US20160318939A1 - Imidazopyrazinones as PDE1 Inhibitors - Google Patents

Imidazopyrazinones as PDE1 Inhibitors Download PDF

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Publication number
US20160318939A1
US20160318939A1 US15/142,116 US201615142116A US2016318939A1 US 20160318939 A1 US20160318939 A1 US 20160318939A1 US 201615142116 A US201615142116 A US 201615142116A US 2016318939 A1 US2016318939 A1 US 2016318939A1
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Prior art keywords
pyrazin
methyl
imidazo
pyran
tetrahydro
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Inventor
Jan Kehler
Lars Kyhn Rasmussen
Morten Langgård
Mikkel Jessing
Paulo Jorge Vieira Vital
Karsten Juhl
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H Lundbeck AS
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H Lundbeck AS
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Assigned to H. LUNDBECK A/S reassignment H. LUNDBECK A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JESSING, Mikkel, JUHL, KARSTEN, KEHLER, JAN, LANGGÅRD, Morten, RASMUSSEN, LARS KYHN, VITAL, PAULO JORGE VIEIRA
Publication of US20160318939A1 publication Critical patent/US20160318939A1/en
Priority to US15/615,380 priority Critical patent/US10011606B2/en
Assigned to H. LUNDBECK A/S reassignment H. LUNDBECK A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JESSING, Mikkel, VITAL, PAULO JORGE VIEIRA, KEHLER, JAN, LANGGARD, MORTEN, JUHL, KARSTEN, RASMUSSEN, LARS KYHN
Priority to US16/002,116 priority patent/US10858362B2/en
Priority to US17/079,951 priority patent/US11472810B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention provides compounds that are PDE1 enzyme inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.
  • the present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the invention.
  • cyclic Nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play a major role in intracellular signal transduction cascade, by regulating cN-dependent protein kinases (PKA and PKG), EPACs (Exchange Protein Activated by cAMP), phosphoprotein phosphatases, and/or cN-gated cation channels.
  • PKA and PKG cN-dependent protein kinases
  • EPACs Exchange Protein Activated by cAMP
  • phosphoprotein phosphatases and/or cN-gated cation channels.
  • Intracellular concentrations of cAMP and cGMP are strictly regulated by the rate of biosynthesis by cyclases and by the rate of degradation by phosphodiesterases (PDEs, EC 3.1.4.17).
  • PDEs are bimetallic hydrolases that inactivate cAMP/cGMP by catalytic hydrolysis of the 3′-ester bond, forming the inactive 5′-monophosphate. Since PDEs provide the only means of degrading the cyclic nucleotides cAMP and cGMP in cells, PDEs play an essential role in cyclic nucleotide signalling.
  • PDEs The catalytic activities of PDEs provide for breakdown of cNs over a spectrum of cN-concentrations in all cells, and their varied regulatory mechanisms provide for integration and crosstalk with myriads of signalling pathways.
  • Particular PDEs are targeted to discrete compartments within cells where they control cN level and sculpt microenvironments for a variety of cN signalosomes (Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91: 651-690).
  • the PDE families can be divided into three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7, and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) the dual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.
  • the cAMP-specific PDEs which include PDE4, PDE7, and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) the dual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.
  • calmodulin-stimulated PDE (CaM-PDE)
  • CaM Ca 2+ -dependently regulated via calmodulin (CaM, a 16 kDa Ca 2+ -binding protein) complexed with four Ca 2+
  • CaM Ca 2+ -dependently regulated via calmodulin
  • PDE1 represents an interesting regulatory link between cyclic nucleotides and intracellular Ca 2+ .
  • the PDE1 family is encoded by three genes: PDE1A (mapped on human chromosome 2q32), PDE1B (human chromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They have alternative promoters and give rise to a multitude of proteins by alternative splicing which differ in their regulatory properties, substrate affinities, specific activities, activation constants for CaM, tissue distribution and molecular weights. More than 10 human isoforms are identified. Their molecular weights vary from 58 to 86 kDa per monomer. The N-terminal regulatory domain that contains two Ca 2+ /CaM binding domains and two phosphorylation sites differentiate their corresponding proteins and modulate their biochemical functions.
  • PDE1 is a dual substrate PDE and the PDE1C-subtype has equal activity towards cAMP and cGMP (Km ⁇ 1-3 ⁇ M), whereas the subtypes PDE1A and PDE1B have a preference for cGMP (Km for cGMP ⁇ 1-3 ⁇ M and for cAMP ⁇ 10-30 ⁇ M).
  • the PDE1 subtypes are highly enriched in the brain and located especially in the striatum (PDE1B), hippocampus (PDE1A) and cortex (PDE1A) and this localization is conserved across species (Amy Bernard et al. Neuron 2012, 73, 1083-1099).
  • PDE1A is present mainly in deep cortical layers 5 and 6 (output layers), and used as a specificity marker for the deep cortical layers.
  • PDE1 inhibitors enhance the levels of the second messenger cNs leading to enhanced neuronal excitability.
  • PDE1 is a therapeutic target for regulation of intracellular signaling pathways, preferably in the nervous system and PDE1 inhibitors can enhance the levels of the second messengers cAMP/cGMP leading to modulation of neuronal processes and to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. These neuronal plasticity enhancement properties together with the modulation of synaptic transmission make PDE1 inhibitors good candidates as therapeutic agents in many neurological and psychiatric conditions.
  • the evaluation of PDE1 inhibitors in animal models see e.g. Blokland et al. Expert Opinion on Therapeutic Patents (2012), 22(4), 349-354; and Medina, A. E.
  • PDE1 inhibitors in neurological disorders, like e.g. Alzheimer's, Parkinson's and Huntington's Diseases and in psychiatric disorders like e.g. Attention Deficit Hyperactivity Disorder (ADHD), restless leg syndrome, depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS).
  • ADHD Attention Deficit Hyperactivity Disorder
  • PCS cognitive impairment
  • PDE1 inhibitors are useful in diseases that may be alleviated by the enhancement of progesterone-signaling such as female sexual dysfunction (e.g. WO 2008/070095).
  • WO 2013/053690 A1 discloses imidazopyrazinones that are inhibitors of the PDE9 enzyme.
  • the compounds of the invention may offer alternatives to current marketed treatments for neurodegenerative and/or psychiatric disorders, treatments which are not efficacious in all patients. Hence, there remains a need for alternative methods of treatment of such diseases.
  • PDE1 enzymes are expressed in the Central Nervous System (CNS), making this gene family an attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders.
  • CNS Central Nervous System
  • the objective of the present invention is to provide compounds that are PDE1 inhibitors, and as such are useful to treat neurodegenerative disorders and psychiatric disorders.
  • said compounds are at least a ten-fold stronger as PDE1 inhibitors than as PDE9 inhibitors in order to prevent potentially unwanted effects associated with PDE9 inhibition.
  • Reference to Compound I includes the free base of Compound I, pharmaceutically acceptable salts of Compound I, such as acid addition salts of Compound I, racemic mixtures of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphic and amorphic forms of Compound I as well as tautomeric forms of Compound I.
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the invention relates to a compound according to formula (I) for use in therapy.
  • the invention relates to a compound according to formula (I), for use in the treatment of a neurodegenerative disorder, selected from the group consisting of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease or for the treatment of a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS), or another brain disease like restless leg syndrome.
  • a neurodegenerative disorder selected from the group consisting of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease or for the treatment of a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS), or another brain disease like restless leg syndrome.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according formula (I), and one or more pharmaceutically acceptable carrier or excipient.
  • the invention relates to a method for the treatment of a neurodegenerative disorder, selected from the group consisting of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease or for the treatment of a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS), or another brain disease like restless leg syndrome, which method comprises the administration of a therapeutically effective amount of a compound according to formula (I) to a patient in need thereof.
  • a neurodegenerative disorder selected from the group consisting of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease or for the treatment of a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS), or another brain disease like restless leg syndrome
  • an embodiment of the invention is identified as Ei, where i is an integer indicating the number of the embodiment.
  • An embodiment Ei′ specifying a specific embodiment a previously listed embodiment Ei is identified as Ei′(Ei), e.g. E2(E1) means “in an embodiment E2 of embodiment E1”.
  • E3(E2 and E1) means “in an embodiment E3 of any of embodiments E2 and E1”
  • E4(E1, E2 and E3) means “in an embodiment E4 of any of embodiments E1, E2 and E3”
  • E2(E1) n is 0 or 1;
  • the PDE1 isozyme family includes numerous splice variant PDE1 isoforms. It has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms.
  • PDE1 and PDE1 enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes as well as their isoforms unless otherwise specified.
  • halo and halogen are used interchangeably and refer to fluorine, chlorine, bromine or iodine.
  • a given range may interchangeably be indicated with “-” (dash) or “to”, e.g. the term “C 1 -C 3 alkyl” is equivalent to “C 1 to C 3 alkyl”.
  • C 1 -C 3 alkyl refers to a linear (i.e. unbranched) or branched saturated hydrocarbon having from one up to eight carbon atoms, inclusive.
  • Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, n-hexyl, n-heptyl and n-octyl.
  • saturated monocyclic C 3 -C 8 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 3 -C 5 cycloalkyl refers to cyclopropyl, cyclobutyl and cyclopentyl.
  • C 1 -C 3 alkoxy refers to a moiety of the formula —OR′, wherein R′ indicates C 1 -C 3 alkyl as defined above.
  • C 3 -C 5 cycloalkoxy refers to a moiety of the formula —OR′, wherein R′ indicates C 3 -C 5 cycloalkyl as defined above.
  • C 3 -C 5 cycloalkyl-methoxy refers to a moiety of the formula —OCH 2 R′, wherein R′ indicates C 3 -C 5 cycloalkyl as defined above.
  • C 1 -C 3 fluoroalkoxy refers to a C 1 -C 3 alkoxy substituted with one or more fluorine.
  • 5-membered heteroaryls are defined as 5 membered aromatic rings containing at least one atom selected frin nitrogen, sulfur and oxygen. Examples include, but are not limited to thiazole, thiophene and isoxazole.
  • lactams containing 4-6 carbon atoms refers to pyrrolidin-2-one, piperidin-2-one or azepan-2-one.
  • a compound is considered to be a PDE1 inhibitor if the amount required to reach the IC 50 level of one or more of the three PDE1 isoforms is 10 micro molar or less, preferably less than 9 micro molar, such as 8 micro molar or less, such as 7 micro molar or less, such as 6 micro molar or less, such as 5 micro molar or less, such as 4 micro molar or less, such as 3 micro molar or less, more preferably 2 micro molar or less, such as 1 micro molar or less, in particular 500 nM or less.
  • the required amount of PDE1 inhibitor required to reach the IC 50 level of PDE1B is 400 nM or less, such as 300 nM or less, 200 nM or less, 100 nM or less, or even 80 nM or less, such as 50 nM or less, for example 25 nM or less.
  • the compounds of the present invention are at least a ten-fold stronger as PDE1 inhibitors as PDE9 inhibitors, i.e. the amount of the compound required to reach the IC 50 level of one or more of the three PDE1 isoforms is at least a ten-fold less than the amount of the same compound required to reach the IC 50 level of the PDE9 enzyme.
  • the present invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-tol
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the term “therapeutically effective amount” of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound.
  • An amount adequate to accomplish this is defined as “therapeutically effective amount”.
  • Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects of the invention.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses.
  • pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 st Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 2005.
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal and parenteral (including subcutaneous, intramuscular and intravenous) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
  • the present invention also provides a process for making a pharmaceutical composition
  • a process for making a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound of formula (I) and at least one pharmaceutically acceptable carrier or diluent.
  • the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section herein.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound which has the same utility as of a free base.
  • a compound of formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula (I) with a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described above.
  • solutions of the compounds of formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the compounds of formula (I) may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • compositions of the invention may be prepared by conventional methods in the art.
  • tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tableting machine prepare tablets.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • the compounds of formula (I) are PDE1 enzyme inhibitors and as such are useful to treat associated neurological and psychiatric disorders.
  • the invention thus provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, as well as a pharmaceutical composition containing such a compound, for use in the treatment of another brain disease which could be a neurodegenerative disorder or a psychiatric disorder.
  • the neurodegenerative disorder is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.
  • the psychiatric disorder is selected from the group consisting of Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS).
  • ADHD Attention Deficit Hyperactivity Disorder
  • CUAS cognitive impairment
  • Other brain diseases could be e.g. restless leg syndrome.
  • the present invention provides a method of treating a mammal, including a human, suffering from a neurodegenerative disorder selected from the group consisting of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).
  • This invention further provides a method of treating a neurodegenerative disorder in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) effective in inhibiting PDE1.
  • This invention also provides a method of treating a subject suffering from a psychiatric disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).
  • psychiatric disorders include Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS).
  • This invention also provides a method of treating a subject suffering from another brain disorder such as restless leg syndrome.
  • the invention is directed to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a neurodegenerative disorder, such as Alzheimer's Disease, Parkinson's Disease and Huntington's Disease or for the treatment of a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS).
  • a neurodegenerative disorder such as Alzheimer's Disease, Parkinson's Disease and Huntington's Disease
  • a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS).
  • ADHD Attention Deficit Hyperactivity Disorder
  • depression depression
  • anxiety anxiety
  • narcolepsy cognitive impairment and cognitive impairment associated with schizophrenia
  • the invention is directed to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of another brain disease, such as restless leg syndrome.
  • the invention is also directed to a compound of formula (I) for use as a medicine.
  • the compound of formula (I) for use in the treatment of a neurodegenerative disorder, such as Alzheimer's Disease, Parkinson's Disease and Huntington's Disease or for the treatment of a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy cognitive impairment and cognitive impairment associated with schizophrenia (CIAS) or for the treatment of another brain disease like restless leg syndrome.
  • a neurodegenerative disorder such as Alzheimer's Disease, Parkinson's Disease and Huntington's Disease
  • a psychiatric disorder such as Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy cognitive impairment and cognitive impairment associated with schizophrenia (CIAS) or for the treatment of another brain disease like restless leg syndrome.
  • Table 1 lists the IC 50 value for inhibition of PDE1 by the compounds of the invention.
  • the IC 50 value refers to the concentration (nM) of the compound required to reach 50% inhibition of the PDE1 enzyme at the specified substrate concentration.
  • the inhibition of PDE is listed as % inhibition at a certain concentration.
  • the table also lists % inhibition of PDE9 at 10 ⁇ M.
  • the compounds of formula (I) may be prepared by methods described below, together with synthetic methods known in the art of organic chemistry, or modifications that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are available commercially or may be prepared by routine methods known in the art, such as those methods described in standard reference books such as “Compendium of Organic Synthetic Methods, Vol. I-XII” (published with Wiley-Interscience, ISSN: 1934-4783). Preferred methods include, but are not limited to, those described below.
  • compounds of the invention can be prepared from the commercial available (3-chloropyrazin-2-yl)methanamine dihydrochloride V (CAS: 867165-53-5). Reacting (3-chloropyrazin-2-yl)methanamine dihydrochloride V with an acid derivative exemplified by but not limited to an acid chloride under conditions appropriate for amide formation, using a base exemplified by but not limited to triethylamine and a solvent/solvent mixture such as dimethylformamide and dichloromethane yields amide IV.
  • Intermediate III can be prepared from IV by treatment with phosphoryl chloride in a solvent such as dioxane.
  • the 8-chloroimidazo[1,5-a]pyrazine III is converted to imidazo[1,5-a]pyrazin-8(7H)-one II under standard hydrolysis conditions exemplified by but not limited to hydrochloric acid in a solvent mixture such as water and 1,4-dioxane.
  • Compound I is formed from imidazo[1,5-a]pyrazin-8(7H)-one II by treatment with an alkylating reagent exemplified by but not limited to an alkyl bromide using a base exemplified but not limited to potassium carbonate in a solvent such as dimethylformamide.
  • compounds of the invention can be prepared from the commercial available 5-amino-3-methoxypyrazine-2-carbonitrile X (CAS: 1137478-55-7).
  • Reaction of 5-amino-3-methoxypyrazine-2-carbonitrile X with di-tert-butyl dicarbonate and a catalyst exemplified by but not limited to N,N-dimethylpyridin-4-amine in a solvent such as dichloromethane gives pyrazine IX.
  • Hydrogenation of IX with a catalyst exemplified but not limited to Raney Nickel under an atmosphere of hydrogen in a solvent such as methanol yields amine VIII.
  • Compounds of formula VII can be prepared by employing compounds of formula VIII and a carboxylic acid using standard amide bond forming conditions exemplified but not limited to HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), a base, exemplified but not limited to triethylamine in a solvent such as dichloromethane.
  • Boc protected compounds of formula VII can be deprotected to compounds of formula VI using standard de-protection conditions exemplified by but not limited to trifluoroacetic acid in a solvent such as dichloromethane.
  • Compounds of formula V can be converted to imidazopyrazines of formula IV by treatment with phosphoryl chloride in a solvent such as 1,4-dioxane.
  • Imidazopyrazines of formula III are prepared from IV using standard cross coupling reaction conditions exemplified by but not limited to a Suzuki-Miyaura cross-coupling reaction.
  • Such conditions for the cross coupling reaction are exemplified by but not limited to using; a boronic acid ester, potassium carbonate as the base, a mixture of 1,4-dioxane and water as the solvent and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ) as the catalyst.
  • Imidazo[1,5-a]pyrazin-8(7H)-ones of formula II are prepared by treating compounds of formula III with an acid exemplified but not limited to hydrochloric acid in a mixture of solvents such as water and methanol.
  • Imidazo[1,5-a]pyrazin-8(7H)-ones of formula I are prepared by alkylation of II with an alkylating reagent exemplified by but not limited to alkylbromide using a base exemplified by but not limited to potassium carbonate in a solvent such as dimethylformamide.
  • compounds of the invention can be prepared from the commercial available methyl 1H-imidazole-5-carboxylate VI (CAS: 17325-26-7). Reaction of methyl 1H-imidazole-5-carboxylate VI with an ⁇ -halogenated ketone exemplified but not limited to an ⁇ -chloroketone, under the influence of a base exemplified but not limited to potassium carbonate in a solvent such as acetone yields the imidazole V.
  • Such conditions for the cross-coupling reaction are exemplified by but not limited to using; a boronic acid ester, potassium carbonate as the base, a mixture of 1,4-dioxane and water as the solvent and Pd(dppf)Cl 2 as the catalyst.
  • R 1 contains an unsaturated carbon-carbon bond which can be reduced by hydrogenation under conditions known to the person skilled in the art.
  • Imidazo[1,5-a]pyrazin-8(7H)-ones of formula I are prepared by alkylation of II with an alkylating reagent exemplified by but not limited to alkylbromide using a base exemplified by but not limited to potassium carbonate in a solvent such as dimethylformamide.
  • compounds of the invention can be prepared from the commercial available 2-chloro-6-methylpyrazine X (CAS: 38557-71-0). Reacting 2-chloro-6-methylpyrazine X with Sodium methoxide in methanol yields pyrazine IX.
  • N-oxide VIII can be prepared from IX, by treatment with an oxidant, not limited to sodium metaborate and hydrogen peroxide, in a solvent such as acetic acid.
  • Reacting VIII with a cyanide source such as trimethylsilyl cyanide and zinc(II)bromide, using a base exemplified by but not limited to triethylamine and a solvent/solvent mixture such as acetonitrile yields cyanide VII.
  • Amine V can be liberated by use of trifluoro acetic acid, but not limited to, from VI.
  • Reacting amine V with an acid derivative exemplified by but not limited to an acid chloride under conditions appropriate for amide formation, using a base exemplified by but not limited to triethylamine and a solvent/solvent mixture such as dimethylformamide and dichloromethane yields amide IV.
  • Intermediate III can be prepared from IV by treatment with phosphoryl chloride in a solvent such as dioxane.
  • the 8-chloroimidazo[1,5-a]pyrazine III is converted to imidazo[1,5-a]pyrazin-8(7H)-one II under standard hydrolysis conditions exemplified by but not limited to hydrochloric acid in a solvent mixture such as water and 1,4-dioxane.
  • Compound I is formed from imidazo[1,5-a]pyrazin-8(7H)-one II by treatment with an alkylating reagent exemplified by but not limited to an alkyl bromide using a base exemplified but not limited to potassium carbonate in a solvent such as dimethylformamide.
  • reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using a gradient of petroleum ether and ethyl acetate to afford tert-butyl (6-methoxy-5-((tetrahydro-2H-pyran-4-carboxamido)methyl)pyrazin-2-yl)carbamate 8 g (69.4%).
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (150 mg, 0.98 mmol) and 4-methyltetrahydro-2H-pyran-4-carboxylic acid (212 mg, 1.5 mmol) in DCM (6 mL) was added HATU (670 mg, 1.8 mmol) and Et 3 N (198 mg, 1.96 mmol). The mixture was stirred at 20-25° C. for 1 hour. The mixture was diluted with DCM (50 mL), washed with water (30 mL) and brine (30 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-4-methyltetrahydro-2H-pyran-4-carboxamide (300 mg, 1.07 mmol) in dioxane (5 mL) was added POCl 3 (660 mg, 4.3 mmol). The solution was stirred at 80-90° C. for 3 hours. The mixture was concentrated in vacuo, diluted with DCM (50 mL) and slowly added into water (30 mL).
  • Step 3 To a solution of 8-methoxy-6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (200 mg, 0.77 mmol) in dioxane (10 mL) was added 2M HCl(aq) (10 mL). The solution was stirred at 80-90° C. for 1 hour. The mixture was cooled and added saturated aqueous NaHCO 3 (100 mL), extracted with DCM (100 mL ⁇ 2).
  • Step 4 To a solution of 6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (200 mg, 0.81 mmol) and 1-(bromomethyl)-3-fluorobenzene (183 mg, 0.97 mmol) in anhydrous DMF (5 mL) was added K 2 CO 3 (168 mg, 1.21 mmol). The mixture was stirred at 60-70° C. for 16 h. The mixture was cooled and diluted with water (20 mL), extracted with EtOAc (30 mL ⁇ 2). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (100 mg, 0.65 mmol) and 4-cyanotetrahydro-2H-pyran-4-carboxylic acid (152 mg, 0.98 mmol) in DCM (6 mL) was added HATU (447 mg, 1.18 mmol) and Et 3 N (132 mg, 1.31 mmol). The mixture was stirred at 20-25° C. for 1 hour. The mixture was diluted with DCM (30 ml), washed with water (20 mL) and brine (20 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of 4-cyano-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide (100 mg, 0.34 mmol) in dioxane (5 mL) was added POCl 3 (330 mg, 2.15 mmol). The solution was stirred at 80-90° C. for 2 h. The mixture was cooled and slowly added into water (50 mL), extracted with EtOAc(30 mL ⁇ 2).
  • Step 3 To a solution of 4-(8-methoxy-6-methylimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile (80 mg, 0.29 mmol) in dioxane (4 mL) was added 2M HCl(aq) (2 mL). The solution was stirred at 80-90° C. for 2 h. The mixture was concentrated in vacuo and added saturated aqueous NaHCO 3 (50 mL). The mixture was extracted with DCM (50 mL ⁇ 2).
  • Step 4 To a solution of 4-(6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile (70 mg, 0.27 mmol) in anhydrous DMF (5 mL) was added 1-(bromomethyl)-3-fluoro-benzene (77 mg, 0.41 mmol) and K 2 CO 3 (75 mg, 0.54 mmol). The mixture was stirred at 70-80° C. for 2 h. The mixture was cooled and filtered.
  • Step 1 To a solution of 3-bromo-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (500 mg, 2.2 mmol) and 1-(bromomethyl)-3-fluorobenzene (497 mg, 2.6 mmol) in DMF (5 mL) was added K 2 CO 3 (605 mg, 4.4 mmol). The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL ⁇ 3).
  • Step 2 To a solution of 3-bromo-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (200 mg, 0.6 mmol) in THF (10 mL) was added n-BuLi (0.31 mL, 0.77 mmol) at ⁇ 78° C. The mixture was stirred at ⁇ 78° C. for 30 minutes. tetrahydro-4H-pyran-4-one (77 mg, 0.77 mmol) was added at ⁇ 78° C. The mixture was stirred at ⁇ 78° C. for 1 hour. The mixture was quenched with saturated aqueous NH 4 Cl (0.5 mL) and evaporated under vacuum.
  • Step 3 To a solution of 7-(3-fluorobenzyl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (80 mg, 0.22 mmol) in THF (5 mL) was added NaH (60% in mineral oil, 13.4 mg, 0.36 mmol) at 0° C. The mixture was stirred at 20° C. for 30 minutes. MeI (64 mg, 0.45 mmol) was added at 0° C. The mixture was stirred at 20° C. for 11.5 hours. The mixture was quenched with saturated aqueous NH 4 Cl (0.5 mL) and evaporated under vacuum.
  • Step 1 To a solution of 3-bromo-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (100 mg, 0.3 mmol) in dry THF (5 mL) was added n-BuLi (2.5 M, 0.15 m ⁇ L) (2.5 M in n-hexane) dropwise. The mixture was stirred at ⁇ 78° C. for 0.5 hours. Then tetrahydro-4H-pyran-4-one (45 mg, 0.45 mmol) was added to the mixture. The mixture was stirred at ⁇ 78° C. for 2 hours. The mixture was quenched with saturated aqueous NH 4 Cl (2 mL).
  • Step 2 To a solution of 7-(3-fluorobenzyl)-3-(4-fluorotetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (40 mg, 111.9 ⁇ mol) in dry DCM (4 mL) was added DAST (diethylaminosulfur trifluoride) (28 mg, 170 ⁇ mol) at 0° C. The mixture was stirred at 0° C. for 2 hours. Water (10 mL) was added to the mixture. The mixture was extracted with DCM (20 mL ⁇ 2). The combined organic layer was washed with H 2 O (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give the crude product.
  • DCM dimethylaminosulfur trifluoride
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (200 mg, 1.31 mmol) in DCM (8 mL) was added tetrahydro-2H-pyran-2-carboxylic acid (255 mg, 1.96 mmol) and HATU (894 mg, 2.35 mmol), Et 3 N (264 mg, 2.61 mmol). The solution was stirred at 20-25° C. for 1 hour. The mixture was diluted with water (30 mL), extracted with DCM (40 mL ⁇ 2). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-2-carboxamide (250 mg, 0.94 mmol) in dioxane (8 mL) was added POCl 3 (480 mg, 3.13 mmol). The solution was stirred at 90° C. for 2 h. The mixture was cooled and concentrated in vacuo. The residue was diluted with DCM (50 mL), washed with saturated aqueous NaHCO 3 (aq) (50 mL) and brine (50 mL).
  • Step 3 To a solution of 8-methoxy-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazine (270 mg, 1.09 mmol) in dioxane (8 mL) was added 2M HCl(aq) (4 mL). The solution was stirred at 90° C. for 1 hour. The mixture was concentrated in vacuo and added saturated aqueous NaHCO 3 (50 mL). The mixture was extracted with DCM (50 mL ⁇ 2).
  • Step 4 To a solution of 6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one (200 mg, 0.86 mmol) in anhydrous DMF (10 mL) was added K 2 CO 3 (237 mg, 1.71 mmol) and 1-(bromomethyl)-3-fluorobenzene (243 mg, 1.29 mmol). The mixture was stirred at 80° C. for 24 h. The mixture was cooled and diluted with water (100 mL), extracted with EtOAc (50 mL ⁇ 3).
  • Step 5 7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one (130 mg, 380.8 ⁇ mol) was purified by SFC. 7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one, stereoisomer 1 (35 mg, 27% yield) was obtained.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (200 mg, 1.3 mmol) in dry DCM (10 mL) was added tetrahydrofuran-3-carboxylic acid (228 mg, 2.0 mmol), Et 3 N (265 mg, 2.6 mmol) and HATU (747 mg, 2.0 mmol). The mixture was stirred at 15° C. for 16 hours. Water (10 mL) was added to the mixture. The organic layer was washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated to give the crude product.
  • Step 3 To a solution of 8-methoxy-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine (300 mg, 1.29 mmol) in dioxane (5 mL) was added 2 N HCl (2 mL). The mixture was heated at 90° C. for 1 hour. The mixture was cooled to 15° C. and extracted with DCM (20 mL ⁇ 2).
  • Step 4 To a solution of 6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (200 mg, 912.24 ⁇ mol) in dry DMF (5 mL) was added 1-(bromomethyl)-3-fluorobenzene (259 mg, 1.37 mmol) and K 2 CO 3 (252 mg, 1.82 mmol). The mixture was stirred at 60° C. for 16 hours. The mixture was concentrated and the residue was dissolved in DCM (20 mL) and H 2 O (10 mL). The aqueous layer was extracted with DCM (20 mL ⁇ 2).
  • Step 5 7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (40 mg, 122.2 ⁇ mol) was purified by SFC to give 7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one, stereoisomer 1 (16.43 mg, 41% yield).
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (200 mg, 1.3 mmol) in DCM (6 mL) was added 3-methyltetrahydrofuran-3-carboxylic acid (255 mg, 1.9 mmol) and HATU (894 mg, 2.4 mmol), Et 3 N (264 mg, 2.6 mmol). The solution was stirred at 20-25° C. for 1 hour. Water (40 ml) was added, the mixture was extracted with DCM (40 mL ⁇ 2). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated in vacuo.
  • 3-methyltetrahydrofuran-3-carboxylic acid 255 mg, 1.9 mmol
  • HATU 894 mg, 2.4 mmol
  • Et 3 N 264 mg, 2.6 mmol
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyltetrahydrofuran-3-carboxamide (400 mg, 1.5 mmol) in dioxane (6 mL) was added POCl 3 (880 mg, 5.7 mmol). The solution was stirred at 80-90° C. for 2 h. The mixture was cooled and concentrated in vacuo. The residue was diluted with DCM (50 mL), washed with saturated aqueous NaHCO 3 (50 mL) and brine (50 mL).
  • Step 3 To a solution of 8-methoxy-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine (300 mg, 1.2 mmol) in dioxane (8 mL) was added 2M HCl(aq) (4 mL). The solution was stirred at 80-90° C. for 1 hour. The mixture was concentrated in vacuo and added saturated aqueous NaHCO 3 (50 mL). The mixture was extracted with DCM (50 mL ⁇ 2).
  • Step 4 To a solution of 6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (260 mg, 1.1 mmol) in anhydrous DMF (10 mL) was added K 2 CO 3 (308 mg, 2.2 mmol) and 1-(bromomethyl)-3-fluorobenzene (316 mg, 1.7 mmol). The mixture was stirred at 70-80° C. for 2 h. The mixture was cooled and diluted with water (50 mL), extracted with EtOAc (50 mL ⁇ 2).
  • Step 5 7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (160 mg, 0.47 mmol) was separated by SFC to give 7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one, stereoisomer 1 (37 mg, 23% yield) as a off-white solid.
  • Step 1 To a solution of 1-methylcyclopropane-1-carboxylic acid (500 mg, 4.99 mmol) in DCM (2 mL) was added (COCl) 2 (3.17 g, 24.95 mmol). The solution was stirred at 40° C. for 2 h. The reaction mixture was concentrated in vacuo to give 1-methylcyclopropane-1-carbonyl chloride (500 mg, 85% yield).
  • Step 2 A solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (100 mg, 0.65 mmol) in anhydrous DCM (3 mL) was cooled to 0° C. Then a solution of 1-methylcyclopropane-1-carbonyl chloride (100 mg, 0.85 mmol) in anhydous DCM (2 mL) was added dropwise and stirred at 0° C. for 15 min. The mixture was diluted with DCM (20 mL), washed with saturated aqueous NaHCO 3 (20 mL), brine (20 mL) and dried over Na 2 SO 4 . The organic layer was concentrated in vacuo to give N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-1-methylcyclopropane-1-carboxamide (120 mg, 78% yield).
  • Step 3 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-1-methylcyclopropane-1-carboxamide (120 mg, 0.51 mmol) in dioxane (5 mL) was added POCl 3 (590 mg, 3.85 mmol). The solution was stirred at 80-90° C. for 2 h. The mixture was cooled and slowly added into water (50 mL), extracted with EtOAc (30 mL ⁇ 2).
  • Step 4 To a solution of 8-methoxy-6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazine (80 mg, 0.37 mmol) in dioxane (5 mL) was added 2M HCl (aq) (2 mL). The solution was stirred at 80-90° C. for 1 hour. The mixture was concentrated in vacuo and added saturated aqueous NaHCO 3 (50 mL). The mixture was extracted with DCM (50 mL ⁇ 2).
  • Step 5 To a solution of 6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one (70 mg, 0.34 mmol) in anhydrous DMF (4 mL) was added 1-(bromomethyl)-3-fluoro-benzene (98 mg, 0.52 mmol) and K 2 CO 3 (95 mg, 0.69 mmol). The mixture was stirred at 70-80° C. for 1 hour. The mixture was cooled and filtered.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (100 mg, 0.65 mmol) in DCM (5 mL) was added 2,2-difluorocyclopropane-1-carboxylic acid (120 mg, 0.98 mmol) and HATU (447 mg, 1.18 mmol), Et 3 N (132 mg, 1.31 mmol). The solution was stirred at 20-25° C. for 1 hour. The mixture was diluted with water (20 mL), extracted with DCM (30 mL ⁇ 2). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of 2,2-difluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide (200 mg, 0.58 mmol, 75% purity) in dioxane (5 mL) was added POCl 3 (1.12 g, 7.3 mmol). The solution was stirred at 90° C. for 2 h. The mixture was cooled and concentrated in vacuo. The residue was diluted with DCM (50 mL), washed with saturated aqueous NaHCO 3 (aq) (50 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give 3-(2,2-difluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine (120 mg, 86% yield).
  • Step 3 To a solution of 3-(2,2-difluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine (120 mg, 0.50 mmol) in dioxane (5 mL) was added 2M HCl(aq) (3 mL). The solution was stirred at 80° C. for 1 hour. The mixture was concentrated in vacuo and added saturated aqueous NaHCO 3 (50 mL). The mixture was extracted with DCM (50 mL ⁇ 2).
  • Step 4 To a solution of 3-(2,2-difluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (100 mg, 0.44 mmol) in anhydrous DMF (5 mL) was added K 2 CO 3 (123 mg, 0.89 mmol) and 1-(bromomethyl)-3-fluorobenzene (126 mg, 0.67 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was cooled and filtered.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (100 mg, 652.8 ⁇ mol) and 2-methylcyclopropane-1-carboxylic acid (98 mg, 979.2 ⁇ mol) in DCM (5 mL) was added HATU (446.8 mg, 1.2 mmol) and triethylamine (132.1 mg, 1.3 mmol). The mixture was stirred at 24° C. for 16 h. The mixture was diluted with DCM (20 mL) and washed with water (15 mL). The aqueous layer was extracted with DCM (2*30 mL).
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methylcyclopropane-1-carboxamide (150 mg, 636 ⁇ mol) in dioxane (5 mL) was added POCl 3 (400 mg, 2.6 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled down to 25° C., neutralized with saturated aqueous NaHCO 3 and extracted with ethyl acetate (3 ⁇ 30 mL).
  • Step 3 A solution of 8-methoxy-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazine (120 mg, 552.3 ⁇ mol) in dioxane (5 mL) and HCl (2 M, 2 mL) was stirred at 80° C. for 1 hour. The mixture was cooled to 25° C., neutralized with saturated aqueous NaHCO 3 and extracted with ethyl acetate (3 ⁇ 20 mL).
  • Step 4 To a solution of 6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one (100 mg, 492.0 ⁇ mol) and 1-(bromomethyl)-3-fluorobenzene (139.5 mg, 738.0 ⁇ mol) in DMF (5 mL) was added K 2 CO 3 (136 mg, 984 ⁇ mol). The mixture was stirred at 60-70° C. for 16 h. The mixture was cooled to 25° C., diluted with water (15 mL), extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Step 5 7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one (100 mg, 321.2 ⁇ mol) was purified by SFC.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (300 mg, 2.0 mmol), 2-methyltetrahydrofuran-3-carboxylic acid (382 mg, 2.9 mmol) in DCM (10 mL) was added HATU (1.3 g, 3.5 mmol) and triethylamine (396 mg, 3.9 mmol). The mixture was stirred at 24° C. for 16 h. The mixture was diluted with DCM (30 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (2 ⁇ 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyltetrahydrofuran-3-carboxamide (350 mg, 1.3 mmol) in dioxane (5 mL) was added POCl 3 (720 mg, 4.7 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to 25° C., neutralized with saturated aq.NaHCO 3 and extracted with ethyl acetate (2 ⁇ 30 mL).
  • Step 3 A solution of 8-methoxy-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine (320 mg, 1.3 mmol) in dioxane (5 mL) and HCl (2 M, 2 mL) was stirred at 80° C.-90° C. for 21.5 hours. The mixture was cooled down to 25° C., neutralized with saturated aq.NaHCO 3 , extracted with DCM (3 ⁇ 30 mL).
  • Step 4 To a solution of 6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (250 mg, 1.1 mmol) in DMF (8 mL) was added 1-(bromomethyl)-3-fluorobenzene (304 mg, 1.6 mmol) and K 2 CO 3 (296 mg, 2.1 mmol). The mixture was stirred at 60-70° C. for 16 h. The mixture was cooled down to 25° C. and diluted with water (15 mL), extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Step 5 7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (220 mg, 644 ⁇ mol) was purified by SFC.
  • Step 1 A solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (400 mg, 2.1 mmol) and triethylamine (662 mg, 6.5 mmol) in DCM (8 mL) was cooled to 0° C., 2-fluorocyclopropane-1-carbonyl chloride (251 mg, 2.1 mmol) was added dropwise and the mixture was stirred at 0° C. for 0.5 h. The mixture was diluted with water (10 mL), extracted with DCM (20 mL ⁇ 2). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of cis-2-fluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide (260 mg, 1.1 mmol) in dioxane (10 mL) was added POCl 3 (500 mg, 3.3 mmol). The solution was stirred at 80-90° C. for 2 h. The mixture was concentrated in vacuo and diluted with NaHCO 3 (30 mL), extracted with DCM (50 mL ⁇ 2).
  • Step 3 A solution of 3-(cis-2-fluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine (220 mg, 994 ⁇ mol) in 2N HCl (aq) (5 mL) and dioxane (10 mL) was stirred at 80-90° C. for 1 hour. The mixture was concentrated in vacuo. The residue was diluted with NaHCO 3 (aq) (30 mL), extracted with DCM (30 mL ⁇ 3).
  • Step 4 To a solution of 3-(cis-2-fluorocyclopropyl)-6-methyl imidazo[1,5-a]pyrazin-8(7H)-one (200 mg, 965 ⁇ mol) in anhydrous DMF (10 mL) was added K 2 CO 3 (133 mg, 965 ⁇ mol) and 1-(bromomethyl)-3-fluorobenzene (274 mg, 1.5 mmol). The mixture was stirred at 60-70° C. for 16 h and 80° C. for 21 h.
  • Step 5 7-(3-fluorobenzyl)-3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (80 mg, 253 ⁇ mol) was separated by SFC.
  • Step 1 To a solution of trans-2-fluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide (280 mg, 1.1 mmol) in dioxane (10 mL) was added POCl 3 (540 mg, 3.5 mmol). The solution was stirred at 80-90° C. for 2 h. The mixture was concentrated in vacuo and diluted with NaHCO 3 (30 mL), extracted with DCM (50 mL ⁇ 2).
  • Step 2 A solution of 3-(trans-2-fluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine (240 mg, 1.1 mmol) in 2N HCl (aq) (5 mL) and dioxane (10 mL) was stirred at 80-90° C. for 1 hour. The mixture was concentrated in vacuo. The residue was diluted with NaHCO 3 (aq) (30 mL), extracted with DCM (30 mL ⁇ 3).
  • Step 3 To a solution of 3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (220 mg, 1.1 mmol) in anhydrous DMF (10 mL) was added K 2 CO 3 (293 mg, 2.1 mmol) and 1-(bromomethyl)-3-fluorobenzene (300 mg, 1.6 mmol). The mixture was stirred at 60-70° C. for 16 h and 80° C. for 21 h.
  • Step 4 7-(3-fluorobenzyl)-3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (250 mg, 793 ⁇ mol) was separated by SFC.
  • Step 1 A solution of 1-bromo-4-cyclopropoxybenzene (900 mg, 4.22 mmol) in THF (20 mL, anhydrous) was added n-BuLi (2.5 M, 2.6 mL) at ⁇ 78° C. and stirred at ⁇ 78° C. for 2 hours under N 2 . Then, thereto was added dropwise DMF (926 mg, 12.66 mmol, anhydrous) at ⁇ 78° C. and it was stirred for 2 hours. The solution was quenched with NH 4 Cl (aq. 1 mL) at ⁇ 78° C. and stirred at 0° C. for 0.5 hour. The mixture was diluted with ethyl acetate (10 mL).
  • Step 3 A solution of (4-cyclopropoxyphenyl)methanol (500 mg, 3.1 mmol) and Et 3 N (617 mg, 6.1 mmol) in anhydrous DCM (10 mL) was cooled to 0° C., then MsCl (1.41 g, 12.3 mmol) was added dropwise. The solution was stirred at 0° C. for 0.5 h. The mixture was diluted with water (50 mL), extracted with DCM (50 mL ⁇ 2). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated in vacuo to afford 4-cyclopropoxybenzyl methanesulfonate (600 mg, 81% yield).
  • Step 4 A mixture of 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (250 mg, 1.07 mmol), 4-cyclopropoxybenzyl methanesulfonate (311 mg, 1.28 mmol) and Cs 2 CO 3 (698 mg, 2.14 mmol) in DMF (6.0 mL, anhydrous) was stirred at 60° C. for 12 hours.
  • Step 2 A solution of 4-(cyclopropylmethoxy)benzaldehyde (1.3 g, 7.4 mmol) in MeOH (30 mL) was cooled to 0° C., then NaBH 4 (558 mg, 14.8 mmol) was added and the mixture was stirred at 0° C. for 1 hour. The mixture was quenched with sat. brine (aq) (50 mL), extracted with EtOAc (50 mL ⁇ 2). The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to afford (4-(cyclopropylmethoxy)phenyl)methanol (1.21 g, 92% yield).
  • Step 3 A solution of (4-(cyclopropylmethoxy)phenyl)methanol (800 mg, 4.5 mmol) and Et 3 N (907 mg, 9.0 mmol) in DCM (10 mL) was cooled to 0° C., then MsCl (617 mg, 5.4 mmol) was added dropwise. The solution was stirred at 0° C. for 0.5 h. The mixture was diluted with water (50 mL), extracted with DCM (50 mL ⁇ 2). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated in vacuo to afford 4-(cyclopropylmethoxy)benzyl methanesulfonate (760 mg, 66% yield).
  • Step 4 A mixture of 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (300 mg, 1.29 mmol), 4-(cyclopropylmethoxy)benzyl methanesulfonate (429 mg, 1.68 mmol) and Cs 2 CO 3 (841 mg, 2.58 mmol) in DMF (6 mL, anhydrous) was stirred at 60° C. for 12 hours. The mixture was filtered and the filtrate was concentrated under vacuum.
  • Step 1 A mixture of 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (200 mg, 858 ⁇ mol), 1-(bromomethyl)-4-nitrobenzene (278 mg, 1.29 mmol) and Cs 2 CO 3 (559 mg, 1.71 mmol) in DMF (4 mL) was stirred at 60° C. for 2 hours. The mixture was filtered and the filtrate was concentrated under vacuum.
  • Step 2 A mixture of 6-methyl-7-(4-nitrobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (200 mg, 542.90 ⁇ mol), Fe (152 mg, 2.71 mmol), NH 4 Cl (88 mg, 1.63 mmol) and MeOH (10 mL) in H 2 O (10 mL) was stirred at 70° C. for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum.
  • Step 3 A mixture of 7-(4-aminobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (120 mg, 354.61 ⁇ mol), acetyl acetate (60 mg, 588.65 ⁇ mol) and triethylamine (144 mg, 1.42 mmol) in dioxane (10 mL) was stirred at 90° C. for 6 hours. The solution was quenched with water (2 mL) and stirred at 60° C. for 2 hours. Then it was concentrated under vacuum.
  • Step 2 A mixture of 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (150 mg, 643 ⁇ mol), 2-ethylbenzyl methanesulfonate (276 mg) and Cs 2 CO 3 (419 mg, 1.29 mmol) in DMF (5 mL) was stirred at 60° C. for 12 hours. The mixture was filtered and the filtrate was concentrated under vacuum.
  • Step 4 A mixture of 3-bromo-6-ethylimidazo[1,5-a]pyrazin-8(7H)-one (500 mg, 2.07 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (522 mg, 2.48 mmol), K 2 CO 3 (572 mg, 4.14 mmol), Pd(dppf)Cl 2 (303 mg, 414 ⁇ mol) and H 2 O (5 mL) in 1,4-dioxane (20 mL) was stirred at 100° C. for 12 hours. The mixture was filtered and the filtrate was concentrated under vacuum.
  • Step 6 A mixture of 6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (300 mg, 1.21 mmol), 1-(bromomethyl)-3-fluorobenzene (297 mg, 1.57 mmol) and K 2 CO 3 (334 mg, 2.42 mmol) in DMF (20 mL) was stirred at 60° C. for 12 hours. The mixture was filtered and the filtrate was concentrated under vacuum.
  • Step 1 To a cooled (0° C.) solution of 2-methyltetrahydrofuran-3-carboxylic acid (110 mg, 845 ⁇ mol) in dry DCM (2 mL) was added oxalyl dichloride (107 mg, 845 ⁇ mol) dropwise. Then one drop of DMF was added and the mixture was stirred at 26° C. for 1 hour. The solution of 2-methyltetrahydrofuran-3-carbonyl chloride (126 mg) in DCM (2 mL) was directly used for the next step.
  • Step 2 To a cooled (0° C.) solution of 2-methyltetrahydrofuran-3-carbonyl chloride (160 mg, 844 ⁇ mol, HCl) in dry DCM (5 mL) was added triethylamine (256 mg, 2.53 mmol) and (3-methoxy-5-methylpyrazin-2-yl)methanamine (125 mg, 843.70 ⁇ mol) in DCM (2 mL) dropwise. The mixture was stirred at 26° C. for 1 hour. LCMS showed the reaction was completed. Water (5 mL) was added to the mixture. The mixture was extracted with DCM (30 mL ⁇ 2).
  • Step 3 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyltetrahydrofuran-3-carboxamide (150 mg, 565 ⁇ mol) in dry dioxane (5 mL) was added POCl 3 (173 mg, 1.13 mmol). The mixture was heated at 80° C. for 2 hours. The mixture was cooled to 26° C. and the brown solution of 8-methoxy-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine (140 mg) in dioxane (5 mL) was directly used for the next step.
  • Step 5 To a solution of 6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (131 mg, 562 ⁇ mol) in dry DMF (5 mL) was added 1-(bromomethyl)-4-methoxybenzene (169 mg, 842 ⁇ mol) and Cs 2 CO 3 (366 mg, 1.12 mmol). The mixture was heated at 60° C. for 16 hours. The mixture was concentrated and water (10 mL) was added. The mixture was extracted with DCM (30 mL ⁇ 2). The combined organic layer was washed with H 2 O (30 mL ⁇ 2), brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • reaction was purified by chromatography on silicagel to obtain 7-((6-methoxypyridin-3-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (127 mg, 0.358 mmol) in 42% yield.
  • Step 1 To a solution of cycloheptanecarboxylic acid (500 mg, 3.52 mmol) in THF (40 mL) was added LiAlH 4 (401 mg, 10.6 mmol) in portions at 0° C. The mixture was stirred at 65° C. for 3 hours. The reaction was quenched with H 2 O (0.4 mL) and 10% NaOH (0.4 mL, aq). To the mixture was added Na 2 SO 4 . The mixture was filtered. The filtrate was concentrated. The residue was purified by flash silica gel chromatography to give cycloheptylmethanol (383 mg, 85% yield).
  • Step 2 To a solution of cycloheptylmethanol (313 mg, 2.44 mmol) and triethylamine (494 mg, 4.88 mmol) in DCM (5 mL) was added MsCl (490 mg, 4.28 mmol) at 0° C. and it was stirred at 20° C. for 40 min. The solution was washed with NaHCO 3 (saturated aqueous 5 mL ⁇ 4), water (5 mL ⁇ 2), brine (3 mL) and then was dried over Na 2 SO 4 , filtered and concentrated to give cycloheptylmethyl methanesulfonate (381 mg) which was used in the next step directly without further purification.
  • NaHCO 3 saturated aqueous 5 mL ⁇ 4
  • water 5 mL ⁇ 2
  • brine brine
  • Step 3 To a solution of 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (150 mg, 643 ⁇ mol) and cycloheptylmethyl methanesulfonate (159 mg, 772 ⁇ mol) in DMF (3 mL) was added Cs 2 CO 3 (419 mg, 1.29 mmol). The mixture was stirred at 60° C. for 6 hours. The mixture was diluted with DCM (20 mL) and washed with water (5 mL ⁇ 2), brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Step 1 To a solution of (4-methylcyclohexyl)methanol (400 mg, 3.12 mmol, 1 eq) in anhydrous DCM (20 mL) was added triethylamine (631 mg, 6.24 mmol, 865 ⁇ L, 2 eq). The mixture was dropwise added methanesulfonyl chloride (465 mg, 4.06 mmol, 314 ⁇ L, 1.30 eq) at 0° C. and it was stirred at 0° C. for 1 hour. The reaction mixture was washed with water (5 mL ⁇ 3), brine (3 mL), dried and concentrated. (4-methylcyclohexyl)methyl methanesulfonate (700 mg) was obtained.
  • Step 2 To a solution of 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (260 mg, 1.11 mmol, 1 eq) and (4-methylcyclohexyl)methyl methanesulfonate (572 mg, 2.78 mmol, 2.50 eq) in anhydrous DMF (6 mL) was added Cs 2 CO 3 (723 mg, 2.22 mmol, 2 eq). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with H 2 O (3 mL) and extracted with DCM (10 mL ⁇ 2).
  • 6-methyl-7-((4-methylcyclohexyl)methyl)-3-(tetrahydro-2H-pyran-4-yl) imidazo[1,5-a]pyrazin-8(7H)-one 160 mg, 466 ⁇ mol, 1 eq was purified by SFC to give 6-methyl-7-(((trans)-4-methylcyclohexyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (60 mg, 37% yield, 98% purity).
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyltetrahydro-2H-pyran-4-carboxamide (220 mg, 788 ⁇ mol, 1 eq) in dioxane (8 mL) was added POCl 3 (242 mg, 1.58 mmol, 146 ⁇ L, 2 eq). The mixture was stirred at 80° C. for 2 hours. The mixture was concentrated. 6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8-ol (223 mg, hydrochloride salt) was used in the next step without further purification.
  • Step 3 To a solution of 6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8-ol (170 mg, 0.6 mmol) in DMF (5 mL) was added Cs 2 CO 3 (586 mg, 1.80 mmol, 3 eq) and 1-(chloromethyl)-4-methoxybenzene (113 mg, 719 ⁇ mol, 98 ⁇ L, 1.20 eq). The mixture was stirred at 60° C. for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude mixture was purified by preparative LC-MS, and then by preparative TLC with ethyl acetate as eluent.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (150 mg, 791 ⁇ mol, 1 eq) in dry DCM (5 mL) was added triethylamine (240 mg, 2.37 mmol, 329 ⁇ L, 3 eq), racemic (1R,2S,4S)-2-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (124 mg, 791 ⁇ mol, 1 eq) and HATU (361 mg, 949 ⁇ mol, 1.20 eq). The mixture was stirred at 15° C. for 16 hours.
  • Step 2 To a solution of racemic (1R,2S,4S)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxamide (150 mg, 515 ⁇ mol, 1 eq) in dry dioxane (5 mL) was added POCl 3 (158 mg, 1.03 mmol, 96 ⁇ L, 2 eq). The mixture was heated at 80° C. for 2 hours. The mixture was cooled to 15° C. and poured into water (5 mL). The mixture was adjusted to pH 8 by saturated aqueous NaHCO 3 and extracted with DCM (20 mL ⁇ 2).
  • Step 3 To a solution of racemic 6-methyl-3-((1R,2R,4S)-2-methyl-7-oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8-ol (100 mg, 386 ⁇ mol, 1 eq) in dry DMF (5 mL) was added 1-(chloromethyl)-4-methoxy-benzene (72 mg, 463 ⁇ mol, 63 ⁇ L, 1.20 eq) and Cs 2 CO 3 (251 mg, 771 ⁇ mol, 2 eq). The mixture was heated at 60° C. for 2 hours. The mixture was concentrated. DCM (20 mL) and H 2 O (10 mL) was added.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (300 mg, 1.58 mmol) and (S)-2-phenylpropanoic acid (261 mg, 1.74 mmol, 237 ⁇ L, 1.10 eq) in DCM (10 mL) was added triethylamine (400 mg, 3.95 mmol, 548 ⁇ L, 2.50 eq) and HATU (901 mg, 2.37 mmol, 1.50 eq). The mixture was stirred at 15° C. for 12 hours. Water (50 mL) was added to the solution. The mixture was extracted with DCM (50 mL ⁇ 2).
  • Step 2 To a solution of (S)—N-((3-methoxy-5-methyl pyrazin-2-yl)methyl)-2-phenylpropanamide (450 mg, 1.58 mmol, 1 eq) in dioxane (10 mL) was added POCl 3 (485 mg, 3.16 mmol, 294 ⁇ L, 2 eq). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was quenched by addition H 2 O (50 mL) at 0° C., basified by addition saturated aqueous NaHCO 3 (10 mL) and then extracted with EtOAc (50 mL ⁇ 2).
  • Step 3 To a solution of (S)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8-ol (128 mg, 505 ⁇ mol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (95 mg, 0.61 mmol, 83 ⁇ L, 1.20 eq) in DMF (10 mL) was added Cs 2 CO 3 (329.29 mg, 1.01 mmol, 2 eq). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (200 mg, 1.05 mmol, 1 eq) and (R)-2-phenylpropanoic acid (190 mg, 1.27 mmol, 173 ⁇ L, 1.20 eq) in DCM (10 mL) was added triethylamine (267 mg, 2.64 mmol, 365 ⁇ L, 2.50 eq) and HATU (602 mg, 1.58 mmol, 1.50 eq). The mixture was stirred at 15° C. for 12 hours. Water (50 mL) was added to the solution. The mixture was extracted with DCM (50 mL ⁇ 2).
  • Step 2 To a solution of (R)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-phenylpropanamide (450 mg, 1.58 mmol, 1 eq) in dioxane (10 mL) was added POCl 3 (727 mg, 4.74 mmol, 440 ⁇ L, 3 eq). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was quenched by addition of H 2 O (50 mL) at 0° C., basified by addition saturated aqueous NaHCO 3 (10 mL) and then extracted with EtOAc (50 mL ⁇ 2).
  • Step 3 To a solution of (R)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8-ol (100 mg, 395 ⁇ mol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (74 mg, 474 ⁇ mol, 65 ⁇ L, 1.20 eq) in DMF (5 mL) was added Cs 2 CO 3 (257 mg, 790 ⁇ mol, 2 eq). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative LC-MS. (R)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one (140 mg, 95% yield) was obtained.
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (150 mg, 791 ⁇ mol) in DCM (5 mL) was added 1,4-dimethylpiperidine-4-carboxylic acid hydrochloride (169 mg, 870 ⁇ mol, 1.10 eq, HCl), triethylamine (240 mg, 2.37 mmol, 329 ⁇ L, 3 eq) and HATU (361 mg, 949 ⁇ mol, 1.20 eq). The mixture was stirred at 15° C. for 16 hours. The mixture was concentrated.
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-1,4-dimethylpiperidine-4-carboxamide (100 mg, 342 ⁇ mol, 1 eq) in dry dioxane (5 mL) was added POCl 3 (105 mg, 684 ⁇ mol, 64 ⁇ L, 2 eq). The mixture was heated at 80° C. for 4 hours. The mixture was cooled to 15° C. and poured into water (5 mL). The mixture was adjusted to pH 8 by saturated aqueous NaHCO 3 and concentrated.
  • Step 3 To a solution of 3-(1,4-dimethylpiperidin-4-yl)-6-methylimidazo[1,5-a]pyrazin-8-ol (60 mg, 230 ⁇ mol, 1 eq) in DMF (2 mL) was added 1-(chloromethyl)-4-methoxybenzene (54 mg, 346 ⁇ mol, 47 ⁇ L, 1.50 eq) and Cs 2 CO 3 (150 mg, 461 ⁇ mol, 2 eq). The mixture was heated at 60° C. for 2 hours. The mixture was concentrated. DCM (20 mL) and H 2 O (10 mL) were added. The mixture was extracted with DCM (20 mL).
  • Step 1 To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (200 mg, 1.05 mmol) and 6-chloro-2,3-dihydro-1H-indene-1-carboxylic acid (206 mg, 1.05 mmol, 1 eq) in DCM (5 mL) was added HATU (479 mg, 1.26 mmol, 1.20 eq) and DIPEA (407 mg, 3.15 mmol, 550 ⁇ L, 3 eq). The mixture was stirred at 18° C. for 16 hours. The mixture washed with H 2 O (20 mL) and extracted with DCM (20 mL ⁇ 3). The combined organic was dried over Na 2 SO 4 and concentrated under vacuum. 6-chloro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide (312 mg, 864 ⁇ mol, 82% yield) was obtained.
  • Step 2 To a solution of 6-chloro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide (0.262 g, 1 eq) in dioxane (10 mL) was added POCl 3 (363 mg, 2.37 mmol, 220 ⁇ L, 3 eq). The mixture was stirred at 80° C. for 3 hours. The mixture was quenched by H 2 O (20 mL) and adjusted pH>7 by saturated aqueous NaHCO 3 . The mixture was extracted with DCM (25 mL ⁇ 3). The combined organic was dried over Na 2 SO 4 and concentrated under vacuum. 3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (236 mg) was obtained and directly used to next step.
  • Step 3 To a solution of 3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (236 mg, 787 ⁇ mol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (148 mg, 945 ⁇ mol, 1.20 eq) in DMF (12 mL) was added Cs 2 CO 3 (513 mg, 1.57 mmol, 2 eq). The mixture was stirred at 60° C. for 2.5 hours. The mixture was concentrated under vacuum. The residue was quenched with H 2 O (15 mL) and extracted with DCM (20 mL ⁇ 3).
  • Step 2 To a cooled (0° C.) solution of 3-methyl-5-oxopyrrolidine-3-carboxylic acid (100 mg, 0.7 mmol, 1 eq) in DCM (2 mL) was added oxalyl dichloride (98 mg, 768 ⁇ mol, 67 ⁇ L, 1.10 eq) and one drop of dry DMF was added. The mixture was stirred at 20° C. for 1 hour. The colorless solution of 3-methyl-5-oxopyrrolidine-3-carbonyl chloride (112.89 mg) in DCM (2 mL) was directly used for the next step.
  • Step 3 To a cooled (0° C.) solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (120 mg, 633 ⁇ mol, 1 eq, HCl) in dry DCM (3 mL) was added triethylamine (192 mg, 1.90 mmol, 263 ⁇ L, 3 eq) and a solution of 3-methyl-5-oxopyrrolidine-3-carbonyl chloride (112 mg, 696 ⁇ mol, 1.10 eq) in dry DCM (2 mL) dropwise. The mixture was stirred at 20° C. for 1 hour. H 2 O (5 mL) was added and the mixture was extracted with DCM (20 mL ⁇ 2).
  • Eaton's reagent 7.7 wt % phosphorus pentoxide solution in methanesulfonic acid
  • Step 5 To a solution of 4-(8-hydroxy-6-methylimidazo[1,5-a]pyrazin-3-yl)-4-methylpyrrolidin-2-one (100 mg, 406 ⁇ mol, 1 eq) in DMF (5 mL) was added 1-(chloromethyl)-4-methoxybenzene (76 mg, 487 ⁇ mol, 66 ⁇ L, 1.20 eq) and Cs 2 CO 3 (265 mg, 812 ⁇ mol, 2 eq). The mixture was heated at 60° C. for 2 h. The mixture was concentrated. DCM (20 mL) and H 2 O (10 mL) was added. The mixture was extracted with DCM (20 mL).
  • Step 1 To a solution of 3-methoxy-2,2-dimethylpropanoic acid (115 mg, 870 ⁇ mol, 1 eq) in DCM (5 mL) was added oxalyl dichloride (121 mg, 957 ⁇ mol, 84 ⁇ L, 1.10 eq) at 0° C., followed by one drop of DMF. The mixture was stirred at 20° C. for 1 hour. The mixture was directly used to next step.
  • oxalyl dichloride 121 mg, 957 ⁇ mol, 84 ⁇ L, 1.10 eq
  • Step 2 To a solution of 3-methoxy-2,2-dimethylpropanoyl chloride (150 mg, 791 ⁇ mol, 1 eq, HCl) and triethylamine (120 mg, 1.19 mmol, 164 ⁇ L, 1.50 eq) in DCM (10 mL) was added (3-methoxy-5-methylpyrazin-2-yl)methanamine (131 mg, 870 ⁇ mol, 1.10 eq) in DCM (5 mL). The mixture was stirred at 20° C. for 1 hour. The mixture was quenched with H 2 O (20 mL) and extracted with DCM (15 mL ⁇ 3). The combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. 3-methoxy-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,2-dimethylpropanamide (142 mg, 522 ⁇ mol, 66% yield) was obtained.
  • Step 3 To a solution of 3-methoxy-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,2-dimethylpropanamide (102 mg, 382 ⁇ mol, 1 eq) in dioxane (5 mL) was added POCl 3 (117 mg, 763 ⁇ mol, 71 ⁇ L, 2 eq). The mixture was stirred at 80° C. for 2 hours. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL ⁇ 3). The combined organic layers were dried with Na 2 SO 4 and concentrated under vacuum. 3-(1-methoxy-2-methylpropan-2-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (45 mg, 191 ⁇ mol, 50% yield) was obtained.
  • Step 4 To a solution of 3-(1-methoxy-2-methylpropan-2-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (62 mg, 264 ⁇ mol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (49.52 mg, 316 ⁇ mol, 43.06 ⁇ L, 1.20 eq) in DMF (5 mL) was added Cs 2 CO 3 (171.72 mg, 527 ⁇ mol, 2 eq). The mixture was stirred at 60° C. for 3 hours. The mixture washed with H 2 O (20 mL) and extracted with DCM (20 mL ⁇ 3). The combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum.
  • Step 1 To a cold (0° C.) solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (150 mg, 791 ⁇ mol), Et 3 N (176 mg, 1.74 mmol, 241 ⁇ L, 2.20 eq) in anhydrous DCM (5 mL) was added isobutyryl chloride (93 mg, 870 ⁇ mol, 91 ⁇ L, 1.10 eq). The solution was stirred at 0° C. for 0.5 h. The mixture was diluted with water (20 mL), extracted with DCM (20 mL ⁇ 2). The organic layer was washed with brine (20 ml), dried over Na 2 SO 4 and concentrated in vacuo. N-((3-methoxy-5-methylpyrazin-2-yl)methyl)isobutyramide (160 mg, 717 ⁇ mol, 91% yield) was obtained.
  • Step 2 To a solution of N-((3-methoxy-5-methylpyrazin-2-yl)methyl)isobutyramide (160 mg, 717 ⁇ mol, 1 eq) in dioxanedioxane (5 mL) was added POCl 3 (220 mg, 1.43 mmol, 133 ⁇ L, 2 eq). The mixture was stirred at 90° C. 2 hours. The mixture was concentrated in vacuo. 3-isopropyl-8-methoxy-6-methylimidazo[1,5-a]pyrazine (130 mg, 633 ⁇ mol, 88% yield) was obtained.
  • Step 4 To a solution of 3-isopropyl-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (120 mg, 628 ⁇ mol, 1 eq) in DMF (8 mL) was added 1-(chloromethyl)-4-methoxy-benzene (118 mg, 753 ⁇ mol, 103 ⁇ L, 1.20 eq) and Cs 2 CO 3 (307 mg, 941 ⁇ mol, 1.50 eq). The mixture was stirred at 60° C. for 16 hours. The mixture was filtered. The filtrate was purified by pre-HPLC (base). 3-isopropyl-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (90 mg, 287 ⁇ mol, 46% yield) was obtained.
  • 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (30 mg, 0.13 mmol), cesium carbonate (84 mg, 0.26 mmol), 4-(chloromethyl)-2-methylthiazole (23 mg, 0.15 mmol) and sodium iodide (23 mg, 0.15 mmol) in DMF (2 mL).
  • the reaction was heated to 70° C., and stirred over night. The mixture was filtered and evaporated and subsequently chromatographed on silicagel to obtain the crude product.
  • 6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (30 mg, 0.129 mmol), cesium carbonate (147 mg, 0.450 mmol), 4-(chloromethyl)thiazole hydrochloride (26 mg, 0.15 mmol) and sodium iodide (23 mg, 0.15 mmol) in DMF (2 mL).
  • the reaction was heated to 70° C., and stirred over night. The mixture was filtered and evaporated and subsequently chromatographed on silicagel to obtain the crude product.

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US10538525B2 (en) 2016-04-12 2020-01-21 H. Lundbeck A/S 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones and 1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-ones as PDE1 inhibitors
US10633382B2 (en) 2016-10-18 2020-04-28 H. Lundbeck A/S Imidazopyrazinones, pyrazolopyrimidinones and pyrazolopyridinones as PDE1 inhibitors
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Publication number Priority date Publication date Assignee Title
US10150771B2 (en) 2014-10-10 2018-12-11 H. Lundbeck A/S Triazolopyrazinones as PDE1 inhibitors
US10011606B2 (en) 2015-04-30 2018-07-03 H. Lundbeck A/S Imidazopyrazinones as PDE1 inhibitors
US10858362B2 (en) 2015-04-30 2020-12-08 H. Lundbeck A/S Imidazopyrazinones as PDE1 inhibitors
US11472810B2 (en) 2015-04-30 2022-10-18 H. Lundbeck A/S Imidazopyrazinones as PDE1 inhibitors
US10538525B2 (en) 2016-04-12 2020-01-21 H. Lundbeck A/S 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones and 1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-ones as PDE1 inhibitors
US11104680B2 (en) 2016-04-12 2021-08-31 H. Lundbeck A/S 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones and 1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-ones as PDE1 inhibitors
US10633382B2 (en) 2016-10-18 2020-04-28 H. Lundbeck A/S Imidazopyrazinones, pyrazolopyrimidinones and pyrazolopyridinones as PDE1 inhibitors
US10905688B2 (en) 2016-10-28 2021-02-02 H. Lundbeck A/S Combinations comprising substituted imidazo[1,5-α]pyrazinones as PDE1 inhibitors
US10912773B2 (en) 2016-10-28 2021-02-09 H. Lundbeck A/S Combinations comprising substituted imidazo[1,5-a]pyrazinones as PDE1 inhibitors
CN111526890A (zh) * 2017-12-14 2020-08-11 H.隆德贝克有限公司 包括施用1h-吡唑并[4,3-b]吡啶的组合治疗

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