Organic compounds

Abstract

Provided are PDE1 inhibitors of Formula I, methods of their production, their use as medicaments, and pharmaceutical compositions containing them.

Description

Technical Field

[0001] This invention relates to novel PDE1 inhibitory compounds of Formula I as described below, their production methods, their use as pharmaceuticals, and pharmaceutical compositions comprising them. Background Technology

[0002] From a therapeutic perspective, PDEs have particular therapeutic significance because their structure is suitable for specific and potent small molecule inhibitors, and cell-specific expression provides selective organ targeting. Eleven families of phosphodiesterases (PDEs) have been identified, comprising over 100 isotypes, but only PDEs in family I, namely Ca2+, are known to be specific. 2+ Calmodulin-dependent phosphodiesterases (CaM-PDEs) have been shown to simultaneously mediate calcium signaling pathways and cyclic nucleotide (cAMP and cGMP) signaling pathways. Therefore, these PDEs become active under stimuli of elevated intracellular calcium levels, leading to increased hydrolysis of cyclic nucleotides. Three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are expressed in human central nervous system tissues. PDE1A is expressed in the brain, with high levels in the CA1-CA3 layers of the hippocampus and the cerebellum, and low levels in the striatum. PDE1A is also expressed in the heart. PDE1B is primarily expressed in the striatum, dentate gyrus, olfactory tract, and prefrontal cortex, and co-localizes with dopamine D1 receptors in the prefrontal cortex. Its expression is generally associated with brain regions with high levels of dopaminergic innervation. Although PDE1B is primarily expressed in the central nervous system, it is also present in neutrophils. PDE1C is expressed more broadly in the brain, and is also expressed in the smooth muscle of the heart and blood vessels.

[0003] PDE1 inhibitors have been found to be useful for the treatment or prevention of many conditions, including: conditions characterized by low levels of cAMP and / or cGMP in cells expressing PDE1; and / or conditions characterized by reduced dopamine D1 receptor signaling activity (e.g., Parkinson's disease, Tourette syndrome, autism, Fragile X syndrome, ADHD, restless legs syndrome, depression, cognitive impairment in schizophrenia, narcolepsy); and / or ophthalmic conditions (e.g., glaucoma, intraocular pressure disorders, etc.); and / or any condition that can be treated or prevented. Diseases or conditions that improve through enhanced progesterone signaling; and / or any disease or condition characterized by adenosine A2 dysfunction or that would benefit from adenosine A2 stimulation (e.g., cardiovascular diseases and conditions, muscular dystrophy (e.g., Duchenne muscular dystrophy), amyotrophic lateral sclerosis, etc.); and / or diseases or conditions characterized by inflammation; and / or cancers or tumors that overexpress PDE1 (e.g., melanoma, neuroblastoma, renal cell carcinoma and colon cancer, osteosarcoma, glioblastoma multiforme (GBM), etc.). This list of conditions is exemplary and not intended to be exhaustive.

[0004] Therefore, there is a persistent need for novel compounds that selectively inhibit PDE1 activity. Summary of the Invention

[0005] In one aspect, this disclosure provides compounds of formula I: Formula I in (i) R1 is H or C 1-4 Alkyl groups (e.g., methyl or ethyl); (ii) R2 and R3 are independently H or C 1-6 Alkyl groups (e.g., methyl or ethyl); (iii) R4 is H or C 1-4 Alkyl groups (e.g., methyl or ethyl); (iv) R5 is an aryl group substituted with -C(=O)-CD3 (e.g., phenyl), where D is deuterium ( 2 H); (v) R6 and R7 are independently H or optionally selected independently from C by one or more of them. 1-6 Aryl groups (e.g., phenyl) substituted with alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl) groups, such as unsubstituted phenyl or phenyl substituted with one or more halogens (e.g., F) or phenyl substituted with one or more C groups. 1-6 alkyl groups and one or more halogen-substituted phenyl groups or those with a C124-C ... 1-6 An alkyl group and a halogen-substituted phenyl group, such as 4-fluorophenyl, 3,4-difluorophenyl, or 4-fluoro-3-methylphenyl; and (vi) n is 1, 2, 3 or 4. It exists in free form, salt form, or prodrug form, such as pharmaceutically acceptable salt forms, including its enantiomers, diastereomers, and racemic compounds.

[0006] In some implementations, the compound of formula I is , It exists in free form, salt form, or prodrug form, such as pharmaceutically acceptable salt forms, including its enantiomers, diastereomers, and racemic compounds.

[0007] In another aspect, this disclosure provides a pharmaceutical composition comprising the compound of the invention in free form, pharmaceutically acceptable salt form, or prodrug form, said compound being mixed with a pharmaceutically acceptable diluent or carrier.

[0008] In another aspect, this disclosure provides a method for preventing or treating a disease or condition selected from: neurodegenerative diseases (e.g., Parkinson's disease, restless legs, tremor, movement disorders, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders); neuroinflammation and / or diseases or conditions related to neuroinflammation and / or microglial function; mental illnesses (e.g., depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety disorder, sleep disorders (e.g., narcolepsy), cognitive impairment (e.g., cognitive impairment in schizophrenia), Tourette syndrome, autism, Fragile X syndrome). The following conditions may be considered: withdrawal from stimulants and drug addiction; "chemotherapy brain" (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself); conditions associated with dementia; circulatory and cardiovascular conditions (e.g., cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and sexual dysfunction); respiratory and inflammatory conditions (e.g., asthma, chronic obstructive pulmonary disease, and allergic rhinitis); conditions that can be relieved by enhancing progesterone signaling (e.g., female sexual dysfunction); psychosis; eye diseases (e.g., glaucoma and elevated intraocular pressure); traumatic brain injury; cancer or tumors (e.g., glioma, nodule, etc.). Colorectal cancer and breast cancer); kidney diseases (e.g., renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, nephritis); cardiac toxicity secondary to the administration of chemotherapy agents and / or radiotherapy; any disease or condition characterized by low levels of cAMP and / or cGMP in cells expressing PDE1 (e.g., angina pectoris, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes-related hypertension, atherosclerosis-related hypertension, renovascular hypertension, congestive heart failure, inflammatory diseases or conditions, fibrosis, cardiac hypertrophy, vascular remodeling, connective tissue diseases). The method may be used to treat conditions such as chronic heart failure, myocarditis, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunction, vascular leakage, acute vasculitis, and amyotrophic lateral sclerosis (ALS); bacterial infection; viral infection; obesity; and any disease or condition characterized by reduced dopamine D1 receptor signaling activity (e.g., attention deficit, cognition, PTSD, memory, and / or inhibitory processing), wherein the method comprises administering a therapeutically effective amount of the compound of the invention, such as a compound of formula I, to a patient in need, such as any compound described in this disclosure. Detailed Implementation

[0009] In one aspect, the present invention provides a compound of formula I (compound 1.0): Formula I in (i) R1 is H or C 1-4 Alkyl groups (e.g., methyl or ethyl); (ii) R2 and R3 are independently H or C 1-6 Alkyl groups (e.g., methyl or ethyl); (iii) R4 is H or C 1-4 Alkyl groups (e.g., methyl or ethyl); (iv) R5 is an aryl group substituted with -C(=O)-CD3 (e.g., phenyl), where D is deuterium ( 2 H); (v) R6 and R7 are independently H or optionally selected independently from C by one or more of them. 1-6 Aryl groups (e.g., phenyl) substituted with alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl) groups, such as unsubstituted phenyl or phenyl substituted with one or more halogens (e.g., F) or phenyl substituted with one or more C groups. 1-6 alkyl groups and one or more halogen-substituted phenyl groups or those with a C124-C ... 1-6 An alkyl group and a halogen-substituted phenyl group, such as 4-fluorophenyl, 3,4-difluorophenyl, or 4-fluoro-3-methylphenyl; and (vi) n is 1, 2, 3 or 4. It exists in free form, salt form, or prodrug form, such as pharmaceutically acceptable salt forms, including its enantiomers, diastereomers, and racemic compounds.

[0010] The present invention also provides compounds of formula I as follows: 1.1 Compound 1.0, where n is 1, 2, or 3; 1.2 Compound 1.0, where n is 1 or 2; 1.3 Compound 1.0, where n is 1; 1.4 Any one of compounds 1.0-1.3, wherein R1 is H or C. 1-3 Alkyl groups (e.g., methyl groups); 1.5 Any one of compounds 1.0-1.3, wherein R1 is H; 1.6 Any one of compounds 1.0-1.3, wherein R1 is C 1-4 alkyl; 1.7 Any one of compounds 1.0-1.3, wherein R1 is a methyl group; 1.8 Any one of compounds 1.0-1.7, wherein R2 and R3 are independently H or C. 1-5 Alkyl groups (e.g., methyl or ethyl); 1.9 Any one of compounds 1.0-1.7, wherein R2 and R3 are independently H or C. 1-4Alkyl groups (e.g., methyl groups); 1.10 Any one of compounds 1.0-1.7, wherein both R2 and R3 are C 1-6 Alkyl (e.g., C10) 1-4 Alkyl groups, such as methyl groups; 1.11 Any one of compounds 1.0-1.7, wherein both R2 and R3 are C 1-4 Alkyl groups (e.g., methyl groups); 1.12 Any one of compounds 1.0-1.7, wherein R2 and R3 are both methyl groups; 1.13 Any one of compounds 1.0-1.12, wherein R4 is H or C. 1-3 Alkyl groups (e.g., methyl or ethyl); 1.14 Any one of compounds 1.0-1.12, wherein R4 is H; 1.15 Any one of compounds 1.0-1.14, wherein R5 is a phenyl group substituted with -C(=O)-CD3.

[0011] 1.16 Any of compounds 1.0-1.15, wherein R6 and R7 are independently H or are selected independently from C by one or more of them. 1-4 Aryl groups (e.g., phenyl) substituted with alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl) groups, such as phenyl groups substituted with one or more (e.g., two) halogens (e.g., F) or phenyl groups substituted with one or more C groups. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and one or more halogens (e.g., F) or a phenyl group substituted with a C12 group. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F), such as 4-fluorophenyl, 3,4-difluorophenyl, or 4-fluoro-3-methylphenyl.

[0012] 1.17 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is a carbon atom independently selected from C6. 1-6 Alkyl (e.g., C) 1-4 An aryl group (e.g., phenyl) substituted with an alkyl group (e.g., methyl) and a halogen group (e.g., F or Cl), such as R6 being a phenyl group substituted with one or more (e.g., two) halogens (e.g., F) or a C group. 1-6 Alkyl (e.g., C) 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F), wherein R6 is 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl.

[0013] 1.18 Any of compounds 1.0-1.15, wherein R7 is H and R6 is a carbon atom independently selected from C6.1-4 An aryl group (e.g., phenyl) substituted with an alkyl (e.g., methyl) and a halogen (e.g., F) group, such as R6 being a phenyl substituted with one or more (e.g., two) halogens (e.g., F) or a C-shaped group. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F), wherein R6 is, for example, 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl.

[0014] 1.19 Any of compounds 1.0-1.15, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with one or more halogens (e.g., F).

[0015] 1.20 Any of compounds 1.0-1.15, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with two halogens (e.g., F).

[0016] 1.21 Any of compounds 1.0-1.15, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with a halogen (e.g., F).

[0017] 1.22 Any of compounds 1.0-1.15, wherein R7 is H and R6 is an aryl group substituted with two F groups (e.g., phenyl).

[0018] 1.23 Any of compounds 1.0-1.15, wherein R7 is H and R6 is an aryl group substituted with an F (e.g., phenyl).

[0019] 1.24 Any of compounds 1.0-1.15, wherein R7 is H and R6 is formed by one or more C atoms. 1-6 Alkyl (e.g., C) 1-4 Aryl groups (e.g., phenyl groups) substituted with alkyl groups (e.g., methyl groups) and one or more halogens (e.g., F groups).

[0020] 1.25 Any of compounds 1.0-1.15, wherein R7 is H and R6 is formed by one or more C atoms. 1-4 Aryl groups (e.g., phenyl) substituted with alkyl groups (e.g., methyl) and one or more halogens (e.g., F).

[0021] 1.26 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is a carbon atomized by a C-terminal ion. 1-6 Alkyl (e.g., C) 1-4 An aryl group (e.g., phenyl) substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0022] 1.27 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is a carbon atomized by a C-terminal ion. 1-4 An aryl group (e.g., phenyl) substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0023] 1.28 Any of compounds 1.0-1.15, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with a methyl group and an F group.

[0024] 1.29 Any of compounds 1.0-1.15, wherein R7 is H and R6 is a phenyl substituted with one or more halogens (e.g., F).

[0025] 1.30 Any of compounds 1.0-1.15, wherein R7 is H and R6 is a phenyl group substituted with two halogens (e.g., F).

[0026] 1.31 Any of compounds 1.0-1.15, wherein R7 is H and R6 is a phenyl group substituted with a halogen (e.g., F).

[0027] 1.32 Any one of compounds 1.0-1.15, wherein R6 is a phenyl group substituted by two F groups.

[0028] 1.33 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is a phenyl group substituted with an F.

[0029] 1.34 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is 3,4-difluorophenyl.

[0030] 1.35 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is 4-fluorophenyl.

[0031] 1.36 Any of compounds 1.0-1.15, wherein R7 is H and R6 is formed by one or more C atoms. 1-6 Alkyl (e.g., C) 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and one or more halogens (e.g., F).

[0032] 1.37 Any of compounds 1.0-1.15, wherein R7 is H and R6 is formed by one or more C atoms. 1-4 Phenyl groups substituted with alkyl groups (e.g., methyl) and one or more halogens (e.g., F); 1.38 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is a carbon atomized by a C-terminus. 1-6 Alkyl (e.g., C) 1-4A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0033] 1.39 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is a carbon atomized by a C-terminal ion. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0034] 1.40 Any of compounds 1.0-1.15, wherein R7 is H and R6 is a phenyl group substituted with a methyl group and an F group.

[0035] 1.41 Any one of compounds 1.0-1.15, wherein R7 is H and R6 is 4-fluoro-3-methylphenyl.

[0036] 1.42 Compound 1.0, wherein (i) R1 is a methyl group; (ii) Both R2 and R3 are methyl groups; (iii) R4 is H; and (iv) n is 1.

[0037] 1.43 Any of compound 1.42, wherein R5 is a phenyl group substituted with -C(=O)-CD3.

[0038] 1.44 Any of compounds 1.42-1.43, wherein R6 and R7 are independently H or are selected independently from C by one or more of them. 1-4 Aryl groups (e.g., phenyl) substituted with alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl) groups, such as phenyl groups substituted with one or more (e.g., two) halogens (e.g., F) or phenyl groups substituted with one or more C groups. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and one or more halogens (e.g., F) or a phenyl group substituted with a C12 group. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F), such as 4-fluorophenyl, 3,4-difluorophenyl, or 4-fluoro-3-methylphenyl.

[0039] 1.45 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a carbon atom independently selected from C6. 1-6 Alkyl (e.g., C) 1-4 An aryl group (e.g., phenyl) substituted with an alkyl group (e.g., methyl) and a halogen group (e.g., F or Cl), such as R6 being a phenyl group substituted with one or more (e.g., two) halogens (e.g., F) or a C group. 1-6 Alkyl (e.g., C) 1-4A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F), wherein R6 is 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl.

[0040] 1.46 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a carbon atom independently selected from C6. 1-4 An aryl group (e.g., phenyl) substituted with an alkyl (e.g., methyl) and a halogen (e.g., F) group, such as R6 being a phenyl substituted with one or more (e.g., two) halogens (e.g., F) or a C-shaped group. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F), wherein R6 is, for example, 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl.

[0041] 1.47 Any of compounds 1.42-1.43, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with one or more halogens (e.g., F).

[0042] 1.48 Any of compounds 1.42-1.43, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with two halogens (e.g., F).

[0043] 1.49 Any of compounds 1.42-1.43, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with a halogen (e.g., F).

[0044] 1.50 Any of compounds 1.42-1.43, wherein R7 is H and R6 is an aryl group substituted by two F groups (e.g., phenyl).

[0045] 1.51 Any of compounds 1.42-1.43, wherein R7 is H and R6 is an aryl group substituted with an F (e.g., phenyl).

[0046] 1.52 Any of compounds 1.42-1.43, wherein R7 is H and R6 is formed by one or more C atoms. 1-6 Alkyl (e.g., C) 1-4 Aryl groups (e.g., phenyl groups) substituted with alkyl groups (e.g., methyl groups) and one or more halogens (e.g., F groups).

[0047] 1.53 Any of compounds 1.42-1.43, wherein R7 is H and R6 is formed by one or more C atoms. 1-4 Aryl groups (e.g., phenyl) substituted with alkyl groups (e.g., methyl) and one or more halogens (e.g., F).

[0048] 1.54 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a carbon atomized by a C-terminal ion. 1-6 Alkyl (e.g., C) 1-4 An aryl group (e.g., phenyl) substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0049] 1.55 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a carbon atomized by a C-terminal oscillation. 1-4 An aryl group (e.g., phenyl) substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0050] 1.56 Any of compounds 1.42-1.43, wherein R7 is H and R6 is an aryl group (e.g., phenyl) substituted with a methyl group and an F group.

[0051] 1.57 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a phenyl substituted with one or more halogens (e.g., F).

[0052] 1.58 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a phenyl group substituted with two halogens (e.g., F).

[0053] 1.59 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a phenyl group substituted with a halogen (e.g., F).

[0054] 1.60 Any of compounds 1.42-1.43, wherein R6 is a phenyl group substituted by two F atoms.

[0055] 1.61 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a phenyl group substituted with an F.

[0056] 1.62 Any one of compounds 1.42-1.43, wherein R7 is H and R6 is 3,4-difluorophenyl.

[0057] 1.63 Any one of compounds 1.42-1.43, wherein R7 is H and R6 is 4-fluorophenyl.

[0058] 1.64 Any of compounds 1.42-1.43, wherein R7 is H and R6 is formed by one or more C atoms. 1-6 Alkyl (e.g., C) 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and one or more halogens (e.g., F).

[0059] 1.65 Any of compounds 1.42-1.43, wherein R7 is H and R6 is formed by one or more C atoms. 1-4 Phenyl groups substituted with alkyl groups (e.g., methyl) and one or more halogens (e.g., F); 1.66 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a carbon atomized by a C. 1-6 Alkyl (e.g., C) 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0060] 1.67 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a carbon atomized by a C. 1-4 A phenyl group substituted with an alkyl group (e.g., methyl) and a halogen (e.g., F).

[0061] 1.68 Any of compounds 1.42-1.43, wherein R7 is H and R6 is a phenyl group substituted with a methyl group and an F group.

[0062] 1.69 Any of compounds 1.42-1.43, wherein R7 is H and R6 is 4-fluoro-3-methylphenyl.

[0063] 1.70 Compound 1.0, wherein the compound is It exists in free form or as a salt.

[0064] 1.71 Any of the foregoing compounds, wherein said compound inhibits phosphodiesterase-mediated (e.g., PDE1-mediated) cGMP hydrolysis, for example, in immobilized-metal affinity particle reagent PDE assays, such as as described in Example 2, wherein its IC50... 50 Less than 1 μM, preferably less than 500 nM, more preferably less than 50 nM, even more preferably less than 10 nM, and most preferably less than or equal to 5 nM.

[0065] Unless otherwise specified or apparent from the context, the following terms in this document shall have the following meanings: (a) As used herein, “alkyl” is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having one to six carbon atoms, preferably having one to four carbon atoms, which may be straight or branched, and may optionally be monosubstituted, disubstituted or trisubstituted, for example by a halogen (e.g., Cl or F) or a carboxyl group.

[0066] (b) As used herein, “hydroxyalkyl” is a saturated hydrocarbon moiety, preferably having one to six carbon atoms, more preferably having one to four carbon atoms, which may be straight-chain or branched and mono-, di-, or tri-substituted with hydroxyl groups.

[0067] (c) As used herein, “haloalkyl” is a saturated hydrocarbon moiety, preferably having one to six carbon atoms, more preferably one to four carbon atoms, and may be straight-chain or branched, and is mono-, di-, or tri-substituted with a halogen. For di- or tri-substituted haloalkyl, the halogen may be the same (e.g., dichloromethyl) or different (e.g., chlorofluoromethyl).

[0068] (d) As used herein, “aryl” is a monocyclic or bicyclic aromatic hydrocarbon, preferably having 5-10 carbon atoms, preferably phenyl, which may optionally be substituted, for example, optionally by one or more carbon atoms independently selected from C10. 1-6 Alkyl (e.g., methyl), halogen (e.g., Cl or F), C 1-6 The aryl group is substituted with a haloalkyl group (e.g., trifluoromethyl), a hydroxyl group, or a carboxyl group. In some embodiments, in addition to being substituted with the groups disclosed herein, the aryl group is also substituted with an aryl or heteroaryl group to form, for example, biphenyl or pyridylphenyl.

[0069] (e) As used herein, “heteroaryl” preferably refers to an aromatic moiety having 5-10 atoms, wherein one or more of the atoms constituting the aromatic ring are sulfur or nitrogen instead of carbon, for example, pyridyl or thiadiazolyl, which may optionally be substituted, for example, optionally selected independently from C10 or C20. 1-6 Alkyl (e.g., methyl), halogen (e.g., Cl or F), C 1-6 The group is replaced by a haloalkyl group (e.g., trifluoromethyl), a hydroxyl group, and a carboxyl group.

[0070] (f) As used in this article, “hydroxyl group” is -OH.

[0071] (g) As used herein, “carboxyl group” is -COOH.

[0072] (h) As used herein, “halogen” means F, Cl, Br or I.

[0073] The compounds of the present invention, for example, compounds of formula I, such as any one of compounds 1.0-1.71, may exist in free form or salt form, for example, as an acid addition salt. In this specification, unless otherwise stated, the terminology such as “compounds of the present invention” should be understood to cover any form of the said compound, such as the free form or acid addition salt form, or, when the compound contains an acidic substituent, also to cover the base addition salt form. The compounds of the present invention are intended for use as pharmaceuticals, and therefore pharmaceutically acceptable salts are preferred. Salts unsuitable for pharmaceutical use may also be useful, for example, for isolating or purifying the free compounds of the present invention or their pharmaceutically acceptable salts, and are therefore also included.

[0074] The compounds of the present invention may also exist in prodrug form in some cases. The prodrug form is a compound that is converted into the compound of the present invention in vivo. For example, when the compounds of the present invention contain hydroxyl or carboxyl substituents, these substituents can form physiologically hydrolyzable and acceptable esters. As used herein, “physiologically hydrolyzable and acceptable ester” refers to such esters of the compounds of the present invention that, under physiological conditions, can be hydrolyzed to produce an acid (in the case of hydroxyl substituents in the compounds of the present invention) or an alcohol (in the case of carboxyl substituents in the compounds of the present invention), and these acids or alcohols are physiologically tolerable at the dose to be administered. Therefore, in the case of compounds of the present invention containing hydroxyl groups (e.g., compound -OH), such acyl ester prodrugs (i.e., compound -OC(O)-C) are physiologically tolerable. 1-4 Alkyl groups can be hydrolyzed in vivo, forming physiologically hydrolyzable alcohols (compounds -OH) and acids (e.g., HOC(O)-C). 1-4 Alkyl group). Alternatively, in the case where the compounds of the present invention contain a carboxylic acid (e.g., compound -C(O)OH), the ester prodrug of such a compound (i.e., compound -C(O)OC) 1-4 Alkyl groups can be hydrolyzed to form compounds -C(O)OH and HO-C 1-4 Alkyl group. As should be understood, this term therefore covers conventional prodrug forms.

[0075] In the compounds of this invention, the aryl group (e.g., phenyl) at the R5 position is substituted with -C(=O)-CD3. The ketone group (-C(=O)-CH3) at the R5 position can be reduced to a hydroxyl group in vivo, while the methyl group in the R5 group of the acetyl group can be oxidized to hydroxymethyl, and then further oxidized to a carboxyl group. Compared with the parent compound containing a ketone group, the ketone reductive metabolite containing a hydroxyl group has lower PDE1 inhibitory activity. The substitution of the hydrogen atom in the ketone group (-C(=O)-CH3) at the R5 position with a deuterium atom can slow down the oxidation of the methyl group due to the stronger CD bond energy. Because deuterium ( 2 H) atoms and ordinary hydrogen atoms 1 The properties of H) are very similar. The compounds of the present invention have similar biological activities to non-deuterated analogs, but are believed to have improved pharmacokinetic properties and a longer duration of action. This is because the oxidation of the less active metabolites produced by the ketone group at the R5 position in vivo is weakened by the substitution of the hydrogen atom at that specific position with a deuterium atom.

[0076] In another aspect, this disclosure provides a pharmaceutical composition comprising the compound of the invention in free form, pharmaceutically acceptable salt form, or prodrug form, such as compounds according to Formula I, for example, any one of compounds 1.0 to 1.71, which is mixed with a pharmaceutically acceptable diluent or carrier. The compounds of the invention may be provided in the form of pharmaceutical compositions (e.g., dosage forms), for example for oral administration, such as in the form of pills (tablets or capsules), or for parenteral administration. In some embodiments, the compounds of the invention are provided as long-acting reservoirs for administration by injection to provide sustained release (e.g., intramuscular or subcutaneous injection). In some embodiments, solid pharmaceutical products for oral administration or as reservoirs may be encapsulated, dissolved, dispersed, or suspended in a suitable polymer matrix to provide delayed release of the active compound, for example, in polymer microspheres or in a solvent-based carrier. In some embodiments, the compounds of the invention are provided as nasal sprays or inhalers.

[0077] In some embodiments, the pharmaceutical composition is in the form of an oral dosage form (such as tablets or capsules), an intranasal dosage form (e.g., nasal spray or nebulizer), a pulmonary dosage form (e.g., an inhaler), or an injectable dosage form (e.g., intravenous, intramuscular, or subcutaneous injection, such as a long-acting reservoir 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, nebulizer, or inhaler. In some embodiments, the composition is in an injectable dosage form (e.g., intravenous, intramuscular, or subcutaneous injection, such as a long-acting reservoir injection).

[0078] In another aspect, this disclosure provides a method for preventing or treating a patient (e.g., a person) suffering from a condition selected from the following: i. Neurodegenerative diseases, including Parkinson's disease, restless legs, tremor, movement disorders, Huntington's disease, Alzheimer's disease, and drug-induced motor disorders; ii. Mental illnesses, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety disorder, sleep disorders (e.g., narcolepsy), cognitive impairment (e.g., cognitive impairment in schizophrenia), dementia, Tourette syndrome, autism, fragile X syndrome, stimulant withdrawal, chemotherapy brain (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself), and substance addiction. iii. Circulatory and cardiovascular diseases, including cerebrovascular diseases, stroke, congestive heart disease, hypertension, pulmonary arterial hypertension (e.g., pulmonary arterial hypertension), and sexual dysfunction, including cardiovascular diseases and related conditions as described in International Application No. PCT / US2014 / 16741, the contents of which are incorporated herein by reference. iv. Respiratory and inflammatory conditions, including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases; v. Diseases that can be alleviated by enhancing progesterone signaling, such as female sexual dysfunction; vi. A disease or ailment such as mental illness, glaucoma, and increased intraocular pressure; vii. Traumatic brain injury; viii. Cancer or tumor, such as brain tumor, glioma (e.g., ependymoma, astrocytoma, oligodendroglioma, brainstem glioma, optic glioma, or mixed glioma, such as oligodendroglioma), astrocytoma (e.g., glioblastoma multiforme), osteosarcoma, melanoma, leukemia, neuroblastoma, or leukemia; ix. Kidney diseases, such as renal fibrosis, chronic kidney disease, kidney 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 / or xi. Any disease or condition characterized by decreased dopamine D1 receptor signaling activity, The method includes administering a therapeutically effective compound of the invention, such as a compound according to Formula I, for example, any one of compounds 1.0 to 1.71, to a patient in need.

[0079] Method for preparing the compounds of the present invention The compounds of the present invention and their pharmaceutically acceptable salts can be prepared using methods as described and illustrated herein, as well as by similar methods and by methods known in the field of chemistry. Such methods include, but are not limited to, those described below. If commercially available, the starting materials for these methods can be prepared using techniques similar to or similar to the synthesis of known compounds, selected from procedures in the field of chemistry. Various starting materials, intermediates, and / or compounds of the present invention can 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 incorporated herein by reference in their entirety.

[0080] The compounds of this invention include their enantiomers, diastereomers, and racemates, as well as their polymorphs, hydrates, solvates, and complexes. Some individual compounds within the scope of this invention may contain double bonds. The representation of double bonds in this invention is intended to include both E- and Z-isomers of the double bond. Additionally, some compounds within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any optically pure stereoisomers and any combination of stereoisomers.

[0081] The compounds of this invention are also intended to cover their stable and unstable isotopes. Stable isotopes are non-radioactive isotopes that contain an extra neutron compared to the most abundant nuclide of the same species (i.e., element). Compounds containing such isotopes are expected to retain their activity, and such compounds will also be useful for measuring the pharmacokinetics of non-isotope analogs. For example, hydrogen atoms at specific positions on the compounds of this invention may be replaced with deuterium (a non-radioactive stable isotope). Examples of known stable isotopes include, but are not limited to, deuterium. 13 C 15 N、 18 O. Or, unstable isotopes (i.e., radioactive isotopes containing an extra neutron compared to the most abundant nuclide of the same species (i.e., element), for example 123 I, 131 I, 125 I, 11 C 18 F can replace the corresponding highest abundance species of I, C, and F. Another example of a useful isotope of the compounds of this invention is... 11 C isotopes. These radioactive isotopes can be used for radiographic imaging and / or pharmacokinetic studies of the compounds of the present invention. Isotopes of the compounds of the present invention can be prepared using the methods for preparing PDE1 inhibitor isotopes disclosed in WO 2011 / 043816 (the entire contents of which are incorporated herein by reference).

[0082] Melting points are uncorrected and (dec) indicates decomposition. Temperatures are given in degrees Celsius (°C); unless otherwise specified, operations are performed at room temperature or ambient temperature, i.e., within the range of 18–25°C. Chromatography refers to silica gel rapid chromatography; thin-layer chromatography (TLC) is performed on silica gel plates. NMR data are given as the δ value of the major diagnostic proton, in parts per million (ppm) relative to tetramethylsilane (TMS) used as an internal standard. Conventional abbreviations for signal peak shapes are used. Coupling constants (J) are given in Hz. For mass spectrometry (MS), the major ion with the lowest mass is reported for molecules that result in multiple mass peaks due to isotopic splitting. Solvent mixture composition is given as a volume percentage or volume ratio. In cases of complex NMR spectra, only the diagnostic signal is reported.

[0083] Terms and abbreviations: BOP = Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate BOC = tert-butoxycarbonyl. CAN = Cerium ammonium nitrate (IV) DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA = diisopropylethylamine DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide Et₂O = diethyl ether, EtOAc = ethyl acetate equiv. = equivalent amount h = hours HPLC = High Performance Liquid Chromatography LDA = Lithium diisopropylaminodimethylamine LiHMDS = bis(trimethylsilyl)aminolithium, MeOH = methanol. NBS = N-bromosuccinimide NCS = N-chlorosuccinimide NMP = N-methyl-2-pyrrolidone, NaHCO3 = Sodium bicarbonate NH4OH = ammonium hydroxide Pd2(dba)3 = tris(dibenzylacetone)dipalladium(0) PMB = p-methoxybenzyl, POCl3 = Phosphorus oxychloride SOCl2 = thionyl chloride TFA = trifluoroacetic acid. TFMSA = trifluoromethanesulfonic acid, and THF = Tetrahydrofuran.

[0084] The synthesis method in this invention is described below. Unless otherwise stated, the R group has the meaning as explained above for Formula I.

[0085] In one aspect of the invention, the intermediate compound of formula IIb can be synthesized by reacting a compound of formula IIa with malonic acid and acetic anhydride in acetic acid under heating (e.g., heating to about 90°C and holding for about 3 hours), and then cooling: Where R1 is H or C 1-4 Alkyl groups, for example, methyl groups; Intermediate IIc can be prepared, for example, by reacting intermediate IIb with, for example, a chlorinated compound such as POCl3, sometimes with the addition of a small amount of water and heating, for example, to about 80°C and holding for about 4 hours, and then cooling: Intermediate IId can be made by mixing intermediate IIc with, for example, P 1 -L is formed by reacting in solvents such as DMF and bases such as K2CO3, sodium bicarbonate, cesium carbonate, sodium hydroxide, triethylamine, diisopropylethylamine, etc., at room temperature or under heating: Where P 1 For protecting groups [e.g., right -Methoxybenzyl group (PMB) or BOC]; L is a leaving group such as halogen, methanesulfonate or toluenesulfonate. Preferably, P 1 It is PMB and the base is potassium carbonate.

[0086] Intermediate IIe can be prepared by reacting intermediate IId with hydrazine or hydrazine hydrate in a solvent such as methanol under heating, for example, reflux for about 4 hours, and then cooling: Intermediate IVa can be formed, for example, by reacting intermediate IIe with POCl3 and DMF: Where R1 is as previously defined for Formula I, for example, such as a methyl group.

[0087] Intermediate IVb can be produced by reacting intermediate IVa with, for example, F. 1-X is formed by reacting in a solvent such as DMF at room temperature with a base such as K2CO3 (reaction 1): Where F 1 X is, for example, a benzyl group substituted with a halogen, such as 4-bromobenzyl, and X is a halogen (e.g., Br).

[0088] Intermediate IVc can be obtained from intermediate IVb by removing the protecting group P using appropriate methods. 1 To synthesize. For example, if P 1 If it is a PMB group, it can be removed at room temperature using CAN or TFA / TFMSA (reaction 2): Where P 1 If it is BOC, the compound can be deprotected by using an acid such as hydrochloric acid or TFA.

[0089] Intermediate IVd can be prepared by reacting intermediate IVc with, for example, a chlorinated compound such as POCl3 and optionally heating, for example, under reflux for about 2 days or longer, or heating in a sealed vial at 150-200°C for about 5-10 minutes using a microwave apparatus, and then cooling (reaction 3). Intermediate IVe can be formed by reacting intermediate IVd with an amino alcohol under basic conditions in a solvent such as DMF or NMP, followed by heating and then cooling (reaction 4A): R1, R2, R3, and R4 are as previously defined for Equation I.

[0090] Alternatively, intermediate IVe can be synthesized directly from intermediate IVc by reacting it with an amino alcohol and a coupling agent such as BOP in the presence of a base such as DBU (reaction 4B): R1, R2, R3, and R4 are as previously defined for Equation I.

[0091] Intermediate IVf can be formed by reacting a compound of IVe with, for example, a dehydrating / halogenating agent such as SOCl2 in a solvent such as CH2Cl2 at room temperature or at 35°C for several hours, followed by cooling (reaction 5): Intermediate IVg can be formed by reacting intermediate IVf with, for example, a catalyst 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 under heating for several hours (reaction 6): Among them, F 2 It is a diaryl ether.

[0092] Intermediate IVh can be formed by reacting intermediate IVg with, for example, TFA and TFMSA in a solvent such as CH2Cl2 at room temperature (reaction 7): Intermediate IVi can be obtained by reacting intermediate IVh with R5-(CH2). n -L is formed by reaction at room temperature in a solvent such as DMF in the presence of a base, such as K2CO3 (reaction 8): Where R5 and n are as previously defined for formula I and L is a leaving group such as a halogen (e.g., Br).

[0093] Where X is a halogen (e.g., Cl), intermediate IVj can be formed by reacting intermediate IVi with, for example, halogenating agents such as hexachloroethane, NCS, NBS, I2 and bases such as LiHMDS in a solvent such as THF at low temperature (reaction 9): The compounds of the present invention can be formed by reacting intermediate IVj, in which X is a halogen (e.g., Cl), with NHR6R7 and a catalyst under heating (reaction 10): R6 and R7 are as previously defined for Equation I.

[0094] In another aspect of the invention, intermediate IIf can be prepared by reacting intermediate IIc with hydrazine or hydrazine hydrate in a solvent such as methoxyethanol, refluxing for about 30 minutes, and then cooling: Intermediate Va can be synthesized by reacting a compound of formula IIe with, for example, an aryl isothiocyanate or an aryl isocyanate in a solvent such as DMF and heating at 110°C for about 2 days, followed by cooling. R6 is as previously defined for Equation I.

[0095] Intermediate Vb can be deprotected by removing the protecting group P using appropriate methods. 1To form. For example, if P 1 If the group is PMB, it can be removed using AlCl3 or TFA / TFMSA at room temperature. The intermediate Vb can also be prepared directly from the IIf compound using a similar method, but in relatively low yields.

[0096] Intermediate Vc can be prepared, for example, by reacting intermediate Vb with, for example, a chlorinated compound such as POCl3. This reaction can be carried out at atmospheric pressure and refluxed for about 2 days, or heated in a sealed vial at 150–200 °C for about 10 minutes using a microwave apparatus, followed by cooling (reaction 11). Intermediate Vd can be prepared by reacting intermediate Vc with an amino alcohol under basic conditions in a solvent such as DMF. The reactants can be heated overnight and then cooled (reaction 12): R1, R2, R3, R4 and R6 are as previously defined for Equation I.

[0097] Intermediate Ve can be formed by reacting intermediate Vd with, for example, a dehydrating agent such as SOCl2 in a solvent such as CH2Cl2 at room temperature overnight or at 35°C for about 4 hours, and then cooling (reaction 13): The compounds of the present invention can be produced by reacting the intermediate Ve with, for example, R5-(CH2). n -L is formed by reacting in solvents such as DMF and bases such as K2CO3 at room temperature or under heating (reaction 14): Where R5 is as previously defined for Formula I and L is a leaving group such as a halogen, methanesulfonate, or toluenesulfonate.

[0098] In the compounds of the present invention, the aryl group (e.g., phenyl) at the R5 position is substituted with -C(=O)-CD3. Compound (VIb) of the present invention can be prepared from compound VIa by reacting it with D2O and K2CO3 in a solvent such as dihydrofolate (DHF) at room temperature (reaction 15).

[0099] Methods using the compounds of this invention The compounds of this invention can be used to prevent or treat a variety of diseases, including any one or more of the following conditions: (i) Neurodegenerative diseases, including Parkinson's disease, restless legs, tremor, movement disorders, Huntington's disease, Alzheimer's disease and drug-induced motor disorders, as well as related conditions and diseases as described in international applications PCT / US2014 / 030412 and PCT / US2015 / 050814, the contents of which are incorporated herein by reference; (ii) Neuroinflammation and / or diseases or conditions 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 prions); neuroinflammation associated with injury resulting from stroke, cardiac arrest, hypoxia, intracerebral hemorrhage, or traumatic brain injury; neuroinflammation associated with chronic CNS infection (e.g., Lyme disease, syphilis) or CNS infection secondary to immunosuppressive conditions (e.g., HIV dementia); and neuroinflammation secondary to chemotherapy; and related conditions as described in International Application No. PCT / US2017 / 051220, the contents of which are incorporated herein by reference. (iii) Mental illnesses, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety disorder, sleep disorders (e.g., narcolepsy), cognitive impairment (e.g., cognitive impairment in schizophrenia), Tourette syndrome, autism, fragile X syndrome, stimulant withdrawal, chemotherapy brain (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself), and substance addiction, as well as related illnesses as described in International Application No. PCT / US2014 / 025666, the contents of which are incorporated herein by reference. (iv) Conditions associated with dementia, including those associated with Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome, geriatric depression, Wernicke-Korsakoff syndrome, corticobasal degeneration, and prions; conditions associated with mild cognitive impairment and dementia, including Alzheimer's disease, Pick's disease, frontotemporal dementia, supranuclear palsy, Lewy body dementia, and vascular dementia; and behavioral or emotional disorders in patients with dementia (particularly Alzheimer's disease), such as agitation / irritability, aggressive / violent behavior, anger, physical or emotional outbursts, psychosis, depression, and sleep disorders (e.g., sleep maintenance insomnia, advanced sleep phase syndrome, delayed sleep phase syndrome, frequent awakenings, and feeling unrested upon waking); and conditions associated with dementia as described in International Application No. PCT / US2017 / 024575, the contents of which are incorporated herein by reference. (v) Circulatory and cardiovascular diseases, including cerebrovascular diseases, stroke, congestive heart disease, hypertension, pulmonary hypertension (e.g., pulmonary hypertension), and sexual dysfunction, including cardiovascular diseases and related conditions as described in International Application No. PCT / US2014 / 016741, the contents of which are incorporated herein by reference. (vi) Respiratory and inflammatory conditions, including asthma, chronic obstructive pulmonary disease and allergic rhinitis, as well as autoimmune and inflammatory diseases, including inflammatory conditions as described in International Application No. PCT / US2019 / 053032, the contents of which are incorporated herein by reference. (vii) Diseases that can be relieved by enhancing progesterone signaling, such as female sexual dysfunction, including those described in International Application No. PCT / US2007 / 024866; (viii) Ophthalmic conditions, such as glaucoma or increased intraocular pressure, and other conditions as described in International Application No. PCT / US2010 / 000534, the contents of which are incorporated herein by reference. (ix) Cancer or tumor, including acoustic neuroma / vestibular schwannoma, astrocytoma, chordoma, CNS lymphoma, craniopharyngioma, glioma (e.g., glioblastoma multiforme, brainstem glioma, ependymoma, mixed glioma, optic glioma), subependymal tumor, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), schwannoma, adenoma (e.g., basophilic adenoma, eosinophilic adenoma, chromophobe adenoma, parathyroid adenoma, islet adenoma, fibroadenoma), fibroma (fibrous histiocytoma), fibroma, hemangioma, lipoma (e.g., angiolipoma, myelolipoma, fibroma). Lipoma, spindle cell lipoma, dormant lipoma, atypical lipoma), myxoma, osteoma, leukemia, preleukemia, rhabdomyosarcoma, papilloma, seborrheic keratosis, tumors of skin appendages, hepatic adenoma, renal tubular adenoma, bile duct adenoma, transitional cell papilloma, hydatidiform mole, ganglioneuroma, meningioma, schwannoma, neurofibroma, C-cell hyperplasia, pheochromocytoma, insulinoma, gastrinoma, carcinoid, chemoreceptor tumor, paraganglioma, nevus, actinic keratosis, cervical dysplasia, metaplasia (e.g., pulmonary metaplasia), leukoplakia, hemangioma, lymphangioma, carcinoma (e.g., squamous cell carcinoma, epidermoid carcinoma, adenocarcinoma, liver cancer, hepatocellular carcinoma). Renal cell carcinoma, bile duct carcinoma, transitional cell carcinoma, embryonal cell carcinoma, parathyroid carcinoma, medullary thyroid carcinoma, bronchial carcinoid, oat cell carcinoma, islet cell carcinoma, malignant carcinoid), sarcomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, neurofibrosarcoma), blastomas (e.g., medulloblastoma and glioblastoma, brain tumor types, retinoblastoma, retinal tumors of the eye, osteoblastoma, bone tumors, neuroblastoma). The following are included in this document: germ cell tumors, mesothelioma, malignant skin appendage tumors, adrenocortical carcinoma (hypernephroma), seminoma, glioma, malignant meningioma, malignant Schwannoma, malignant pheochromocytoma, malignant paraganglioma, melanoma, Merkel cell tumor, phyllodes sarcoma, Wilms' tumor, colorectal cancer, breast cancer, and related conditions as described in international applications PCT / US2019 / 033941, PCT / US2020 / 012578, PCT / US2020 / 049248 and PCT / US2023 / 064202; the contents of these applications are incorporated herein by reference. (x) Any disease or condition characterized by low levels of cAMP / PKA and / or cGMP / PKG in cells expressing PDE1 (or inhibition of cAMP and / or cGMP signaling pathways), such as angina pectoris, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes-related hypertension, atherosclerosis-related hypertension, renovascular hypertension, congestive heart failure, inflammatory diseases or conditions, fibrosis, cardiac hypertrophy, vascular remodeling, connective tissue diseases or conditions (e.g., Ma...). Rfan syndrome), chronic heart failure (e.g., chronic systolic heart failure), myocarditis, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunction (e.g., myocardial infarction, ventricular dilation), vascular leakage (i.e., secondary to hypoxia), acute vasculitis (i.e., secondary to vascular injury), cardiac hypertrophy, muscular dystrophy (e.g., Duchenne muscular dystrophy), or amyotrophic lateral sclerosis, and related conditions as described in U.S. Publication No. 2020 / 0289519, the contents of which are incorporated herein by reference. (xi) Cardiac poisoning secondary to the administration of chemotherapy agents and / or radiation therapy, as described in U.S. Publication No. 2020 / 0289519, the contents of which are incorporated herein by reference; (xii) Kidney conditions, including renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, nephritis, and related conditions as described in International Application No. PCT / US2020 / 047451, the contents of which are incorporated herein by reference; and / or (xiii) Any disease or condition characterized by reduced dopamine D1 receptor signaling activity, including but not limited to attention deficit, cognition, PTSD, memory and / or inhibitory processing, as discussed in International Applications PCT / US2019 / 057260 and PCT / US2020 / 062400, the contents of each of which are incorporated herein by reference.

[0100] In one embodiment, the present invention provides a method for treating or preventing narcolepsy. In this embodiment, a PDE1 inhibitor may be used as the sole therapeutic agent, but may also be used in combination with or co-administered with other active agents. Therefore, the present invention also includes a method for treating narcolepsy comprising administering, simultaneously, sequentially, or concurrently, a therapeutically effective amount in a free form, a pharmaceutically acceptable salt form, or a prodrug form to a human or animal patient in need: (i) PDE1 inhibitors, such as compounds according to Formula I, such as any one of compounds 1.0 to 1.71, and (ii) Compounds that promote wakefulness or regulate sleep, such as those selected from: (a) central nervous system stimulants—amphetamines and amphetamine-like compounds, such as methylphenidate, dextroamphetamine, methamphetamine and pimox; (b) modafinil; (c) antidepressants, such as tricyclic antidepressants (including imipramine, desipramine, clomipramine and protriptyline) and selective serotonin reuptake inhibitors (including fluoxetine and sertraline); and / or (d) gamma-hydroxybutyric acid (GHB).

[0101] In another embodiment, the invention also provides a method for treating or preventing conditions that can be alleviated by enhancing progesterone signaling, comprising administering to a human or animal patient in need an effective amount of the compound of the invention, in free form or in a pharmaceutically acceptable salt form or as a prodrug, such as compounds according to Formula I, such as any one of compounds 1.0 to 1.71. Diseases or conditions that can be improved by enhancing progesterone signaling include, but are not limited to: female sexual dysfunction, secondary amenorrhea (e.g., exercise-induced amenorrhea, anovulation, menopause, menopausal symptoms, hypothyroidism), premenstrual syndrome, preterm birth, infertility (e.g., infertility due to recurrent miscarriage), irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, autoimmune diseases, multiple sclerosis, benign prostatic hyperplasia, prostate cancer, and hypothyroidism. For example, by enhancing progesterone signaling, PDE1 inhibitors can be used to promote implantation of a fertilized egg by influencing the endometrium and help maintain pregnancy in women with a tendency to miscarry due to an immune response to pregnancy or low progesterone function. For example, novel PDE1 inhibitors as described herein can also be used to enhance the efficacy of hormone replacement therapy, for instance, in combination with estrogen / estradiol / estriol and / or progesterone / progestin in postmenopausal women, and for estrogen-induced endometrial hyperplasia and endometrial cancer. The methods of this invention can also be used in animal breeding, for example, to induce sexual receptivity and / or estrus in non-human female mammals intended for breeding.

[0102] In this embodiment, the PDE1 inhibitor may be used as the sole therapeutic agent in the aforementioned treatment or prevention methods, but may also be used in combination with or co-administered with other active agents, such as in combination with hormone replacement therapy. Therefore, the invention also includes a method for treating a condition that can be improved by enhancing progesterone signaling, comprising administering, simultaneously, sequentially, or concurrently, a therapeutically effective amount in a free form, a pharmaceutically acceptable salt form, or a prodrug form to a human or animal patient in need: (i) PDE1 inhibitors, such as compounds according to Formula I, such as any one of compounds 1.0 to 1.71, and (ii) Hormones, such as those selected from estrogens or estrogen analogs (e.g., estradiol, estriol, estradiol esters) and progesterone and progesterone analogs (e.g., progestins).

[0103] In yet another embodiment, the present invention provides a method for treating neuroinflammation and / or diseases or conditions associated with neuroinflammation and / or microglial function, comprising administering to a patient in need—that is, a patient with elevated levels of one or more pro-inflammatory cytokines (e.g., IL1β, TNF-α, and Ccl2 or combinations thereof)—a therapeutically effective amount of a compound of the present invention, in free form, pharmaceutically acceptable salt form, or prodrug form, such as a compound according to formula I, for example, any one of compounds 1.0 to 1.71. In this embodiment, the therapeutic amount of the compound of the present invention is an amount effective for the patient in need of (i) reducing or inhibiting the activation of M1 microglia and / or (ii) effectively reducing the levels of one or more pro-inflammatory cytokines (e.g., IL1β, TNF-α, and Ccl2 or combinations thereof). Neuroinflammation and / or diseases or conditions 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 prions); neuroinflammation associated with damage resulting from stroke, cardiac arrest, hypoxia, intracerebral hemorrhage, or traumatic brain injury; neuroinflammation associated with chronic CNS infections (e.g., Lyme disease, syphilis) or CNS infections secondary to immunosuppressive conditions (e.g., HIV dementia); and neuroinflammation secondary to chemotherapy.

[0104] The present invention also provides a method for promoting inflammation resolution for treating or preventing inflammation and / or diseases related to inflammation and / or microglial function, the method comprising administering to a patient in need a compound of the present invention, in free form or in a pharmaceutically acceptable salt form or as a prodrug, such as a compound according to formula I, for example, any one of compounds 1.0 to 1.71. In this context, it is believed that an effective amount of the compound of the present invention is an amount that will be effective in promoting the activation of macrophages from an M1 activated state to an M2 activated state. Diseases or conditions associated with inflammation and / or microglial function, including bacterial infections (e.g., Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium ulcerativelis, and Mycobacterium avium infections); 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 type 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., severe acute respiratory syndrome coronavirus (e.g., SARS-CoV, SARS-CoV)). (oV-2, COVID-19), 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 infections (e.g., fat-headed tapeworm, Toxoplasma gondii, Leishmania infantis, Schistosoma mansoni infection); atopic dermatitis; pneumonia; cardiovascular diseases such as atherosclerosis; obesity and insulin resistance; asthma; pulmonary fibrosis; obstructive pulmonary disease (COPD); neuropathic pain; stroke; diabetes; sepsis; non-alcoholic steatohepatitis (NASH); autoimmune hepatitis; systemic lupus erythematosus (SLE); wound healing; pleurisy; peritonitis; and cystic fibrosis.

[0105] In another embodiment, the present invention provides a method for treating cancer or tumor characterized by an increase in PDE1 (i.e., PDE1C) expression relative to normal cells of the same tissue type as cancer or tumor cells, the method comprising administering, alone or in combination with an antitumor agent, chemotherapy, gene therapy, immunotherapy, corticosteroids and / or antihistamines, a pharmaceutically acceptable amount of a compound of formula I, such as any one of compounds 1.0 to 1.71, in free, pharmaceutically acceptable salt, or prodrug form. Increased PDE1 expression refers to an increase in PDE1 RNA expression, DNA copy number, PDE1 binding (e.g., PET or radioisotope retention of a PDE1 inhibitor molecule), or PDE1 enzyme activity (e.g., as measured in an enzymological assay or as reflected by low cAMP levels in cancer cells or subcellular domains of cancer cells (e.g., microtubule domains) relative to normal cells of the same tissue type as cancer or tumor cells.These types of cancers or tumors include, but are not limited to, acoustic neuroma / vestibular schwannoma, astrocytoma, chordoma, CNS lymphoma, craniopharyngioma, glioma (e.g., brainstem glioma, ependymoma, mixed glioma, optic nerve glioma), subependymal tumor, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), schwannoma, adenoma (e.g., basophilic adenoma, eosinophilic adenoma, chromophobe adenoma, parathyroid adenoma, islet adenoma, fibroadenoma), and fibroma (fibrous histiocytoma). ), fibroma, hemangioma, lipoma (e.g., angiolipoma, myelolipoma, fibrolipoma, spindle cell lipoma, dormant lipoma, atypical lipoma), myxoma, osteoma, preleukemia, rhabdomyosarcoma, papilloma, seborrheic keratosis, skin appendage tumors, hepatic adenoma, renal tubular adenoma, bile duct adenoma, transitional cell papilloma, hydatidiform mole, ganglioneuroma, meningioma, schwannoma, neurofibroma, C-cell hyperplasia, pheochromocytoma, insulinoma, gastrinoma, carcinoid, chemoreceptor tumor, paraganglioma, nevus, actinic keratosis Cervical dysplasia, metaplasia (e.g., pulmonary metaplasia), leukoplakia, hemangioma, lymphangioma, carcinoma (e.g., squamous cell carcinoma, epidermoid carcinoma, adenocarcinoma, liver cancer, hepatocellular carcinoma, renal cell carcinoma, bile duct carcinoma, transitional cell carcinoma, embryonic cell carcinoma, parathyroid carcinoma, medullary thyroid carcinoma, bronchial carcinoid, oat cell carcinoma, islet cell carcinoma, malignant carcinoid), sarcoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma, angiosarcoma, angiosarcoma). (osarcoma), lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, neurofibrosarcoma), blastoma (e.g., medulloblastoma and glioblastoma, brain tumor types, retinoblastoma, ocular retinal tumors, osteoblastoma, bone tumors, neuroblastoma), germ cell tumors, mesothelioma, malignant skin appendage tumors, adrenocortical carcinoma, seminoma, glioma, malignant meningioma, malignant Schwannoma, malignant pheochromocytoma, malignant paraganglioma, melanoma, Merkel cell tumor, phyllodes cystosarcoma, or Wilms' tumor.

[0106] In another embodiment, this application provides a method for inhibiting cytokine release syndrome, the method comprising administering to a patient in need an effective amount of the compound of the invention in free form or pharmaceutically acceptable salt form or prodrug form, such as a compound according to formula I, such as any one of compounds 1.0 to 1.71, for example, wherein the patient has cancer and is receiving one or more of chemotherapy, immunotherapy, gene therapy and / or antibody therapy (including antibodies against cancer antigens and / or antibodies against immune checkpoint targets), and wherein the method optionally further comprises administering to the patient corticosteroids and / or antihistamines.

[0107] The present invention also provides a method for preventing or treating dementia-related conditions, the method comprising administering to a patient a combination of: (i) a therapeutically effective amount of a compound of the present invention in a free form, a pharmaceutically acceptable salt form, or a prodrug form, such as compounds of formula I, such as any one of compounds 1.0 to 1.71; and (ii) a therapeutically effective amount of a 5-HT2A or 5-HT2A / D2 receptor ligand in a free form, a pharmaceutically acceptable salt form, or a prodrug form, such as a substituted heterocyclic fused γ-carbaline as described herein. The present invention also covers compositions comprising: (i) a therapeutically effective amount of a compound of the present invention in a free form, a pharmaceutically acceptable salt form, or a prodrug form, such as compounds of formula I, such as any one of compounds 1.0 to 1.71; 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 PCT / US2017 / 024575, the contents of which are incorporated herein by reference.

[0108] In this implementation plan, dementia-related conditions include those associated with Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome, geriatric depression, Wernicke-Korsakoff syndrome, corticobasal degeneration, and prions; conditions associated with mild cognitive impairment and dementia, including Alzheimer's disease, Pick's disease, frontotemporal dementia, paranuclear palsy, Lewy body dementia, and vascular dementia; and behavioral or emotional disorders in patients with dementia (especially Alzheimer's disease), such as agitation / irritability, aggressive / violent behavior, anger, physical or emotional outbursts, psychosis, depression, and sleep disorders (e.g., sleep maintenance insomnia, advanced sleep phase syndrome, delayed sleep phase syndrome, frequent awakenings, and feeling unrested upon waking).

[0109] The present invention also provides a method for treating diseases characterized by disruption or impairment of cGMP / PKG and / or cAMP / PKA signaling pathways, such disruption or impairment being caused, for example, by increased PDE1 expression or by reduced expression of cGMP / PKG or cAMP / PKA activity due to inhibition or decreased levels of cyclic nucleotide synthesis inducers such as dopamine and nitric oxide (NO). It is believed that by inhibiting, for example, PDE1, this effect can reverse or prevent the attenuation of cGMP / PKG or cAMP / PKA signaling (e.g., by enhancing cGMP or cAMP, respectively). Therefore, the administration or use of preferred PDE1 inhibitors as described herein (e.g., PDE1 inhibitors as described above) can provide a potential means of treating various cardiovascular diseases and conditions.

[0110] In this embodiment, the present invention provides a method for enhancing the effect of adenosine A2 receptor agonists in the treatment, relief, or prevention of diseases or conditions characterized by positive inotropic and / or diastolic dysfunction, the method comprising administering to a patient in need an effective amount of the compound of the present invention in free form or in a pharmaceutically acceptable salt form or in a prodrug form, such as a compound according to formula I, such as any one of compounds 1.0 to 1.71. Diseases and conditions characterized by impaired positive inotropic and / or diastolic function include, but are not limited to, angina pectoris, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes-related hypertension, atherosclerosis-related hypertension, renovascular hypertension, congestive heart failure, inflammatory diseases or conditions, fibrosis, cardiac hypertrophy, vascular remodeling, connective tissue diseases or conditions (e.g., Marfan syndrome), chronic heart failure, myocardial inflammation, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunction (e.g., myocardial infarction, ventricular dilatation), vascular leakage (i.e., secondary to hypoxia), acute vasculitis (i.e., secondary to vascular injury), cardiac hypertrophy, muscular dystrophy (e.g., Duchenne muscular dystrophy), or amyotrophic lateral sclerosis. In such methods, the compounds of the present invention may be administered in combination with other therapeutic agents such as adenosine A2 receptor agonists, β-adrenergic receptor antagonists (i.e., β-blockers), ACE inhibitors, calcium channel blockers, angiotensin receptor blockers (ARBs), neprilysin inhibitors, or combinations thereof.

[0111] In one related embodiment, the present invention provides a method for treating, alleviating, or preventing cardiotoxicity secondary to the administration of chemotherapeutic agents and / or radiotherapy, the method comprising administering to a patient in need an effective amount of a compound of the present invention, in free form or in a pharmaceutically acceptable salt form or in a prodrug form, such as a compound according to Formula I, for example, any one of compounds 1.0 to 1.71. Chemotherapeutic agents known to cause cardiotoxicity include, but are not limited to, cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, nitrogen mustard, mitomycin, paclitaxel, etoposide, teniposide, vinca alkaloids, fluorouracil, cytarabine, acridine, cladribine, asparaginase, retinoic acid, pentostatin, and antagonists of human epidermal growth factor receptor 2 (HER2) / neu (e.g., trastuzumab).

[0112] In another related embodiment, the present invention provides a method for treating diseases or conditions mediated by cyclic nucleotides (cAMP or cGMP) and / or epoxidized fatty acids, the method comprising administering to a patient in need an effective amount of a compound of the present invention, in free form or a pharmaceutically acceptable salt form or a prodrug form, such as a compound of formula I, such as any one of compounds 1.0 to 1.71, optionally in combination with a soluble epoxide hydrolase (sEH) inhibitor. Such diseases and conditions include, but are not limited to, pain, neurodegenerative diseases, psychiatric disorders, circulatory and cardiovascular disorders, respiratory disorders, inflammatory disorders, and other conditions described in International Application No. PCT / US2020 / 066138, the entire contents of which are incorporated herein by reference.

[0113] This also covers methods of treating kidney conditions (including, but not limited to, renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, and nephritis) by administering an effective amount of the compounds of the invention (e.g., compounds according to Formula I, such as any one of compounds 1.0 to 1.71) in free form, pharmaceutically acceptable salt form, or prodrug form to a patient in need. The kidney condition being treated may be secondary to diabetes, kidney injury, hypertension, cancerous growth (e.g., polycystic kidney disease) or cardiovascular conditions (e.g., angina, stroke, primary hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes-related hypertension, atherosclerosis-related hypertension, renovascular hypertension, congestive heart failure, myocardial infarction, angina and stroke, hypertension, inflammatory diseases or conditions, fibrosis, cardiac hypertrophy, vascular remodeling, and connective tissue diseases or conditions (e.g., Marfan syndrome)).

[0114] This disclosure also provides a method for enhancing or strengthening dopamine D1 intracellular signaling activity in cells or tissues, the method comprising contacting the cells or tissues with an amount of the compound of the invention (e.g., a compound according to formula I, such as any one of compounds 1.0 to 1.71) in a free form, a pharmaceutically acceptable salt form, or a prodrug form sufficient to inhibit PDE1 activity.

[0115] This disclosure also provides a method for treating PDE1-related conditions, dopamine D1 receptor intracellular signaling pathway conditions, or conditions that can be alleviated by enhancing progesterone signaling pathways in patients with such needs, the method comprising administering to the patient an effective amount of a compound of the invention (e.g., a compound according to formula I, such as any one of compounds 1.0 to 1.71) in a free form, a pharmaceutically acceptable salt form, or a prodrug form that inhibits PDE1, wherein PDE1 activity regulates phosphorylation of DARPP-32 and / or GluR1 AMPA receptors.

[0116] This disclosure also provides a method for enhancing the positive effects of dopamine replacement therapy and reducing its side effects in patients suffering from diseases or conditions associated with the dopamine D1 receptor intracellular pathway, the method comprising administering to a patient in need (i.e., a patient with Parkinson's disease receiving dopamine replacement therapy) a therapeutically effective amount of a compound of the invention in free or pharmaceutically acceptable salt or prodrug form, such as a compound according to formula I, for example, any one of compounds 1.0 to 1.71. In some aspects of this embodiment, side effects cover motor disturbances and impaired motor function. The method for enhancing the positive effects of dopamine replacement therapy and reducing its side effects in patients suffering from diseases or conditions associated with the dopamine D1 receptor intracellular pathway is discussed in International Application No. PCT / US2019 / 57260, the contents of which are incorporated herein by reference.

[0117] In another aspect, this disclosure also provides a method for treating glaucoma or elevated intraocular pressure, the method comprising topically administering a therapeutically effective amount of the present invention's PDE1 inhibitor, in a free form or a pharmaceutically acceptable salt form in an ophthalmologically compatible carrier, such as a compound according to formula I, for example, any one of compounds 1.0 to 1.71, to the eye of a patient in need. However, treatment may alternatively include systemic therapy. Systemic therapy includes, for example, treatments that can directly reach the bloodstream or oral administration.

[0118] This disclosure also provides a pharmaceutical composition for topical ophthalmic use comprising a PDE1 inhibitor; for example, an ophthalmic solution, suspension, cream, or ointment comprising an ophthalmic solution, suspension, cream, or ointment comprising, in free form or in ophthalmologically acceptable salt form, a PDE1 inhibitor of the present invention (e.g., a compound according to Formula I, such as any one of compounds 1.0 to 1.71), the inhibitor being combined or combined with an ophthalmologically acceptable diluent or carrier, optionally administered sequentially or simultaneously with a second drug for the treatment of glaucoma or elevated intraocular pressure.

[0119] In addition to the methods described above, the PDE1 inhibitors of the present invention (e.g., compounds according to Formula I, such as any one of compounds 1.0 to 1.71) in free form or in pharmaceutically acceptable salt form may also be used to treat psychosis, such as any condition characterized by psychotic symptoms such as hallucinations, paranoid or bizarre delusions, or speech and thought disorders, such as schizophrenia, schizophrenic disorder, schizophrenia-like disorder, psychotic disorder, paranoid disorder, and mania, such as acute manic episodes and bipolar disorder.

[0120] In the aforementioned treatment or prevention methods, PDE 1 inhibitors may be used as the sole treatment agent or in combination or co-administered with other active agents known to be effective in treating or preventing specific diseases or conditions.

[0121] This disclosure also provides (i) The compounds of the invention in free form or in pharmaceutically acceptable salt form, such as compounds of formula I as described above, such as any one of compounds 1.0 to 1.71, for example, used in any of the methods described above or in the treatment of any disease or condition described above. (ii) Use of the compounds of the invention in free form or in pharmaceutically acceptable salt form (e.g., compounds of formula I as described above, such as any one of compounds 1.0 to 1.71) in the manufacture of a medicine for treating any disease or condition as described above. (iii) A pharmaceutical composition comprising the compound of the invention in free form or in a pharmaceutically acceptable salt form, such as a compound of formula I as described above, such as any one of compounds 1.0 to 1.71, said compound being combined or combined with a pharmaceutically acceptable diluent or carrier, and (iv) A pharmaceutical composition comprising the compound of the invention in free form or in a pharmaceutically acceptable salt form, such as a compound of formula I as described above, such as any one of compounds 1.0 to 1.71, said compound being combined or combined with a pharmaceutically acceptable diluent or carrier for the treatment of any disease or condition as described above.

[0122] Therefore, this disclosure provides the use of the compounds of the invention in free form or pharmaceutically acceptable salt form (e.g., compounds of formula I as described above, such as any one of compounds 1.0 to 1.71) or in pharmaceutical composition form (in manufacture) for the treatment or preventive treatment of any one or more diseases or conditions as described above (in a medicament).

[0123] The phrase “compounds of the present invention” or “PDE1 inhibitors of the present invention” covers any and all compounds disclosed herein, such as compounds of formula I as described above, such as any one of compounds 1.0 to 1.71, in free or salt form.

[0124] The terms "treatment" and "treating" should be understood accordingly to encompass the prevention and treatment or relief of disease symptoms as well as the treatment of the cause of the disease. In one embodiment, the present invention provides a method for treating the disease or condition disclosed herein. In another embodiment, the present invention provides a method for preventing the disease or condition disclosed herein.

[0125] Regarding treatment methods, the term "effective dose" is intended to encompass the effective dose for treating a specific disease or condition.

[0126] The term "patient" includes human patients or non-human (i.e., animal) patients. In one embodiment, the invention covers both humans and non-humans. In another embodiment, the invention covers non-humans. In still other embodiments, the term covers humans.

[0127] As used in this disclosure, the term "comprising" is intended to be open-ended and does not exclude other unlisted elements or method steps.

[0128] The compounds of this invention, in free form or in pharmaceutically acceptable salt form, can be used as the sole therapeutic agent or in combination with other active agents or co-administered. For example, because the compounds of this invention enhance the activity of D1 agonists (such as dopamine), they can be administered simultaneously, sequentially, or concurrently with conventional dopaminergic drugs (such as levodopa and levodopa adjuvants (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergic agents), for example, to treat patients with Parkinson's disease. Additionally, novel PDE1 inhibitors, such as those described herein, can also be administered in combination with estrogen / estradiol / estriol and / or progesterone / progestin to enhance the efficacy of hormone replacement therapy or to treat estrogen-induced endometrial hyperplasia or endometrial cancer. Novel PDE1 inhibitors, such as those described herein, can also be administered in combination with antitumor agents, chemotherapy, gene therapy, immunotherapy, corticosteroids, and / or antihistamines to treat cancers or tumors characterized by increased PDE1 expression. The compounds of the present invention can also be administered in combination with therapeutically effective amounts of 5-HT2A or 5-HT2A / D2 receptor ligands to prevent or treat dementia-related conditions. Additionally, the novel PDE1 inhibitors of the present invention can be administered in combination with adenosine A2 agonists to treat, alleviate, or prevent diseases or conditions characterized by positive inotropic and / or diastolic dysfunction. Furthermore, the compounds of the present invention can be administered in combination with soluble epoxide hydrolase (SHE) inhibitors in methods for treating diseases or conditions mediated by cAMP or cGMP and / or epoxidized fatty acids.

[0129] The dosage used in practicing this invention will naturally vary depending on, for example, the specific disease or condition to be treated, the specific compound of the invention used, the method of administration, and the desired therapy. The compounds of the invention can be administered by any suitable route, including oral, parenteral, transdermal, or inhalation, but oral administration is preferred. Generally, for example, for the treatment of diseases as described above, satisfactory results are obtained by oral administration at doses in the range of about 0.01 to 2.0 mg / kg. In larger mammals (e.g., humans), the indicated daily dose for oral administration is correspondingly in the range of about 0.75 to 150 mg, administered once daily for convenience, or divided into 2 to 4 daily doses, or in a sustained-release form. Therefore, the unit dose form for oral administration (e.g., oral administration) may, for example, contain about 0.2 to 150 or 300 mg of the compound of the invention, such as about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150 or 200 mg, about 1 to 100 mg, about 1 to 50 mg, about 1 to 10 mg, about 5 to 10 mg, about 10 to 50 mg, 1 mg, 3 mg, 5 mg, 10 mg, 30 mg, or 90 mg, and pharmaceutically acceptable diluents or carriers thereof.

[0130] Pharmaceutical compositions comprising the compounds of the present invention can be prepared using conventional diluents or excipients and techniques known in the field of galenic formulations. Therefore, oral dosage forms may include tablets, capsules, solutions, suspensions, etc. In some embodiments, the compositions are in the form of oral dosage forms (such as tablets or capsules), intranasal dosage forms (e.g., nasal sprays or nebulizers), pulmonary dosage forms (e.g., inhalers), or injectable dosage forms (e.g., intravenous, intramuscular, or subcutaneous injections, such as long-acting reservoir injections). Example

[0131] The following describes a method for synthesizing the compounds of the present invention. Intermediates of the compounds of the present invention, as well as other compounds of the present invention and their salts, can be prepared using methods similarly described below and / or by methods similar to those generally described in the detailed description, and by methods known in the field of chemistry.

[0132] Example 1: Synthesis of 2-(4-(acetyl-d3)benzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-one (Compound 1) Compound 1 A mixture of K₂CO₃ (54 mg, 0.390 mmol), D₂O (2.8 mL), and 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (900 mg, 1.952 mmol) in THF (10 mL) was stirred at room temperature for 7 days. The reaction solvent was removed, and the residue was extracted with dichloromethane (3 x 20 mL). The extract was evaporated to dryness and further dried under high vacuum for 24 hours. The resulting product (compound 1) was a grayish-white solid (900 mg, 100% yield). MS (ESI) m / z 464.25 [M + H] + . 1 H NMR (300MHz, CDCl3) δ 7.87 – 7.79 (m, 2H), 7.07 – 6.99 (m, 2H), 6.98 – 6.85 (m, 4H), 6.83 (s, 1H), 4.87 (s, 2H), 3.68 (s, 2H), 3.34 (s, 3H), 1.60 (s, 2H), 1.39 (s, 6H). 13C NMR (126 MHz, DMSO) δ 197.55, 197.51, 157.64, 156.99, 155.76, 150.85, 148.63, 141.95, 141.91, 139.14, 135.96, 128.40, 127.19, 117.61,117.55, 115.22, 115.04, 89.67, 64.32, 57.35, 50.36, 29.40, 28.35.

[0133] Example 2 Measured using the IMAP phosphodiesterase assay kit in vitro PDE1 inhibition Phosphodiesterase 1 (PDE1) is a calcium / calmodulin-dependent phosphodiesterase that converts cyclic guanosine monophosphate (cGMP) to 5'-guanosine monophosphate (5'-GMP). PDE1 also converts modified cGMP substrates (such as the fluorescent molecule cGMP-luciferin) to the corresponding GMP-luciferin. The generation of GMP-luciferin from cGMP-luciferin can be quantified using metal affinity particle reagents immobilized, for example, by IMAP (Molecular Devices, Sunnyvale, CA).

[0134] In short, the IMAP reagent binds with high affinity to free 5'-phosphate present in GMP-fluorescein but absent in cGMP-fluorescein. The resulting GMP-fluorescein-IMAP complex is larger in volume than cGMP-fluorescein. The small fluorophores bound in the large, slowly rotating complex can be distinguished from unbound fluorophores because the photons emitted when they produce fluorescence retain the same polarization as the photons used to excite fluorescence.

[0135] In phosphodiesterase assays, cGMP-luciferin cannot bind to IMAP and therefore retains almost no fluorescence polarization, while its converted form, GMP-luciferin, produces a large increase in fluorescence polarization (Δmp) upon binding to IMAP. Therefore, inhibition of phosphodiesterase is detected by a decrease in Δmp.

[0136] Enzyme assay Materials: Except for IMAP reagents (reaction buffer, binding buffer, FL-GMP and IMAP beads) which were obtained from Molecular Devices (Sunnyvale, California), all chemicals were obtained from Sigma-Aldrich (St. Louis, Missouri).

[0137] Assay: The following phosphodiesterases can be used: 3',5'-cyclic nucleotide-specific bovine brain phosphodiesterase (Sigma, St. Louis, Missouri) and recombinant full-length human PDE1A and PDE1B (r-hPDE1A and r-hPDE1B, respectively), the latter of which can be produced by those skilled in the art in, for example, HEK or SF9 cells. The PDE1 enzyme was reconstituted with 50% glycerol to 2.5 U / ml. At pH 7.5 and 30°C, one unit of enzyme hydrolyzed 1.0 µmole of 3',5'-cAMP to 5'-AMP per minute. One unit of enzyme was added to 1999 units of reaction buffer (30 µM CaCl2, 10 U / ml calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM MgCl2, 0.1% BSA, 0.05% NaN3) to obtain a final concentration of 1.25 mU / ml. Add 99 µl of diluted enzyme solution to each well of a 96-well flat-bottomed polystyrene plate, and add 1 µl of the test compound dissolved in 100% DMSO. Mix the test compound with the enzyme and incubate at room temperature for 10 minutes.

[0138] In a 384-well microtiter plate, the FL-GMP conversion reaction was initiated by combining four portions of the enzyme and inhibitor mixture with one portion of the substrate solution (0.225 µM). The reaction mixture was incubated at room temperature in the dark for 15 minutes. The reaction was terminated by adding 60 µl of binding reagent (1:400 dilution of IMAP beads in binding buffer, supplemented with 1:1800 dilution of antifoaming agent) to each well of the 384-well plate. The plate was incubated at room temperature for 1 hour to allow complete IMAP binding, and then placed in an Envision multimode microplate reader (PerkinElmer, Sheldon, Connecticut) to measure fluorescence polarization (Δmp).

[0139] A decrease in GMP concentration, measured as a reduction in Δmp, indicates inhibition of PDE activity. IC 50 The values ​​were determined by measuring enzyme activity in the presence of 8 to 16 compound concentrations (ranging from 0.0037 nM to 80,000 nM) and then plotting the relationship between drug concentration and ΔmP. This allowed for the estimation of IC50 using nonlinear regression software (XLFit; IDBS, Cambridge, MA). 50 value.

[0140] The PDE1 inhibitory activity of the compounds of the present invention was tested. Example compounds of the present invention (e.g., compound 1) have an IC50 of less than or equal to 10 nm. 50 Value. IC50 of compound 1 50 The values ​​are shown in Table 1 below.

[0141] Table 1

Claims

1. A compound of formula I: Formula I in (i) R1 is H or C 1-4 Alkyl groups (e.g., methyl or ethyl); (ii) R2 and R3 are independently H or C 1-6 Alkyl groups (e.g., methyl or ethyl); (iii) R4 is H or C 1-4 Alkyl groups (e.g., methyl or ethyl); (iv) R5 is an aryl group substituted with -C(=O)-CD3 (e.g., phenyl), where D is deuterium ( 2 H); (v) R6 and R7 are independently H or optionally selected independently from C by one or more of them. 1-6 Aryl groups (e.g., phenyl) substituted with alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl) groups, such as unsubstituted phenyl or phenyl substituted with one or more halogens (e.g., F) or phenyl substituted with one or more C groups. 1-6 alkyl groups and one or more halogen-substituted phenyl groups or those with a C124-C ... 1-6 An alkyl group and a halogen-substituted phenyl group, such as 4-fluorophenyl, 3,4-difluorophenyl, or 4-fluoro-3-methylphenyl; and (vi) n is 1, 2, 3 or 4. It exists in free form, salt form, or prodrug form, such as pharmaceutically acceptable salt forms, including its enantiomers, diastereomers, and racemic compounds.

2. The compound according to claim 1, wherein R1 is methyl.

3. The compound according to claim 1 or 2, wherein R2 and R3 are both methyl groups.

4. The compound according to any one of the preceding claims, wherein R4 is H.

5. The compound according to any one of the preceding claims, wherein R5 is a phenyl group substituted with -C(=O)-CD3.

6. The compound according to any one of the preceding claims, wherein R7 is H and R6 is 4-fluorophenyl.

7. The compound according to any one of the preceding claims, wherein n is 1.

8. The compound according to claim 1, wherein... (i) R1 is a methyl group; (ii) Both R2 and R3 are methyl groups; (iii) R4 is H; and (iv) n is 1.

9. The compound according to claim 8, wherein R5 is a phenyl group substituted with -C(=O)-CD3.

10. The compound according to claim 8 or 9, wherein R7 is H and R6 is 4-fluorophenyl.

11. The compound according to claim 1, wherein the compound is It exists in free form or as a salt.

12. A pharmaceutical composition comprising a compound according to any one of claims 1-11, in free form or in a pharmaceutically acceptable salt form, said compound being mixed with a pharmaceutically acceptable diluent or carrier.

13. The composition of claim 12, wherein the composition is in the form of an oral dosage form (such as tablets or capsules), an intranasal dosage form (e.g., nasal spray or nebulizer), a pulmonary dosage form (e.g., inhaler), or an injectable dosage form (e.g., intravenous, intramuscular, or subcutaneous injection, such as a long-acting reservoir injection).

14. A method for preventing or treating a disease or condition, said disease or condition being selected from: neurodegenerative diseases (e.g., Parkinson's disease, restless legs, tremor, movement disorders, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders); neuroinflammation and / or diseases or conditions related to neuroinflammation and / or microglial function; mental illnesses (e.g., depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety disorder, sleep disorders (e.g., narcolepsy), cognitive impairment (e.g., cognitive impairment in schizophrenia), Tourette syndrome, autism, Fragile X syndrome, and stimulants). Withdrawal and drug addiction; "chemotherapy brain" (cognitive impairment caused by cancer treatment (e.g., chemotherapy) or cancer itself); conditions associated with dementia; circulatory and cardiovascular conditions (e.g., cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and sexual dysfunction); respiratory and inflammatory conditions (e.g., asthma, chronic obstructive pulmonary disease, and allergic rhinitis); conditions that can be relieved by enhancing progesterone signaling (e.g., female sexual dysfunction); psychosis; eye diseases (e.g., glaucoma and elevated intraocular pressure); traumatic brain injury; cancer or tumors (e.g., glioma, colon cancer). And breast cancer); kidney diseases (e.g., renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis, nephritis); cardiac toxicity secondary to the administration of chemotherapy agents and / or radiotherapy; any disease or condition characterized by low levels of cAMP and / or cGMP in cells expressing PDE1 (e.g., angina pectoris, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes-related hypertension, atherosclerosis-related hypertension, renovascular hypertension, congestive heart failure, inflammatory diseases or conditions, fibrosis, cardiac hypertrophy, vascular remodeling, connective tissue...). The method comprises administering to a patient in need a therapeutically effective amount of the compound according to any one of claims 1-11 or a therapeutically effective amount of the pharmaceutical composition according to claim 12 or 13. This includes treatment of diseases or conditions such as myocardial infarction, chronic heart failure, myocardial inflammation, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunction, vascular leakage, acute vasculitis, and amyotrophic lateral sclerosis (ALS); bacterial infections; viral infections; obesity; and any disease or condition characterized by reduced dopamine D1 receptor signaling activity (e.g., attention deficit, cognitive, PTSD, memory, and / or inhibitory processing), wherein the method comprises administering to a patient in need a therapeutically effective amount of the compound according to any one of claims 1-11 or a therapeutically effective amount of the pharmaceutical composition according to claim 12 or 13.

Images