical" refers to second-generation antipsychotic medications, which have somewhat improved side effect profiles compared to the first-generation antipsychotics, such as haloperidol. Atypical antipsychotics exert their antipsychotic efficacy through D2 dopamine receptor antagonism with additional effects on receptors for other neurotransmitters, e.g., serotonin. Non-limiting examples of atypical antipsychotic agents include amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine. In some embodiments, the antipsychotic agent is olanzapine.

[0087] Overweight or obesity increases the risk of developing various diseases. In some embodiments, the subject suffers from at least a disease or condition associated with overweight or obesity. The diseases or conditions associated with overweight or obesity include, but are not limited to, cardiovascular disease, stroke, insulin resistance, type 2 diabetes, fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and. steatohepatitis), ncurodcgcncrativc disease, and respiratory diseases. In some embodiments, the administration of the PDE1 inhibitor ameliorates or treats the disease or condition associated with overweight or obesity.

[0088] The PDE1 inhibitor may be administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain(e.g., a therapeutic agent suppressing appetite) to the subject. The term “combination” as used herein, embraces simultaneous, sequential, or contemporaneous administration of the PDE1 inhibitor and the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain. The combination therapy may be achieved by administering a single composition or pharmacological formulation that includes the PDE1 inhibitor and the additional therapeutic agent, or by administration of two distinct compositions or formulations, separately, simultaneously or sequentially, wherein one composition includes the PDE1 inhibitor and the other includes the additional therapeutic agent. The term “simultaneously” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by the same route of administration. The term “separately” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by different route of administration.

[0089] Any weight loss drugs known in the art may be used in combination with the PDE1 inhibitor. In some embodiments, the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from bupropionnaltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, tirzepatide, NNCOO90- 2746, ZP-I-98, ZP-DI-70, and SAR438335, setmelanotide, exenatide, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, phlorizin, apitegromab, domagrozumab, landogrozumab, stamulumab, and bimagrumab.

[0090] In some embodiments, the PDE1 inhibitor may be administered in combination with a therapeutic agent suppressing appetite to the subject. In some embodiments, the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist (e.g., semaglutide, exenatide, liraglutide, and tirzepatide), SGLT2 inhibitor (e.g., atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, and phlorizin) or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide). In some embodiments, the therapeutic agent suppressingappetite is a GLP-1 receptor agonist. In some embodiments, the therapeutic agent suppressing appetite is selected from semaglutide, exenatide, liraglutide, and tirzepatide. In some embodiments, the therapeutic agent suppressing appetite is a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide), In some embodiments, the therapeutic agent suppressing appetite is a dual GLP-1 receptor / GIPR agonist. Non-limiting examples of dual GLP-1 receptor / GIPR agonist are tirzepatide, NNCOO90-2746, ZP-I-98, ZP- DI-70, and SAR438335.

[0091] In some embodiments, the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab). Myostatin inhibitors may be anti-myostatin antibodies, e.g., monoclonal anti-myostatin antibodis. Nonlimiting examples of monoclonal anti-myostatin antibodies are apitegromab, domagrozumab, landogrozumab, and stamulumab.

[0092] In some embodiments, the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a melanocortin-4 receptor agonist, e.g., setmelanotide.

[0093] In some embodiments, the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a lipase inhibitor, e.g., orlistat.

[0094] The PDE1 inhibitor may be administered alone without any additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain to the subject. In some embodiments, any active agent that increases circulating glucagon (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide) is not administered to the subject. In some embodiments, any therapeutic agent suppressing appetite is not administered to the subject. In some embodiments, any therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain other than the PDE1 inhibitor is not administered to the subject. In some embodiments, the PDE1 inhibitor is administered to the subject after a therapeutic agent promoting or maintaining body weight loss or suppressing body weight gain that has been administered to the subject has ceased.

[0095] The PDE1 inhibitor can be used in combination with additional weight loss drugs and also as monotherapy to maintain body weight loss or suppress body weight gain. Therefore,the disclosure provides a treatment paradigm where the PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain (e.g., a therapeutic agent suppressing appetite) to the subject but the treatment with the PDE1 inhibitor is continued as monotherapy once the administration of the additional therapeutic agent is stopped, e.g., because of intolerance. In certain embodiments, the PDE1 inhibitor is administered in combination with semaglutide to the subject but the PDE1 inhibitor continues to be administered as monotherapy once the administration of semaglutide is stopped.

[0096] In some embodiments, the PDE1 inhibitor may be provided in the form of a pharmaceutical composition (e.g., a dosage form), for example for oral administration, e.g., in the form of pills (tablets or capsules), or for parenteral administration. In some embodiments, the PDE1 inhibitor is provided in the form of a long-acting depot for administration by injection to provide sustained release (e.g., intramuscular or subcutaneous injection). In some embodiments, the solid drug for oral administration or as a depot may be embedded, dissolved, dispersed, or suspended, in a suitable polymer matrix to provide delayed release of the active compound, for example, in polymeric microspheres or in a solvent-based carrier. In some embodiments, the PDE1 inhibitor is provided in the form of nasal spray or inhaler.Methods of Making Compounds of the Disclosure

[0097] The PDE1 inhibitors of the Disclosure and their pharmaceutically acceptable salts may be made using the methods as 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 thereto and by methods known in the chemical art. Such methods include, but not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.

[0098] Various PDE1 inhibitors and starting materials therefor may be prepared using methods described in US 2008-0188492 Al, US 2010-0173878 Al, US 2010-0273754 Al, US2010-0273753 Al, 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 hereby incorporated by reference in their entirety.

[0099] The Compounds of the Disclosure (PDE1 inhibitors) 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 are meant to include both the E and the Z isomer 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 of the optically pure stereoisomers as well as any combination of stereoisomers.

[0100] It is also intended that the Compounds of the Disclosure (PDE1 inhibitors) encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non- isotopic analogs. For example, the hydrogen atom at a certain position on the Compounds of the Disclosure may be replaced with deuterium (a stable isotope which is non-radioactive).Examples of known stable isotopes include, but not limited to, deuterium, 13 C, 15 N, 18 O. Alternatively, unstable isotopes, which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., 1231, 1311, 1251, 11C, 18F, may replace the corresponding abundant species of I, C and F. Another example of useful isotope of the compound of the disclosure is the 11C isotope. These radio isotopes are useful for radio-imaging and / or pharmacokinetic studies of the compounds of the disclosure.

[0101] The terms "treatment" and "treating" are to be understood accordingly as embracing treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.

[0102] For methods of treatment, the term “effective amount” is intended to encompass a therapeutically effective amount to promote or maintain body weight loss or suppress bodyweight gain, reduce the accumulation of fat in adipose tissue and / or liver, or prevent or treat obesity.

[0103] The terms “patient” and “subject” include human or non-human (i.e., animal) patient, and are understood to be interchangeable within the context of this disclosure. In particular embodiment, the disclosure encompasses both human and nonhuman. In another embodiment, the disclosure encompasses nonhuman. In other embodiment, the term encompasses human.

[0104] The term “comprising” as used in this disclosure is intended to be open-ended and does not exclude additional, un-recited elements or method steps.

[0105] The PDE-1 inhibitors may be administered by any suitable route, including orally, parenterally (intravenously, intramuscular or subcutaneous), transdermally, or by inhalation (e.g., nasal spray or inhaler), preferably administered orally. In certain embodiments, PDE-1 inhibitors, e.g., in depot formulation, are preferably administered parenterally, e.g., by injection. Immune checkpoint inhibitors may be administered by any suitable route, including orally, parenterally (intravenously, intramuscular or subcutaneous), transdermally, or by inhalation, preferably administered intravenously.

[0106] In general, satisfactory results, e.g., for promoting or maintaining body weight loss or suppressing body weight gain, may be obtained on oral administration of a PDE-1 inhibitor at dosages of the order from about 0.01 to 2.0 mg / kg. In larger mammals, for example humans, an indicated daily dosage for oral administration of PDE-1 inhibitors will accordingly be in the range of from about 0.50 to 300 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for administration (e.g., oral administration) thus, for example, may comprise from about 0.2 to 150 or 300 mg, e.g., from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, or 200 mg, from about 1 to 100 mg, from about 1 to 50 mg, from about 1 to 10 mg, from about 5 to 10 mg, from about 10 to 50 mg, 1 mg, 3 mg, 5 mg, 10 mg, 30 mg, or 90 mg, of a PDE1 inhibitor, together with a pharmaceutically acceptable diluent or carrier therefor.

[0107] Pharmaceutical compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions and the like. In some embodiments, the composition is in theform of an oral dosage form (such as a tablet or capsule), an intranasal dosage form (e.g., a nasal spray or mister), a pulmonary dosage form (e.g., an inhaler), or an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection).EXAM PLES -Effect of PDE1 inhibitor treatment in mousse model of diet-induced obesityMaterials and MethodsAnimals and diets

[0108] The study was performed in accordance with the Mispro Institutional Animal Care and Use Committee (IACUC) policy. C56B1 / 6J male mice were obtained from Jackson Laboratories at 8 weeks of age. Mice were housed in ventilated cages with free access to food and water. Food was formulated by and obtained from Envigo ( TD.120321 - Purina Picolab Rodent Diet 20 (#5053) (Chow diet) providing 18% of total kcals from fat, TD.210141 - Compound 1 900ppm formulated Purina Picolab Rodent Diet 20 (#5053), TD.06414 - adjusted calories diet (60 / fat) (HFD) providing 60% of total kcals from fat, TD.220237 - Compound 1 900ppm formulated adjusted calories diet(60 / fat)). After the standard acclimation period, mice were divided into 4 groups (n=8 mice per group), and followed for 16 weeks: (control diet, Compound 1 900ppm formulated diet, 60% adjusted calories diet (HFD), Compound 1 900ppm formulated HFD.Body weight (BW) and food intake (FI)

[0109] BW was measured twice a week. FI was calculated by subtracting the amounts of feed offered (250g) and the feed not consumed after each measurement timepoint (every 3-5 days).Blood glucose

[0110] To measure blood glucose levels, animals were fasted for 4hrs. After the fasting period, glucose levels were measured by clipping the end of the mouse tail and expressing a droplet of blood onto the test strip of a glucometer (Contour next, Bayer). Fasting glucose levels were taken at study begin, 8, 14, and 16 weeks on study.Glucose Sensitivity

[0111] Glucose sensitivity reflects the efficiency with which mice can store and eliminate a bolus dose of glucose. A glucose tolerance test (GTT) was performed on mice that were fastedfor 16 hours. For GTT, intraperitoneal injections of 1.0 g / kg dextrose in 0.9% saline were administered after the fasting period and glucose was measured from tail-vein blood with a Bayer CONTOUR glucometer and glucose test strips.ELISA detection of plasma insulin and cholesterol

[0112] Plasma insulin levels were determined using the mouse ultrasensitive insulin ELISA kit (ALPCO, 80-INSMSU-E01) as per manufacturers’ instructions. Plasma Cholesterol levels were determined using the Fujifilm Cholesterol E kit (Wako, 999-02601).Assay of liver extracts for measurement of triglycerides (TGs)

[0113] Evaporated liver extracts were resuspended for assay in 500-1000uL of 100% ethanol. Liver TG levels were measured using the L-Type Triglyceride M kit (FUJIFILM Product number 944-02891) kit instructions. Levels of TGs were expressed as mg / dL for each experimental group.Body fat composition

[0114] The total fat mass, lean mass, and bone mineral density (BMD) of mice were assessed after 15 weeks of HFD feeding using the iNSiGHT DXA bone densitometer (Scintica). Mice were anesthetized by continuous inhalation of isoflurane and placed in a prone position on the detector tray to scan the entire mouse body. This non-invasive technique provides quantitative data on the fat tissue content, the lean tissue content, and BMD.Metabolic measurement of energy expenditure

[0115] Energy balance phenotyping was performed using the PhenoMaster automated home cage phenotyping system (TSE Systems, Bad Homberg, Germany). The system comprises metabolic cages enclosed within a medium TS air-cooled climate chamber (2018) that was set to maintain consistent environmental temperature (22 °C) and humidity (50%) and control the circadian light cycle (12:12; lights on at 06:30). The metabolic cage bottoms were identical to the animals’ standard housing conditions (GreenLine IVC; Techniplast, West Chester, PA). Mice were singly housed and acclimated for 48 h within the metabolic cages. Mice had ad libitum access to food and water. A frame of infrared beams positioned along the x (lower long side), y (lower short side), and z (upper long side) axes of the cages enabled continuous assessment of activity levels. Repeated breakage of the same beam defined fine movement of the animal while consecutive disruption of adjacent beams defined locomotor activity. Oxygen (02) consumptionand carbon dioxide (CO2) production were measured via open circuit indirect calorimetry (LabMaster, TSE Systems, Bad Homberg, Germany). A constant flow rate of 0.35 L / min and sample flow rate of 0.25 L / min was used, with sensors sampling air from each cage once every 30 min. Rates of 02 consumption (VO2; mL / h) and CO2 production (VCO2; mL / h) were calculated by TSE software, using the empty reference cage to provide an adjusted index of oxygen and carbon dioxide inflow. These rates were used to calculate the energy expenditure (EE = [(3.941*VO2) + (1.106*VCO2)] / 1000; kcal / h). All measurements were obtained across two consecutive circadian cycles (48H) after the acclimatization period.Sacrifice and tissue extraction

[0116] Animals were deeply anesthetized using CO2, and various tissues were collected postmortem for further analyses. Tissues collected included: perigonadal white adipose tissue (pWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), and whole liver. Tissues were weighed on a scale to record and difference in tissue size between the treatment groups.Flow Cytometry

[0117] One portion of the pWAT sample was digested (100ml DMEM, 2g BSA, 650ul liberase, and 250ul DNAse I) for flow cytometry. Red blood cells were lysed with red blood cell lysis buffer (Sigma- Aldrich), and cells were resuspended in 2% FC block (BD biosciences 564220) for 30min at 4degrees. Cells were then stained with PerCP / Cy5.5 anti-mouse CD45 (BD biosciences 550994), APCCy7 anti-mouse F4 / 80 (Invitrogen 47-4801-82), BV780 anti-mouse CDllb (Invitrogen 78-0112-80), FITC anti-mouse iNOS / NOS (BD biosciences 610330), BV510 anti-mouse CD80 (BD biosciences 740130), PECy7 anti-mouse Arginasel (Invitrogen 25-3697- 82), and APC anti-mouse CD206 (BD biosciences 141708). Total macrophages and the Ml and M2 subpopulations were identified by flow cytometry using the Cytoflex analyzer (Beckman Coulter).Results

[0118] The effect of PDE1 inhibitors on body weight is investigated in a syngeneic mouse model of diet-induced obesity. The mice in this study are not genetically obese but obesity is induced by a high fat diet (HFD). The effect of Compound 1 delivered in diet(900ppm) is assessed on body weight of high fat diet (HFD)-fed mice or Chow diet-fed mice (control).HFD-fed mice gain more weight than Chow diet-fed mice (FIG. 1). The treatment of 900 ppm Compound 1 significantly suppresses the weight gain observed in HFD-fed mice but does not alter the body weight of Chow diet-fed mice (FIG. 1). The treatment of 900 ppm Compound 1 does not decrease food intake in both Chow diet-fed mice and HFD-fed mice, indicating that Compound 1 does not suppress appetite (FIG. 2).

[0119] Fasting glucose level is higher in HFD-fed mice than Chow diet-fed mice over time (weeks 8, 14, and 16), indicating that obesity-induced type 2 Diabetes Mellitus phenotype develops in high fat diet-fed mice. The treatment of 900 ppm Compound 1 significantly decreases fasting glucose level in HFD-fed mice (FIG. 3A). Glucose sensitivity is further investigated by a glucose tolerance test (GTT) conducted at week 12. The response to a bolus dose of glucose is measured at a 2h time point. At this time point, HFD-fed mice show a significant increase in the plasma glucose AUC level, compared with Chow diet-fed mice (FIG. 3B). The treatment of 900 ppm Compound 1 significantly reduces the the plasma glucose AUC level in HFD-fed mice (FIG. 3B). These results suggest that PDE1 inhibitors can treat not only obesity but also obesity-associated diseases such as type 2 Diabetes. Consistent with the improvement in glucose sensitivity observed in mice fed with HFD + Compound 1, the treatment of 900 ppm Compound 1 reduces other metabolic measures such as plasma insulin level, plasma cholestreol level and liver triglyceride (TG) level in HFD-fed mice (FIG. 4A-C).

[0120] Fat accumulation in adipose tissue and liver is examined by measuring the weights of perigonadal white adipose fat (pWAT), subcutaneous white adipose fat (scWAT), brown adipose fat (BAT), and fat in liver at week 16. The weights of perigonadal white adipose fat (pWAT), subcutaneous white adipose fat (scWAT), and fat in the liver are higher in HFD-fed mice than in Chow diet-fed mice, while the weight of brown adipose fat (BAT) is comparable between HFD-fed mice and Chow diet-fed mice (FIG. 5). The treatment of 900 ppm Compound 1 reduces the weights of perigonadal white adipose fat (pWAT), subcutaneous white adipose fat (scWAT), and fat in liver in HFD -fed mice significantly but does not reduce the weights of these fats in Chow diet-fed mice (FIG. 5). The reduction in fat mass, measured as tissue weights, is confirmed by non-invasive measures of body mass conducted using Dexa Scan (Dual-energy X- ray absorptiometry) in an independent experiment. In this experiment, mice fed with HFD or HFD + Compound 1 for 16 weeks are monitored for fat and lean mass as well as bone mass. As shown in FIG. 6, Compound 1 treatment significantly reduces both fat mass and % body fat in HFD-fed mice. A reduction in lean mass is also observed but bone mass is unaffected (FIG. 6).

[0121] Mice fed with HFD or HFD + Compound 1 for 16 weeks are monitored for metabolic activity in calorimeter chambers for 3 days. Locomotor activity (expressed as distance travelled) is unaffected by the treatment of 900 ppm Compound 1 (FIG. 7 A). However, energy expenditure, corrected for body weight, is significantly higher in mice fed with HFD + Compound 1, compared with HFD control during the dark cycle (16.25 vs 13.56 kcal / hr / kg, p<0.001) and light cycle (12.90 vs 10.9 kcal / hr / kg, p<0.001) (FIG. 7B).

[0122] Next, macrophage populations in the pWAT (perigonadal white adipose tissue) samples are analyzed by flow cytometry (FIG. 8A-C). Mlmacrophages are pro-inflammatory, while M2 macrophages are anti-inflammatory. The proportion of CD45+ cells and the ratio of M1 / M2 in the pWAT are higher in HFD mice than in Chow diet-fed mice (FIG. 8A-C). The treatment of 900 ppm Compound 1 significantly decreases the ratio of M1 / M2 in the pWAT of HFD mice (FIG. 8B and C). These results suggest that PDE1 inhibitors reduce HFD-induccd inflammation in white adipose tissue (WAT).

Claims

CLAIMS1. A method of treatment or prophylaxis for a metabolic disorder, reducing high blood glucose level, and / or promoting or maintaining body weight loss or suppressing body weight gain, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof.

2. The method of claim 1, wherein the metabolic disorder is selected from obesity, fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and steatohepatitis), type 2 diabetes, pre-diabetic conditions, and conditions associated with fat-induced inflammation,3. The method of claim 1 of 2, wherein the subject is overweight or obese, optionally wherein body mass index (BMI) of the subject is over 25.

4. The method of any of the preceding claims, wherein the subject has consumed and / or consumes a high fat diet.

5. The method of any of the preceding claims, wherein the subject suffers from metabolic syndrome.

6. The method of any of the preceding claims, wherein the subject suffers from at least a disease or condition associated with overweight or obesity.

7. The method of claim 6, wherein the disease or condition associated with overweight or obesity is selected from cardiovascular disease, stroke, insulin resistance, type 2 diabetes, fatty liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), hepatosteatosis, and steatohepaiitis), neurodegenerative disease, and respiratory diseases.

8. The method of any of the preceding claims, wherein the subject has taken or takes an antipsychotic agent, optionally wherein the antipsychotic agent is an atypical antipsychotic agent.

9. The method of any of the preceding claims, wherein administering the pharmaceutically acceptable amount of the PDE1 inhibitor to the subject reduces the accumulation of fat in adipose tissue and / or liver, optionally wherein the adipose tissue is white adipose tissue (WAT).

10. The method of any of the preceding claims, wherein The PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain to the subject.

11. The method of claim 10, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is a therapeutic agent suppressing appetite, optionally wherein the therapeutic agent suppressing appetite is an active agent that increases circulating glucagon or increases glucagon receptor activity (e.g., glucagon, glucagon receptor agonist (e.g., GLP-1 receptor agonist, e.g., semaglutide), SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) or a GIPR (glucose-dependent insulinotropic polypeptide receptor) agonist (e.g., tirzepatide).

12. The method of claim 10, wherein the additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain is selected from myostatin inhibitors and activin type 2 receptor agonists (e.g., ACVR2B receptor agonists, e.g., bimagrumab).

13. The method of any of claims 1 to 9, wherein any active agent that increases circulating glucagon is not administered to the subject.

14. The method of any of claims 1 to 9, wherein the PDE1 inhibitor is administered to the subject as a sole adjunct to a reduced-calorie diet and increased physical activity for chronic weight management.

15. The method of any of claims 1 to 9 or claims 13 to 14, wherein the PDE1 inhibitor is administered to the subject as monotherapy for weight maintenance following weight loss induced by treatment with a therapeutic agent suppressing appetite to the subject.

16. The method of any of claims 1 to 9, wherein the PDE1 inhibitor is administered in combination with an additional therapeutic agent that promotes or maintains body weight loss or suppresses body weight gain to the subject but the PDE1 inhibitor continues to be administered to the subject as monotherapy once the administration of the additional therapeutic agent is stopped.

17. The method according to any of the preceding claims, wherein the PDE1 inhibitor is a compound selected from:(A) Formula I:wherein(i) R1is H or C1-4alkyl (e.g., methyl);(ii) R4is H or C1-4alkyl and R2and R3are, independently, H, C1-4alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl (e.g., R2and R3are both methyl, or R2is H and R3is isopropyl); or R2is H and R3and R4together form a di-, tri- or tetramethylene bridge(pref, wherein the R3and R4together have the cis configuration, e.g., where the carbons carrying R3and R4have the R and S configurations, respectively);(iii) R5is a substituted heteroarylalkyl, e.g., substituted with haloalkyl; or R5is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula Awherein X, Y and Z are, independently, N or C, and R8, R9, R11 and R12are independently H or halogen (e.g., Cl or F), and R10is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl) optionally substituted with halogen, thiadiazolyl (e.g., l,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, R8, R9, or R10, respectively, is not present;(iv) Ro is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N,N-dialkylamino, N,N -diarylamino, or N-aryl-N- (arylalkyl)amino (e.g., N-phenyl-N-(1,1’-biphen-4-ylmethyl)amino); and(v) n=0 or 1;(vi) provided that when n=1, A is -C(R13R14)- wherein R13 and R14, are, independently, H, C1-4alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(B) Formula II:wherein(i) X is C1-6alkylene (e.g., methylene, ethylene or prop-2-yn-l-ylene);(ii) Y is a single bond, alkynylene (e.g., — OC — ), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene);(iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloC1-6alkyl (e.g., trifluoromethyl), — C(O) — R1, — N(R2)(R3), or C3-7cycloalkyl 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) R1is C1-6alkyl, haloC1-6alkyl, — OH or — OC1-6alkyl (e.g., — OCH3);(v) R2and R3are independently H or C1-6alkyl;(vi) R4and R5are independently H, C1-6alkyl, or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxy phenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl), or C1-6alkoxy; and(vii) wherein X, Y and Z are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), C1-6alkyl (e.g., methyl), or haloC1-6alkyl (e.g., trifluoromethyl), for example, Z is heteroaryl, e.g., pyridyl substituted with one or more halo (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), haloC1-6alkyl (e.g., 5-trifluoromethylpyrid-2- yl), or C1-6-alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl), in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(C) Formula III:wherein(i) R1is H or C1-4alkyl (e.g., methyl or ethyl);(ii) R2and R3are independently H or C1-6alkyl (e.g., methyl or ethyl);(iii) R4is H or C1-4alkyl (e.g., methyl or ethyl);(iv) R5is aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from -C(=O)-C1-6alkyl (e.g., -C(=O)-CH3) and C1-6-hydroxyalkyl (e.g., 1- hydroxy ethyl);(v) R6and R7are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F), or phenyl substituted with one or more C1-6alkyl and one or more halogen, or phenyl substituted with one C1-6alkyl and one halogen, for example, 4- fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and(vi) n is 1, 2, 3, or 4, in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(D) Formula IVin free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof , wherein:(i) R1is C1-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2is phenyl optionally substituted with halo (e.g., fluoro), for example, 4- fluorophenyl;(ii) X, Y and Z are, independently, N or C;(iii) R3, R4and R5are independently H or C1-4alkyl (e.g., methyl); or R3is H and R4and R5together form a tri-methylene bridge (pref, wherein the R4and R5together have the cis configuration, e.g., where the carbons carrying R4and R5have the R and S configurations, respectively),(iv) R6, R7and R8are independently H, C1-4alkyl (e.g., methyl), pyrid-2-yl substituted with hydroxy, or -S(O)2-NH2; provided that when X, Y and / or Z are N, then R6, R7and / or R8, respectively, are not present; and when X, Y and Z are all C, then at least one of R6, R7or R8is -S(O)2-NH2or pyrid-2-yl substituted with hydroxy;(E) Formula la:wherein(i) R2and R5are independently H or hydroxy and R3and R4together form a tri- or tetramethylene bridge [pref, with the carbons carrying R3and R4having the R and S configuration respectively]; or R2and R3are each methyl and R4and R5are each H; or R2, R4and R5are H and R3is isopropyl [pref, the carbon carrying R3having the R configuration];(ii) R6is (optionally halo-substituted of hydroxy-substituted) phenylamino, (optionally halo- substituted or hydroxy-substituted) benzylamino, C1-4alkyl, or C1-4alkyl sulfide, for example, phenylamino or 4-fluorophenylamino;(iii) R10is C1-4alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl (for example 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl), or R10is -CH(CH3)-O- C(O)-R11, wherein R11is C1-6alkyl (e.g., methyl, ethyl, or propyl), or R10is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g., saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl), or R10is -C(=O)-X1, wherein X1is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g., saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl); and(iv) X and Y are independently CH or N,in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(F) Formula Vwherein(i) R1is -NH(R4), wherein R4is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophcnyl;(ii) R2is H or C1-6alkyl (e.g., methyl, isobutyl or neopentyl); and(iii) R3is -SO2NH2or -COOH; in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(G) Formula VIwherein(i) R1is -NH(R4), wherein R4is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) R2is H or C1-6alkyl (e.g., methyl or ethyl); and(iii) R3is H, halogen (e.g., bromo), C1-6alkyl (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl); in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof, and(H) Formula Vllwherein(i) R1is H or C1-4alkyl (e.g., methyl or ethyl);(ii) R2and R3are independently H or C1-6alkyl (e.g., methyl or ethyl);(iii) R4is H or C1-4alkyl (e.g., methyl or ethyl);(iv) R5is aryl (e.g., phenyl) substituted with -C(=O)-CD3, wherein D is deuterium(2H);(v) R6and R7are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F) or phenyl substituted with one or more C1-6alkyl and one or more halogen or phenyl substituted with one C1-6alkyland one halogen, for example 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3- methylphenyl; and(vi) n is 1, 2, 3, or 4, in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

18. The method according to any of the preceding claims, wherein the PDE1 inhibitor is selected from any of the following:in free or pharmaceutically acceptable salt form.

19. A method of reducing the accumulation of fat in adipose tissue and / or liver, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof.

20. A pharmaceutical composition comprising a pharmaceutically effective amount of a PDE1 inhibitor for use in the method of any of the preceding claims.

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