Organic compounds

Abstract

The disclosure relates to the use of phosphodiesterase 1 (PDE1) inhibitors for preventing or treating chemobrain, e.g., inhibiting or mitigating one or more symptoms of chemobrain, e.g., feeling of mental fogginess, deficit in attention, disorganized behavior or thinking, confusion, impaired concentration, difficulty finding the right word, difficulty learning new skills, difficulty multitasking, memory impairment (e.g., short-term memory problems, long-term memory problems, impaired verbal memory, impaired visual memory), and / or fatigue.

Description

ORGANIC COMPOUNDS FIELD OF DISCLOSURE

[0001] The field relates to the use of phosphodiesterase 1 (PDE1) inhibitors for preventing or treating chemobrain and symptoms associated with chemotherapy such as fatigue and memory loss. 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] The development of a wide range of chemotherapeutic drugs has significantly improved cancer survival rate. However, some patients receiving chemotherapy experience cognitive impairments such as memory impairment and difficulty concentrating, referred to as chemobrain. Chemobrain can be a frustrating and debilitating side effect of chemotherapy. It may last for a short time or for many years. Although the underlying mechanism of chemobrain is not well understood, there may be multiple causes. For example, some chemotherapeuticdrugs produce reactive oxygen species and inflammatory cytokines that disrupt the blood-brain barrier (BBB) and activate microglia. Chemotherapeutic drugs can also cause neuronal damage through BBB disruption, neuroinflammation, oxidative stress, myelin degradation, impaired neurogenesis, production of damage associated molecular patterns, and changes in brain blood flow. These neuronal damages may lead to cognitive impairment.

[0004] With the rapid increase in the number of cancer survivors, there is a need for the development of safe and efficacious pharmaceutical treatments for chemobrain. SUMMARY OF THE DISCLOSURE

[0005] In an aspect, the disclosure provides a method of preventing or treating chemobrain, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof. In some embodiments, administering the PDE1 inhibitor to the subject inhibits or mitigates one or more symptoms of chemobrain. The one or more symptoms of chemobrain may be selected from feeling of mental fogginess, deficit in attention, disorganized behavior or thinking, confusion, impaired concentration, difficulty finding the right word, difficulty learning new skills, difficulty multitasking, memory impairment (e.g., short-term memory problems, long-term memory problems, impaired verbal memory, impaired visual memory), fatigue, and combinations thereof. In some embodiments, the subject has received or is receiving an anticancer treatment, e.g., chemotherapy, radiotherapy, immunotherapy, hormone therapy, or surgery. In some embodiments, the one or more symptoms of chemobrain are consequent to the anticancer treatment, e.g., chemotherapy. In certain embodiments, the anticancer treatment is chemotherapy. In other embodiments, the anticancer treatment is radiotherapy.

[0006] In some embodiments, the PDE1 inhibitor is administered to the subject before the initiation of anticancer treatment for preventing chemobrain. In other embodiments, the PDE1 inhibitor is administered to the subject during anticancer treatment. In still other embodiments, the PDE1 inhibitor is administered to the subject after anticancer treatment.

[0007] In some embodiments, the PDE1 inhibitor is a PDE1 inhibitor of Formulas I, Ia, II, III, IV, V, VI, and / or VII described hereinbelow in free or pharmaceutically acceptable salt form.

[0008] 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 a method of preventing or treating chemobrain, e.g., any of methods described in the disclosure. DETAILED DESCRIPTION OF THE DISCLOSURE Compounds for use in the methods of the disclosure

[0009] In one embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are selective PDE1 inhibitors. PDE1 Inhibitors

[0010] In one embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula I:Formula I wherein (i) R1 is H or C1-4 alkyl (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., R2 and R3 are both methyl, or R2 is H and R3 is 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 R3 and R4 have the R and S configurations, respectively); (iii) R5 is 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 AFormula A wherein X, Y, and Z are, independently, N or C, and R8, R9, R11and R12are independently H or halogen (e.g., Cl or F), and R10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (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=1, A is -C(R13R14)- wherein R13 and R14, are, independently, H, C1-4 alkyl, 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.

[0011] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula Ia:wherein (i) R2and R5are independently H or hydroxy and R3and R4together form a tri- or tetra- methylene bridge [pref. with the carbons carrying R3 and R4 having the R and S configuration respectively]; or R2 and R3 are each methyl and R4 and R5 are each H; or R2, R4 and R5 are H and R3is isopropyl [pref. the carbon carrying R3having the R configuration]; (ii) R6 is (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-fluoropyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-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.

[0012] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula II:Formula II wherein (i) X is C1-6alkylene (e.g., methylene, ethylene or prop-2-yn-1-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 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.

[0013] In yet another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula III:Formula III wherein (i) R1is H or C1-4alkyl (e.g., methyl or ethyl); (ii) R2 and R3 are independently H or C1-6 alkyl (e.g., methyl or ethyl); (iii) R4 is H or C1-4 alkyl (e.g., methyl or ethyl); (iv) 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- hydroxyethyl); (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 C1-6 alkyl 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.

[0014] In yet another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula IV:Formula IV in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof, wherein: (i) R1 is C1-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl; (ii) X, Y and Z are, independently, N or C; (iii) R3, R4 and R5 are independently H or C1-4alkyl (e.g., methyl); or R3 is H and R4 and R5 together form a tri-methylene bridge (pref. wherein the R4 and R5 together have the cis configuration, e.g., where the carbons carrying R4and R5have the R and S configurations, respectively), (iv) R6, R7 and R8 are 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, R7 or R8 is –S(O)2-NH2 or pyrid- 2-yl substituted with hydroxy.

[0015] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula V:Formula V wherein (i) R1 is -NH(R4), wherein R4 is 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) R3 is -SO2NH2 or –COOH; in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, or racemates, thereof.

[0016] 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) R2 is 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.

[0017] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula VII:wherein (i) R1 is H or C1-4 alkyl (e.g., methyl or ethyl); (ii) R2 and R3 are independently H or C1-6 alkyl (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) R6 and R7 are 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 ormore 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.

[0018] 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, Ia, II, III, IV, V, VI, and / or VII), is a compound according to one or more of the following:each in free or salt form, e.g., pharmaceutically acceptable salt form.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[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 some embodiments, the PDE1 inhibitors of the any of the preceding formulae (e.g., Formulas I, Ia, II, III, IV, V, VI, and / or VII) inhibit phosphodiesterase-mediated (e.g., PDE1-mediated, especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC50 of 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.

[0052] 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.

[0053] 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 Publication WO2009075784A1; U.S. Patent 8,273,751; U.S. Patent 8,829,008; U.S. Patent 9,403,836; International Publication WO2014151409A1, U.S. Patent 9,073,936; U.S. Patent 9,598,426; U.S. Patent 9,556,186; U.S. Publication 2017 / 0231994A1, International Publication WO2016022893A1, and U.S. Publication 2017 / 0226117A1, each of which are incorporated by reference in their entirety.

[0054] Still further examples of PDE1 inhibitors suitable for use in the methods and treatments discussed herein can be found in International Publication WO2018007249A1; U.S. Publication 2018 / 0000786; International Publication WO2015118097A1; U.S. Patent 9,718,832; International Publication WO2015091805A1; U.S. Patent 9,701,665; U.S. Publication 2015 / 0175584A1; U.S. Publication 2017 / 0267664A1; International Publication WO2016055618A1; U.S. Publication 2017 / 0298072A1; International Publication WO2016170064A1; U.S. Publication 2016 / 0311831A1; International Publication WO2015150254A1; U.S. Publication 2017 / 0022186A1; International Publication WO2016174188A1; U.S. Publication 2016 / 0318939A1; U.S. Publication 2017 / 0291903A1;International Publication WO2018073251A1; International Publication WO2017178350A1; U.S. Publication 2017 / 0291901A1; International Publication WO2018 / 115067; U.S. Publication 2018 / 0179200A; U.S. Publication US20160318910A1; U.S. Patent 9,868,741; International Publication WO2017 / 139186A1; International Application WO2016 / 040083; U.S. Publication 2017 / 0240532; International Publication WO 2016033776A1; U.S. Publication 2017 / 0233373; International Publication WO2015130568; International Publication WO2014159012; U.S. Patent 9,034,864; U.S. Patent 9,266,859; International Publication WO2009085917; U.S. Patent 8,084,261; International Publication WO2018039052; U.S. Publication US20180062729; and International 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 are incompatible with any statements made in the present disclosure, the statements of the present disclosure shall be understood as controlling.

[0055] 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 least 100-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 nineatoms, 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. “Heteroaryl” 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.

[0056] 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.

[0057] 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 themselvesphysiologically 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

[0058] In an aspect, the present invention provides a method (Method 1.0) of preventing or treating chemobrain, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof. 1.1 Method 1.0, wherein the subject has suffered or is suffering from a cancer. 1.2 Any preceding method, wherein the cancer is selected from Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma, osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Leiomyosarcoma, Myxosarcoma, Fibrocartilaginous mesenchymoma, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma. Ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioblastoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Inflammatory breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Mammary secretory carcinoma, Papillary carcinomas of the breast, Adrenocortical carcinoma, Islet cell carcinoma, Multiple endocrine neoplasia syndrome, Pancreatic Cancer, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Optic nerve glioma, Anal cancer. Appendix cancer. Cholangiocarcinoma. Carcinoid tumor, Colon cancer, Duodenal cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer,Rectal cancer, Small intestine cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Penile cancer, Kidney cancer, Renal cell carcinoma, Prostate cancer Testicular cancer, Gestational trophoblastic tumor, Urothelial carcinoma, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Intravascular large B- cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma / plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sézary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, Basal cell carcinoma, Squamous cell carcinoma, Squamous cell skin cancer, Skin adnexal tumors (e.g. sebaceous carcinoma), Melanoma, Merkel cell carcinoma, Keratoacanthoma, Sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans), Lymphomas of primary cutaneous origin (e.g. mycosis fungoides), Lung cancer, Adenocarcinoma of the lung, Basaloid squamous cell lung carcinoma, Bronchial adenomas / carcinoids Small cell lung cancer, Mesothelioma Non-small cell lung cancer, Non-small cell lung carcinoma, Pleuropulmonary blastoma Laryngeal cancer, Thymoma and thymic carcinoma,Squamous-cell carcinoma of the lung, AIDS-related cancers, Kaposi sarcoma Epithelioid hemangioendothelioma (EHE), Desmoplastic small round cell tumor, and Liposarcoma. 1.3 Method 1.2, wherein the cancer is selected from breast cancer, lung cancer, colon cancer, ovarian cancer, and prostate cancer. 1.4 Method 1.2, wherein the cancer is brain cancer. 1.5 Any preceding method, wherein administering the PDE1 inhibitor to the subject inhibits or mitigates one or more symptoms of chemobrain, optionally wherein the one or more symptoms of chemobrain are selected from feeling of mental fogginess, deficit in attention, disorganized behavior or thinking, confusion, impaired concentration, difficulty finding the right word, difficulty learning new skills, difficulty multitasking, memory impairment (e.g., short-term memory problems, long-term memory problems, impaired verbal memory, impaired visual memory), fatigue, and combinations thereof. 1.6 Method 1.5, wherein the one or more symptoms of chemobrain comprise feeling of mental fogginess. 1.7 Method 1.5 or Method 1.6, wherein the one or more symptoms of chemobrain comprise deficit in attention. 1.8 Any of Methods 1.5-1.7, wherein the one or more symptoms of chemobrain comprise disorganized behavior or thinking. 1.9 Any of Methods 1.5-1.8, wherein the one or more symptoms of chemobrain comprise confusion. 1.10 Any of Methods 1.5-1.9, wherein the one or more symptoms of chemobrain comprise impaired concentration. 1.11 Any of Methods 1.5-1.10, wherein the one or more symptoms of chemobrain comprise difficulty finding the right word, difficulty learning new skills, and / or difficulty multitasking. 1.12 Any of Methods 1.5-1.11, wherein the one or more symptoms of chemobrain comprise memory impairment, optionally wherein the one or more symptoms of chemobrain comprise short-term memory problems, long-term memory problems, impaired verbal memory, and / or impaired visual memory.1.13 Any of Methods 1.5-1.12, wherein the one or more symptoms of chemobrain comprise fatigue. 1.14 Any preceding method, wherein the subject has received, is receiving, or plans to receive an anticancer treatment, optionally wherein the subject has received or is receiving an anticancer treatment. 1.15 Method 1.14, wherein the anticancer treatment is selected from chemotherapy, radiotherapy, immunotherapy, hormone therapy, and surgery. 1.16 Method 1.15, wherein the anticancer treatment is chemotherapy. 1.17 Method 1.16, wherein the chemotherapeutic agent is selected from Alkylating agents (e.g., Altretamine, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Chlormethine, Chlorozotocin, Cyclophosphamide, Dacarbazine, Fotemustine, Ifosfamide, Lomustine, Melphalan, Melphalan flufenamide, Mitobronitol, Nimustine, Nitrosoureas, Pipobroman, Ranimustine, Semustine, Streptozotocin, Temozolomide, Thiotepa, Treosulfan, Triaziquone, Triethylenemelamine, Trofosfamide, Uramustine), Anthracyclines (e.g., Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, Valrubicin, Zorubicin), Cytoskeletal disruptors (taxanes) (e.g., Abraxane, Cabazitaxel, Docetaxel, Larotaxel, Paclitaxel, Taxotere, Tesetaxel), Epothilones (e.g., Ixabepilone), Histone deacetylase inhibitors (e.g., Entinostat, Romidepsin, Vorinostat, Zabadinostat), Inhibitors of topoisomerase I (Belotecan, Camptothecin, Exatecan, Gimatecan, Irinotecan, Topotecan), Inhibitors of topoisomerase II (e.g., Etoposide, Teniposide, Tafluposide), Kinase inhibitors (Bortezomib, Erlotinib, Gefitinib, Imatinib, Vemurafenib, Vismodegib), Nucleotide analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabin,e Doxifluridine, Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine, Methotrexate, Tioguanine), Peptide antibiotics (e.g., Actinomycin, Bleomycin), Platinum-based agents (e.g., Carboplatin, Cisplatin, Dicycloplatin, Oxaliplatin, Nedaplatin, Satraplatin), Retinoids (e.g., Alitretinoin, Bexarotene, Tretinoin), Vinca alkaloids and derivatives (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine), and combinations thereof. 1.18 Method 1.15, wherein the anticancer treatment is radiotherapy.1.19 Any of Methods 1.14-1.18, the one or more symptoms of chemobrain are consequent to the anticancer treatment, e.g., chemotherapy. 1.20 Any of Methods 1.14-1.18, wherein the PDE1 inhibitor is administered to the subject before the initiation of the anticancer treatment, optionally wherein the administration of the PDE1 inhibitor is continued during the anticancer treatment, further optionally wherein the administration of the PDE1 inhibitor is continued after the anticancer treatment ends. 1.21 Any of Methods 1.14-1.18, wherein the PDE1 inhibitor is administered to the subject during the anticancer treatment, optionally wherein the administration of the PDE1 inhibitor is continued after the anticancer treatment ends. 1.22 Any of Methods 1.14-1.18, wherein the PDE1 inhibitor is administered to the subject after the anticancer treatment. 1.23 Any of Methods 1.0-1.13, wherein the one or more symptoms of chemobrain are consequent to cancer itself, e.g., brain cancer. 1.24 Any preceding method, wherein the PDE1 inhibitor is administered to the subject in combination with an additional therapeutic agent that prevents or treats chemobrain. 1.25 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, Ia, II, III, IV, V, VI, and / or VII. 1.26 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula Ia. 1.27 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound according to the following:in free or pharmaceutically acceptable salt form. 1.28 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form. 1.29 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.30 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.31 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.32 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.33 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.34 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.35 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.36 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.37 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.38 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.39 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.40 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.41 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.42 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.43 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.44 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.45 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.46 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.47 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.48 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.49 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.50 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.51 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.52 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.53 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.54 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.55 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.56 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.57 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.58 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.59 Any of Methods 1.0-1.24, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form. 1.60 Any preceding methods, wherein the subject is human. 1.61 Any preceding method, wherein the PDE1 inhibitor is administered orally, optionally wherein the PDE1 inhibitor is administered as a tablet or capsule. 1.62 Any of Methods 1.0-1.60, wherein the PDE1 inhibitor is administered by inhalation, optionally wherein the PDE1 inhibitor is administered as a nasal spray or inhaler. 1.63 Any of Methods 1.0-1.60, 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.

[0059] 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, Ia, II, III, IV, V, VI, and / or VII) for use in any of methods 1, et seq.

[0060] The PDE1 inhibitors described in this disclosure may be administered to a subject who has suffered or is suffering from cancer for preventing or treating chemobrain. As used herein, cancer refers to a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Non-limiting examples of cancers areChondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma, osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Leiomyosarcoma, Myxosarcoma, Fibrocartilaginous mesenchymoma, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma. Ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioblastoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Inflammatory breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Mammary secretory carcinoma, Papillary carcinomas of the breast, Adrenocortical carcinoma, Islet cell carcinoma, Multiple endocrine neoplasia syndrome, Pancreatic Cancer, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Optic nerve glioma, Anal cancer. Appendix cancer. Cholangiocarcinoma. Carcinoid tumor, Colon cancer, Duodenal cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, Rectal cancer, Small intestine cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Penile cancer, Kidney cancer, Renal cell carcinoma, Prostate cancer Testicular cancer, Gestational trophoblastic tumor, Urothelial carcinoma, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma / plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sézary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, Basal cell carcinoma, Squamous cell carcinoma, Squamous cell skin cancer, Skin adnexal tumors (e.g. sebaceous carcinoma), Melanoma, Merkel cell carcinoma, Keratoacanthoma, Sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans), Lymphomas of primary cutaneous origin (e.g. mycosis fungoides), Lung cancer, Adenocarcinoma of the lung, Basaloid squamous cell lung carcinoma, Bronchial adenomas / carcinoids Small cell lung cancer, Mesothelioma Non- small cell lung cancer, Non-small cell lung carcinoma, Pleuropulmonary blastoma Laryngeal cancer, Thymoma and thymic carcinoma, Squamous-cell carcinoma of the lung, AIDS-related cancers, Kaposi sarcoma Epithelioid hemangioendothelioma (EHE), Desmoplastic small round cell tumor, and Liposarcoma. In certain embodiments, the cancer is selected from breast cancer, lung cancer, colon cancer, ovarian cancer, and prostate cancer. In other embodiments, the cancer is brain cancer.

[0061] As used herein, chemobrain refers to cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself, e.g., brain cancer. Cancer patients may experience one or more symptoms of chemobrain. Non-limiting examples of symptoms of chemobrain include feeling of mental fogginess, deficit in attention, disorganized behavior or thinking, confusion, impaired concentration, difficulty finding the right word, difficulty learning new skills, difficulty multitasking, memory impairment (e.g., short-term memory problems, long-term memory problems, impaired verbal memory, impaired visual memory), and fatigue. In some embodiments, the one or more symptoms of chemobrain comprise feeling of mental fogginess. In some embodiments, the one or more symptoms of chemobrain comprise deficit in attention. In some embodiments, the one or more symptoms of chemobrain comprise disorganized behavior or thinking. In some embodiments, the one or more symptoms of chemobrain comprise confusion. In some embodiments, the one or more symptoms of chemobrain comprise impaired concentration. In some embodiments, the one or more symptoms of chemobrain comprise difficulty finding the right word, difficulty learning new skills, and / ordifficulty multitasking. In some embodiments, the one or more symptoms of chemobrain comprise memory impairment (e.g., short-term memory problems, long-term memory problems, impaired verbal memory, and / or impaired visual memory). In some embodiments, the one or more symptoms of chemobrain comprise fatigue.

[0062] In some embodiments, the one or more symptoms of chemobrain that the subject experiences may be consequent to anticancer treatment, e.g., chemotherapy. In other embodiments, the one or more symptoms of chemobrain that the subject experiences may be caused by cancer itself, e.g., brain cancer.

[0063] In some embodiments, the PDE1 inhibitor may be administered to a subject who experiences one or more symptoms of chemobrain for treating chemobrain, e.g., mitigating one or more symptoms of chemobrain. In other embodiments, the PDE1 inhibitor may be administered to a subject who does not experience any symptom of chemobrain for preventing chemobrain, e.g., inhibiting one or more symptoms of chemobrain.

[0064] In some embodiments, the subject has received or is receiving an anticancer treatment. In other embodiments, the subject plans to receive an anticancer treatment.

[0065] The anticancer treatment may be chemotherapy, radiotherapy, immunotherapy, hormone therapy, or surgery. In some embodiment, the anticancer treatment is chemotherapy. Any known anti-cancer drugs (chemotherapeutic agents) may be used in the chemotherapy. Non- limiting examples of chemotherapeutic agents include Alkylating agents (e.g., Altretamine, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Chlormethine, Chlorozotocin, Cyclophosphamide, Dacarbazine, Fotemustine, Ifosfamide, Lomustine, Melphalan, Melphalan flufenamide, Mitobronitol, Nimustine, Nitrosoureas, Pipobroman, Ranimustine, Semustine, Streptozotocin, Temozolomide, Thiotepa, Treosulfan, Triaziquone, Triethylenemelamine, Trofosfamide, Uramustine), Anthracyclines (e.g., Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, Valrubicin, Zorubicin), Cytoskeletal disruptors (taxanes) (e.g., Abraxane, Cabazitaxel, Docetaxel, Larotaxel, Paclitaxel, Taxotere, Tesetaxel), Epothilones (e.g., Ixabepilone), Histone deacetylase inhibitors (e.g., Entinostat, Romidepsin, Vorinostat, Zabadinostat), Inhibitors of topoisomerase I (Belotecan, Camptothecin, Exatecan, Gimatecan, Irinotecan, Topotecan), Inhibitors of topoisomerase II (e.g., Etoposide, Teniposide, Tafluposide), Kinase inhibitors (Bortezomib, Erlotinib, Gefitinib, Imatinib,Vemurafenib, Vismodegib), Nucleotide analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabin,e Doxifluridine, Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine, Methotrexate, Tioguanine), Peptide antibiotics (e.g., Actinomycin, Bleomycin), Platinum-based agents (e.g., Carboplatin, Cisplatin, Dicycloplatin, Oxaliplatin, Nedaplatin, Satraplatin), Retinoids (e.g., Alitretinoin, Bexarotene, Tretinoin), and Vinca alkaloids and derivatives (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine). In other embodiments, the anticancer treatment is radiotherapy.

[0066] In some embodiments, the PDE1 inhibitor is administered to the subject before the initiation of the anticancer treatment, e.g., chemotherapy, optionally wherein the administration of the PDE1 inhibitor is continued during the anticancer treatment, further optionally wherein the administration of the PDE1 inhibitor is continued after the anticancer treatment ends.

[0067] In some embodiments, the PDE1 inhibitor is administered to the subject during the anticancer treatment, e.g., chemotherapy, optionally wherein the administration of the PDE1 inhibitor is continued after the anticancer treatment ends.

[0068] In some embodiments, the PDE1 inhibitor is administered to the subject after the anticancer treatment, e.g., chemotherapy.

[0069] The PDE1 inhibitor may be administered in combination with an additional therapeutic agent that prevents or treats chemobrain, e.g., prevents or mitigates one or more symptoms of chemobrain, 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 treats chemobrain. 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.

[0070] 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

[0071] 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.

[0072] Various PDE1 inhibitors and starting materials therefor may be prepared using methods described in US 2008-0188492 A1, US 2010-0173878 A1, US 2010-0273754 A1, US 2010-0273753 A1, WO 2010 / 065153, WO 2010 / 065151, WO 2010 / 065151, WO 2010 / 065149, WO 2010 / 065147, WO 2010 / 065152, WO 2011 / 153129, WO 2011 / 133224, WO 2011 / 153135, WO 2011 / 153136, WO 2011 / 153138. All references cited herein are hereby incorporated by reference in their entirety.

[0073] 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 Zisomer 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.

[0074] 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., 123I, 131I, 125I, 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.

[0075] The terms "treatment" and "treating" are to be understood as embracing treatment or amelioration of one or more symptoms of chemobrain. For methods of treatment, the term “effective amount” is intended to encompass a therapeutically effective amount to treat or mitigate symptoms of chemobrain.

[0076] The terms “prevention” and “preventing” are to be understood as embracing inhibition of one or more symptoms of chemobrain and reduction of the likelihood of chemobrain. For methods of prevention, the term “effective amount” is intended to encompass a therapeutically effective amount to inhibit one or more symptoms of chemobrain or reduce the likelihood of chemobrain.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] In general, satisfactory results, e.g., for preventing or treating chemobrain, 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 a PDE-1 inhibitor 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.

[0081] 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 the form 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).

Claims

CLAIMS 1. A method of preventing or treating chemobrain, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof.

2. The method of claim 1, wherein the subject has suffered or is suffering from a cancer.

3. The method of any of the preceding claims, wherein administering the PDE1 inhibitor to the subject inhibits or mitigates one or more symptoms of chemobrain selected from feeling of mental fogginess, deficit in attention, disorganized behavior or thinking, confusion, impaired concentration, difficulty finding the right word, difficulty learning new skills, difficulty multitasking, memory impairment (e.g., short-term memory problems, long-term memory problems, impaired verbal memory, impaired visual memory), fatigue, and combinations thereof.

4. The method of claim 3, wherein the one or more symptoms of chemobrain comprises feeling of mental fogginess.

5. The method of claim 3, wherein the one or more symptoms of chemobrain comprise disorganized behavior or thinking.

6. The method of claim 3, wherein the one or more symptoms of chemobrain comprise confusion.

7. The method of claim 3, wherein the one or more symptoms of chemobrain comprise impaired concentration.

8. The method of claim 3, wherein the one or more symptoms of chemobrain comprise difficulty finding the right word, difficulty learning new skills, and / or difficulty multitasking.

9. The method of claim 3, wherein the one or more symptoms of chemobrain comprise memory impairment (e.g., short-term memory problems, long-term memory problems, impaired verbal memory, impaired visual memory).

10. The method of claim 3, wherein the one or more symptoms of chemobrain comprise fatigue.

11. The method of any of the preceding claims, wherein the subject has received, is receiving, or plans to receive an anticancer treatment.

12. The method of claim 11, wherein the anticancer treatment is selected from chemotherapy, radiotherapy, immunotherapy, hormone therapy, and surgery.

13. The method of claim 12, wherein the anticancer treatment is chemotherapy.

14. The method of claim 13, wherein the chemotherapeutic agent is selected from Alkylating agents (e.g., Altretamine, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Chlormethine, Chlorozotocin, Cyclophosphamide, Dacarbazine, Fotemustine, Ifosfamide, Lomustine, Melphalan, Melphalan flufenamide, Mitobronitol, Nimustine, Nitrosoureas, Pipobroman, Ranimustine, Semustine, Streptozotocin, Temozolomide, Thiotepa, Treosulfan, Triaziquone, Triethylenemelamine, Trofosfamide, Uramustine), Anthracyclines (e.g., Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, Valrubicin, Zorubicin), Cytoskeletal disruptors (taxanes) (e.g., Abraxane, Cabazitaxel, Docetaxel, Larotaxel, Paclitaxel, Taxotere, Tesetaxel), Epothilones (e.g., Ixabepilone), Histone deacetylase inhibitors (e.g., Entinostat, Romidepsin, Vorinostat, Zabadinostat), Inhibitors of topoisomerase I (Belotecan, Camptothecin, Exatecan, Gimatecan, Irinotecan, Topotecan), Inhibitors of topoisomerase II (e.g., Etoposide, Teniposide, Tafluposide), Kinase inhibitors (Bortezomib, Erlotinib, Gefitinib, Imatinib, Vemurafenib, Vismodegib), Nucleotide analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabin,e Doxifluridine, Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine, Methotrexate, Tioguanine), Peptide antibiotics (e.g., Actinomycin, Bleomycin), Platinum-based agents (e.g., Carboplatin, Cisplatin, Dicycloplatin, Oxaliplatin, Nedaplatin, Satraplatin), Retinoids (e.g., Alitretinoin, Bexarotene, Tretinoin), Vinca alkaloids and derivatives (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine), and combinations thereof.

15. The method of any of claims 11-14, wherein the PDE1 inhibitor is administered to the subject before the initiation of the anticancer treatment, e.g., chemotherapy, optionally wherein the administration of the PDE1 inhibitor is continued during the anticancer treatment, further optionally wherein the administration of the PDE1 inhibitor is continued after the anticancer treatment ends.

16. The method of any of claims 11-14, wherein the PDE1 inhibitor is administered to the subject during the anticancer treatment, e.g., chemotherapy, optionally wherein the administration of the PDE1 inhibitor is continued after the anticancer treatment ends.

17. The method of any of claims 11-14, wherein the PDE1 inhibitor is administered to the subject after the anticancer treatment, e.g., chemotherapy.

18. The method according to any of the preceding claims, wherein the PDE1 inhibitor is a compound selected from: (A) Formula I:Formula I wherein (i) R1is H or C1-4alkyl (e.g., methyl); (ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H, C1-4 alkyl , aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl (e.g., R2 and R3are both methyl, or R2is H and R3is isopropyl); or R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge (pref. wherein the R3 and R4 together 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 AFormula A wherein X, Y and Z are, independently, N or C, and R8, R9, R11 and R12 are independently H or halogen (e.g., Cl or F), and R10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (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) R6 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 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;(B) Formula II:Formula II wherein (i) X is C1-6alkylene (e.g., methylene, ethylene or prop-2-yn-1-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), forexample, 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:Formula III wherein (i) R1 is H or C1-4 alkyl (e.g., methyl or ethyl); (ii) R2 and R3 are independently H or C1-6 alkyl (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)-C1-6 alkyl (e.g., -C(=O)-CH3) and C1-6 -hydroxyalkyl (e.g., 1- hydroxyethyl);(v) R6and R7are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6 alkyl (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 IVFormula IV in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof , wherein: (i) R1 is C1-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl; (ii) X, Y and Z are, independently, N or C; (iii) R3, R4 and R5 are independently H or C1-4alkyl (e.g., methyl); or R3 is H and R4 and R5 together form a tri-methylene bridge (pref. wherein the R4 and R5 together 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, R7 and / 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 Ia:wherein (i) R2and R5are independently H or hydroxy and R3and R4together form a tri- or tetra- methylene bridge [pref. with the carbons carrying R3 and R4 having the R and S configuration respectively]; or R2 and R3 are each methyl and R4 and R5 are each H; or R2, R4 and R5 are 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., 1,2,3-thiadiazol-4-yl), or R10 is -CH(CH3)-O- C(O)-R11, wherein R11is C1-6alkyl (e.g., methyl, ethyl, or propyl), or R10is saturated orunsaturated 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 R10 is -C(=O)-X1, wherein X1 is 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-fluorophenyl; (ii) R2 is H or C1-6alkyl (e.g., methyl, isobutyl or neopentyl); and (iii) R3 is -SO2NH2 or –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) R2 is 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 VIIwherein (i) R1 is H or C1-4 alkyl (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) R5 is 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 C1-6 alkyl (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 C1-6 alkyl and one or more halogen or phenyl substituted with one C1-6 alkyl 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.

19. The method according to any of claims 1-17, wherein the PDE1 inhibitor is selected from any of the following:in free or pharmaceutically acceptable salt form.

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

Images