Organic compounds

Abstract

Provided are PDE1 inhibitors of Formula I, processes for their production, their use as pharmaceuticals, and pharmaceutical compositions comprising them.

Description

Attorney Docket No.: IT-212-PCTORGANIC COMPOUNDSTECHNICAL FIELD

[0001] The present invention relates to novel PDE1 inhibitory compounds of Formula I as described below, processes for their production, and their use as pharmaceuticals and pharmaceutical compositions comprising them.BACKGROUND OF THE INVENTION

[0002] From a therapeutic standpoint, PDEs are of particular therapeutic interest, as their structure is amenable to specific and potent small molecule inhibitors, and cell-specific expression provides selective organ targeting. Eleven families of phosphodiesterases (PDEs) have been identified totaling over 100 isoforms, but only PDEs in Family I, the Ca2+-calmodulin-dependent phosphodiesterases (CaM-PDEs), have been shown to mediate both the calcium and cyclic nucleotide (e.g., cAMP and cGMP) signaling pathways. These PDEs are therefore active in stimulated conditions when intra-cellular calcium levels rise, leading to increased hydrolysis of cyclic nucleotides. The three known CaM-PDE genes, PDE1 A, PDE1B, and PDE1C, are all expressed in human central nervous system tissue. PDE1 A is expressed in the brain with high levels in the CAI to CA3 layers of the hippocampus and cerebellum and at a low level in the striatum. PDE1 A is also expressed in the heart. PDE1B is predominately expressed in the striatum, dentate gyrus, olfactory tract and in the prefrontal cortex colocalized with the dopamine DI receptor. Its expression generally correlates with brain regions having high levels of dopaminergic innervation. Although PDE1B is primarily expressed in the central nervous system, it is present in neutrophils. PDE1C is more ubiquitously expressed in the brain and is expressed in the heart and vascular smooth muscle.

[0003] PDE1 inhibitors have been found to be useful for the treatment or prophylaxis of many disorders, including those characterized by low levels of cAMP and / or cGMP in cells expressing PDE1; and / or reduced dopamine DI receptor signaling activity (e.g., Parkinson’s disease, Tourette’s Syndrome, Autism, fragile X syndrome, ADHD, restless leg syndrome, depression, cognitive impairment of schizophrenia, narcolepsy); and / or ophthalmic disorders (e.g., glaucoma, elevated intraocular pressure, etc.); and / or any disease or condition that may be ameliorated by the enhancement of progesterone signaling; and / or any disease or condition characterized by adenosine A2 dysfunction or which would benefit from adenosine A2Attorney Docket No.: IT-212-PCTstimulation (e.g., cardiovascular diseases and disorders, muscular dystrophy (e.g., Duchenne muscular dystrophy), amyotrophic lateral sclerosis, etc.); and / or diseases or disorders characterized by inflammation; and / or cancers or tumors which over-express PDE1 (e.g., melanoma, neuroblastoma, renal cell and colon carcinomas, osteosarcoma, glioblastoma multiforme (GBM), etc.). This list of disorders is exemplary and not intended to be exhaustive.

[0004] There is thus a continued need for novel compounds that selectively inhibit PDE1 activity.SUMMARY OF THE INVENTION

[0005] In an aspect, the present disclosure provides a compound of Formula I:Formula Iwherein(i) Ri 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) R4 is H or C1-4 alkyl (e.g., methyl or ethyl);(iv) R5 is aryl (e.g., phenyl) substituted with a group selected from:(a) -CH(CH3)-O-C(O)-Ra, wherein Rais -N(Rb)(Rc), heteroaryl (e.g., imidazolyl), or -CH(NH2)-Ra, wherein Rb and Rcare independently C1-4 alkyl (e.g. methyl) and wherein Rd is H or C1-4 alkyl (e.g., isopropyl),(b) -C(=C)-O-Re, wherein Reis C1-4 alkyl (e.g., methyl, ethyl, or butyl).Attorney Docket No.: IT-212-PCT(c) -CH(CH3)-O-CH2-O-C(O)-Rf, wherein Rfis C alkyl (e.g., methyl), and(d) -C(O)-N(Rg)(Rh), wherein Rgand Rh are independently C1-4 alkyl (e.g., methyl);(v) Re and R7 are 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 or salt form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers and racemates, thereof.

[0006] In some embodiments, the present disclosure provides a compound of Formula I, wherein(i) Ri is methyl;(ii) R2 and R3 are both methyl;(iii) R4 is H;(iv) Rs is aryl (e.g., phenyl) substituted with a group selected from:(a) -CH(CH3)-O-C(O)-Ra, wherein Rais -N(Rb)(Rc), heteroaryl (e.g., imidazolyl), or -CH(NH2)-Ra, wherein Rb and Rcare independently C1-4 alkyl (e.g., methyl) and wherein Rd is H or C1-4 alkyl (e.g. isopropyl),(b) -C(=C)-O-Re, wherein Reis C1-4 alkyl (e.g., methyl, ethyl, or butyl). (c) -CH(CH3)-O-CH2-O-C(O)-Rf, wherein Rfis C1-4 alkyl (e.g., methyl), and(d) -C(O)-N(Rg)(Rh), wherein Rgand Rh are independently C1-4 alkyl (e.g., methyl);(v) R7 is H and Re is 4-fluorophenyl; and(vi) n is 1,Attorney Docket No.: IT-212-PCTin free or salt form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers and racemates, thereof.

[0007] In some embodiments, the compound of Formula I is selected from:Attorney Docket No.: IT-212-PCTandin free or salt form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers and racemates, thereof.

[0008] In another aspect, the present disclosure provides a pharmaceutical composition comprising a Compound of the Invention, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

[0009] In another aspect, the present disclosure provides a method for the prophylaxis or treatment of a disease or disorder selected from neurodegenerative diseases (e.g., Parkinson’s disease, restless leg, tremors, dyskinesias, Huntington’s disease, Alzheimer’s disease, and drug-induced movement disorders); neuroinflammation and / or diseases or disorders associated with neuroinflammation and / or microglial function; mental disorders (e.g., depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive impairment, e.g., cognitive impairment of schizophrenia, Tourette’s syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and drug addiction); chemobrain (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself); disorders associated with dementia; circulatory and cardiovascular disorders (e.g., cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and sexual dysfunction); respiratory and inflammatory disorders (e.g., asthma, chronic obstructive pulmonary disease, and allergic rhinitis); diseases which may be alleviated by the enhancement of progesterone signaling (e.g., female sexual dysfunction); psychosis; ophthalmic disorders (e.g., glaucoma and elevated intraocular pressure); traumatic brain injury; cancers or tumors (e.g., glioma, colon cancer, and breast cancer); renal disorders (e.g., kidney fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, nephritis); cardiotoxicity consequent to administration of a chemotherapeutic agent and / or radiation therapy; any disease or condition characterized by low levels of cAMP and / or cGMP in cells expressing PDEl(e.g., angina, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolicAttorney Docket No.: IT-212-PCThypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, an inflammatory disease or disorder, fibrosis, cardiac hypertrophy, vascular remodeling, a connective tissue disease or disorder, chronic heart failure, myocardial inflammation, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunctions, vascular leakage, acute vascular inflammation, and amyotrophic lateral sclerosis); bacterial infections; viral infections; obesity; metabolic disorders; fatty liver disease; conditions associated with fat-induced inflammation; nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting); and any disease or condition characterized by reduced dopamine DI receptor signaling activity (e.g., attention deficit, cognition, PTSD, memory, and / or inhibitory processing), wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of the compound of the invention, e.g., compounds of Formula I, e.g., any compounds described in this disclosure.DETAILED DESCRIPTION OF THE INVENTION

[0010] In an aspect, the invention provides a compound of Formula I (Compound 1.0):wherein(i) Ri 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) R4 is H or C1-4 alkyl (e.g., methyl or ethyl);(iv) R5 is aryl (e.g., phenyl) substituted with a group selected from:Attorney Docket No.: IT-212-PCT(a) -CH(CH3)-0-C(0)-Ra, wherein Rais -N(Rb)(Rc), heteroaryl (e.g., imidazolyl), or -CH(NH2)-Rd, wherein Rb and Rcare independently Ci-4 alkyl (e.g., methyl) and wherein Rd is H or C1-4 alkyl (e.g. isopropyl),(b) -C(=C)-O-Re, wherein Reis Ci-4 alkyl (e.g., methyl, ethyl, or butyl). (c) -CH(CH3)-O-CH2-O-C(O)-Rf, wherein Rfis C alkyl (e.g., methyl), and(d) -C(O)-N(Rg)(Rh), wherein Rgand Rh are independently C1-4 alkyl (e.g., methyl);(v) Re and R7 are 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 or salt form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers and racemates, thereof.

[0011] The invention further provides compounds of Formula I as follows:1.1 Compound 1.0, wherein n is 1, 2, or 3;1.2 Compound 1.0, wherein n is 1 or 2;1.3 Compound 1.0, wherein n is 1;1.4 Any of Compounds 1.0-1.3, wherein Ri is H or C1-3 alkyl (e.g., methyl);1.5 Any of Compounds 1.0-1.3, wherein Ri is H;1.6 Any of Compounds 1.0-1.3, wherein Ri is C1-4 alkyl;1.7 Any of Compounds 1.0-1.3, wherein Ri is methyl;1.8 Any of Compounds 1.0-1.7, wherein R2 and R3 are independently H or C1-5 alkyl (e.g., methyl or ethyl);1.9 Any of Compounds 1.0-1.7, wherein R2 and R3 are independently H or C1-4 alkyl (e.g., methyl);Attorney Docket No.: IT-212-PCTAny of Compounds 1.0-1.7, wherein R2 and R3 are both C1-6 alkyl (e.g., C1-4 alkyl, e.g., methyl);Any of Compounds 1.0-1.7, wherein R2 and R3 are both C1-4 alkyl (e.g., methyl);Any of Compounds 1.0-1.7, wherein R2 and R3 are both methyl;Any of Compounds 1.0-1.12, wherein R4 is H or C1-3 alkyl (e.g., methyl or ethyl);Any of Compounds 1.0-1.12, wherein R4 is H;Any of Compounds 1.0-1.14, wherein R5 is aryl (e.g., phenyl) substituted with -CH(CH3)-O-C(O)-Ra, wherein Rais -N(Rb)(Rc), heteroaryl (e.g., imidazolyl), or -CH(NH2)-Rd, wherein Rb and Rc are independently C1-4 alkyl (e.g. methyl) and wherein Rd is H or C1-4 alkyl (e.g. isopropyl),Compound 1.15, wherein Ra is -N(Rb)(Rc) and wherein Rb and Rc are independently C1-4 alkyl (e.g. methyl).Compound 1.16, wherein Rb and Rcare both methyl .Compound 1.15, wherein Ra is heteroaryl, optionally wherein Rais selected from furanyl, pyrrolyl, thiophenyl, pyridinyl, imidazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, purinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl.Compound 1.18, wherein Ra is imidazolyl.Compound 1.15, wherein Ra is -CH(NH2)-Rd and wherein Rd is H or C1-4 alkyl (e.g. isopropyl).Compound 1.20, wherein Rd is H.Compound 1.20, wherein Rd is isopropyl (-CH(CH3)2).Any of Compounds 1.0-1.14, wherein R5 is aryl (e.g., phenyl) substituted with -C(=C)-O-Re, wherein Reis C1-4 alkyl (e.g., methyl, ethyl, or butyl).Compound 1.23, wherein Re is methyl.Compound 1.23, wherein Re is ethyl.Compound 1.23, wherein Re is butyl.Any of Compounds 1.0-1.14, wherein R5 is aryl (e.g., phenyl) substituted with -CH(CH3)-O-CH2-O-C(O)-Rf, wherein Rfis C1-4 alkyl (e.g., methyl).Compound 1.27, wherein Rfis methyl.Attorney Docket No.: IT-212-PCTAny of Compounds 1.0-1.14, wherein Rs is aryl (e.g., phenyl) substituted with -C(O)-N(Rg)(Rh), wherein Rgand Rh are independently Ci-4 alkyl (e.g., methyl).Compound 1.29, wherein Rgand Rh are both methyl.Any of Compounds 1.0-1.30, wherein Re and R7 are independently H or aryl (e.g., phenyl) substituted with one or more groups independently selected from C1-4 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example phenyl substituted with one or more (e.g., two) halogen (e.g., F) or phenyl substituted with one or more C1-4 alkyl (e.g., methyl) and one or more halogen (e.g., F) or phenyl substituted with one C1-4 alkyl (e.g., methyl) and one halogen (e.g., F), for example 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3 -methylphenyl .Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one or more groups independently selected from C1-6 alkyl (e.g., C1-4 alkyl, e.g., methyl) and halogen (e.g., F or Cl), for example Re is phenyl substituted with one or more (e.g., two) halogen (e.g., F) or phenyl substituted with one C1-6 alkyl (e.g., C1-4 alkyl, e.g., methyl) and one halogen (e.g., F), for example wherein Re is 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3 -methylphenyl .Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one or more groups independently selected from C1-4 alkyl (e.g., methyl) and halogen (e.g., F), for example Re is phenyl substituted with one or more (e.g., two) halogen (e.g., F) or phenyl substituted with one C1-4 alkyl (e.g., methyl) and one halogen (e.g., F), for example wherein Re is 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3 -methylphenyl.Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one or more halogen (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with two halogens (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one halogen (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with two F.Attorney Docket No.: IT-212-PCTAny of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one F.Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one or more C1-6 alkyl (e.g., C1-4 alkyl, e.g., methyl) and one or more halogen (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one or more C1-4 alkyl (e.g., methyl) and one or more halogen (e g-, F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one C1-6 alkyl (e.g., C1-4 alkyl, e.g., methyl) and one halogen (e g-, F).Any of Compounds 1.0-1.30, wherein R7 is H and Rs is aryl (e.g., phenyl) substituted with one C1-4 alkyl (e.g., methyl) and one halogen (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is aryl (e.g., phenyl) substituted with one methyl and one F.Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one or more halogen (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with two halogens (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one halogen (e.g., F).Any of Compounds 1.0-1.30, wherein Re is phenyl substituted with two F; Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one F.Any of Compounds 1.0-1.30, wherein R7 is H and Re is 3,4-difluorophenyl. Any of Compounds 1.0-1.30, wherein R7 is H and Re is 4-fluorophenyl. Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one or more C1-6 alkyl (e.g., C1-4 alkyl, e.g., methyl) and one or more halogen (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one or more C1-4 alkyl (e.g., methyl) and one or more halogen (e.g., F); Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one C1-6 alkyl (e.g., C1-4 alkyl, e.g., methyl) and one halogen (e.g., F).Attorney Docket No.: IT-212-PCTAny of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one C1-4 alkyl (e.g., methyl) and one halogen (e.g., F).Any of Compounds 1.0-1.30, wherein R7 is H and Re is phenyl substituted with one methyl and one F.Any of Compounds 1.0-1.30, wherein R7 is H and Re is 4-fluoro-3-methylphenyl.Compound 1.0, wherein(i) Ri is methyl;(ii) R2 and R3 are both methyl;(iii) R4 is H;(iv) R7 is H and Re is 4-fluorophenyl; and(v) n is 1.Compound 1.57, wherein R5 is aryl (e.g., phenyl) substituted with -CH(CH3)-O-C(O)-Ra, wherein Rais -N(Rb)(Rc), heteroaryl (e.g., imidazolyl), or -CH(NH2)-Rd, wherein Rb and Rc are independently C1-4 alkyl (e.g. methyl) and wherein Rd is H or C1-4 alkyl (e.g. isopropyl),Compound 1.58, wherein Ra is -N(Rb)(Rc) and wherein Rb and Rc are independently C1-4 alkyl (e.g. methyl).Compound 1.59, wherein Rb and Rcare both methyl.Compound 1.58, wherein Ra is heteroaryl, optionally wherein Rais selected from furanyl, pyrrolyl, thiophenyl, pyridinyl, imidazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, purinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl.Compound 1.61, wherein Ra is imidazolyl.Compound 1.58, wherein Ra is -CH(NH2)-Rd and wherein Rd is H or C1-4 alkyl (e.g. isopropyl).Compound 1.63, wherein Rd is H.Compound 1.63, wherein Rd is isopropyl (-CH(CH3)2).Compound 1.57, wherein R5 is aryl (e.g., phenyl) substituted with -C(=C)-O-Re, wherein Reis C1-4 alkyl (e.g., methyl, ethyl, or butyl).Compound 1.66, wherein Re is methyl.Compound 1.66, wherein Re is ethyl.Compound 1.66, wherein Re is butyl.Attorney Docket No.: IT-212-PCTCompound 1.57, wherein R5 is aryl (e.g., phenyl) substituted with -CH(CH3)- O-CH2-O-C(O)-Rf, wherein Rfis C1-4 alkyl (e.g., methyl).Compound 1.70, wherein Rfis methyl.Compound 1.57, wherein R5 is aryl (e.g., phenyl) substituted with -C(O)- N(Rg)(Rh), wherein Rgand Rh are independently C1-4 alkyl (e.g., methyl). Compound 1.72, wherein Rgand Rh are both methyl.Compound 1.0, wherein the compound is selected from:Attorney Docket No.: IT-212-PCTandin free or salt form.1.75 Compound 1.0, wherein the compound is Compound 1 :in free or salt form.1.76 Compound 1.0, wherein the compound is Compound 2:in free or salt form.1.77 Compound 1.0, wherein the compound is Compound 3 :Attorney Docket No.: IT-212-PCTin free or salt form.1.78 Compound 1.0, wherein the compound is Compound 4:in free or salt form.1.79 Compound 1.0, wherein the compound is Compound 5:in free or salt form.1.80 Compound 1.0, wherein the compound is Compound 6:in free or salt form.1.81 Compound 1.0, wherein the compound is Compound 7:Attorney Docket No.: IT-212-PCTin free or salt form.1.82 Compound 1.0, wherein the compound is Compound 8:in free or salt form.1.83 Compound 1.0, wherein the compound is Compound 9:in free or salt form.1.84 Any of the preceding compounds, wherein the compound inhibits phosphodiesterase-mediated (e.g., PDE1 -mediated) hydrolysis of cGMP, e.g., with an IC50 of less than 1 pM, preferably less than 500 nM, more preferably less than 50 nM, still more preferably less than 10 nM, most preferably less than or equal to 5 nM in an immobilized-metal affinity particle reagent PDE assay.

[0012] If not otherwise specified or clear from context, the following terms herein have the following meanings:(a) “Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety,Attorney Docket No.: IT-212-PCTpreferably saturated, preferably having one to six carbon atoms, preferably having one to four carbon atoms, which may be linear or branched, and may be optionally mono-, di- or tri- substituted, e.g., with halogen (e.g., Cl or F) or carboxy.(b) “Haloalkyl” as used herein is a saturated hydrocarbon moiety, preferably having one to six carbon atoms, preferably having one to four carbon atoms, which may be linear or branched, and is mono-, di- or tri- substituted with halogen. For di- or tri- substituted haloalkyl, the halogens may be the same (e.g., dichloromethyl) or different (e.g., chlorofluoromethyl).(c) “Aryl” as used herein is a mono or bicyclic aromatic hydrocarbon, preferably having 5-10 carbon atoms, preferably phenyl, which may be optionally substituted, e.g., optionally substituted with one or more groups independently selected from Ci-6 alkyl (e.g., methyl), halogen (e.g., Cl or F), Ci-6-haloalkyl (e.g., trifluoromethyl), hydroxy, and carboxy. In some embodiments, aryl, in addition to being substituted with the groups disclosed herein, is further substituted with an aryl or a heteroaryl to form, e.g., biphenyl or pyridylphenyl.(d) “Heteroaryl” as used herein is an aromatic moiety preferably having 5-10 atoms wherein one or more of the atoms making up the aromatic ring is sulfur, oxygen, or nitrogen rather than carbon, e.g., imidazolyl, pyridyl or thiadiazolyl, which may be optionally substituted, e.g., optionally substituted with one or more groups independently selected from Ci-6 alkyl (e.g., methyl), halogen (e.g., Cl orF), Ci-6-haloalkyl (e.g., trifluoromethyl), hydroxy, and carboxy.(e) “Hydroxy” as used herein is -OH.(f) “Carboxy” as used herein is -COOH.(g) “Halogen” as used herein is F, Cl, Br, or I.

[0013] Compounds of the Invention, e.g., compounds of Formula I, e.g., any of Compounds 1.0-1.84, 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 Invention” 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 Invention are intended for use as pharmaceuticals, thereforeAttorney Docket No.: IT-212-PCTpharmaceutically 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 Invention or their pharmaceutically acceptable salts, are therefore also included.

[0014] In another aspect, the present disclosure provides a pharmaceutical composition comprising a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. The Compound of the Invention 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 Compound of the Invention 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 Compound of the Invention is provided in the form of nasal spray or inhaler.

[0015] In some embodiments, the pharmaceutical 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). In some embodiments, the composition is in the form of a tablet or capsule. In some embodiments, the composition is in the form of a nasal spray, mister, or inhaler. In some embodiments, the composition is in the form of an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection).

[0016] In some embodiments, the pharmaceutical composition is in the form of an enteric-coated tablet or capsule, e.g., an enteric-coated tablet. In some embodiments, the enteric coating is insoluble at a pH below 5.5, but soluble at pH 5.5 or higher. Exemplary enteric coating materials include, but not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxyl propyl methyl cellulose phthalate (HPMCP), hydroxyl propyl methyl cellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), and methacrylic acid polymers. The enteric coating allows the tablet to remain intact as it passes through the acidic stomach. The tablet then dissolves in the less acidic smallAttorney Docket No.: IT-212-PCTintestine to be absorbed. The enteric coating helps prevent the ester group in the R5 position of the compounds of the invention from being hydrolyzed in the acidic stomach.

[0017] In another aspect, the present disclosure provides a method for the prophylaxis or treatment of a patient, e.g., a human, suffering from a disorder selected from the following disorders:i. Neurodegenerative diseases, including Parkinson’s disease, restless leg, tremors, dyskinesias, Huntington’s disease, Alzheimer’s disease, and drug-induced movement disorders;ii. Mental disorders, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive impairment, e.g., cognitive impairment of schizophrenia, dementia, Tourette’s syndrome, autism, fragile X syndrome, psychostimulant withdrawal, chemobrain (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself), and drug addiction;iii. Circulatory and cardiovascular disorders, including cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, e.g., pulmonary arterial hypertension, and sexual dysfunction, including cardiovascular diseases and related disorders as described in International Application No. PCT / US2014 / 16741, the contents of which are incorporated herein by reference;iv. Respiratory and inflammatory disorders, including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases;v. Diseases that may be alleviated by the enhancement of progesterone-signaling such as female sexual dysfunction;vi. A disease or disorder such as psychosis, glaucoma, or elevated intraocular pressure;vii. Traumatic brain injury;viii. Cancers or tumors, e.g., brain tumors, a glioma (e.g., ependymoma, astrocytoma, oligodendrogliomas, brain stem glioma, optic nerve glioma, or mixed gliomas, e.g., oligoastrocytomas), an astrocytoma (e.g., glioblastoma multiforme), osteosarcoma, melanoma, leukemia, neuroblastoma or leukemia;Attorney Docket No.: IT-212-PCTix. Renal disorders, e.g., kidney fibrosis, chronic kidney disease, renal failure, glomerulosclerosis and nephritis;x. Any disease or condition characterized by low levels of cAMP and / or cGMP (or inhibition of cAMP and / or cGMP signaling pathways) in cells expressing PDE1; and / orxi. Any disease or condition characterized by reduced dopamine DI receptor signaling activity,comprising administering to a patient in need thereof a therapeutically effective of compound of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84.Methods of Making Compounds of the Invention

[0018] The Compounds of the Invention and their pharmaceutically acceptable salts may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but are 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. Various starting materials, intermediates and / or Compounds of the Invention may be prepared using methods described or similarly described in WO 2006 / 133261, WO 2009 / 075784, WO 2010 / 065148, WO 2010 / 065149, WO 2010 / 065151, and / or WO2014 / 151409. All references cited herein are hereby incorporated by reference in their entirety.

[0019] The Compounds of the Invention include their enantiomers, diastereoisomers and racemates, as well as their polymorphs, hydrates, solvates and complexes. Some individual compounds within the scope of this invention may contain double bonds.Representations of double bonds in this invention are meant to include both the E and the Z isomer of the double bond. In addition, some compounds within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.

[0020] It is also intended that the Compounds of the Invention 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, andAttorney Docket No.: IT-212-PCTsuch 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 Invention may be replaced with deuterium (a stable isotope which is non-radioactive).Examples of known stable isotopes include, but not limited to, deuterium,13C,15N,18O. 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.,1231,131I,125I,nC,18F, may replace the corresponding abundant species of I, C, and F. Another example of useful isotope of the compound of the invention is thenC isotope. These radio isotopes are useful for radio-imaging and / or pharmacokinetic studies of the compounds of the invention. Methods of making isotopes of PDE1 inhibitors disclosed in WO 2011 / 043816, the contents of which are incorporated by reference in their entirety, may be used for making the isotopes of the compounds of the current invention.

[0021] Melting points are uncorrected and (dec) indicates decomposition.Temperatures are given in degrees Celsius (°C); unless otherwise stated, operations are carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 °C. Chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) is carried out on silica gel plates. NMR data is in the delta values of major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Conventional abbreviations for signal shape are used. Coupling constants (J) are given in Hz. For mass spectra (MS), the lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks. Solvent mixture compositions are given as volume percentages or volume ratios. In cases where the NMR spectra are complex, only diagnostic signals are reported.

[0022] Terms and abbreviations:BOP = benzotriazole- l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphateBOC = tert-butyloxycarbonyl,CAN = ammonium cerium (IV) nitrate,DBU = l,8-diazabicyclo[5.4.0]undec-7-eneDIPEA = diisopropylethylamine,DMF = N,N-dimethylformamide,DMSO = dimethyl sulfoxide,Et2O = diethyl ether,Attorney Docket No.: IT-212-PCTEtOAc = ethyl acetate,equiv. = equivalent(s),h = hour(s),HPLC =high performance liquid chromatography,LDA = lithium diisopropylamide,LiHMDS = lithium bis(trimethylsilyl)amide,MeOH = methanol,NBS = N-bromosuccinimide,NCS = N-chlorosuccinimide,NMP = N-methyl-2-pyrrolidone,NaHCCh = sodium bicarbonate,NH4OH = ammonium hydroxide,Pd2(dba)s = tris[dibenzylideneacetone]dipalladium(0)PMB = p-methoxybenzyl,POCI3 = phosphorous oxychloride,SOCI2 = thionyl chloride,TFA = tri fluoroacetic acid,TFMSA = trifluoromethanesulfonic acid, andTHF = tetrahydrofuran.

[0023] The synthetic methods in this invention are illustrated below. The significances for the R groups are as set forth above for Formula I unless otherwise indicated.

[0024] In an aspect of the invention, intermediate compounds of formula lib can be synthesized by reacting a compound of formula Ila with malonic acid and acetic anhydride in acetic acid with heating, e.g., to about 90°C for about 3 hours, and then cooled:wherein Ri is H or C1-4 alkyl, e.g., methyl.Attorney Docket No.: IT-212-PCT

[0025] Intermediate lie can be prepared by for example reacting intermediate lib with for example a chlorinating compound such as POCI3, sometimes with small amounts of water and heat, e.g., heating to about 80°C for about 4 hours, and then cooled:(He)

[0026] Intermediate lid may be formed by reacting intermediate lie with for example P^L in a solvent such as DMF and a base such as K2CO3, sodium bicarbonate, cesium carbonate, sodium hydroxide, triethylamine, diisopropylethylamine or the like at room temperature or with heating:base P1— Lwherein P1is a protective group [e.g., p-m ethoxybenzyl group (PMB) orBOC]; L is a leaving group such as a halogen, mesylate, or tosylate. Preferably, P1is PMB and the base is potassium carbonate.

[0027] Intermediate He may be prepared by reacting intermediate Hd with hydrazine or hydrazine hydrate in a solvent such as methanol and with heating, e.g. refluxed for about 4 hours, and then cooled:Attorney Docket No.: IT-212-PCTo(nd) (lie)

[0028] Intermediate IVa may be formed by for example reacting intermediate He with POCI3 and DMF :(He) (IVa) wherein Ri is as defined previously for Formula I, e.g., such as a methyl group.

[0029] Intermediate IVb may be formed by reacting intermediate IVa with for example Fx-X in a solvent such as DMF with a base such as K2CO3 at room temperature (Reaction 1):pi (IVa) <IVb>wherein F1is for example benzyl substituted with a halogen such as 4-bromobenzyl and X is a halogen (e.g., Br).

[0030] Intermediate IVc may be synthesized from intermediate IVb by removing the protective group P1with an appropriate method. For example, if P1is a PMB group, then it can be removed with CAN or TFA / TFMSA at room temperature (Reaction 2):Attorney Docket No.: IT-212-PCTdeprotectionHpl (IVc)(IVb)wherein if P1is BOC, the compound may be deprotected by using acid such as hydrochloric acid or TFA.

[0031] Intermediate IVd can be prepared by reacting intermediate IVc with for example a chlorinating compound such as POCI3 and optionally with heating, e.g., reflux for about 2 days or more, or heated at 150~200°C for about 5-10 minutes in a sealed vial with a microwave instrument and then cooled (Reaction 3):IH (IVd)(IVc)

[0032] Intermediate IVe can be formed by reacting intermediate IVd with an amino alcohol under basic condition in a solvent such as DMF or NMP and heated then cooled (Reaction 4A):wherein Ri, R2, R3, and R4 are as defined previously for Formula I.Attorney Docket No.: IT-212-PCT

[0033] Alternatively, intermediate IVe can be synthesized directly from intermediate IVc by reacting with an amino alcohol and a coupling reagent such as BOP in the presence of a base such as DBU (Reaction 4B):(IVc)wherein Ri, R2, R3, and R4 are as defined previously for Formula I.

[0034] Intermediate IVf may be formed by reacting a compound of IVe with, for example, a dehydrating / halogenating agent such as SOCI2 in a solvent such as CH2CI2 at room temperature or heated at 35 °C for several hours, and then cooled (Reaction 5):Q

[0035] Intermediate IVg may be formed by reacting intermediate IVf with, for example, catalysts such as a copper salt and 2,2,6,6-tetramethylheptane-3,5-dione and a base such as cesium carbonate in a solvent such as NMP with heat for several hours (Reaction 6):Attorney Docket No.: IT-212-PCT(IVf) (IVg)wherein, F2is a diaryl ether.

[0036] Intermediate IVh may be formed by reacting intermediate IVg with, for example, TFA and TFMSA in a solvent such as CH2CI2 at room temperature (Reaction 7):

[0037] Intermediate IVi may be formed by reacting intermediate IVh withR5- (CH2)n“ L in the presence of a base, for example K2CO3, in a solvent such as DMF at room temperature (Reaction 8):Attorney Docket No.: IT-212-PCT(IVh) wherein Rs and n are as defined previously for Formula I and L is a leaving group such as a halogen (e.g., Br).

[0038] Intermediate IVj wherein X is halogen (e.g., Cl) may be formed by reacting intermediate IVi with, for example, a halogenating agent such as hexachloroethane, NCS, NBS, I2 and a base such as LiHMDS in a solvent such as THF at low temperature (Reaction 9):

[0039] Compounds of the Invention may be formed by reacting intermediate IVj wherein X is halogen (e.g., Cl) with NHReR? and a catalyst with heating (Reaction 10):Attorney Docket No.: IT-212-PCTFormula I wherein Re and R7 are as defined previously for Formula I.

[0040] In another aspect of the invention, intermediate Ilf may be prepared by reacting intermediate lie with hydrazine or hydrazine hydrate in a solvent such as methoxy ethanol and refluxed for about 30 minutes and then cooled:NH2NH2NH2

[0041] Intermediate Va can be synthesized by reacting a compound of formula He with for example an aryl isothiocyanate or isocyanate in a solvent such as DMF and heated at 110° C for about 2 days and then cooled:Pipi(lie) (Va)wherein Re is as defined previously for Formula I.

[0042] Intermediate Vb may be formed by removing the protective group P1with an appropriate method. For example, if P1is a PMB group, then it can be removed with AlCh orAttorney Docket No.: IT-212-PCTTFA / TFMSA at room temperature. Intermediate Vb may also be prepared directly from a compound of Ilf using the similar methods, but the yields are relatively low.(Va) (Vb)Rp N — C — 0 or Rg N — C — S DMF, heating(Ilf) (Vb)

[0043] Intermediate Vc can be prepared by for example reacting intermediate Vb with for example a chlorinating compound such as POCI3. The reaction may be carried out at atmospheric pressure and refluxed for about 2 days or heated at 150~200°C for about 10 minutes in a sealed vial with a microwave instrument and then cooled (Reaction 11):H(Vb) (Vc)

[0044] Intermediate Vd can be prepared by reacting intermediate Vc with an amino alcohol under basic condition in a solvent such as DMF. The reaction may be heated overnight and then cooled (Reaction 12):Attorney Docket No.: IT-212-PCT(Vc) wherein Ri, R2, R3, R4, and Re are as defined previously for Formula I.

[0045] Intermediate Ve can be formed by reacting intermediate Vd with for example a dehydrating agent such as SOCI2 in a solvent such as CH2CI2 at room temperature overnight or heated at 35° C for about 4 hours, and then cooled (Reaction 13):

[0046] Compounds of the Invention may be formed by reacting intermediate Ve with for example Rs-(CH2)n“L in a solvent such as DMF and a base such as K2CO3 at room temperature or with heating (Reaction 14):Attorney Docket No.: IT-212-PCT(Ve)Compounds of Formula Iwherein Rs is as defined previously for Formula I and L is a leaving group such as a halogen, mesylate, or tosylate.

[0047] In some embodiments, R5 is phenyl substituted with -CH(CH3)-O-C(O)-Ra, wherein Ra is -N(Rb)(Rc) or heteroaryl (e.g., imidazolyl), wherein Rb and Rcare independently C1-4 alkyl (e.g. methyl). The compound of formula VIb may be formed by reacting the compound of formula Via with X-C(O)-Ra(where X is chloride or imidazole) in the presence of 4-dimethylaminopyridine in DCM at room temperature.Attorney Docket No.: IT-212-PCT(Vlb)

[0048] In some embodiments, Rs is phenyl substituted with -CH(CH3)-O-C(O)-Ra, wherein Ra is -CH(NH2)-Rd, wherein Rd is H or C1-4 alkyl (e.g. isopropyl). Intermediate compound of formula Vic may be formed by reacting the compound of formula Via with Boc (tert-butoxylcarbonyl)-amino acid in the presence of N,N'-dicyclohexyl-carbodiimide and 4-dimethylaminopyridine at room temperature. The compound of formula Vid may be formed by removing the Boc group from the Intermediate compound of formula Vic.Attorney Docket No.: IT-212-PCT(Vid)

[0049] In some embodiments, Rs is phenyl substituted with -C(=C)-O-Re, wherein Reis Ci-4 alkyl (e.g., methyl, ethyl, or butyl). The compound of formula Vllb may be formed by reacting the compound of formula Vila with an alkyl vinyl ether (Re-O-CH=CH2) in the presence of Pd(OAc)2, dppp, K2CO3 and DMF with heat.+ RS-O-CH=CH2(Vila)Attorney Docket No.: IT-212-PCT

[0050] Alternatively, The compound of formula Vllb may be formed by reacting the compound of formula Villa with the compound of formula VUIb in the presence of an alcohol (e.g., methanol, alcohol) and an acid (e.g., p-toluenesulfonic acid, H2SO4)with heat, followed by reaction with methylene chloride.

[0051] In some embodiments, Rs is phenyl substituted with-CH(CH3)-O-CH2-O- C(O)-Rf, wherein Rfis Ci-4 alkyl (e.g., methyl). The compound of formula Vie may be formed by reacting the compound of formula Via with a base (e.g., sodium hydride) at room temperature, followed by reaction with chloromethyl alkanoate (Rf -COO-CH2-CI) at 20 °C.Attorney Docket No.: IT-212-PCT(Via)

[0052] In some embodiments, R5 is phenyl substituted with-C(O)-N(Rg)(Rh), wherein Rgand Rh are independently C1-4 alkyl (e.g., methyl). The compound of formula Vile may be formed by reacting the compound of formula Vila with dialkylamine hydrochloride as follows. To chamber A of a two-chamber reactor at room temperature are added palladium(II) acetate, xantphos and sodium carbonate, and dialkylamine hydrochloride (e.g., dimethylamine hydrochloride), followed by the compound of formula Vila in anhydrous toluene. To chamber B are added anhydrous toluene, mesyl chloride and formic acid. The reaction mixture is degassed and backfilled with argon twice. Triethylamine is added by injection through the septum in chamber B at room temperature. After 2 minutes, the reactor is immersed in an oil-bath at 100 °C and the reaction mixture is stirred to obtain the compound of formula Vile.Attorney Docket No.: IT-212-PCTMethods of using Compounds of the Invention

[0053] The Compounds of the Invention are useful to inhibit PDE1 activity in a patient in need thereof, for example, for example in the prophylaxis or treatment of a variety of diseases including any one or more of the following conditions:(i) Neurodegenerative diseases, including Parkinson’s disease, restless leg, tremors, dyskinesias, Huntington’s disease, Alzheimer’s disease, and drug- induced movement disorders, and related disorders and diseases as described in International Application No. PCT / US2014 / 030412 and PCT / US2015 / 050814, the contents of which are incorporated herein by reference;(ii) Neuroinflammation and / or diseases or disorders associated with neuroinflammation and / or microglial function, such as neuroinflammation associated with neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and demyelinating conditions, e.g., multiple sclerosis and prion diseases; neuroinflammation associated with damage sue to stroke, cardiac arrest, hypoxia, intracerebralAttorney Docket No.: IT-212-PCThemorrhage or traumatic brain injury; neuroinflammation associated with chronic CNS infections, e.g., Lyme disease, syphilis, or CNS infection consequent to an immunosuppressive condition, e.g., HIV dementia; and neuroinflammation consequent to chemotherapy; and related disorders as described in International Application No. PCT / US2017 / 051220, the contents of which are incorporated herein by reference;(iii) Mental disorders, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive impairment, e.g., cognitive impairment of schizophrenia, Tourette’s syndrome, autism, fragile X syndrome, psychostimulant withdrawal, chemobrain (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself), and drug addiction, and related disorders as described in International Application No.PCT / US2014 / 025666, the contents of which are incorporated herein by reference;(iv) Disorders associated with dementia, including disorders associated with Huntington's disease, Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis, Down syndrome, Elderly depression, Wernicke- Korsakoff s syndrome, corticobasal degenerations, and prion disease; disorders associated with mild cognition impairment and dementing illnesses including senile dementia, Alzheimer’s disease, Pick’s disease, frontotemporal dementia, parasupranculear palsy, dementia with Lewy bodies, and vascular dementia; and behavioral or mood disorders such as agitation / irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts, psychosis, depression and sleep disorders in patients suffering from dementia, particularly Alzheimer’s disease (e.g., sleep maintenance insomnia, advanced sleep-phase syndrome, delayed sleepphase syndrome, frequent awakenings, and waking up feeling unrefreshed); and related disorders as described in International Application No. PCT / US2017 / 024575, the contents of which are incorporated herein by reference;(v) Circulatory and cardiovascular disorders, including cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonaryAttorney Docket No.: IT-212-PCThypertension, e.g., pulmonary arterial hypertension, and sexual dysfunction, including cardiovascular diseases and related disorders as described in International Application No. PCT / US2014 / 016741, the contents of which are incorporated herein by reference;(vi) Respiratory and inflammatory disorders, including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases, including the inflammatory disorders as described in International Application No. PCT7US2019 / 053032, the contents of which are incorporated herein by reference;(vii) Diseases that may be alleviated by the enhancement of progesterone- signaling such as female sexual dysfunction, including the diseases as described in International Application No. PCT7US2007 / 024866;(viii) Ophthalmic disorders, such as glaucoma, or elevated intraocular pressure, and other disorders as described in International Application No.PCT / US2010 / 000534, the contents of which are incorporated herein by reference;(ix) Cancers or tumors, including acoustic neuroma / vestibular schwannoma, astrocytoma, chordoma, CNS lymphoma, craniopharyngioma, gliomas (e.g., glioblastoma multiforme, Brain stem glioma, ependymoma, mixed glioma, optic nerve glioma), subependymoma, medulloblastoma, meningioma, metastatic brain tumors, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET), schwannoma, adenomas (e.g., basophilic adenoma, eosinophilic adenoma, chromophobe adenoma, parathyroid adenoma, islet adenoma, fibroadenoma), fibroids (fibrous histiocytoma), fibromas, hemangiomas, lipomas (e.g., angiolipoma, myelolipoma, fibrolipoma, spindle cell lipoma, hibernoma, atypical lipoma), myxoma, osteoma, leukemias, preleukemias, rhadomyoma, papilloma, seborrheic keratosis, skin adnexal tumors, hepatic adenomas, renal tubular adenoma, bile duct adenoma, transitional cell papilloma, hydatidiform moles, ganglioneuroma, meningoma, neurilemmoma, neurofibroma, C cell hyperplasia, pheochromocytoma, insulinoma, gastrinoma, carcinoids, chemodectoma, paraganglioma, nevus, actinic keratosis, cervical dysplasia, metaplasia (e.g., metaplasia of the lung),Attorney Docket No.: IT-212-PCTleukoplakia, hemangioma, lymphangioma, carcinoma (e.g., squamous cell carcinoma, epidermoid carcinoma, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, cholangiocarcinoma, transitional cell carcinoma, embryonal cell carcinoma, parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, oat cell carcinoma, islet cell carcinoma, malignant carcinoid,), sarcoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, neurofibrosarcoma), blastoma (e.g., medulloblastoma and glioblastoma, types of brain tumor, retinoblastoma, a tumor in the retina of the eye, osteoblastoma, bone tumors, neuroblastoma), germ cell tumor, mesothelioma, malignant skin adnexal tumors, hypernephroma, seminoma, glioma, malignant meningioma, malignant shwannoma, malignant pheochromocytoma, malignant paraganglioma, melanoma, mercell cell neoplasm, cystosarcoma phylloides, Wilms tumor, colorectal cancer, breast cancer, and related disorders as described in International Application No. PCT / US2019 / 033941, PCT / US2020 / 012578, PCT / US2020 / 049248, and PCT / US2023 / 064202, the contents of which are incorporated herein by reference;(x) Any disease or condition characterized by low levels of cAMP / PKA and / or cGMP / PKG (or inhibition of cAMP and / or cGMP signaling pathways) in cells expressing PDE1, such as angina, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, an inflammatory disease or disorder, fibrosis, cardiac hypertrophy, vascular remodeling, a connective tissue disease or disorder (e.g., Marfan Syndrome), chronic heart failure (e.g., chronic systolic heart failure), myocardial inflammation, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunctions (e.g., myocardial infarction, ventricular expansion), vascular leakage (i.e., consequent to hypoxia), acute vascular inflammation (i.e., consequent toAttorney Docket No.: IT-212-PCTvascular injury), cardiac hypertrophy muscular dystrophy (e.g., Duchenne muscular dystrophy), or amyotrophic lateral sclerosis, and related disorders as described in U.S. Pub. No. 2020 / 0289519, the contents of which are incorporated herein by reference;(xi) Cardiotoxicity consequent to administration of a chemotherapeutic agent and / or radiation therapy, as described in U.S. Pub. No. 2020 / 0289519, the contents of which are incorporated herein by reference;(xii) Renal disorders, including kidney fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, nephritis, and related disorders as described in International Application No. PCT / US2020 / 047451, the contents of which are incorporated herein by reference;(xiii) obesity, metabolic disorders, 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;(xiv) nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting) and / or(xv) Any disease or condition characterized by reduced dopamine DI receptor signaling activity, including but not limited to attention deficit, cognition, PTSD, memory, and / or inhibitory processing, as discussed in International Application No. PCT / US2019 / 057260 and International Application No. PCT / US2020 / 062400, the contents of each of which are incorporated herein by reference.

[0054] In an embodiment, the invention provides methods of treatment or prophylaxis for narcolepsy. In this embodiment, PDE1 Inhibitors may be used as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents. Thus, the invention further comprises a method of treating narcolepsy comprising administering simultaneously, sequentially, or contemporaneously therapeutically effective amounts of (i) a PDE1 Inhibitor, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, and(ii) a compound to promote wakefulness or regulate sleep, e.g., selected from (a) central nervous system stimulants-amphetamines and amphetamine like compounds, e.g., methylphenidate, dextroamphetamine, methamphetamine, and pemoline; (b)Attorney Docket No.: IT-212-PCTmodafinil, (c) antidepressants, e.g., tricyclics (including imipramine, desipramine, clomipramine, and protriptyline) and selective serotonin reuptake inhibitors (including fluoxetine and sertraline); and / or (d) gamma hydroxybutyrate (GHB), in free or pharmaceutically acceptable salt form, to a human or animal patient in need thereof.

[0055] In another embodiment, the invention further provides methods of treatment or prophylaxis of a condition which may be alleviated by the enhancement of the progesterone signaling comprising administering an effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, to a human or animal patient in need thereof.Diseases or conditions that may be ameliorated by enhancement of progesterone signaling include, but are not limited to, female sexual dysfunction, secondary amenorrhea (e.g., exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism), pre-menstrual syndrome, premature labor, infertility, for example infertility due to repeated miscarriage, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, autoimmune disease, multiple sclerosis, prostate enlargement, prostate cancer, and hypothyroidism. For example, by enhancing progesterone signaling, the PDE1 inhibitors may be used to encourage egg implantation through effects on the lining of uterus, and to help maintain pregnancy in women who are prone to miscarriage due to immune response to pregnancy or low progesterone function. The novel PDE1 inhibitors, e.g., as described herein, may also be useful to enhance the effectiveness of hormone replacement therapy, e.g., administered in combination with estrogen / estradiol / estriol and / or progesterone / progestins in postmenopausal women, and estrogen-induced endometrial hyperplasia and carcinoma. The methods of the invention are also useful for animal breeding, for example to induce sexual receptivity and / or estrus in a nonhuman female mammal to be bred.

[0056] In this embodiment, PDE1 Inhibitors may be used in the foregoing methods of treatment or prophylaxis as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents, for example in conjunction with hormone replacement therapy. Thus, the invention further comprises a method of treating disorders that may be ameliorated by enhancement of progesterone signaling comprising administering simultaneously, sequentially, or contemporaneously therapeutically effective amounts of (i) a PDE1 Inhibitor, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, andAttorney Docket No.: IT-212-PCT(ii) a hormone, e.g., selected from estrogen and estrogen analogues (e.g., estradiol, estriol, estradiol esters) and progesterone and progesterone analogues (e.g., progestins) in free or pharmaceutically acceptable salt form, to a human or animal patient in need thereof.

[0057] In yet another embodiment, the invention provides a method of treating neuroinflammation and / or diseases or disorders associated with neuroinflammation and / or microglial function comprising administering a therapeutically acceptable amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form to a patient in need thereof, i.e., a patient with increased levels of one or more pro-inflammatory cytokines (e.g., ILip, TNF-a, and Ccl2, or combinations thereof). In this embodiment, a therapeutic amount of a Compound of the Invention is an amount effective to (i) reduce or inhibit activation of Ml microglia, and / or (ii) an amount effective to reduce levels of one or more pro-inflammatory cytokines (e.g., ILip, TNF- a, and Ccl2, or combination thereof); to a patient in need thereof. Neuroinflammation and / or diseases or disorders associated with neuroinflammation and / or microglial function include, but are not limited to, neuroinflammation associated with neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and demyelinating conditions, e.g., multiple sclerosis and prion diseases; neuroinflammation associated with damage sue to stroke, cardiac arrest, hypoxia, intracerebral hemorrhage or traumatic brain injury; neuroinflammation associated with chronic CNS infections, e.g., Lyme disease, syphilis, chemobrain (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself), or CNS infection consequent to an immunosuppressive condition, e.g., HIV dementia; and neuroinflammation consequent to chemotherapy.

[0058] The invention further provides a method of promoting resolution of inflammation for the treatment or prophylaxis of inflammation and / or diseases related to inflammation and / or microglial function, the method comprising administering a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, to a patient in need thereof. In this context, it is believed that an effective amount of a Compound of the Invention is an amount effective to promote macrophage activation from the Ml activation state to the M2 activation state.Diseases or disorders associated with inflammation and / or microglial function, e.g., including bacterial infections (e.g., Salmonella typhi, Salmonella lyphimurium. Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium aviumAttorney Docket No.: IT-212-PCTinfections),' viral infections (e.g., African Swine Fever Virus, Classical Swine Fever Virus, Dengue Virus, Foot and Mouth Disease Virus, Human Immunodeficiency Virus (HIV) (e.g., HIV1), Influenza A Virus, Porcine Circovirus-2, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Pseudorabies Virus, Respiratory Syncytial Virus, Severe Acute Respiratory Syndrome Coronavirus, West Nile Virus, Viral Hepatitis (e.g., Hepatitis A, Hepatitis B, Hepatitis C), and coronavirus infections (e.g., a Severe Acute Respiratory Syndrome Coronavirus (e.g., SARS-CoV, SARS-CoV-2, COVID-19), a Middle East Respiratory Syndrome coronavirus (MERS), 229E coronavirus, NL63 coronavirus, OC43 coronavirus, HKU1 coronavirus)) (see U.S. Publication No. 2021 / 0369715, the contents of which are incorporated herein by reference); parasitic infestations (e.g., Taenia crassiceps, Toxoplasma gondii, Leishmania infantum, Schistosoma mansoni infestations),' atopic dermatitis; pneumonia; cardiovascular diseases, such as atherosclerosis; and insulin resistance; asthma; pulmonary fibrosis; cardiac obstructive pulmonary disease (COPD); neuropathic pain; stroke; diabetes; sepsis; nonalcoholic steatoheptatitis (NASH); autoimmune hepatitis; systemic lupus erythematosus (SLE); wound healing; pleurisy; peritonitis; and cystic fibrosis.

[0059] In another embodiment, the invention provides a method for preventing or treating obesity, metabolic disorders, 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 acceptable amount of a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, to a patient in need thereof..

[0060] In another embodiment, the invention provides a method for preventing or treating nausea and / or vomiting, e.g., CINV (chemotherapy -induced nausea and vomiting), comprising administering a pharmaceutically acceptable amount of a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, either alone or in combination with an antiemetic agent, such as antipsychotic agents, e.g., olanzapine, to a patient in need thereof.

[0061] In another embodiment, the invention provides a method for treating a cancer or tumor characterized by an increased expression of PDE1 (i.e., PDE1C) relative to normal cells of the same tissue type as the cancerous or tumorous cells comprising administering a pharmaceutically acceptable amount of a compound according to Formula I, e.g., any ofAttorney Docket No.: IT-212-PCTCompounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, either alone or in combination with an antitumor agent, chemotherapeutic, gene therapeutic, immunologic treatment, corticosteroid, and / or an antihistamine. By increased expression of PDE1 it is means an increased PDE1 RNA expression, DNA copy number, PDE1 binding (e.g., PET or radio-isotope retention of PDE1 inhibitor molecules), or PDE1 enzymatic activity (e.g., as measured in an enzymatic assay or as reflected in low levels of cAMP in the cancer cells or subcellular domain, e.g. microtubule domains, of the cancer cells) relative to normal cells of the same tissue type as the cancer or tumor cells. Such cancers or tumors include, but are not limited to, acoustic neuroma / vestibular schwannoma, astrocytoma, chordoma, CNS lymphoma, craniopharyngioma, gliomas (e.g., Brain stem glioma, ependymoma, mixed glioma, optic nerve glioma), subependymoma, medulloblastoma, meningioma, metastatic brain tumors, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET), schwannoma, adenomas (e.g., basophilic adenoma, eosinophilic adenoma, chromophobe adenoma, parathyroid adenoma, islet adenoma, fibroadenoma), fibroids (fibrous histiocytoma), fibromas, hemangiomas, lipomas (e.g., angiolipoma, myelolipoma, fibrolipoma, spindle cell lipoma, hibernoma, atypical lipoma), myxoma, osteoma, preleukemias, rhadomyoma, papilloma, seborrheic keratosis, skin adnexal tumors, hepatic adenomas, renal tubular adenoma, bile duct adenoma, transitional cell papilloma, hydatidiform moles, ganglioneuroma, meningoma, neurilemmoma, neurofibroma, C cell hyperplasia, pheochromocytoma, insulinoma, gastrinoma, carcinoids, chemodectoma, paraganglioma, nevus, actinic keratosis, cervical dysplasia, metaplasia (e.g., metaplasia of the lung), leukoplakia, hemangioma, lymphangioma, carcinoma (e.g., squamous cell carcinoma, epidermoid carcinoma, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, cholangiocarcinoma, transitional cell carcinoma, embryonal cell carcinoma, parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, oat cell carcinoma, islet cell carcinoma, malignant carcinoid,), sarcoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, neurofibrosarcoma), blastoma (e.g., medulloblastoma and glioblastoma, types of brain tumor, retinoblastoma, a tumor in the retina of the eye, osteoblastoma, bone tumors, neuroblastoma), germ cell tumor, mesothelioma, malignant skin adnexal tumors, hypernephroma, seminoma, glioma, malignant meningioma, malignant shwannoma, malignant pheochromocytoma, malignant paraganglioma, melanoma, mercell cell neoplasm,Attorney Docket No.: IT-212-PCTcystosarcoma phylloides, or Wilms tumor.

[0062] In another embodiment, the present application provides a method of inhibiting cytokine release syndrome, comprising administering an effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, to a patient in need thereof, e.g. wherein the patient is suffering from cancer and is receiving one or more of chemotherapeutic treatment, immunologic treatment, gene therapy and / or antibody therapy (including antibodies directed to cancer antigens and / or antibodies to immune checkpoint targets), and wherein the method optionally further comprises administration of corticosteroids and / antihistamines to the patient.

[0063] The invention also provides a method for the prophylaxis or treatment of disorders associated with dementia comprising administering to the patient a combination of (i) a therapeutically effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form; and (ii) a therapeutically effective amount of a 5-HT2A or 5-HT2A / D2 receptor ligand, for example a substituted heterocycle fused gamma-carbolines as described herein, in free, pharmaceutically acceptable salt form. Also encompassed by the present invention are compositions comprising (i) a therapeutically effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form; and (ii) a therapeutically effective amount of a 5-HT2A or 5-HT2A / D2 receptor ligand. Similar methods and compositions are set forth in International Application No. PCT / US2017 / 024575, the contents of which are incorporated herein by reference.

[0064] In this embodiment, the disorders associated with dementia include disorders associated with Huntington's disease, Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis, Down syndrome, Elderly depression, Wernicke-Korsakoff s syndrome, corticobasal degenerations, and prion disease; disorders associated with mild cognition impairment and dementing illnesses including senile dementia, Alzheimer’s disease, Pick’s disease, frontotemporal dementia, parasupranculear palsy, dementia with Lewy bodies, and vascular dementia; and behavioral or mood disorders such as agitation / irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts, psychosis, depression and sleep disorders in patients suffering from dementia, particularly Alzheimer’s disease (e.g., sleep maintenance insomnia, advanced sleep-phase syndrome, delayed sleep-phaseAttorney Docket No.: IT-212-PCTsyndrome, frequent awakenings, and waking up feeling unrefreshed).

[0065] The invention also provides a method for treating diseases characterized by disruption of or damage to cGMP / PKG and / or cAMP / PKA signaling mediated pathways, e.g., as a result of increased expression of PDE1 or decreased expression of cGMP / PKG or cAMP / PKA activity due to inhibition or reduced levels of inducers of cyclic nucleotide synthesis, such as dopamine and nitric oxide (NO). It is believed that by inhibiting PDE1, for example, that this action could reverse or prevent the attenuation of cGMP / PKG or cAMP / PKA signaling (e.g., enhance cGMP or cAMP, respectively). Therefore, administration or use of a preferred PDE1 inhibitor as described herein, e.g., a PDE1 inhibitor as hereinbefore described could provide a potential means to provide a treatment for various cardiovascular diseases and disorders.

[0066] In this embodiment, the present invention provides for a method of enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and / or lusitropic dysfunction comprising administration of an effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, to a patient in need thereof. Diseases and conditions characterized by inotropic and / or lusitropic dysfunction include, but are not limited to, angina, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, an inflammatory disease or disorder, fibrosis, cardiac hypertrophy, vascular remodeling, a connective tissue disease or disorder (e.g., Marfan Syndrome), chronic heart failure, myocardial inflammation, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunctions (e.g., myocardial infarction, ventricular expansion), vascular leakage (i.e., consequent to hypoxia), acute vascular inflammation (i.e., consequent to vascular injury), cardiac hypertrophy muscular dystrophy (e.g., Duchenne muscular dystrophy), or amyotrophic lateral sclerosis. In such methods, the Compound of the Invention may be administered in conjunction with an additional therapeutic agent, such as an adenosine A2 agonist, a beta-adrenergic receptor antagonist (i.e., a beta-blocker); ACE inhibitor, a calcium channel blocker; angiotensin receptor blockers (ARBs); neprilysin inhibitors or combinations thereof.

[0067] In a related embodiment, the invention provides for a method of treating, mitigating or preventing cardiotoxicity consequent to administration of a chemotherapeuticAttorney Docket No.: IT-212-PCTagent and / or radiation therapy, comprising administration of an effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form to a patient in need thereof. Chemotherapeutic agents known to cause cardiotoxicity include, but are not limited to, cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine, mitomycin, paclitaxel, etoposide, teniposide, the vinca alkaloids, fluorouracil, cytarabine, amsacrine, cladribine, asparaginase, tretinoin, pentostatin, and antagonists of human epidermal growth factor receptor 2 (HER2) / neu, e.g., trastuzumab.

[0068] In yet another related embodiment, the invention provides for a method of treating diseases or disorders mediated by cyclic nucleotides (cAMP or cGMP) and / or epoxygenated fatty acids, comprising administering an effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form to a patient in need thereof, optionally in combination with a soluble epoxide hydrolase (sEH) inhibitor. Such diseases and disorders include, but are not limited to, pain, neurodegenerative disorders, mental disorders, circulatory and cardiovascular disorders, respiratory disorders, inflammatory disorders, and other disorders set forth in International Application No. PCT / US2020 / 066138, the contents of which are incorporated herein by reference in their entirety.

[0069] Methods of treating a renal disorder, including but not limited to kidney fibrosis, chronic kidney disease, renal failure, glomerulosclerosis and nephritis, by administering to a patient in need thereof an effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, are also contemplated. The renal disorder being treated may be consequent to diabetes, an injury to a kidney, high blood pressure, a cancerous growth (e.g., polycystic kidney disease), or a cardiovascular disorder (e.g. angina, stroke, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, myocardial, angina, and stroke, hypertension, an inflammatory disease or disorder, fibrosis, cardiac hypertrophy, vascular remodeling, and an connective tissue disease or disorder, e.g., Marfan Syndrome).

[0070] The present disclosure also provides a method for enhancing or potentiating dopamine DI intracellular signaling activity in a cell or tissue comprising contacting said cell or tissue with an amount of a Compound of the Invention, e.g., a compound according toAttorney Docket No.: IT-212-PCTFormula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, sufficient to inhibit PDE1 activity.

[0071] The present disclosure also provides a method for treating a PDEl-related disorder, a dopamine DI receptor intracellular signaling pathway disorder, or disorders that may be alleviated by the enhancement of the progesterone signaling pathway in a patient in need thereof comprising administering to the patient an effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, that inhibits PDE1, wherein PDE1 activity modulates phosphorylation of DARPP-32 and / or the GluRl AMPA receptor.

[0072] The present disclosure further provides a method for enhancing the positive effects, and mitigating side effects, of dopamine replacement therapy in a patient suffering from a disease or disorder associated with the dopamine DI receptor intracellular pathway, comprising administering a therapeutically effective amount of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, to a patient in need thereof (i.e., a patient suffering from Parkinson’s Disease and receiving dopamine replacement therapy). In some aspects of this embodiment, the side effects encompass dyskinesias and motor impairment. Methods for enhancing the positive effects, and mitigating side effects, of dopamine replacement therapy in a patient suffering from a disease or disorder associated with the dopamine DI receptor intracellular pathway are discussed in International Application No. PCT / US2019 / 57260, the contents of which are incorporated herein by reference.

[0073] In another aspect, the present disclosure also provides a method for the treatment for glaucoma or elevated intraocular pressure comprising topical administration of a therapeutically effective amount of a PDE1 Inhibitor of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form, in an ophthalmically compatible carrier to the eye of a patient in need thereof. However, treatment may alternatively include a systemic therapy. Systemic therapy includes treatment that can directly reach the bloodstream, or oral methods of administration, for example.

[0074] The present disclosure further provides a pharmaceutical composition for topical ophthalmic use comprising a PDE1 inhibitor; for example an ophthalmic solution, suspension, cream or ointment comprising a PDE1 Inhibitor of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free orAttorney Docket No.: IT-212-PCTophthalmologically acceptable salt form, in combination or association with an ophthalmologically acceptable diluent or carrier, optionally administered sequentially or simultaneously with a second drug useful for treatment of glaucoma or elevated intraocular pressure.

[0075] In addition to the above-mentioned methods, the PDE1 Inhibitor of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, in free or pharmaceutically acceptable salt form is useful to treat psychosis, for example, any conditions characterized by psychotic symptoms such as hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder.

[0076] PDE 1 Inhibitors may be used in the foregoing methods of treatment or prophylaxis as a sole therapeutic agent, but may also be used in combination or for coadministration with other active agents known to be effective for the treatment or prophylaxis of a particular disease or disorder.

[0077] The present disclosure also provides(i) a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, as hereinbefore described, in free or pharmaceutically acceptable salt form for example for use in any method or in the treatment of any disease or condition as hereinbefore set forth, (ii) the use of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, as hereinbefore described, in free or pharmaceutically acceptable salt form, (in the manufacture of a medicament) for treating any disease or condition as hereinbefore set forth, (iii) a pharmaceutical composition comprising a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, as hereinbefore described, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier, and(iv) a pharmaceutical composition comprising a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, as hereinbefore described, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptableAttorney Docket No.: IT-212-PCTdiluent or carrier for use in the treatment of any disease or condition as hereinbefore set forth.

[0078] Therefore, the present disclosure provides use of a Compound of the Invention, e.g., a compound according to Formula I, e.g., any of Compounds 1.0 to 1.84, as hereinbefore described, in free or pharmaceutically acceptable salt form, or a Compound of the Invention in a pharmaceutical composition form (in the manufacture of a medicament) for the treatment or prophylactic treatment of any one or more of the diseases or conditions as hereinbefore set forth.

[0079] The phrase “Compounds of the Invention” or “PDE1 Inhibitor of the Invention” encompasses any and all of the compounds disclosed herewith, e.g., compounds according to Formula I, e.g., any of Compounds 1.0 to 1.84, as hereinbefore described, in free or salt form.

[0080] The words “treatment” and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease. In one embodiment, the invention provides a method for the treatment of the disease or disorder disclosed herein. In another embodiment, the invention provides a method for the prophylaxis of a disease or disorder as disclosed herein.

[0081] For methods of treatment, the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.

[0082] The term “patient” includes human or non-human (i.e., animal) patient. In one embodiment, the invention encompasses both human and nonhuman. In another embodiment, the invention encompasses nonhuman. In other embodiment, the term encompasses human.

[0083] The term “comprising” as used in this disclosure is intended to be open-ended and does not exclude additional, unrecited elements or method steps.

[0084] Compounds of the Invention, in free or pharmaceutically acceptable salt form, may be used as a sole therapeutic agent, but may also be used in combination or for coadministration with other active agents. For example, as Compounds of the Invention potentiate the activity of DI agonists, such as dopamine, they may be simultaneously, sequentially, or contemporaneously administered with conventional dopaminergic medications, such as levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, e.g., in the treatment of a patient having Parkinson’s disease. In addition, the novel PDE1 inhibitors, e.g., as described herein, mayAttorney Docket No.: IT-212-PCTalso be administered in combination with estrogen / estradiol / estriol and / or progesterone / progestins to enhance the effectiveness of hormone replacement therapy or treatment of estrogen-induced endometrial hyperplasia or carcinoma. The novel PDE1 inhibitors as described herein may also be administered in combination with an antitumor agent, chemotherapeutic, gene therapeutic, immunologic treatment, corticosteroid, and / or an antihistamine to treat a cancer or tumor characterized by an increased expression of PDE1. The Compounds of the Invention may also be administered in combination with a therapeutically effective amount of a 5-HT2A or 5-HT2A / D2 receptor ligand for the prophylaxis or treatment of disorders associated with dementia. In addition, the novel PDE1 inhibitors of the Invention may be administered in combination with an adenosine A2 agonist for the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and / or lusitropic dysfunction. Furthermore, the Compounds of the Invention may be administered in combination with a soluble epoxide hydrolase (she) inhibitor in a method of treating diseases or disorders mediated by cAMP or cGMP and / or epoxygenated fatty acids.

[0085] Dosages employed in practicing the present invention will of course vary depending, e.g., on the particular disease or condition to be treated, the particular Compound of the Invention used, the mode of administration, and the therapy desired. Compounds of the Invention may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g., for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration 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 will accordingly be in the range of from about 0.75 to 150 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 Compound of the Invention, together with a pharmaceutically acceptable diluent or carrier therefor.

[0086] Pharmaceutical compositions comprising Compounds of the Invention 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 orAttorney Docket No.: IT-212-PCTcapsule), 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).EXAMPLES

[0087] The synthetic methods for various Compounds of the Invention are illustrated below. The intermediates of Compounds of the Invention as well as other Compounds of the Invention and their salts may be made using the methods as similarly described below and / or by methods similar to those generally described in the detailed description and by methods known in the chemical art.Example 1: Synthesis of l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl dimethylcarbamate (Compound 1).Compound 1

[0088] Dimethylcarbamyl chloride added dropwise to a mixture of 3-((4-fluorophenyl)amino)-2-(4-(l-hydroxyethyl)benzyl)-5,7,7-trimethyl-7,8-dihydro-2J / imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5J7)-one , 4-dimethylaminopyridine in DCM at room temperature. The resulting mixture is stirred at room temperature until LC-MS analysis confirms the reaction is complete. The reaction solvent is then removed under reduced pressure. The residue is purified by silica-gel column chromatography to give compound 1.Example 2: Synthesis of l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2Z / -imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl 1H-imidazole-l-carboxylate (Compound 2).Attomey Docket No.: IT-212-PCTCompound 2

[0089] To a solution of 3-((4- fluorophenyl)amino)-2-(4-( 1 -hydroxy ethyl)benzyl)-5,7,7-trimethyl-7,8-dihydro-2JT imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5J7)-one and 4-dimethylaminopyridine in DCM at 0 °C is added dropwise l,l'-carbonyldiimidazole. The resulting mixture is warmed up to room temperature and stirred until LC-MS analysis confirms the reaction is complete. The reaction solvent is then removed under reduced pressure. The residue is purified by silica-gel column chromatography to obtain compound 2.Example 3: Synthesis of l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2Z / -imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl L-valinate (Compound 3).Compound 3Step a. l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl (tert-butoxycarbonyl)-L-valinate (Boc-compound 3)

[0090] To a mixture of 3-((4- fluorophenyl)amino)-2-(4-(l -hydroxy ethyl)benzyl)- 5,7,7-trimethyl-7,8-dihydro-2JT imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5J7)-one and Boc- L-valine (223 mg, 1.03 mmol) in CH2CI2 are added N,N'-dicyclohexyl-carbodiimide and 4-Attorney Docket No.: IT-212-PCTdimethylaminopyridine. The resulting mixture is stirred at room temperature until LC-MS analysis confirms the reaction is complete, and then quenched by the addition of water. The mixture is concentrated under reduced pressure. The residue is purified by silica-gel column chromatography to produce Boc-compound 3,Step b. l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl (tert-butoxycarbonyl)-L-valinate (compound 3).

[0091] TFA is added to a solution of Boc-compound 3 in CH2CI2 at room temperature. The resulting solution is stirred at room temperature until LC-MS analysis confirms the reaction is complete. The reaction solvent is removed under reduced pressure. The residue is co-evaporated with toluene three times to remove the excessive TFA to give compound 3.Example 4: Synthesis of l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl glycinate (Compound 4).Compound 4Step a. l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl (tert-butoxycarbonyl)glycinate (BOC-compound 4).

[0092] To a mixture of 3-((4- fluorophenyl)amino)-2-(4-(l -hydroxy ethyl)benzyl)-5,7,7-trimethyl-7,8-dihydro-2Z7 imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5J7)-one and tert-butoxycarbonyl)glycine in CH2CI2 is added dropwise N,N'-dicyclohexyl-carbodiimide, followed by 4-dimethylaminopyridine. The resulting mixture is stirred at room temperature until LC-MS analysis confirms the reaction is complete, and then quenched by the addition of water. The layers are separated, and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over MgSCh and filtered. The filtrate is concentrated underAttorney Docket No.: IT-212-PCTreduced pressure. The residue is purified by silica-gel column chromatography to give Boc-compound 4.Step b. l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phenyl)ethyl glycinate (compound 4).

[0093] TFA is added to a solution of Boc-compound 4 in at room temperature. The resulting solution is stirred at room temperature until LC-MS analysis confirms the reaction is complete. The reaction solvent is removed under reduced pressure. The residue is coevaporated with toluene three times to remove the excessive TFA to give compound 4.Example 5: Synthesis of 3-((4-fluorophenyl)amino)-2-(4-(l-methoxyvinyl)benzyl)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (Compound 5).Compound 5

[0094] Trimethylorthoformate is added to a suspension of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one and p-toluenesulfonic acid monohydrate in methanol at room temperature. The resulting mixture is stirred at 40 °C until LC-MS analysis confirms the reaction is complete. The reaction solvent is removed under reduced pressure and methylene chloride is added to the residue. The resulting mixture is washed with saturated NaHCCh solution The organic layer is dried over Na2SC>4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica-gel column chromatography to give compound 5.Attorney Docket No.: IT-212-PCTExample 6: Synthesis of 2-(4-(l-ethoxyvinyl)benzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (Compound 6).Compound 6

[0095] To a suspension of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one in ethanol at room temperature is added triethylorthoformate, followed by 3 drops of concentrated H2SO4. The resulting suspension is stirred at 80 °C until LC-MS analysis verifies the completion of the reaction. The reaction solvent is then removed under reduced pressure, and methylene chloride is added to the residue. The resulting mixture is washed with saturated NaHCCh solution. The organic layer is dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica-gel column chromatography to yield compound 6.Example 7: Synthesis of 2-(4-(l-butoxyvinyl)benzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (Compound 7).Compound 7

[0096] Potassium carbonate, palladium acetate, l,3-bis(diphenylphosphino)propane and 2-(4-bromobenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one are placed in a 250mL three-neck round bottom flask under argon at room temperature. Butyl vinyl ether, water and DMF are addedAttorney Docket No.: IT-212-PCTvia syringe. The mixture is bubbled with argon at room temperature for 10 mins. The resulting mixture is gradually heated up to 90 °C and stirred until LC-MS analysis confirms the reaction is complete. The reaction solvent is then removed under reduced pressure, and methylene chloride is added to the residue. The resulting suspension is washed with water twice. The organic layer is dried over Na2SC>4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica-gel column chromatography to produce compound 7.Example 8: Synthesis of (l-(4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)phe°°nyl)ethoxy)methyl acetate (Compound 8).Compound 8

[0097] To a suspension of 60% sodium hydride in oil in DMF at -20 °C is added a solution of 3-((4- fluorophenyl)amino)-2-(4-(l-hydroxyethyl)benzyl)-5,7,7-trimethyl-7,8-dihydro-2J / imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5J7)-one in DMF. The resulting suspension is warmed up to room temperature and stirred for 10 minutes. The suspension is then cooled to -20 °C and chloromethyl acetate in DMF is added. The resulting mixture is warmed up to room temperature and stirred until LC-MS analysis confirms that the reaction is finished. The reaction is then quenched with methanol and the solvent is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with water. The organic layer is separated, dried over Na2SC>4, and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica-gel column chromatography to give compound 8.Example 9: Synthesis of 4-((3-((4-fluorophenyl)amino)-5,7,7-trimethyl-4-oxo-4,5,7,8-tetrahydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-2-yl)methyl)-N,N-dimethylbenzamide (Compound 9).Attorney Docket No.: IT-212-PCTCompound 9

[0098] To chamber A of a two-chamber reactor at room temperature are added palladium(II) acetate, xantphos, sodium carbonate, and dimethylamine hydrochloride, followed by 2-(4-bromobenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one in anhydrous toluene. To chamber B are added anhydrous toluene, mesyl chloride and formic acid. The reaction mixture is degassed and backfilled with argon twice. Tri ethylamine is added by injection through the septum in chamber B at room temperature. After 2 minutes, the reactor is immersed in an oil-bath at 100 °C and the reaction mixture is stirred until LC-MS analysis affirms that the reaction is finished. The reaction mixture in chamber A is evaporated to dryness under reduced pressure. The residue is dissolved in water and extracted with methylene chloride. The combined extracts are dried over Na2SC>4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica-gel column chromatography to give compound 9.

Claims

Attorney Docket No.: IT-212-PCTCLAIMSWhat is claimed is:

1. A compound of Formula I:Formula Iwherein(i) Ri 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) R4 is H or C1-4 alkyl (e.g., methyl or ethyl);(iv) R5 is aryl (e.g., phenyl) substituted with a group selected from:(a) -CH(CH3)-0-C(0)-Ra, wherein Rais -N(Rb)(Rc), heteroaryl (e.g., imidazolyl), or -CH(NH2)-Ra, wherein Rb and Rcare independently C1-4 alkyl (e.g., methyl) and wherein Rd is H or C1-4 alkyl (e.g. isopropyl),(b) -C(=C)-O-Re, wherein Reis C1-4 alkyl (e.g., methyl, ethyl, or butyl). (c) -CH(CH3)-O-CH2-O-C(O)-Rf, wherein Rfis C1-4 alkyl (e.g., methyl), and(d) -C(O)-N(Rg)(Rh), wherein Rgand Rh are independently C1-4 alkyl (e.g., methyl);(v) Re and R7 are 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 halogenAttorney Docket No.: IT-212-PCT(e.g., F) or phenyl substituted with one or more Ci-6 alkyl and one or more halogen or phenyl substituted with one Ci-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 or salt form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers and racemates, thereof.

2. The compound according to claim 1, wherein(i) Ri is methyl;(ii) R.2 and R3 are both methyl;(iii) R4 is H;(iv) R7 is H and Rs is 4-fluorophenyl; and(v) n is 1.

3. The compound according to claim 1 or 2, wherein R5 is phenyl substituted with - CH(CH3)-0-C(0)-Ra, wherein Ra is -N(Rb)(Rc), heteroaryl or -CH(NH2)-Rd, wherein Rb and Rcare independently C1-4 alkyl, and wherein Rd is H or C1-4 alkyl.

4. The compound according to claim 3, wherein Rais -N(Rb)(Rc) and Rb and Rcare independently C1-4 alkyl (e.g. methyl).

5. The compound according to claim 4, wherein Rb and Rc are both methyl.

6. The compound according to claim 3, wherein Rais heteroaryl.

7. The compound according to claim 6, wherein Rais imidazolyl.

8. The compound according to claim 3, wherein Rais -CH(NH2)-Rd and wherein Rd is H or C1-4 alkyl.

9. The compound according to claim 8, wherein Rd is H.

10. The compound according to claim 8, wherein Rd is isopropyl (-CH(CH3)2).

11. The compound according to claim 1 or 2, wherein R5 is aryl (e.g., phenyl) substituted with -C(=C)-O-Re, wherein Reis C1-4 alkyl, optionally wherein Reis methyl, ethyl, or butyl.

12. The compound according to claim 1 or 2, wherein R5 is aryl (e.g., phenyl) substituted with -CH(CH3)-O-CH2-O-C(O)-Rf, wherein Rfis C1-4 alkyl.

13. The compound according to claim 12, wherein Rfis methyl.

14. The compound according to claim 1 or 2, wherein R5 is aryl (e.g., phenyl) substituted with -C(O)-N(Rg)(Rh), wherein Rgand Rh are independently C1-4 alkyl.Attorney Docket No.: IT-212-PCT15. The compound according to claim 14, wherein Rgand Rh are both methyl.

16. The compound according to claim 1, wherein the compound is selected fromAttorney Docket No.: IT-212-PCTandin free or salt form.

17. A pharmaceutical composition comprising a compound according to any of claims 1-16, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

18. The composition of claim 17, wherein 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).

19. The composition of claim 17, wherein the composition is in the form of an enteric-coated tablet.

20. A method of inhibiting PDE1 activity in a patient in need thereof, e.g., a method of preventing or treating a disease or disorder selected from neurodegenerative diseases (e.g., Parkinson’s disease, restless leg, tremors, dyskinesias, Huntington’s disease, Alzheimer’s disease, and drug-induced movement disorders); neuroinflammation and / or diseases or disorders associated with neuroinflammation and / or microglial function; mental disorders (e.g., depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive impairment, e.g., cognitive impairment of schizophrenia, Tourette’s syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and drug addiction); chemobrain (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself); disorders associated with dementia; circulatory and cardiovascular disorders (e.g., cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and sexual dysfunction); respiratory and inflammatory disorders (e.g., asthma, chronic obstructive pulmonary disease, and allergic rhinitis); diseases which may be alleviated by the enhancement of progesterone signaling (e.g., female sexual dysfunction); psychosis;Attorney Docket No.: IT-212-PCTophthalmic disorders (e.g., glaucoma and elevated intraocular pressure); traumatic brain injury; cancers or tumors (e.g., glioma, colon cancer, and breast cancer); renal disorders (e.g., kidney fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, nephritis); cardiotoxicity consequent to administration of a chemotherapeutic agent and / or radiation therapy; any disease or condition characterized by low levels of cAMP and / or cGMP in cells expressing PDEl(e.g., angina, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, an inflammatory disease or disorder, fibrosis, cardiac hypertrophy, vascular remodeling, a connective tissue disease or disorder, chronic heart failure, myocardial inflammation, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunctions, vascular leakage, acute vascular inflammation, and amyotrophic lateral sclerosis); bacterial infections; viral infections; obesity; metabolic disorders; fatty liver disease; conditions associated with fat-induced inflammation; nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting); and any disease or condition characterized by reduced dopamine DI receptor signaling activity (e.g., attention deficit, cognition, PTSD, memory, and / or inhibitory processing), wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of the compound according to any of claims 1-16 or a therapeutically effective amount of the pharmaceutical composition according to any of claims 17-19.

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