Methods of treatment

Abstract

To provide a method for preventing and / or treating a condition, disease, or disorder associated with the dopamine D1 receptor intracellular pathway, for example, a condition, disease, or disorder characterized by a deficit in attention, cognition, memory, and / or inhibitory processing.SOLUTION: A method comprising administering to a subject in need of prevention and / or treatment a pharmaceutically effective amount of a phosphodiesterase 1 (PDE1) inhibitor (for example, a compound represented by formula V).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international patent application claims priority to and the benefit of U.S. Provisional Application No. 62 / 941,542, filed November 27, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Disclosed technical field The field relates to inhibitors of phosphodiesterase 1 (PDE1) useful in central nervous system involvement. The field also relates to the administration of inhibitors of phosphodiesterase 1 (PDE1) for the treatment of conditions, diseases, or disorders associated with the dopamine D1 receptor intracellular pathway, such as conditions, diseases, or disorders characterized by deficits in attention, cognition, memory, and / or inhibitory processing. [Background technology]

[0003] Background to the disclosure Although 11 families of phosphodiesterases (PDEs) have been identified, only family I PDEs, the Ca2+ / calmodulin-dependent phosphodiesterases (CaM-PDEs), have been shown to mediate calcium and cyclic nucleotide (e.g., cAMP and cGMP) signaling pathways. The three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in central nervous system tissues. PDE1A is expressed throughout 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 lung and heart. PDE1B is primarily expressed in the striatum, dentate gyrus, olfactory tract, and cerebellum, and its expression correlates with brain regions with high levels of dopaminergic innervation. PDE1B is primarily expressed in the central nervous system, but can also be detected in the heart. PDE1C is primarily expressed in the olfactory epithelium, cerebellar granule cells, and striatum. PDE1C is also expressed in the heart and vascular smooth muscle.

[0004] Cyclic nucleotide phosphodiesterases reduce intracellular cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to their respective inactive 5'-monophosphates (5'AMP and 5'GMP). CaM-PDEs play a key role in mediating signal transduction in brain cells, particularly within the brain region known as the basal ganglia or striatum. For example, activation of NMDA-type glutamate receptors and / or dopamine D2 receptors increases intracellular calcium levels, activating effectors such as calmodulin-dependent kinase II (CaMKII) and calcineurin, which activate CaM-PDEs and reduce cAMP and cGMP. On the other hand, activation of dopamine D1 receptors activates calcium-dependent nucleotide cyclases, increasing cAMP and cGMP. These cyclic nucleotides then activate protein kinase A (PKA; cAMP-dependent protein kinase) and / or protein kinase G (PKG; cAMP-dependent protein kinase), which phosphorylate downstream signaling pathway elements such as DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) and cAMP-response element-binding protein (CREB).

[0005] Thus, CaM-PDE can affect dopamine-regulated and other intracellular signaling pathways in the basal ganglia (striatum), including, but not limited to, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP), and endorphin intracellular signaling pathways.

[0006] Phosphodiesterase (PDE) activity, especially phosphodiesterase 1 (PDE1) activity, functions as the regulator of locomotor activity and learning and memory in brain tissue.PDE1 is the therapeutic target for regulating intracellular signaling pathways, preferably in nervous system, and this intracellular signaling pathway includes but is not limited to the intracellular signaling pathways of dopamine D1 receptor, dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (for example, NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (for example, A2A receptor), cannabinoid receptor, natriuretic peptide (for example, ANP, BNP, CNP) or endorphin.For example, inhibiting PDE1B acts to enhance the effect of dopamine D1 agonist by protecting cGMP and cAMP from degradation, and similarly inhibiting PDE1 activity inhibits dopamine D2 receptor signaling pathway.

[0007] Dopamine modulators such as methylphenidate or modafinil have been observed to improve cognitive function through enhanced extinction of contextual fear in animal models and, more recently, through enhanced fear extinction learning in humans. A recent study also observed an attenuating effect of methylphenidate on the bilateral anterior insula during a fear extinction task in healthy humans. Methylphenidate and modafinil have also been shown to improve inhibitory ability and increase activation of the frontal gyrus during a stop-signal task.

[0008] However, while such drugs address cognitive deficits, they are associated with limiting side effects. For example, commonly used drugs such as methylphenidate can be addictive for some patients. There remains a significant unmet need for cognitive treatments, including treatment of inhibitory control disorders. Summary of the Invention

[0009] Disclosure Overview Provided herein is a method for treating the condition, disease or disorder associated with dopamine D1 receptor intracellular pathway, for example, the condition, disease or disorder characterized by the lack of attention, cognition, memory and / or inhibitory processing.For example, disorders such as ADHD and PTSD are partly characterized by the impaired inhibitory processing and reactivity of the frontal gyrus, which is an important brain region for the ability to inhibit response or to stop responding after receiving a signal to "stop".The inventors have unexpectedly found that the PDE1 inhibitor disclosed herein regulates brain activation in a region-selective and task-specific manner.The administration of the PDE1 inhibitor disclosed herein increases the activation of the frontal gyrus, similar to the response seen with methylphenidate, and is consistent with the improvement of cognition, suggesting that it is clinically effective in a wide range of disorders characterized by the lack of attention, cognition, memory and / or inhibitory processing.

[0010] Therefore, in a first aspect, the present disclosure provides a method for preventing and / or treating conditions, diseases or disorders associated with the dopamine D1 receptor intracellular pathway, such as conditions, diseases or disorders characterized by a deficit in attention, cognition, memory and / or inhibitory processing, the method comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (i.e., a compound represented by Formula I, Ia, II, III, IV, V and / or VI) to a subject in need of the prevention and / or treatment.In some aspects of the embodiment, the method further comprises administering a dopamine reuptake inhibitor. In certain aspects of the embodiments, the condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, night eating disorder, other specified eating or eating disorder (OSFED)), substance use disorder (e.g., addiction (e.g., to amphetamine, cocaine, opioids and / or nicotine, etc.) These include: stimulant substance addiction, alcoholism), obsessive-compulsive disorders (e.g., checking, contamination, mental contamination, hoarding, rumination, intrusive thoughts, symmetry / order), attention-deficit hyperactivity disorder (ADHD), premature ejaculation disorder, post-traumatic stress disorder (PTSD), gambling disorders (e.g., gambling addiction, compulsive gambling), Tourette's syndrome and / or impulse control / conduct disorders (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania).

[0011] In a second aspect, the present disclosure provides a method for treating an inhibitory processing disorder, the method comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a PDE1 inhibitor (i.e., a compound represented by Formula I, Ia, II, III, IV, V and / or VI).

[0012] In some embodiments, the present disclosure provides a combination therapy comprising a PDE1 inhibitor (e.g., a compound represented by Formula I, Ia, II, III, IV, V, and / or VI) and a dopamine reuptake inhibitor (e.g., methylphenidate). [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows brain activity measured in human dorsal anterior insula during a fear abolition task following administration of a PDE1 inhibitor according to the present disclosure.

[0014] [Figure 2] FIG. 2 shows brain activity measured in the human inferior frontal gyrus during a stop signal task following administration of a PDE1 inhibitor according to the present disclosure.

[0015] [Figure 3] FIG. 3 shows brain activity measured in the human dorsolateral prefrontal cortex during a stop signal task following administration of a PDE1 inhibitor according to the present disclosure.

[0016] [Figure 4] FIG. 4 shows brain activity measured in human dorsal anterior cingulate cortex during a stop signal task following administration of a PDE1 inhibitor according to the present disclosure.

[0017] [Figure 5] FIG. 5 shows brain activity measured in human anterior insula during a stop signal task following administration of a PDE1 inhibitor according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description of Disclosure Compounds for use in the disclosed methods In one embodiment, the PDE1 inhibitors for use in the methods of treatment and prevention described herein are selective PDE1 inhibitors.

[0019] PDE1 inhibitors In one embodiment, the present invention provides a PDE1 inhibitor for use in the methods of treatment and prevention described herein, which is a compound of formula I: [ka] [In the formula, (i) R1 is H or C 1-4 alkyl (e.g., methyl); (ii) R4 is H or C 1-4 alkyl, and R2 and R3 are independently H or C 1-4 alkyl (e.g., R2 and R3 are both methyl, or R2 is H and R3 is isopropyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; or R2 is H, and R3 and R4 together form a dimethylene, trimethylene or tetramethylene bridge (preferably, R3 and R4 together have a cis configuration, e.g., the carbons bearing R3 and R4 have the R and S configurations, respectively); (iii) R5 is a substituted heteroarylalkyl, e.g., substituted with haloalkyl; or R5 is attached to one of the nitrogens of the pyrazolo moiety of formula I and is represented by formula A: [ka] (Wherein X, Y and Z are independently N or C, R, R, R 11 and R 12 are independently H or halogen (e.g., Cl or F), and R 10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (e.g., pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl) optionally substituted with halogen), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, then R, R, or R, respectively. 10 does not exist) The part indicated by; (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino (e.g., N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino); (v) n is 0 or 1; (vi) When n is 1, A is -C(R 13 R 14 )-(where R 13 and R 14 are independently H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy or (optionally hetero)arylalkyl)] The compound is represented by the formula:

[0020] In another embodiment, the present invention provides that the PDE1 inhibitor for use in the methods described herein is a compound of formula 1a: [ka] [In the formula, (i) R2 and R5 are independently H or hydroxy, and R3 and R4 together form a trimethylene or tetramethylene bridge (preferably, the carbons bearing R3 and R4 have the R and S configurations, respectively); or R2 and R3 are each methyl, and R4 and R5 are each H; or R2, R4, and R5 are H, and R3 is isopropyl (preferably, the carbon bearing R3 has the R configuration); (ii) R6 is (optionally halo-substituted) phenylamino, (optionally halo-substituted) benzylamino, C 1-4 Alkyl, or C1-4 alkyl sulfide; for example, phenylamino or 4-fluorophenylamino; (iii) R 10 is C 1-4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl (e.g., 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl); X and Y are independently C or N. Provide that.

[0021] In another embodiment, the present invention provides a PDE1 inhibitor for use in the methods of treatment and prevention described herein, comprising a compound of formula II: [ka] [In the formula, (i) X is C 1-6 alkylene (e.g., methylene, ethylene, or prop-2-yn-1-ylene); (ii) Y is a single bond, alkynylene (e.g., —C≡C—), arylene (e.g., phenylene), or heteroarylene (e.g., pyridylene); (iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloC 1-6 alkyl (e.g., trifluoromethyl), —C(O)—R 1 , -N(R 2 )(R 3 ), or C optionally containing at least one atom selected from the group consisting of N or O 3-7 cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl); (iv) R 1 is C1-6 Alkyl, HaloC 1-6 Alkyl, -OH or -OC 1-6 alkyl (e.g., -OCH3); (v) R 2 and R 3 are independently H or C 1-6 is alkyl; (vi) R 4 and R 5 are independently H, C 1-6 alkyl, or one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) or C 1-6 aryl (e.g., phenyl) optionally substituted with alkoxy; (vii) where X, Y, and Z are independently one or more halo (e.g., F, Cl, or Br), C 1-6 Alkyl (e.g., methyl), haloC 1-6 Z may be substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC 1-6 Alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C 1-6 Z is heteroaryl, e.g., pyridyl, substituted with alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl). The compound is represented by the formula:

[0022] In yet another embodiment, the present invention provides a PDE1 inhibitor for use in the methods of treatment and prevention described herein, comprising a compound of formula III: [ka] [In the formula, (i) R1 is H or C 1-4 alkyl (e.g., methyl or ethyl); (ii) R2 and R3 are independently H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R4 is H or C 1-4 alkyl (e.g., methyl or ethyl); (iv) R5 independently represents -C(=O)-C 1-6 Alkyl (e.g., -C(=O)-CH3) and C 1-6 -aryl (e.g., phenyl) optionally substituted with one or more groups selected from hydroxyalkyl (e.g., 1-hydroxyethyl); (v) R6 and R7 are independently H or independently C 1-6 Aryl (e.g., phenyl) optionally substituted with one or more groups selected from alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example, unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F), or one or more C 1-6 Phenyl substituted with alkyl and one or more halogens, or one C 1-6 phenyl substituted with alkyl and one halogen, such as 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; (vi) n is 1, 2, 3, or 4. The compound is represented by the formula:

[0023] In yet another embodiment, the present invention provides a PDE1 inhibitor for use in the methods of treatment and prevention described herein, comprising a compound of formula IV: [ka] [In the formula, (i) R1 is C 1-4alkyl (e.g., methyl or ethyl), or -NH(R2) (wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), such as 4-fluorophenyl); (ii) X, Y, and Z are independently N or C; (iii) R3, R4 and R5 are independently H or C 1-4 alkyl (e.g., methyl); or R3 is H and R4 and R5 together form a trimethylene bridge (preferably, R4 and R5 together have the cis configuration, e.g., the carbons bearing R4 and R5 have the R and S configurations, respectively); (iv) R6, R7 and R8 are independently H, C 1-4 alkyl (e.g., methyl), hydroxy-substituted pyrid-2-yl, or -S(O)2-NH2 and; (v) provided that when X, Y, and / or Z are N, R6, R7, and / or R8, respectively, are absent; and when X, Y, and Z are all C, at least one of R6, R7, or R8 is -S(O)2-NH2, or pyrid-2-yl substituted with hydroxy. Provide that.

[0024] In another embodiment, the present invention provides a PDE1 inhibitor for use in the methods described herein, comprising a compound of formula V: [ka] [In the formula, (i) R1 is -NH(R4) (wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl); (ii) R2 is H or C 1-6 alkyl (e.g., methyl, isobutyl, or neopentyl); (iii) R3 is -SO2NH2 or -COOH] Provide that.

[0025] In another embodiment, the present invention provides a PDE1 inhibitor for use in the methods described herein, comprising a compound of formula VI: [ka] [In the formula, (i) R1 is -NH(R4) (wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl); (ii) R2 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R3 is H, halogen (e.g., bromo), C 1-6 alkyl (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl). Provide that.

[0026] In one embodiment, the disclosure provides for the administration of a PDE1 inhibitor (e.g., a compound of Formula I, Ia, II, III, IV, V, and / or VI) for use in the methods described herein, wherein the inhibitor is a compound selected from the group consisting of: [ka] [ka] [ka] [ka] The administration is provided.

[0027] In one embodiment, the present invention provides the administration of a PDE1 inhibitor for the treatment or prevention of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound of the following formula, in free form or in pharmaceutically acceptable salt form: [ka] The administration is provided.

[0028] In yet another embodiment, the present invention provides the administration of a PDE1 inhibitor for the treatment or prevention of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound of the following formula, in free form or in pharmaceutically acceptable salt form: [ka] The administration is provided.

[0029] In yet another embodiment, the present invention provides the administration of a PDE1 inhibitor for the treatment or prevention of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound of the following formula, in free form or in pharmaceutically acceptable salt form: [ka] The administration is provided.

[0030] In yet another embodiment, the present invention provides the administration of a PDE1 inhibitor for the treatment or prevention of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound of the following formula, in free form or in pharmaceutically acceptable salt form: [ka] The administration is provided.

[0031] In yet another embodiment, the present invention provides the administration of a PDE1 inhibitor for the treatment or prevention of inflammation or an inflammation-related disease or disorder, wherein the inhibitor is a compound of the following formula, in free form or in pharmaceutically acceptable salt form: [ka] The administration is provided.

[0032] In one embodiment, the selective PDE1 inhibitor represented by any of the above formulas (e.g., Formula I, Ia, II, III, IV, V and / or VI) is a compound that inhibits phosphodiesterase-mediated (e.g., PDE1-mediated, particularly PDE1B-mediated) hydrolysis of cGMP, e.g., preferred compounds have an IC50 in the immobilized metal affinity particle reagent PDE assay, in free or salt form, of less than 1 μM, preferably less than 500 nM, preferably less than 50 nM, preferably less than 5 nM.

[0033] In other embodiments, the present invention provides the administration of a PDE1 inhibitor for treatment according to the methods described herein, wherein the inhibitor is a compound selected from the group consisting of: [ka] providing an administration

[0034] Further examples of PDE1 inhibitors suitable for use in the methods and treatments described herein are disclosed in WO 2006133261 (A2); U.S. Pat. No. 8,273,750; U.S. Pat. No. 9,000,001; U.S. Pat. No. 9,624,230; WO 2009075784 (A1); U.S. Pat. No. 8,273,751; U.S. Pat. No. 8,829,008; U.S. Pat. No. 9,403,836 ... No. 2014151409 (A1), U.S. Patent Nos. 9,073,936; 9,598,426; 9,556,186; U.S. Patent Application Publication No. 2017 / 0231994 (A1), WO 2016022893 (A1), and U.S. Patent Application Publication No. 2017 / 0226117 (A1), each of which is incorporated herein by reference in its entirety.

[0035] Still further examples of PDE1 inhibitors suitable for use in the methods and treatments described herein are described in WO 2018007249 (A1); U.S. Patent Application Publication No. 2018 / 0000786; WO 2015118097 (A1); U.S. Patent No. 9,718,832; WO 2015091805 (A1); U.S. Patent No. 9,701,665; U.S. Patent Application Publication No. 2015 / 0175584 (A1); U.S. Patent Application Publication No. 2017 / 0267664 (A1); WO 2015091805 (A1); U.S. Patent No. 9,701,665; 016055618(A1); U.S. Patent Application Publication No. 2017 / 0298072(A1); WO 2016170064(A1); U.S. Patent Application Publication No. 2016 / 0311831(A1); WO 2015150254(A1); U.S. Patent Application Publication No. 2017 / 0022186(A1); WO 2016174188(A1); U.S. Patent Application Publication No. 2016 / 0318939(A1); U.S. Patent Application Publication No. 2017 / 0291903(A1); WO 201807 3251 (A1); WO 2017178350 (A1); U.S. Patent Application Publication No. 2017 / 0291901 (A1); WO 2018 / 115067; U.S. Patent Application Publication No. 2018 / 0179200 (A); U.S. Patent Application Publication No. 20160318910 (A1); U.S. Patent No. 9,868,741; WO 2017 / 139186 (A1); WO 2016 / 040083; U.S. Patent Application Publication No. 2017 / 0240532; WO 2016033776 ( A1); U.S. Patent Application Publication No. 2017 / 0233373; WO 2015130568; WO 2014159012; U.S. Patent No. 9,034,864; U.S. Patent No. 9,266,859; WO 2009085917; U.S. Patent No. 8,084,261; WO 2018039052; U.S. Patent Application Publication No. 20180062729; and WO 2019027783 (each incorporated herein by reference in its entirety). In the event that the statements in any document incorporated herein by reference conflict or are incompatible with the statements in this disclosure, the statements in this disclosure shall be understood to control.In the event that statements in any document incorporated herein by reference contradict or are inconsistent with statements in this disclosure, the statements in this disclosure shall be understood to control.

[0036] Further examples of PDE1 inhibitors and suitable methods of use are disclosed in International Application No. PCT / US2019 / 033941 and U.S. Provisional Application No. 62 / 789,499, both of which are incorporated herein by reference.

[0037] Unless otherwise specified or clear from context, the following terms used herein have the following meanings:

[0038] (a) "Selective PDE1 inhibitor," as used herein, refers to a PDE1 inhibitor that is at least 100-fold more selective for inhibiting PDE1 than for inhibiting other PDE isoforms.

[0039] (b) "Alkyl," as used herein, refers to a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having 1 to 6 carbon atoms, which may be straight or branched, and which may be mono-, di-, or tri-substituted, for example, with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.

[0040] (c) "Cycloalkyl," as used herein, refers to a saturated or unsaturated non-aromatic hydrocarbon moiety, preferably saturated, containing preferably 3 to 9 carbon atoms, at least some of which form a non-aromatic monocyclic, bicyclic, or bridged ring structure, and which may be optionally substituted, for example, with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. When the cycloalkyl optionally contains one or more atoms selected from N and O and / or S, the cycloalkyl may be a heterocycloalkyl.

[0041] (d) "Heterocycloalkyl" means, unless otherwise specified, a saturated or unsaturated non-aromatic hydrocarbon moiety, preferably saturated, containing preferably from 3 to 9 carbon atoms, at least some of which form a non-aromatic monocyclic, bicyclic or bridged ring structure, in which at least one carbon atom is replaced by N, O, or S, and the heterocycloalkyl may be optionally substituted, for example, by halogen (e.g., chloro or fluoro), hydroxy, or carboxy.

[0042] (e) "Aryl," as used herein, refers to a monocyclic or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted with, for example, alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or further aryl or heteroaryl (e.g., biphenyl or pyridylphenyl).

[0043] (f) "Heteroaryl," as used herein, refers to an aromatic moiety in which one or more of the atoms in the aromatic ring is sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy, or carboxy.

[0044] The disclosed compounds, for example, the PDE1 inhibitors described herein, can exist in free form or salt form, for example, as acid addition salt.In this specification, unless otherwise specified, the phrase "disclosed compounds" and the like should be understood to include any form of compound, for example, the compound in free form or acid addition salt form, or if the compound contains acidic substituent, the compound in base addition salt form.Since the disclosed compounds are intended for use as pharmaceuticals, pharmaceutically acceptable salts are preferred.Salts that are not suitable for pharmaceutical use may be useful, for example, for isolating or purifying the disclosed compounds or their pharmaceutically acceptable salts, and therefore also include such salts.

[0045] The disclosed compounds may also exist in prodrug form in some cases. Prodrug forms are compounds that are converted to the disclosed compounds in the body. For example, when the disclosed compounds contain hydroxy or carboxy substituents, these substituents can form physiologically hydrolyzable and acceptable esters. As used herein, "physiologically hydrolyzable and acceptable esters" refers to esters of the disclosed compounds that are hydrolyzable under physiological conditions and produce physiologically acceptable acids (in the case of the disclosed compounds having hydroxy substituents) or alcohols (in the case of the disclosed compounds having carboxy substituents) at the doses to be administered. Thus, when the disclosed compounds contain a hydroxy group, for example, compound -OH, an acyl ester prodrug of the compound, i.e., compound -OC(O)-C 1-4 Alkyl groups hydrolyze in the body to form physiologically hydrolyzable alcohols (compounds -OH) on the one hand, and acids (e.g., HOC(O)-C 1-4 Alternatively, when a compound of the present disclosure contains a carboxylic acid, for example Compound -C(O)OH, an acid ester prodrug of that compound, Compound -C(O)OC 1-4 The alkyl undergoes hydrolysis to give the compounds -C(O)OH and HO-C 1-4 Alkyl can be formed. Thus, as will be understood, this term encompasses conventional pharmaceutical prodrug forms.

[0046] In another embodiment, the present disclosure further provides a pharmaceutical composition comprising a PDE1 inhibitor in combination with a dopamine reuptake inhibitor, each in free form or pharmaceutically acceptable salt form, mixed with a pharmaceutically acceptable carrier.The term "combination" as used herein includes simultaneous, sequential or contemporaneous administration of a PDE1 inhibitor and a dopamine reuptake inhibitor.In another embodiment, the present disclosure provides a pharmaceutical composition containing such a compound.In some embodiments, the combination of a PDE1 inhibitor and a dopamine reuptake inhibitor allows the dopamine reuptake inhibitor to be administered in an amount lower than the amount that would be effective if administered as a single monotherapy.

[0047] Methods of Using the Disclosed Compounds In another embodiment, the present application provides a method [Method 1] for the prevention and / or treatment of a condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway, for example, a condition, disease or disorder characterized by deficits in attention, cognition, memory and / or inhibitory processing, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (i.e., a compound represented by Formula I, Ia, II, III, IV, V and / or VI) to a subject in need of such prevention and / or treatment.

[0048] Further methods are provided as follows:

[0049] 1.1 Method 1, wherein the condition, disease or disorder is characterized by deficits in attention, cognition, memory and / or inhibitory processing.

[0050] 1.2 Any of the above methods, wherein the condition, disease or disorder is selected from eating disorders (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating or eating disorders (OSFED)), substance use disorders (e.g., addictions (e.g., stimulant substance addictions such as amphetamines, cocaine, opiates and / or nicotine), alcoholism), obsessive-compulsive disorders (e.g., checking, contamination, mental contamination, hoarding, rumination, intrusive thoughts, symmetry / order), attention deficit hyperactivity disorder (ADHD), premature ejaculation disorder, post-traumatic stress disorder (PTSD), gambling disorders (e.g., gambling addiction, compulsive gambling), Tourette's syndrome and / or impulse control / conduct disorders (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania).

[0051] 1.3 Any of the above methods, wherein the condition, disease or disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating disorder or eating disorder (OSFED)).

[0052] 1.4 The above method, wherein the eating disorder is anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating and / or feeding disorder (OSFED).

[0053] 1.5 Any of the above methods wherein the condition, disease or disorder is a substance use disorder (e.g., addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates and / or nicotine), alcoholism).

[0054] 1.6 The above method, wherein the substance abuse disorder is addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates, and / or nicotine) or alcoholism.

[0055] 1.7 Any of the above methods, wherein the condition, disease, or disorder is Obsessive-Compulsive Disorder (OCD) (e.g., Inspection OCD, Contamination OCD, Mental Contamination OCD, Hoarding OCD, Rumination OCD, Intrusive Thoughts OCD, Symmetry / Order OCD).

[0056] 1.8 The method above, wherein the obsessive-compulsive disorder is inspection OCD, contamination OCD, mental contamination OCD, hoarding OCD, rumination OCD, intrusive thoughts OCD, and / or symmetry / order OCD.

[0057] 1.9 Any of the above methods, wherein the condition, disease, or disorder is attention deficit hyperactivity disorder (ADHD).

[0058] 1.10 Any of the above methods wherein the condition, disease or disorder is premature ejaculation.

[0059] 1.11 Any of the above methods, wherein the condition, disease, or disorder is post-traumatic stress disorder (PTSD).

[0060] 1.12 Any of the above methods, wherein the condition, disease or disorder is gambling disorder (e.g., gambling addiction, compulsive gambling).

[0061] 1.13 The method above, wherein the gambling disorder is gambling addiction or compulsive gambling.

[0062] 1.14 Any of the above methods, wherein the condition, disease, or disorder is Tourette's syndrome.

[0063] 1.15 Any of the above methods, wherein the condition, disease, or disorder is an impulse control / conduct disorder (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania).

[0064] 1.16 The method as described above, wherein the impulse control / conduct disorder is oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, and / or pyromania.

[0065] 1.17 Any of the above methods, wherein the PDE1 inhibitor is administered in an amount of about 0.01 to about 20 mg / kg, e.g., about 0.1 to about 5 mg / kg, e.g., about 1 mg / kg.

[0066] 1.18 Any of the above methods wherein the PDE1 inhibitor is administered orally.

[0067] 1.19 Any of the above methods wherein the PDE1 inhibitor is administered by injection.

[0068] 1.20 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with an additional therapeutic agent.

[0069] 1.21 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with a monoamine reuptake inhibitor (e.g., a dopamine reuptake inhibitor, a serotonin reuptake inhibitor and / or a norepinephrine reuptake inhibitor).

[0070] 1.22 PDE1 inhibitors include 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl-4-methylphenyl ketone, adrafinil, amantadine, atomoxetine, amfonelic acid, amineptine, amitriptyline, amoxapine, benztropine, bupropion, hydroxybupropion, butriptyline, chlorphenamine, citalopram, clomipramine, cocaethylene, desipramine, and descemetidine. Tircitalopram, desmethylsertraline, desmethylsibutramine, desoxipipradrol, desvenlafaxine, dextroamphetamine, dextromethamphetamine, didesmethylsibutramine, diphenhydramine, dosulepin, doxepin, duloxetine, escitalopram, etoperidone, femoxetine, fluorenol, fluoxetine, fluvoxamine, GBR-12783, GBR -12935, GBR-13069, GBR-13098, GYKI-52895, imipramine, indatraline, iprindole, iometopan, levomilnacipran, lofepramine, maprotiline, mazindol, medifoxamine, Metafit, methylenedioxypyrovalerone (MDPV), methylphenidate, ethylphenidate, mianserin, milnacipran, mirtazapine, modafinil, almo Any of the above methods administered in conjunction with one or more of the following: dafinil, nefazodone, nefopam, nisoxetine, nomifensine, norfluoxetine, nortriptyline, oxaprotiline, paroxetine, protriptyline, reboxetine, rimcazole, RTI-229, sertraline, sibutramine, trazodone, trimipramine, vanoxerine, venlafaxine, vilazodine, viloxazine, vortioxetine, zimelidine, Chaenomeles speciose extract, and / or oroxylin A.

[0071] 1.23 Any of the above methods wherein the PDE1 inhibitor is administered with one or more of atomoxetine, reboxetine, nisoxetine, desvenlafaxine, venlafaxine, duloxetine, milnacipran, fluoxetine, sertraline, citalopram, escitalopram, bupropion, and / or nomifensine.

[0072] 1.24 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with a dopamine reuptake inhibitor.

[0073] 1.25 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with a dopamine reuptake inhibitor selected from 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl-4-methylphenylketone, altropane, amfonelic acid, amineptine, BTCP, 3C-PEP, DBL-583, difluoropine, GBR-12783, GBR-12935, GBR-13069, GBR-13098, GYKI-52895, iometopan, methylphenidate, ethylphenidate, modafinil, armodafinil, RTI-229, vanoxerine, adrafinil, amantadine, benztropine, bupropion, fluorenol, medifoxamine, metafit, rimcazole, venlafaxine, Chaenomeles speciose extract, oroxylin A, or a combination thereof.

[0074] 1.26 Any of the above methods wherein a PDE1 inhibitor is administered in conjunction with a norepinephrine-serotonin reuptake inhibitor.

[0075] 1.27 The PDE1 inhibitor is a compound of formula VII, in free or salt form: [ka] [In the formula, R1 and R2 are independently H or C 1-4 alkyl (e.g., methyl or ethyl); R3 is nC 2-4-OC optionally substituted with alkyl (e.g., ethyl or n-propyl), or hydroxy 1-4 alkyl (e.g., methoxy or ethoxy)] Any of the above methods, wherein the compound is administered in combination with a norepinephrine-serotonin reuptake inhibitor indicated by

[0076] 1.28 PDE1 inhibitors [ka] Any of the above methods, wherein the compound is administered in combination with a norepinephrine-serotonin reuptake inhibitor indicated by

[0077] 1.29 Any of the above methods wherein the PDE1 inhibitor is a compound having any of Formulas I, Ia, II, III, IV, V and / or VI.

[0078] 1.30 Any of the above methods wherein the PDE1 inhibitor is a compound of formula Ia.

[0079] 1.31 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] [ka] [ka] [ka] Any of the above methods, wherein the compound is

[0080] 1.32 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0081] 1.33 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0082] 1.34 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0083] 1.35 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0084] 1.36 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0085] 1.37 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0086] 1.38 Any of the above methods wherein the patient is a human.

[0087] The present disclosure further provides PDE1 inhibitors for use in methods for the prevention and / or treatment of conditions, diseases or disorders associated with the dopamine D1 receptor intracellular pathway, such as conditions, diseases or disorders characterized by deficits in attention, cognition, memory and / or inhibitory processing, e.g., for use in any of methods 1 onwards.

[0088] The present disclosure further provides the use of a PDE1 inhibitor in the manufacture of a medicament for use in a method for the prevention and / or treatment of a condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway, e.g., a condition, disease or disorder characterized by deficits in attention, cognition, memory and / or inhibitory processing, e.g., a medicament for use in any of methods 1 onwards.

[0089] The present invention further provides a pharmaceutical composition for use in any of Methods 1 and subsequent thereto, comprising a PDE1 inhibitor, for example, any of the compounds of Formula I, Ia, II, III, IV, V and / or VI.

[0090] In another embodiment, the present application provides a method (Method 2) for treating an inhibitory processing disorder, comprising administering to a patient in need of such treatment a pharmaceutically acceptable amount of a PDE1 inhibitor (i.e., a PDE1 inhibitor represented by Formula I, Ia, II, III, IV, V and / or VI).

[0091] Further methods are provided as follows:

[0092] 2.1 Method 2, wherein the patient is suffering from a condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway.

[0093] 2.2 The patient is diagnosed with an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating or eating disorder (OSFED)), substance use disorder (e.g., addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates and / or nicotine), alcoholism), obsessive-compulsive disorder (e.g., checking, contamination, mental any of the foregoing methods, wherein the patient is suffering from a condition, disease or disorder selected from: cognitive impairment, cognitive impairments, cognitive impairments (e.g., cognitive impairment, cognitive impairments, cognitive impairments), attention deficit hyperactivity disorder (ADHD), premature ejaculation disorder, post-traumatic stress disorder (PTSD), gambling disorders (e.g., gambling addiction, compulsive gambling), Tourette's syndrome and / or impulse control / conduct disorders (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania).

[0094] 2.3 Any of the above methods, wherein the patient is suffering from an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, night eating disorder, other specified eating disorder or eating disorder (OSFED)).

[0095] 2.4 The above method, wherein the eating disorder is anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating and / or feeding disorder (OSFED).

[0096] 2.5 Any of the above methods, wherein the patient is suffering from a substance use disorder (e.g., addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates and / or nicotine), alcoholism).

[0097] 2.6 The above method, wherein the substance abuse disorder is addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates, and / or nicotine) or alcoholism.

[0098] 2.7 Any of the above methods, wherein the patient is suffering from Obsessive-Compulsive Disorder (OCD) (e.g., Inspection OCD, Contamination OCD, Mental Contamination OCD, Hoarding OCD, Rumination OCD, Intrusive Thought OCD, Symmetry / Order OCD).

[0099] 2.8 The method above, wherein the obsessive-compulsive disorder is inspection OCD, contamination OCD, mental contamination OCD, hoarding OCD, rumination OCD, intrusive thoughts OCD, and / or symmetry / order OCD.

[0100] 2.9 Any of the above methods, wherein the patient is suffering from attention deficit hyperactivity disorder (ADHD).

[0101] 2.10 Any of the above methods, wherein the patient is suffering from premature ejaculation.

[0102] 2.11 Any of the above methods, wherein the patient is suffering from post-traumatic stress disorder (PTSD).

[0103] 2.12 Any of the above methods, wherein the patient is suffering from a gambling disorder (e.g., gambling addiction, compulsive gambling).

[0104] 2.13 The above method, wherein the gambling disorder is gambling addiction or compulsive gambling.

[0105] 2.14 Any of the above methods, wherein the condition, disease, or disorder is Tourette's syndrome.

[0106] 2.15 Any of the above methods, wherein the patient is suffering from an impulse control / conduct disorder (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania).

[0107] 2.16 The above method, wherein the impulse control / conduct disorder is oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, and / or pyromania.

[0108] 2.17 Any of the above methods, wherein the PDE1 inhibitor is administered in an amount of about 0.01 to about 20 mg / kg, e.g., about 0.1 to about 5 mg / kg, e.g., about 1 mg / kg.

[0109] 2.18 Any of the above methods wherein the PDE1 inhibitor is administered orally.

[0110] 2.19 Any of the above methods wherein the PDE1 inhibitor is administered by injection.

[0111] 2.20 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with an additional therapeutic agent.

[0112] 2.21 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with a monoamine reuptake inhibitor (e.g., a dopamine reuptake inhibitor, a serotonin reuptake inhibitor, and / or a norepinephrine reuptake inhibitor).

[0113] 2.22 PDE1 inhibitors include 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl-4-methylphenylketone, adrafinil, amantadine, atomoxetine, amfonelic acid, amineptine, amitriptyline, amoxapine, benztropine, bupropion, hydroxybupropion, butriptyline, chlorphenamine, citalopram, clomipramine, cocaethylene, desipramine, and descemetidine. Tircitalopram, desmethylsertraline, desmethylsibutramine, desoxipipradrol, desvenlafaxine, dextroamphetamine, dextromethamphetamine, didesmethylsibutramine, diphenhydramine, dosulepin, doxepin, duloxetine, escitalopram, etoperidone, femoxetine, fluorenol, fluoxetine, fluvoxamine, GBR-12783, GBR -12935, GBR-13069, GBR-13098, GYKI-52895, imipramine, indatraline, iprindole, iometopan, levomilnacipran, lofepramine, maprotiline, mazindol, medifoxamine, Metafit, methylenedioxypyrovalerone (MDPV), methylphenidate, ethylphenidate, mianserin, milnacipran, mirtazapine, modafinil, almo Any of the above methods administered in conjunction with one or more of the following: dafinil, nefazodone, nefopam, nisoxetine, nomifensine, norfluoxetine, nortriptyline, oxaprotiline, paroxetine, protriptyline, reboxetine, rimcazole, RTI-229, sertraline, sibutramine, trazodone, trimipramine, vanoxerine, venlafaxine, vilazodine, viloxazine, vortioxetine, zimelidine, Chaenomeles speciose extract, and / or oroxylin A.

[0114] 2.23 Any of the above methods wherein the PDE1 inhibitor is administered with one or more of atomoxetine, reboxetine, nisoxetine, desvenlafaxine, venlafaxine, duloxetine, milnacipran, fluoxetine, sertraline, citalopram, escitalopram, bupropion, and / or nomifensine.

[0115] 2.24 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with a dopamine reuptake inhibitor.

[0116] 2.25 Any of the above methods wherein the PDE1 inhibitor is administered in conjunction with a dopamine reuptake inhibitor selected from 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl-4-methylphenyl ketone, altropane, amfonelic acid, amineptine, BTCP, 3C-PEP, DBL-583, difluoropine, GBR-12783, GBR-12935, GBR-13069, GBR-13098, GYKI-52895, iometopan, methylphenidate, ethylphenidate, modafinil, armodafinil, RTI-229, vanoxerine, adrafinil, amantadine, benztropine, bupropion, fluorenol, medifoxamine, metafit, rimcazole, venlafaxine, Chaenomeles speciose extract, oroxylin A, or a combination thereof.

[0117] 2.26 Any of the above methods wherein a PDE1 inhibitor is administered in conjunction with a norepinephrine-serotonin reuptake inhibitor.

[0118] 2.27 The PDE1 inhibitor is a compound of formula VII: [ka] [In the formula, R1 and R2 are independently H or C 1-4 alkyl (e.g., methyl or ethyl); R3 is nC 2-4-OC optionally substituted with alkyl (e.g., ethyl or n-propyl), or hydroxy 1-4 alkyl (e.g., methoxy or ethoxy)] The norepinephrine-serotonin reuptake inhibitor indicated above is administered by any of the methods described above.

[0119] 2.28 PDE1 inhibitors [ka] Any of the above methods, wherein the compound is administered in combination with a norepinephrine-serotonin reuptake inhibitor indicated by

[0120] 2.29 Any of the above methods wherein the PDE1 inhibitor is a compound having any of Formulas I, Ia, II, III, IV, V and / or VI.

[0121] 2.30 Any of the above methods wherein the PDE1 inhibitor is a compound of Formula Ia.

[0122] 2.31 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] [ka] [ka] [ka] Any of the above methods, wherein the compound is

[0123] 2.32 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0124] 2.33 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0125] 2.34 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0126] 2.35 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0127] 2.36 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0128] 2.37 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above methods, wherein the compound is

[0129] 2.38 Any of the above methods wherein the patient is a human.

[0130] The present disclosure further provides PDE1 inhibitors for use in methods for treating inhibitory processing disorders, eg, for use in any of Methods 2 et seq.

[0131] The disclosure further provides the use of a PDE1 inhibitor in the manufacture of a medicament for use in a method for treating an inhibitory processing disorder, such as a medicament for use in any of Methods 2 et seq.

[0132] The present invention further provides pharmaceutical compositions for use in any of Methods 2 and subsequent methods, comprising a PDE1 inhibitor, e.g., any of the compounds of Formula I, Ia, II, III, IV, V and / or VI.

[0133] Combination therapy with PDE1 inhibitors In some embodiments, PDE1 inhibitor is administered in combination with other therapeutic modalities.Therefore, in addition to the above-mentioned therapy, more pharmaceutical therapy can also be provided to patients for the treatment of the condition, disease or disorder related to dopamine D1 receptor intracellular pathway, for example, the condition, disease or disorder characterized by the lack of attention, cognition, memory and / or inhibitory processing.For example, the patient suffering from such condition, disease or disorder can be administered with monoamine reuptake inhibitor (for example, dopamine reuptake inhibitor, serotonin reuptake inhibitor, and / or norepinephrine reuptake inhibitor) in addition to the therapy described herein.A specific form of combined therapy includes the use of PDE1 inhibitor.

[0134] Combinations can be achieved by administering a single composition or pharmacological formulation containing a PDE1 inhibitor and one or more additional therapeutic agents, or by administering two different compositions or formulations, one containing a PDE1 inhibitor and the other containing an additional therapeutic agent, separately, simultaneously, or sequentially. Treatment with a PDE1 inhibitor may precede or follow administration of the other agent by an interval ranging from minutes to weeks. In embodiments in which the other agent and the expression construct are applied to cells separately, generally, no significant time elapses between each delivery, so that the agent and the expression construct can still exert their beneficial combined effect on the cells. In some embodiments, it is contemplated that both modalities will typically be contacted with cells within about 12 to 24 hours of each other, more preferably within about 6 to 12 hours of each other, with a delay of only about 12 hours being most preferred. However, in some situations, it may be desirable to significantly extend the treatment period, with days (2, 3, 4, 5, 6, or 7) to weeks (1, 2, 3, 4, 5, 6, 7, or 8) elapsed between each administration.

[0135] It is also conceivable that it is desired to administer either the PDE1 inhibitor or the additional therapeutic agent more than once.In this regard, various combinations can be used.For example, when the PDE1 inhibitor is "A" and the additional therapeutic agent is "B", the following sequences are exemplified based on a total of three and four administrations: [ka]

[0136] The monoamine reuptake inhibitors described herein include norepinephrine reuptake inhibitors, serotonin reuptake inhibitors, and dopamine reuptake inhibitors, including those with single, dual, or triple functions in inhibiting one or more of the norepinephrine transporter, serotonin transporter, and dopamine transporter.Non-limiting examples of monoamine transporters that can be used in the present invention include atomoxetine, reboxetine, nisoxetine, desvenlafaxine, venlafaxine, duloxetine, milnacipran, fluoxetine, sertraline, citalopram, escitalopram, bupropion, and / or nomifensine.Additional monoamine transporters are disclosed in International Publication No. 2016 / 154027 and U.S. Patent No. 10,188,758 (both of which are incorporated herein by reference in their entirety).

[0137] By way of further example, the dopamine reuptake inhibitors described herein include selective or non-selective dopamine reuptake inhibitors. In some embodiments, the dopamine reuptake inhibitor is a dual norepinephrine reuptake inhibitor and a dopamine reuptake inhibitor. Non-limiting examples of dopamine reuptake inhibitors that can be used in the present invention include 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl-4-methylphenylketone, altropane, amfonelic acid, amineptine, BTCP, 3C-PEP, DBL-583, difluoropine, GBR-12783, GBR-12935, GBR-13069, GBR-13098, GYKI-52895, iometopan, methylphenidate, ethylphenidate, modafinil, armodafinil, RTI-229, vanoxerine, adrafinil, amantadine, benztropine, bupropion, fluorenol, medifoxamine, metafit, rimcazole, venlafaxine, Chaenomeles speciose extract, oroxylin A, or combinations thereof.Other combinations are also contemplated. Some specific agents are listed below.

[0138] Accordingly, in various embodiments, the present disclosure also provides a pharmaceutical combination [Combination 1] therapy comprising a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a compound of Formula I, II, III, IV, V and / or VI) and a monoamine reuptake inhibitor (e.g., a dopamine reuptake inhibitor, a serotonin reuptake inhibitor, and / or a norepinephrine reuptake inhibitor) for administration to a patient in need thereof in a method for the prevention and / or treatment of a condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway, e.g., a condition, disease or disorder characterized by deficits in attention, cognition, memory and / or inhibitory processing, e.g., according to any of Methods 1 et seq., or for treating an inhibitory processing disorder, e.g., according to any of Methods 2 et seq.

[0139] For example, the present disclosure provides the following combinations:

[0140] 1.1 Combination 1, wherein the patient is suffering from a condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway.

[0141] 1.2 The patient is diagnosed with an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating or eating disorder (OSFED)), substance use disorder (e.g., addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates and / or nicotine), alcoholism), obsessive-compulsive disorder (e.g., checking, soiling, mental contamination) Suffering from a condition, disease or disorder selected from: anxiety disorder, hoarding, rumination, intrusive thoughts, symmetry / order), attention deficit hyperactivity disorder (ADHD), premature ejaculation disorder, post-traumatic stress disorder (PTSD), gambling disorder (e.g., gambling addiction, compulsive gambling), Tourette's syndrome and / or impulse control / conduct disorder (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania), or any combination of the above.

[0142] 1.3 The patient suffers from an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating or feeding disorder (OSFED)), or any combination of the above.

[0143] 1.4 The eating disorder is anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating and / or feeding disorders (OSFED), or any combination of the above.

[0144] 1.5 The patient suffers from a substance use disorder (e.g., addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates and / or nicotine), alcoholism), any combination of the above.

[0145] 1.6 Combination of the above, wherein the substance abuse disorder is addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates, and / or nicotine) or alcoholism.

[0146] 1.7 The patient suffers from Obsessive-Compulsive Disorder (OCD) (e.g., Inspection OCD, Contamination OCD, Mental Contamination OCD, Hoarding OCD, Rumination OCD, Intrusive Thought OCD, Symmetry / Order OCD), or any combination of the above.

[0147] 1.8 Combinations of the above where the Obsessive-Compulsive Disorder is Inspection OCD, Contamination OCD, Mental Contamination OCD, Hoarding OCD, Rumination OCD, Intrusive Thought OCD, and / or Symmetry / Order OCD.

[0148] 1.9 The patient suffers from Attention Deficit Hyperactivity Disorder (ADHD), any combination of the above.

[0149] 1.10 Any combination of the above, where the patient suffers from premature ejaculation.

[0150] 1.11 Any combination of the above, where the patient suffers from post-traumatic stress disorder (PTSD).

[0151] 1.12 The patient suffers from a gambling disorder (e.g., gambling addiction, compulsive gambling), or any combination of the above.

[0152] 1.13 A combination of the above where the gambling disorder is gambling addiction or compulsive gambling.

[0153] 1.14 Any combination of the above, where the condition, disease, or disorder is Tourette's syndrome.

[0154] 1.15 The patient suffers from an impulse control / conduct disorder (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania), or any combination of the above.

[0155] 1.16 Impulse control-conduct disorder is oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania and / or pyromania, or a combination of the above.

[0156] 1.17 Any of the above combinations, wherein the PDE1 inhibitor is administered in an amount of about 0.01 to about 20 mg / kg, for example, about 0.1 to about 5 mg / kg, for example, about 1 mg / kg.

[0157] 1.18 Any of the above combinations where the PDE1 inhibitor is administered orally.

[0158] 1.19 Any of the above combinations where the PDE1 inhibitor is administered by injection.

[0159] 1.20 Any of the above combinations wherein the monoamine reuptake inhibitor is one or more of a dopamine reuptake inhibitor, a serotonin reuptake inhibitor, or a norepinephrine reuptake inhibitor.

[0160] 1.21 Monoamine reuptake inhibitors include 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl-4-methylphenyl ketone, adrafinil, amantadine, atomoxetine, amfonelic acid, amineptine, amitriptyline, amoxapine, benztropine, bupropion, hydroxybupropion, butriptyline, chlorphenamine, citalopram, clomipramine, cocaethylene, and desipramine. , desmethylcitalopram, desmethylsertraline, desmethylsibutramine, desoxypipradrol, desvenlafaxine, dextroamphetamine, dextromethamphetamine, didesmethylsibutramine, diphenhydramine, dosulepin, doxepin, duloxetine, escitalopram, etoperidone, femoxetine, fluorenol, fluoxetine, fluvoxamine, GBR-12783, GBR-12935, GBR-13069, GBR-13098, GYKI-52895, imipramine, indatraline, iprindole, iometopan, levomilnacipran, lofepramine, maprotiline, mazindol, medifoxamine, Metafit, methylenedioxypyrovalerone (MDPV), methylphenidate, ethylphenidate, mianserin, milnacipran, mirtazapine, modafinil, Any of the above combinations with one or more of the following: lumodafinil, nefazodone, nefopam, nisoxetine, nomifensine, norfluoxetine, nortriptyline, oxaprotiline, paroxetine, protriptyline, reboxetine, rimcazole, RTI-229, sertraline, sibutramine, trazodone, trimipramine, vanoxerine, venlafaxine, vilazodine, viloxazine, vortioxetine, zimelidine, Chaenomeles speciose extract, and / or oroxylin A.

[0161] 1.22 Any of the above combinations where the monoamine reuptake inhibitor is one or more of atomoxetine, reboxetine, nisoxetine, desvenlafaxine, venlafaxine, duloxetine, milnacipran, fluoxetine, sertraline, citalopram, escitalopram, bupropion, and / or nomifensine.

[0162] 1.23 Any of the above combinations wherein the monoamine reuptake inhibitor is a dopamine reuptake inhibitor.

[0163] 1.24 Any of the above combinations wherein the dopamine reuptake inhibitor is selected from 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl-4-methylphenyl ketone, altropane, amfonelic acid, amineptine, BTCP, 3C-PEP, DBL-583, difluoropine, GBR-12783, GBR-12935, GBR-13069, GBR-13098, GYKI-52895, iometopan, methylphenidate, ethylphenidate, modafinil, armodafinil, RTI-229, vanoxerine, adrafinil, amantadine, benztropine, bupropion, fluorenol, medifoxamine, metafit, rimcazole, venlafaxine, Chaenomeles speciose extract, oroxylin A, or a combination thereof.

[0164] 1.25 Any of the above combinations in which the monoamine reuptake inhibitor is a norepinephrine-serotonin reuptake inhibitor.

[0165] 1.26 The monoamine reuptake inhibitor is a compound of formula VII, in free or salt form: [ka] [In the formula, R1 and R2 are independently H or C 1-4 alkyl (e.g., methyl or ethyl); R3 is nC 2-4-OC optionally substituted with alkyl (e.g., ethyl or n-propyl), or hydroxy 1-4 alkyl (e.g., methoxy or ethoxy)] Any of the above combinations is a norepinephrine-serotonin reuptake inhibitor indicated by:

[0166] 1.27 Monoamine reuptake inhibitors are [ka] Any of the above combinations is a norepinephrine-serotonin reuptake inhibitor indicated by:

[0167] 1.28 Any of the above combinations wherein the PDE1 inhibitor is a compound of any of formulas I, Ia, II, III, IV, V and / or VI.

[0168] 1.29 Any of the above combinations wherein the PDE1 inhibitor is a compound of formula Ia.

[0169] 1.30 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] [ka] [ka] [ka] Any of the above combinations, wherein the compound is

[0170] 1.31 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above combinations, wherein the compound is

[0171] 1.32 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above combinations, wherein the compound is

[0172] 1.33 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above combinations, wherein the compound is

[0173] 1.34 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above combinations, wherein the compound is

[0174] 1.35 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above combinations, wherein the compound is

[0175] 1.36 The PDE1 inhibitor is, in free form or in pharmaceutically acceptable salt form, [ka] Any of the above combinations, wherein the compound is

[0176] 1.37 Any of the above combinations, wherein said combination is administered to a human.

[0177] Methods for producing the disclosed compounds The PDE1 inhibitors and pharmaceutically acceptable salts thereof of the present disclosure are disclosed in U.S. Patent No. 8,273,750, U.S. Patent Application Publication No. 2006 / 0173878, U.S. Patent No. 8,273,751, U.S. Patent Application Publication No. 2010 / 0273753, U.S. Patent No. 8,697,710, U.S. Patent No. 8,664,207, U.S. Patent No. 8,633,180, U.S. Patent No. 8,536,159, U.S. Patent Application Publication No. 2012 / 0136013, U.S. Patent Application Publication No. 201 ... The starting materials for these processes can be prepared using methods such as those described and exemplified in U.S. Patent Application Publication Nos. 81832, 2013 / 0085123, 2013 / 0324565, 2013 / 0338124, 2013 / 0331363, WO 2012 / 171016, and WO 2013 / 192556, or by methods similar thereto, and by methods known in the chemical arts. Such methods include, but are not limited to, those described below. If the starting materials for these processes are not commercially available, they can be prepared by procedures selected from chemical techniques similar to or employing techniques similar to those used to synthesize known compounds.

[0178] Various PDE1 inhibitors and their starting materials are disclosed in U.S. Patent Application Publication No. 2008-0188492 (A1), U.S. Patent Application Publication No. 2010-0173878 (A1), U.S. Patent Application Publication No. 2010-0273754 (A1), U.S. Patent Application Publication No. 2010-0273753 (A1), WO 2010 / 065153, WO 2010 / 065151, WO 2010 / 065152, WO 2010 / 065153, WO 2010 / 065154, WO 2010 / 065155, WO 2010 / 065156, WO 2010 / 065157, WO 2010 / 065158, WO 2010 / 065159 ... and WO 2011 / 153138. All references cited herein are incorporated by reference in their entirety.

[0179] Further PDE1 inhibitors and related methods are disclosed in U.S. Provisional Application No. 62 / 833,481 (incorporated herein by reference in its entirety). Further related PDE1 inhibitors and related methods are disclosed in WO 2018 / 049417 (incorporated herein by reference in its entirety).

[0180] The disclosed compounds include their enantiomers, diastereomers and racemates, as well as their polymorphs, hydrates, solvates and complexes.Some individual compounds within the scope of the disclosure may contain double bonds.The expression of a double bond in the disclosure means that it includes both the E isomer and the Z isomer of the double bond.In addition, some compounds within the scope of the disclosure may contain one or more asymmetric centers.The disclosure includes the use of any optically pure stereoisomer and a combination of stereoisomers.

[0181] The compounds of the present disclosure are also intended to encompass their stable and unstable isotopes.Stable isotopes are non-radioactive isotopes that contain one additional neutron compared to the abundant nuclide of the same species (i.e., element).The activity of compounds containing such isotopes is maintained, and such compounds are also believed to be useful for measuring the pharmacokinetics of non-isotopic analogs.For example, hydrogen atoms at certain positions in the compounds of the present disclosure can be replaced with deuterium (a non-radioactive stable isotope).Examples of known stable isotopes include deuterium, 13 C. 15 N, 18 Alternatively, unstable isotopes, which are radioactive isotopes that contain additional neutrons compared to the abundant nuclide of the same species (i.e., element), such as, but not limited to, O. 123 I, 131 I, 125 I, 11 C. 18 F may be replaced by the corresponding abundant species of I, C, and F. Another example of a useful isotope of the compounds of the present disclosure is: 11C isotope. These radioisotopes are useful for radioimaging and / or pharmacokinetic studies of the compounds of the present disclosure.

[0182] Melting points are uncorrected, and (dec) indicates decomposition. Temperatures are given in degrees Celsius (°C); unless otherwise noted, operations are performed at room or ambient temperature, i.e., in the range of 18-25°C. Chromatography refers to silica gel flash chromatography; thin-layer chromatography (TLC) is performed on silica gel plates. NMR data are given as delta values ​​of major diagnostic protons expressed in parts per million (ppm) relative to tetramethylsilane (TMS) as the internal standard. Conventional abbreviations for signal shape are used. Coupling constants (J) are expressed in Hz. For mass spectra (MS), the major ion with the lowest mass is reported for molecules in which isotopic splitting results in multiple mass spectral peaks. The composition of solvent mixtures is given as volume percentages or volume ratios. When NMR spectra are complex, only diagnostic signals are reported.

[0183] The terms "treatment" and "treating" should be understood to include treating or ameliorating symptoms of disease as well as treating the cause of the disease, as appropriate.

[0184] With respect to treatment methods, the term "effective amount" is intended to encompass a therapeutically effective amount for treating a particular disease or disorder.

[0185] The term "patient" includes human or non-human (i.e., animal) patients. In certain embodiments, the disclosure encompasses both humans and non-humans. In another embodiment, the disclosure encompasses non-humans. In other embodiments, the term encompasses humans.

[0186] As used in this disclosure, the term "comprising" is intended to be open-ended and does not exclude additional, unrecited elements or method steps.

[0187] Dosages used in practicing the present disclosure will, of course, vary depending, for example, on the particular disease or condition being treated, the particular disclosed compound used, the mode of administration, and the desired therapy. The disclosed compounds can be administered by any suitable route, including oral, parenteral, transdermal, or inhalation, but are preferably administered orally. Generally, satisfactory results for the treatment of diseases such as those described above have been demonstrated to be obtained by oral administration at doses on the order of about 0.01 to 2.0 mg / kg. Thus, in large mammals, such as humans, the recommended daily dosage for oral administration of both PDE1 inhibitors ranges from about 0.50 to 300 mg, conveniently administered once daily, in divided doses two to four times daily, or in sustained-release form. Thus, a unit dosage form for oral administration can contain, for example, about 0.2 to 150 or 300 mg of the disclosed compound, e.g., about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, or 200 mg, together with a pharmaceutically acceptable diluent or carrier.

[0188] The disclosed compounds, particularly for use or administration in any of Methods 1 and later or 2 and later, can be administered in higher doses, if necessary. It is contemplated that the administration of PDE1 inhibitors for such methods can range from about 50 mg to 1000 mg daily. For example, a patient receiving a PDE1 inhibitor for a condition according to any of Methods 1 onwards through 6 onwards may be administered the PDE1 inhibitor of Formula I, Ia, II, III, IV, V and / or VI in an amount of 50 mg to 1000 mg per day, 50 mg to 900 mg per day, 50 mg to 800 mg per day, 50 mg to 700 mg per day, 50 mg to 600 mg per day, 50 mg to 500 mg per day, 50 mg to 400 mg per day, 50 mg to 350 mg per day, 50 mg to 300 mg per day, 50 mg to 250 mg per day, 50 mg to 200 mg per day, 50 mg to 150 mg per day, or 50 mg to 100 mg per day.

[0189] The disclosed compounds can be administered by any suitable route, including oral, parenteral (intravenous, intramuscular or subcutaneous) or transdermal, but are preferably administered orally. In certain embodiments, the disclosed compounds, for example in depot formulations, are preferably administered parenterally, for example by injection.

[0190] The disclosed compounds and pharmaceutical compositions can be used in combination with one or more additional therapeutic agents, particularly at lower doses than when the individual agents are used as monotherapies, to enhance the therapeutic activity of the combined agents without causing the undesirable side effects commonly associated with conventional monotherapies. Thus, the disclosed compounds can be administered simultaneously, separately, sequentially, or contemporaneously with other agents useful for treating diseases. In another example, side effects can be reduced or minimized by administering the disclosed compounds in combination with one or more additional therapeutic agents in free or salt form, where the dose of (i) the second therapeutic agent or (ii) both the disclosed compound and the second therapeutic agent is lower than when the agent / compound is administered as monotherapy. By way of non-limiting example, such additional therapeutic agents can include ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, and the like.

[0191] The term "simultaneously" when referring to therapeutic use means that two or more active ingredients are administered at or near the same time by the same route of administration.

[0192] The term "separately" when referring to therapeutic use means that two or more active ingredients are administered simultaneously or at about the same time by different routes of administration.

[0193] Pharmaceutical compositions containing the disclosed compounds can be prepared using conventional diluents or excipients and techniques known in the galenical art. Thus, oral dosage forms can include tablets, capsules, solutions, suspensions, etc. [Example]

[0194] Example 1: Determining the involvement of PDE1 inhibitors in the human brain To determine whether the PDE1 inhibitors disclosed herein induce changes in blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) signals in the dorsal anterior insula (dAI) during the extinction phase of a fear conditioning task, a randomized, double-blind, placebo-controlled, intrasubject study was conducted in healthy human subjects.To verify these effects, Compound 1 was administered to healthy human patients.Compound 1 (ITI-214) is shown below: [ka]

[0195] The insula is a small brain region essential for the mind-body connection, converting bodily sensations into emotions.Anterior insula reactivity is associated with the anticipation of important events, and increased anterior insula activity is associated with anxiety.Conditioning, including fear conditioning and extinction, is brain activity during learning.It has been previously known that the PDE1 inhibitors disclosed herein enhance dopamine and enhance learning in animal models.To test this hypothesis, a neutral abstract image (CSplus) is repeatedly paired with a scream.The task consists of three components: a short habituation period, fear acquisition, and fear extinction.A neutral stimulus (CSminus) that is not paired with the unconditioned stimulus is used as a control.

[0196] Patients were administered a single oral dose of 1 mg or 10 mg of Compound 1, or a placebo. Brain activity was then measured during BOLD-fMRI scans at 3 Tesla. All fMRI analyses were performed in AFNI. Region-of-interest (ROI) analyses of the dAI, IFG, and other prespecified regions were calculated using linear mixed models in R. Brain responses for each subject were measured during fMRI scans and are summarized in Figure 1. As shown, in this study, administration of Compound 1 slightly attenuated insula activity during fear extinction.

[0197] Further studies were carried out to determine whether PDE1 inhibitors according to the present disclosure induce changes in BOLD-fMRI signals in the inferior frontal gyrus (IFG) during a stop-signal task. The inferior frontal gyrus is a brain region important for response inhibition, or the ability to refrain from performing a response after receiving a signal to stop. The stop-signal task is a method for measuring behavioral and neural responses to inhibitory processing.

[0198] Patients were again administered a placebo or a single oral dose of 1 mg or 10 mg of Compound 1. Brain activity was then measured during BOLD-fMRI scans at 3 Tesla. In this study, participants were presented with visual and / or auditory cues and two buttons. They were instructed to press the left button as quickly as possible when an "X" appeared on the screen, and the right button as quickly as possible when an "O" appeared. Participants were also instructed not to press either button when a tone was heard, which constituted a stop trial. Two types of stop trials were provided during the task: easy trials and difficult trials. Easy trials consisted of a visual "X" or "O" and an audio cue presented simultaneously, facilitating response inhibition. Difficult trials consisted of a delayed tone, making tone processing and response inhibition more difficult. Brain activity in the IFG was measured during fMRI scans for each subject and is summarized in Figure 2. As shown, administration of Compound 1 (1 mg) significantly increased activation in the inferior frontal gyrus during correctly inhibited stop trials during both correcteasy and correcthard trials.

[0199] A pattern of increased activity similar to that observed in the inferior frontal gyrus was observed in the dorsolateral prefrontal cortex (Fig. 3), dorsal anterior cingulate cortex (Fig. 4), and anterior insula (Fig. 5). This consistency lends credence to the findings.

[0200] Compound 1 improved cognitive performance without psychomotor hyperactivity in preclinical models and was predicted to improve cognitive performance in humans by increasing activation of the frontal gyrus. Compound 1 (1 mg) also increased activation of the frontal gyrus, consistent with improved cognition in disorders such as ADHD and improved inhibitory processing in disorders such as PTSD. These results provide evidence of central nervous system involvement and enhanced cognitive processing, consistent with Compound 1's mechanism of action, and demonstrate its potential utility in treating a range of disorders associated with impaired inhibitory processing.

[0201] Alternative combinations and variations of the examples provided will become apparent based on this disclosure, and while it is not possible to provide specific examples of all of the many possible variations of the described embodiments, such combinations and variations may ultimately be made into issued claims.

Claims

1. A method for the prevention and / or treatment of a condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway, for example a condition, disease or disorder characterized by deficits in attention, cognition, memory and / or inhibitory processing, the method comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (i.e., a compound represented by Formula I, Ia, II, III, IV, V and / or VI) to a subject in need of said prevention and / or treatment.

2. 10. The method of claim 1, wherein the condition, disease or disorder is characterized by deficits in attention, cognition, memory and / or inhibitory processing.

3. 3. The method of claim 1 or 2, wherein the condition, disease or disorder is selected from eating disorders (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating or eating disorders (OSFED)), substance use disorders (e.g., addictions (e.g., stimulant substance addictions such as amphetamines, cocaine, opiates and / or nicotine), alcoholism), obsessive-compulsive disorders (e.g., checking, contamination, mental contamination, hoarding, rumination, intrusive thoughts, symmetry / organization), attention deficit hyperactivity disorder (ADHD), premature ejaculation disorder, post-traumatic stress disorder (PTSD), gambling disorders (e.g., gambling addiction, compulsive gambling), Tourette's syndrome and / or impulse control / conduct disorders (e.g., oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania).

4. A method for treating an inhibitory processing disorder, the method comprising administering to a patient in need of said treatment a pharmaceutically effective amount of a PDE1 inhibitor (i.e., a compound represented by Formula I, Ia, II, III, IV, V and / or VI).

5. 5. The method of claim 4, wherein the patient is suffering from a condition, disease or disorder associated with the dopamine D1 receptor intracellular pathway.

6. The patient is diagnosed with an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, avoidant / restrictive eating disorder, purging disorder, nighttime eating disorder, other specified eating or eating disorder (OSFED)), substance use disorder (e.g., addiction (e.g., stimulant substance addiction such as amphetamine, cocaine, opiates and / or nicotine), alcoholism), obsessive-compulsive disorder (e.g., checking, contamination, mental contamination), 6. The method of claim 4 or 5, wherein the patient is suffering from a condition, disease or disorder selected from: anxiety disorder, depression, hoarding, rumination, intrusive thoughts, symmetry / order), attention deficit hyperactivity disorder (ADHD), premature ejaculation disorder, post-traumatic stress disorder (PTSD), gambling disorder (e.g. gambling addiction, compulsive gambling), Tourette's syndrome and / or impulse control / conduct disorder (e.g. oppositional defiant disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania).

7. PDE1 inhibitors, (A) A compound of formula I: in free form, in salt form or in prodrug form (including its enantiomers, diastereoisomers and racemates): 【Chemical 1】 [In the formula, (i) R 1 is H or C 1-4 alkyl (e.g., methyl); (ii) R 4 is H or C 1-4 alkyl, and R 2 and R 3 are independently H or C 1-4 Alkyl (e.g., R 2 and R 3 are both methyl, or R 2 is H and R 3 is isopropyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; or R 2 is H and R 3 and R 4 together form a dimethylene bridge, a trimethylene bridge or a tetramethylene bridge (preferably, R 3 and R 4 together have a cis configuration, e.g., R 3 and R 4 wherein the carbons carrying the (iii) R 5 is a substituted heteroarylalkyl, e.g., substituted with haloalkyl; or R 5 is attached to one of the nitrogens of the pyrazolo moiety of formula I, and is represented by formula A: 【Chemistry 2】 wherein X, Y, and Z are independently N or C; 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F), and R 10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (e.g., pyrid-2-yl) or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl) optionally substituted with halogen), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, then R 8 , R 9 or R 10 does not exist) The part indicated by (iv) R 6 is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino); (v) n is 0 or 1; (vi) When n is 1, A is -C(R 13 R 14 )- (where R 13 and R 14 are independently H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy or (optionally hetero)arylalkyl); (B) A compound of formula II: in free form, a salt form, or a prodrug form: 【Chemistry 3】 [In the formula, (i) X is C 1-6 alkylene (e.g., methylene, ethylene, or prop-2-yn-1-ylene); (ii) Y is a single bond, alkynylene (e.g., —C≡C—), arylene (e.g., phenylene), or heteroarylene (e.g., pyridylene); (iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloC 1-6 alkyl (e.g., trifluoromethyl), —C(O)—R 1 , -N(R 2 )(R 3 ), or C optionally containing at least one atom selected from the group consisting of N or O 3-7 cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl); (iv) R 1 is C 1-6 Alkyl, haloC 1-6 Alkyl, —OH or —OC 1-6 Alkyl (e.g., —OCH 3 ) and (v) R 2 and R 3 are independently H or C 1-6 is alkyl; (vi) R 4 and R 5 are independently H, C 1-6 alkyl, or one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) or C 1-6 aryl (e.g., phenyl) optionally substituted with alkoxy; (vii) wherein X, Y, and Z are independently one or more halo (e.g., F, Cl, or Br), C 1-6 Alkyl (e.g., methyl), haloC 1-6 and optionally substituted with alkyl (e.g., trifluoromethyl), for example, Z is one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC 1-6 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C 1-6 Z is heteroaryl, such as pyridyl, substituted with alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, such as phenyl, substituted with one or more halo (e.g., 4-fluorophenyl); (C) Formula III, in free or salt form: 【Chemistry 4】 [In the formula, (i) R 1 is H or C 1-4 alkyl (e.g., methyl or ethyl); (ii) R 2 and R 3 are independently H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 4 is H or C 1-4 alkyl (e.g., methyl or ethyl); (iv) R 5 are independently -C(=O)-C 1-6 Alkyl (e.g., —C(═O)—CH 3 ) and C 1-6 -aryl (e.g., phenyl) optionally substituted with one or more groups selected from hydroxyalkyl (e.g., 1-hydroxyethyl); (v) R 6 and R 7 are independently H or independently C 1-6 Aryl (e.g., phenyl) optionally substituted with one or more groups selected from alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example, unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F), or one or more C 1-6 Phenyl substituted with alkyl and one or more halogens, or one C 1-6 phenyl substituted with alkyl and one halogen, for example 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; (vi) n is 1, 2, 3 or 4; (D) Formula IV, in free or salt form: 【Chemistry 5】 [In the formula, (vi) R 1 is C 1-4 alkyl (e.g., methyl or ethyl), or —NH(R 2 ) (where R 2 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl; (vii) X, Y and Z are independently N or C; (viii) R 3 , R 4 and R 5 are independently H or C 1-4 alkyl (e.g., methyl); or R 3 is H and R 4 and R 5 together form a trimethylene bridge (preferably R 4 and R 5 together have a cis configuration, e.g., R 4 and R 5 and the carbons carrying the R and S configurations, respectively. (ix) R 6 , R 7 and R 8 is, independently, H. C 1-4 alkyl (e.g., methyl), hydroxy-substituted pyrid-2-yl, or -S(O) 2 -NH 2 and However, when X, Y and / or Z are N, then R 6 , R 7 and / or R 8 does not exist; and when X, Y and Z are all C, then R 6 , R 7 or R 8 At least one of is -S(O) 2 -NH 2 or pyrid-2-yl substituted with hydroxy; (E) A compound of formula 1a: in free form, in the form of a pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates: 【Chemistry 6】 [In the formula, (iv) R 2 and R 5 are independently H or hydroxy, and R 3 and R 4 together form a trimethylene or tetramethylene bridge, preferably R 3 and R 4 the carbons carrying R and S configurations, respectively; or 2 and R 3 are each methyl, and R 4 and R 5 are each H; or R 2 , R 4 and R 5 is H and R 3 is isopropyl, preferably R 3 the carbon bearing the has the R configuration; (v) R 6 represents (optionally halo-substituted) phenylamino, (optionally halo-substituted) benzylamino, C 1-4 Alkyl, or C 1-4 alkylsulfide; for example, phenylamino or 4-fluorophenylamino; (vi) R 10 is C 1-4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl (e.g., 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl); X and Y are independently C or N; (F) a compound of formula V, in free or salt form: 【Chemistry 7】 [In the formula, (iv) R 1 is -NH(R 4 ) (where R 4 is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl); (v) R 2 is H or C 1-6 alkyl (e.g., methyl, isobutyl, or neopentyl); (vi) R 3 is -SO 2 NH 2 or —COOH; and / or (G) a compound of formula V, in free or salt form: 【Chemistry 8】 [In the formula, (iv) R 1 is -NH(R 4 ) (where R 4 is phenyl optionally substituted with halo (e.g., fluoro), e.g., 4-fluorophenyl); (v) R 2 is H or C 1-6 alkyl (e.g., methyl or ethyl); (vi) R 3 is H, halogen (e.g., bromo), C 1-6 alkyl (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl). The method according to any of the preceding claims, wherein the compound is selected from:

8. The PDE1 inhibitor is one of the following, in free form or in pharmaceutically acceptable salt form: 【Chemistry 9】 10. The method according to any of the preceding claims, selected from any of the following:

9. 10. The method of any of the above claims, wherein the PDE1 inhibitor is administered in combination with a monoamine reuptake inhibitor (e.g. a dopamine reuptake inhibitor, a serotonin reuptake inhibitor and / or an epinephrine reuptake inhibitor).

10. 10. A pharmaceutical combination therapy comprising a pharmaceutically effective amount of a PDE1 inhibitor and a monoamine reuptake inhibitor (e.g., a dopamine reuptake inhibitor, a serotonin reuptake inhibitor and / or an epinephrine reuptake inhibitor) for administration in the method of any one of claims 1 to 9.

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