Heteroaromatic compounds, methods of making and uses thereof

Abstract

The present application discloses a heteroaromatic compound, a preparation method and uses thereof. The present application provides a compound as shown in formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof. The novel heteroaromatic compound is a selective dopamine D1 / D5 ligand, has good affinity and selectivity to the target, and can be used for treating D1 / D5 mediated (or D1 / D5 related) disorders, including schizophrenia, cognitive impairment, age-related cognitive decline, dementia and Parkinson's disease.

Description

[0001] This application claims priority to Chinese Patent Application No. 202511059684.7, filed on July 30, 2025, and Chinese Patent Application No. 202511282442.4, filed on September 9, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicinal chemistry, specifically relating to aromatic hetero compounds, their preparation methods, and their uses. Background Technology

[0003] G protein-coupled receptors (GPCRs) are a superfamily of receptors with seven transmembrane helical domains, participating in a variety of physiological processes in the human body. Dopamine receptors are important targets of GPCRs and have therapeutic potential for treating motor deficits caused by Parkinson's disease (PD) and cognitive impairments caused by neuropsychiatric disorders such as Alzheimer's disease, PD, and schizophrenia. Dopamine receptors can be divided into two subfamilies: including D1-like receptors (D1R and D5R), which mainly interact with G... s Protein coupling stimulates the production of adenylate cyclase (cAMP) and D2-like receptors (D2R, D3R, and D4R), which in turn interact with G... i / o The protein couples with and inhibits the production of cAMP.

[0004] D1-like receptors are highly expressed in multiple brain regions and are involved in various physiological functions, such as synaptic plasticity, cognitive and memory functions, goal-oriented motor functions, and potential reward processes. However, there are currently no marketed drugs that target only D1-like receptors in the central nervous system. Tavapadon (CVL-751), developed by Pfizer, is a selective D1 / D5 receptor partial agonist that targets human D1 receptors. K i With a value of 8.54 nM, it is currently in Phase III clinical trials for the treatment of early-stage PD. Tavapadon has been reported to provide patients with a balance of motor control, safety, and tolerability by selectively activating D1 / D5 receptors along the substantia nigra-striatal pathway, while avoiding overstimulation of D2 / D3 receptors, which is the root cause of side effects from current dopamine receptor agonists. Furthermore, international patent application WO2015162518A1 discloses a series of furano[2,3-d]pyrimidine heteroaromatic compounds, represented by Example 9.

[0005] Clinically, there is still a need to develop novel and more effective drugs (such as agonists or partial agonists) to obtain drugs with better D1-like receptor agonist activity, D1 receptor affinity and / or in vivo efficacy to meet the huge market demand. Summary of the Invention

[0006] The technical problem to be solved by this invention is to provide an aromatic heterocyclic compound, its preparation method, and its uses. This type of compound, as a dopamine D1-like receptor agonist, can be used to treat and / or prevent neurological diseases, particularly Parkinson's disease. Compared to compounds known in the prior art, this type of compound has a novel structure, can be administered orally, and possesses advantages such as good D1-like receptor agonist activity, D1 receptor affinity, and / or significantly enhanced in vivo efficacy, providing a new option for the treatment of Parkinson's disease or for reducing its severity.

[0007] The object of this invention is to provide a compound of Formula I, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] X3 is either O or S;

[0011] When present, R1 can be hydrogen, deuterium, halogen, or C independently. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O and S, 5-10 membered aryl, or 5-10 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O and S;

[0012] R2 can be hydrogen, deuterium, halogen, or C independently. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl;

[0013] R 3a R 3b R4 and R4 are independently hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -(CR cc R dd ) y C(O)R aa 、-(CR cc R dd ) y C(O)OR aa 、-(CR cc R dd ) y C(O)NR aa R bb 、-(CR cc R dd ) y OR aa 、-(CR cc R dd ) y OS(O)2R aa 、-(CR cc R dd ) y NR aa R bb 、-(CR cc R dd ) y OC(O)R aa or -(CR) cc R dd ) y OP(O)(OR aa )2;

[0014] When it exists, R aa R bb R cc and R dd Each is independently hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl;

[0015] m is an integer between 0 and 3;

[0016] n is an integer from 1 to 4; and

[0017] y is an integer from 0 to 5. In a further preferred embodiment of the invention, at least one R2 is not hydrogen.

[0018] In a further preferred embodiment of the invention, when present, R1 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl groups are preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl, and more preferably hydrogen.

[0019] In a further preferred embodiment of the invention, R2 is independently hydrogen, deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl groups, preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, or cyclopropyl.

[0020] In a further preferred embodiment of the invention, R2 is independently hydrogen, deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl groups, preferably deuterium, halogens, or C464. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy or C 3-6 Cycloalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CD3, -CF3, -CHF2 or -CH2F; and at least one R2 is not hydrogen.

[0021] In a further preferred embodiment of the invention, R 3a R 3b R4 and R4 are independently hydrogen, deuterium, and C.1-6 Alkyl, C 1-6 Deuterated alkyl, -(CR cc R dd ) y C(O)R aa 、-(CR cc R dd ) y OC(O)R aa or -(CR) cc R dd ) y OP(O)(OR aa )2, preferably hydrogen, methyl, ethyl, , or R is preferred. 3a For hydrogen, R 3b R4 is methyl.

[0022] In a further preferred embodiment of the invention, when present, R aa R bb R cc and R dd Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-10 Cycloalkyl, preferably hydrogen, deuterium, methyl, ethyl, tert-butyl or adamantyl.

[0023] In a further preferred embodiment of the present invention, m is 0, 1 or 2, preferably 0.

[0024] In a further preferred embodiment of the present invention, n is 1 or 2, preferably 1.

[0025] In a further preferred embodiment of the present invention, y is an integer from 0 to 3, preferably 0, 1 or 2.

[0026] In a further preferred embodiment of the present invention, Formula I is further shown as Formula II:

[0027]

[0028] in:

[0029] X3 is either O or S;

[0030] R2 is deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C3-8 Cycloalkyl groups, preferably deuterium, halogens, or C464. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy or C 3-6 Cycloalkyl, more preferably deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, -CD3, -CHF2 or -CH2F;

[0031] R1, R 3a R 3b R4 and m are as described above.

[0032] In a further preferred embodiment of the invention, formula II is further shown as in formula II-A or II-B:

[0033] or

[0034] in:

[0035] X3, R1, R2, R 3a R 3b R4 and m are as described above.

[0036] In a further preferred embodiment of the present invention, Formula I is further shown as in Formula III:

[0037]

[0038] in:

[0039] X3 is either O or S;

[0040] R2 is deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl groups, preferably deuterium, halogens, or C464. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy or C 3-6Cycloalkyl, more preferably deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, -CD3, -CHF2 or -CH2F.

[0041] In a further preferred embodiment of the invention, Formula III is further shown as in Formula III-A or III-B:

[0042] or

[0043] in:

[0044] X3 is either O or S;

[0045] R2 is deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl groups, preferably deuterium, halogens, or C464. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy or C 3-6 Cycloalkyl, more preferably deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, -CD3, -CHF2 or -CH2F.

[0046] In a further preferred embodiment of the present invention, Formula I is further shown as in Formula IV:

[0047]

[0048] in:

[0049] R2 is deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl groups, preferably deuterium, halogens, or C464. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3Halogenated alkoxy or C 3-6 Cycloalkyl, more preferably deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, -CD3, -CHF2 or -CH2F.

[0050] In a further preferred embodiment of the invention, formula IV is further shown as in formula IV-A or IV-B:

[0051] or

[0052] in:

[0053] R2 is deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl groups, preferably deuterium, halogens, or C464. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy or C 3-6 Cycloalkyl, more preferably deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, -CD3, -CHF2 or -CH2F.

[0054] In a further preferred embodiment of the present invention, the compound has any of the following structures:

[0055]

[0056]

[0057]

[0058] The present invention also provides a method for preparing a compound of formula I, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0059]

[0060] Among them, X3, R1, R2, R 3a R 3b R4, m, and n are as described above.

[0061] Lg is a suitable leaving group, preferably a halogen, and more preferably fluorine or chlorine.

[0062] Compounds of Formula I-1 and Formula I-2 are commercially available or can be prepared by the methods described herein or other methods known to those skilled in the art.

[0063] Compound I can be prepared by coupling compound I-1 with compound I-2 under suitable conditions. For example, coupling can be carried out by mixing compound I-1 and compound I-2 at room temperature or by heating in a suitable solvent such as dimethyl sulfoxide (DMSO) in the presence of a base such as Cs₂CO₃. Alternatively, coupling with a metal catalyst (e.g., using a palladium or copper catalyst) can be used to carry out the above coupling.

[0064] The present invention also provides a method for preparing the compound of formula II, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0065]

[0066] in:

[0067] LG is a suitable leaving group, preferably halogen, more preferably fluorine or chlorine;

[0068] X3, R1, R2, R 3a R 3b R4 and m are as described above.

[0069] Compounds of Formula II-1 and II-2 are commercially available or can be prepared by the methods described herein or other methods known to those skilled in the art.

[0070] Compound II can be prepared by coupling compound II-1 with compound II-2 under suitable conditions. For example, coupling can be carried out by mixing compound II-1 and compound II-2 at room temperature or by heating in a suitable solvent such as dimethyl sulfoxide (DMSO) in the presence of a base such as Cs₂CO₃. Alternatively, coupling with a metal catalyst (e.g., using a palladium or copper catalyst) can be used to carry out the above coupling.

[0071] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound of formula I, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0072] In some preferred embodiments of the invention, the pharmaceutical composition may be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, non-enteric administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of an external implantation device, wherein oral, intraperitoneal, or intravenous administration is preferred.

[0073] When administered orally, the compounds of this application can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Tablets typically use carriers including lactose and corn starch, and lubricants such as magnesium stearate may also be added. Capsule formulations typically use diluents including lactose and dried corn starch. Aqueous suspension formulations usually involve mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or colorings may also be added to the above oral dosage forms.

[0074] As tablets, including but not limited to lozenges, sublingual tablets, oral patches, chewable tablets, dispersible tablets, effervescent tablets, immediate-release or sustained-release or controlled-release tablets, and enteric-coated tablets.

[0075] When used topically, especially for treating affected areas or organs that are easily accessible through topical application, such as the eyes, skin, or lower ileus, the compounds of this application can be formulated into different topical formulations depending on the affected area or organ, as detailed below.

[0076] When applied topically to the eye, the compounds of this application can be formulated as a micronized suspension or solution, using an isotonic sterile saline solution of a specific pH as the carrier, with or without preservatives such as benzyl alkyl chloride. For ophthalmic use, the compounds can also be formulated as an ointment, such as petrolatum.

[0077] When applied topically to the skin, the compounds of this application can be formulated into suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified waxes, and water; carriers that may be used in lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0078] The present invention also provides the use of compounds represented by the various general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of dopamine D1-like receptor-mediated diseases.

[0079] The present invention also provides the use of compounds represented by the various general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of neurological diseases.

[0080] The present invention also relates to a method for treating dopamine D1-like receptor-mediated diseases, comprising administering to a mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

[0081] The present invention also relates to treatment methods for neurological diseases, comprising administering to mammals a therapeutically effective amount of the compound of the present invention, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the present invention also provides a method for treating dopamine D1-like receptor-mediated diseases in mammals. The method comprises administering to the mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

[0083] In a further preferred embodiment of the invention, the dopamine D1-like receptor is a D1 and / or D5 receptor. The present invention seeks protection for the preparation of D1 / D5 agonists or partial agonists.

[0084] In some embodiments of the present invention, the related diseases are selected from schizophrenia, cognitive impairment, attention deficit hyperactivity disorder, impulsivity, compulsive gambling, overeating, autism spectrum disorder, dementia, restless legs syndrome, Parkinson's disease, mild cognitive impairment, age-related cognitive decline, major depressive disorder, treatment-resistant depression, postpartum depression, Alzheimer's disease, Huntington's disease, anxiety, depression, bipolar disorder, chronic apathy, loss of interest, chronic fatigue, post-traumatic stress disorder, and seasonal affective disorder. Social anxiety disorder, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette syndrome, tardive dyskinesia, somnolence, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction, migraine, systemic lupus erythematosus, hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, renal tubular necrosis after ischemia, renal failure, hyponatremia, refractory edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, and pain (one or more of these).

[0085] In a further preferred embodiment of the present invention, the related diseases are selected from one or more of the following: schizophrenia, cognitive impairment, dementia, Parkinson's disease, mild cognitive impairment, age-related cognitive decline, major depressive disorder, treatment-resistant depression, postpartum depression, and Alzheimer's disease dementia.

[0086] Detailed Description of the Invention

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0088] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, more preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethyl... The following compounds are used: 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, n-undecyl or n-pentadecanyl, and their various branched isomers; preferably methyl, ethyl, n-propyl or isopropyl. The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, cyano, amino or carboxyl; preferably fluorine, chlorine or bromine.

[0089] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include: vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. The alkenyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable connection point, preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, cyano, amino, or carboxyl.

[0090] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. The alkynyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linker. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, cyano, amino, or carboxyl.

[0091] The term "aryl" refers to a monocyclic group with a conjugated π-electron system (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl), having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group preferably has 6 to 10 carbon atoms (i.e., C64). 6-10 Aryl), more preferably phenyl or naphthyl, and even more preferably phenyl. The monocyclic aryl group is, for example, phenyl (-Ph). Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthrene, etc. The aryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker, preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or carboxyl.

[0092] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12). 3-12 cycloalkyl), more preferably having 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) carbon atoms, i.e., C 3-8 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 6 carbon atoms (i.e., C64). 3-6 cycloalkyl groups), most preferably cycloalkyl groups having 3 to 5 carbon atoms (i.e., C14-C5 ... 3-5 Cycloalkyl groups), or cycloalkyl groups having 5 to 6 carbon atoms (i.e., C1646). 5-6(Cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, adamantyl, and cyclooctyl, etc.; preferably cyclopropyl or adamantyl. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, halogen, hydroxyl, amino, cyano, or oxo.

[0093] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic group) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heterocyclic group comprises heteroatoms (where m and n are integers from 0 to 2), excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. The heterocyclic group preferably has 3 to 12 ring atoms (i.e., a 3-12 membered heterocyclic group), including 1 to 4 heteroatoms selected from N, O, and S atoms; more preferably, it has 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring atoms (i.e., a 3-8 membered heterocyclic group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) nThe heterocyclic group comprises heteroatoms (where m and n are integers from 0 to 2), but excludes the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. The heterocyclic group preferably has 3 to 6 ring atoms (i.e., a 3-6 membered heterocyclic group), containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S atoms; most preferably, it has 5 to 6 ring atoms (i.e., a 5-6 membered heterocyclic group), containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S atoms. Non-limiting examples of the monocyclic heterocyclic group include piperidinyl, piperazineyl, and morpholinyl groups. Non-limiting examples of the polycyclic heterocyclic group include spirocyclic, fused heterocyclic, and bridged heterocyclic groups. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, halogen, hydroxyl, amino, cyano, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0094] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a 5-10 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S, more preferably a 5-6 membered monocyclic heteroaryl group containing 1-3 heteroatoms independently selected from N, O, and S, or a 9-10 membered fused-ring heteroaryl group containing 1-3 heteroatoms independently selected from N, O, and S. The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group). Non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group with a 5-6 membered heteroaryl group or a 5-10 membered heteroaryl group with a C-shaped ring. 6-10 Aryl or C 6-10Aryl 5-10-membered heteroaryl, more preferably 5-6-membered heteroaryl 5-6-membered heteroaryl, 5-6-membered heteroaryl phenyl or phenyl 5-6-membered heteroaryl, non-limiting examples include: indolyl, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, carbazoyl, benzimidazolyl, benzothiophene, thiophene-phenyl, benzothiozolyl, thiophene-pyridyl, pyridothiophene, pyridopyrroleyl, pyrimidinothiophene, thiophene-pyrimidinyl, pyrimidinofuranyl, furan-pyrimidinyl, etc. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, halogen, hydroxyl, amino, cyano, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0095] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0096] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2 -Chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl; more preferably difluoromethyl or trifluoromethyl.

[0097] The term “deuterated alkyl” refers to an alkyl group that is substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0098] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C2). 1-10Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups), more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups), preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.; preferably methoxy or ethoxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable linking point, preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or carboxyl.

[0099] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples of halomethoxy groups include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, and trifluoromethoxy. Non-limiting examples of halogenated ethoxy groups include: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, etc.

[0100] The term "carboxyl group" refers to -COOH.

[0101] The term "hydroxyl group" refers to -OH.

[0102] The term "amino" refers to -NH2.

[0103] The term "cyano" refers to -CN.

[0104] The term "nitro" refers to -NO2.

[0105] The term "oxo" or "oxo group" refers to =O.

[0106] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0107] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0108] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0109] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0110] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C 2-8 "Covering a range of 2-8 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..." 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, stating "C1-C6" or "C..." 1-6"The term 'covers' the range of 1-6 carbon atoms and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression 'ternary to decaary' should be understood to include any subrange within this range and each point value, such as ternary to pentary, ternary to hexaary, ternary to octary, quaternary to pentary, quaternary to hexaary, quaternary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, octary to octary, quinary to decaary, etc., and tri-, quadri-, quinary, quinary, quinary, quinary, octary, quinary, octary, quinary, decaary, etc. Other similar expressions in this text should also be understood in a similar manner."

[0111] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0112] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes both cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0113] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a chosen substituent from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing the optional substitution of each carbon atom in a group with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in the present case and that a stable compound is formed.

[0114] If a substituent is described as "optionally...substituted," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be substituted by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "unsubstituted." Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0115] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0116] When any variable (e.g., R), and variables with labels (e.g., R0, R1, R...) 1a R 1b R2, R3, R 3a R 3b R4, R aa R bb R cc R dd R ee When a group (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each instance. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each instance are independent of each other.

[0117] The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds of this invention, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art. The terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other. The terms "cis-trans isomers" or "geometric isomers" arise from the fact that double bonds or single bonds on cyclic carbon atoms cannot rotate freely. The term "diastereomers" refers to stereoisomers of molecules with two or more chiral centers, and where the molecules are not mirror images of each other. The terms "(D)" or "(+)" indicate dextrorotatory, "(L)" or "(-)" indicate levorotatory, and "(DL)" or "(±)" indicate racemic. The terms "tautomers" or "tautomeric forms" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers, also known as prototropic tautomers, include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions resulting from the rearrangement of bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.The compounds of the present invention all include two enantiomers, P1 and P2. For example, 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 1) includes (+) 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 1-P1) and (-) 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 1-P2), which is a mixture of compound 1-P1 and compound 1-P2.

[0118] The compounds of this invention include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes suitable for inclusion in the compounds of this invention (including their salts) include isotopes of the following elements: hydrogen, for example... 2 H and 3 H, carbon, for example 11 C 13 C and 14 C, chlorine, for example 36 C1, fluorine, for example 18 F, iodine, for example 123 I and 125 I, nitrogen, for example 13 N and 15 N, oxygen, for example 15 O、 17 O and 18 O, phosphorus, for example 32 P, sulfur, for example 35 S. Using heavier isotopes (e.g., deuterium, i.e.) 2 H) substitution can impart some therapeutic advantages due to its greater metabolic stability, such as an increased in vivo half-life or a reduced dose requirement, and may therefore be preferred in some cases. Isotopically labeled compounds of formula I (including their salts) can typically be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the examples and preparations described below, using a suitable isotopically labeled reagent to replace the previously used unlabeled reagent.

[0119] All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete, and partial deuterium substitution means that at least one hydrogen atom is replaced by at least one deuterium atom.

[0120] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0121] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0122] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, as well as other components such as physiologically / pharmaceutical acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0123] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0124] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0125] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0126] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0127] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0128] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0129] As used herein, “individual” includes humans or non-human animals. Exemplary human individuals include individuals with a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0130] The term “room temperature” or its abbreviation “RT” or “RT” refers to a temperature of 10-40°C. In some embodiments, “room temperature” refers to a temperature of 15-30°C; in other embodiments, “room temperature” refers to a temperature of 18-25°C.

[0131] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, with the basic raw material used in each step as a reference (1 equivalent).

[0132] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the terms "about" or "approximately" mean within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0133] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application.

[0134] In some embodiments, compounds of Formula I (including their salts) may exist as trans-restricted isomers and / or be isolated as trans-restricted isomers (e.g., one or more trans-restricted enantiomers). Those skilled in the art will recognize that trans-restricted enantiomerism can occur in compounds having two or more aromatic rings (e.g., two aromatic rings linked by a single bond).

[0135] Beneficial technical effects

[0136] This invention discloses a novel class of D1-like receptor agonist compounds with aromatic heterocyclic structures. These compounds can be used to treat and / or prevent neurological disorders, such as schizophrenia, cognitive impairment, mild cognitive impairment, age-related cognitive decline, dementia, and Parkinson's disease, providing new options for the treatment or mitigation of these diseases. In particular, these compounds exhibit good anti-Parkinson's disease effects.

[0137] In some embodiments, the compounds shown herein exhibit good agonistic activity against D1 and / or D5 receptors. In some embodiments, the compounds shown herein exhibit good affinity for the D1 receptor. In some embodiments, the compounds of the present invention exhibit favorable pharmacokinetic properties (e.g., suitable half-life and duration of action, favorable plasma concentrations, area under the curve, and / or bioavailability). In some embodiments, the compounds of the present invention exhibit favorable in vivo efficacy.

[0138] Specifically, compared to compounds known in the prior art, the present disclosure has the following effect on the EC function of D1 and / or D5 receptors: 50The assay results show that the compound of the present invention has a significant activating effect on D1 and / or D5 receptors, and is an effective D1 and / or D5 agonist. The D1 receptor binding capacity test results show that the compound of the present invention has a strong binding capacity to the D1 receptor, exhibiting a strong affinity for the D1 receptor. In vitro liver microsomal stability assay results show that the compound of the present invention has good stability in liver microsomes of different species (human, cynomolgus monkey, dog, and rat), especially in human liver microsomes. In vivo pharmacokinetic experiments in cynomolgus monkeys show that the compound of the present invention exhibits a suitable half-life and good exposure after oral administration, demonstrating good pharmacokinetic properties. Pharmacodynamic experiments in a reserpine-induced Parkinson's model show that the compound of the present invention significantly increases spontaneous activity in mice after oral administration, has a lower half-maximal effective dose (LD50), and exhibits a stronger pharmacodynamic effect. Detailed Implementation

[0139] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0140] Example

[0141] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0142] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE III 400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as the internal standard.

[0143] The determinations were performed using liquid chromatography-mass spectrometry (LC-MS) on a Shimadzu LCMS2020 mass spectrometer (Japan). The determinations were performed using a Shimadzu LC20A liquid chromatograph (Japan).

[0144] Reversed-phase chromatography column: Luknova C18, 50 μm, 100 Å, 20–150 g.

[0145] Biotage 40-63 μm normal phase chromatography column, 5~80 g.

[0146] The silica gel plates used for thin-layer chromatography are from Yantai Jiangyou. The TLC specification is 0.2mm±0.03mm, and the specification used for thin-layer chromatography separation and purification products is 0.4mm-0.5mm.

[0147] Example 1:

[0148] Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 1)

[0149]

[0150]

[0151] Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H, 3H)-diketone hydrochloride (compound C1)

[0152] A methanol solution of sodium methoxide (5.4 M, 3.5 mL, 1.2 eq) was added to a solution of ethyl 2-cyanopropionate (2 g, 1.0 eq) and methylurea (1.28 g, 1.1 eq) in methanol (15 mL). The reaction mixture was refluxed and heated for 18 hours, then cooled to room temperature. After removing the solvent under vacuum, the residue was reacted with acetonitrile (3... The mixture was repeatedly evaporated under reduced pressure (10 mL) and then partitioned between acetonitrile (20 mL) and water (20 mL). A 6 M hydrochloric acid aqueous solution was slowly added until the pH reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected by filtration and washed with tert-butyl methyl ether to give the product as a white solid. Yield: 1.98 g, 81%. LCMS m / z: 156.1.

[0153] Step 2. Synthesis of 6-bromo-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound C2)

[0154] A 1:1 mixture of acetonitrile and water (24 mL) was added to a mixture of compound C1 (1.8 g, 1.0 eq), sodium nitrite (0.98 g, 1.5 eq), and copper(II) bromide (4.2 g, 2.0 eq). The reaction mixture was stirred at room temperature for 48 hours. An aqueous solution of sulfuric acid (1 N, 40 mL) and ethyl acetate (20 mL) were added, resulting in a precipitate. The precipitate was collected by filtration and washed with water and ethyl acetate to give the product as a pale yellow solid (1.26 g). Overall yield: 1.26 g, 62%. LCMS m / z: 220.1.

[0155] Step 3. Synthesis of methyl neopentanoate (compound C3) of (4-bromo-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0156] To a mixture of C2 (2 g, 1.0 eq) and methyl tertivarate (2.1 g, 1.5 eq) in acetonitrile (40 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.1 g, 1.5 eq) was added, and the reaction mixture was stirred at 60 °C for 18 hours. After concentrating the mixture under vacuum, the residue was diluted with water (50 mL) and then with ethyl acetate (3... Extracted by 30 mL. The combined organic layers were concentrated; purified by silica gel chromatography (gradient: 20%–50% ethyl acetate in petroleum ether) to give the product as a white solid. Yield: 2.9 g, 91%. LCMS m / z: 334.1.

[0157] Step 4. Synthesis of methyl neopentanoate (compound C4) of (4-(4-(benzyloxy)-2-methylphenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0158] (4-(benzyloxy)-2-methylphenyl)boronic acid (1.0 g, 1.5 eq) was added to a solution of C3 (0.92 g, 1.0 eq) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.3 g, 0.15 eq) in 15 mL of dioxane, followed by the addition of cesium carbonate (2.69 g, 3.0 eq). The reaction mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was diluted with water (50 mL) and then with ethyl acetate (3... Extracted (30 mL). The combined organic layers were concentrated; purified by silica gel chromatography (gradient: 20%–50% ethyl acetate in petroleum ether) to give the product. Yield: 1.05 g, 85%. LCMS m / z: 451.5.

[0159] Step 5. Synthesis of methyl neopentanoate (4-(4-hydroxy-2-methylphenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) (compound C5)

[0160] Compound C4 (1.0 g) was added to a methanol (50 mL) solution of palladium hydroxide (0.1 g), and the reaction was stirred at room temperature for 24 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product. Yield: 0.72 g, 90%. LCMS m / z: 361.4.

[0161] Step 6. Synthesis of 6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C6)

[0162] Compound C5 (0.5 g, 1.0 eq) was added to a methanol (10 mL) solution of sodium hydroxide (0.08 g, 1.5 eq), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was diluted with water (15 mL) and then with ethyl acetate (3... Extracted (10 mL). The combined organic layers were concentrated; purified by silica gel chromatography (gradient: 20%–50% ethyl acetate in petroleum ether) to give the product. Yield: 0.29 g, 85%. LCMS m / z: 247.2.

[0163] Step 7. Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 1)

[0164] Compound C6 (0.2 g, 1.0 eq) was added to a solution of cesium carbonate (0.8 g, 3.0 eq) in dimethyl sulfoxide (6 mL), followed by 4-chlorofurano[2,3-d]pyrimidine (0.19 g, 1.5 eq). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (15 mL) and ethyl acetate (3 mL) were added. Extracted with 10 mL of ethyl acetate. The combined organic layers were concentrated to obtain the crude product; the crude product was added to ethyl acetate (2 mL) and stirred at room temperature for 1 hour, filtered, and washed with ethyl acetate to obtain the product. Yield: 0.22 g, 75%.

[0165] LCMS m / z: 365.4. 1 H-NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.54 (d, J =6.1 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.25 (dd, J = 7.8, 2.4 Hz, 2H), 7.19(d, J = 8.2 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 3.07 (s, 3H), 2.23 (s, 3H), 1.69 (s, 3H).

[0166] (+)-6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 1-P1) and (-)-6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 1-P2)

[0167]

[0168] Compound 1 was separated into compounds 1-P1 and 1-P2 by axial chiral separation using supercritical carbon dioxide chromatography.

[0169] Compound 1-P1:

[0170] LCMS m / z: 365.4. 1 H-NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 8.52 (d, J =6.1 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 7.8, 2.4 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.68 (s, 3H).

[0171] Compound 1-P2:

[0172] LCMS m / z: 365.4. 1 H-NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.55 (d, J =6.1 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.24 (dd, J = 7.8, 2.4 Hz, 2H), 7.18(d, J = 8.2 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 3.08 (s, 3H), 2.24 (s, 3H), 1.69 (s, 3H).

[0173] Example 2:

[0174] Synthesis of 6-(4-(thieno[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 2)

[0175]

[0176] Following the method used to synthesize compound 1 in Example 1, compound C6 and 4-chlorothiophene[2,3-d]pyrimidine were reacted to yield the target product. Yield: 0.24 g, 73%.

[0177] LCMS m / z: 381.4. 1 H-NMR (400 MHz, CDCl3): δ 8.99 (s, 1H), 8.65 (s, 1H), 7.57 – 7.53 (m, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 3.08(s, 3H), 2.24 (s, 3H), 1.69 (s, 3H).

[0178] Example 3:

[0179] Synthesis of 6-(2-fluoro-4-(furano[2,3-d]pyrimidin-4-ylmethyl)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 3)

[0180]

[0181]

[0182] Step 1. Synthesis of methyl neopentanoate (compound C7) of (4-(4-(benzyloxy)-2-fluorophenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0183] (4-(benzyloxy)-2-fluorophenyl)boronic acid (1.1 g, 1.5 eq) was added to a solution of compound C3 (0.92 g, 1.0 eq) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.3 g, 0.15 eq) in dioxane (15 mL), followed by the addition of cesium carbonate (2.69 g, 3.0 eq). The reaction mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was diluted with water (50 mL) and then with ethyl acetate (3... Extracted by 30 mL. The combined organic layers were concentrated; purified by silica gel chromatography (gradient: 20%–50% ethyl acetate in petroleum ether) to give the product. Yield: 1.0 g, 80%. LCMS m / z: 483.5.

[0184] Step 2. Synthesis of methyl neopentanoate (compound C8) of (4-(4-hydroxy-2-fluorophenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0185] Compound C7 (1.0 g) was added to a methanol (50 mL) solution of palladium hydroxide (0.1 g), and the reaction was stirred at room temperature for 24 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product. Yield: 0.70 g, 88%. LCMS m / z: 365.4.

[0186] Step 3. Synthesis of 6-(4-hydroxy-2-fluorophenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound C9)

[0187] Compound C8 (0.5 g, 1.0 eq) was added to a methanol (10 mL) solution of sodium hydroxide (0.08 g, 1.5 eq), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was diluted with water (15 mL) and then with ethyl acetate (3... Extracted by 10 mL. The combined organic layers were concentrated; purified by silica gel chromatography (gradient: 20%–50% ethyl acetate in petroleum ether) to give the product. Yield: 0.32 g, 90%. LCMS m / z: 250.2.

[0188] Step 4. Synthesis of 6-(2-fluoro-4-(furano[2,3-d]pyrimidin-4-ylmethyl)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 3)

[0189] Compound C9 (0.2 g, 1.0 eq) was added to a solution of cesium carbonate (0.8 g, 3.0 eq) in dimethyl sulfoxide (6 mL), followed by 4-chlorofurano[2,3-d]pyrimidine (0.13 g, 1.5 eq). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (15 mL) and ethyl acetate (3 mL) were added. Extracted with 10 mL. The combined organic layers were concentrated to obtain the crude product; the crude product was added to ethyl acetate (2 mL) and stirred at room temperature for 1 hour, filtered, and washed with ethyl acetate to obtain the product. Yield: 0.22 g, 76%.

[0190] LCMS m / z: 369.4. 1H-NMR (400 MHz, CDCl3): 9.06 (s, 1H), 8.55 – 8.46 (m,1H), 7.69 (dd, J = 19.0, 2.5 Hz, 1H), 7.27 – 7.21 (m, 2H), 7.20 – 7.19 (m,1H), 6.88 (d, J = 2.5 Hz, 1H), 3.10 (s, 3H), 1.74 – 1.69 (m, 3H).

[0191] Example 4:

[0192] Synthesis of 6-(2-chloro-4-(furano[2,3-d]pyrimidin-4-ylmethyl)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 4)

[0193]

[0194] It was prepared according to the method used to synthesize compound 3 in Example 3. LCMS m / z: 385.1.

[0195] Example 5:

[0196] Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-oxy)-2-trifluoromethyl-phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 5)

[0197]

[0198]

[0199] Step 1. Synthesis of methyl neopentanoate (4-(4-(benzyloxy)phenyl)-2-trifluoromethyl-phenyl)3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)neopentaate (compound C10)

[0200] (4-(benzyloxy)-2-trifluoromethylphenyl)boronic acid (0.54 g, 1.2 eq) was added to a toluene (4 mL) solution of compound C3 (0.50 g, 1.0 eq), followed by a cesium carbonate (1.47 g, 3.00 eq) solution in purified water (2 mL), and tris(dibenzylacetone)dipalladium(0) (0.05 g, 0.03 eq). The reaction mixture was stirred at 84 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, separated, and the organic layer was concentrated under vacuum. The product was purified by silica gel chromatography (gradient: 0%–17.1% ethyl acetate in petroleum ether solution) to obtain the product. Yield: 0.54 g, 71%. LCMS m / z: 505.2.

[0201] Step 2. Synthesis of methyl neopentanoate (compound C11) of (4-(2-trifluoromethyl-4-hydroxyphenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0202] Compound C10 (0.54 g) was added to a solution of 10% palladium hydroxide on carbon (0.05 g) in methanol (8 mL) and dichloromethane (4 mL), and the mixture was stirred at 30–35 °C for 5 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product. Yield: 0.41 g, 93%. LCMS m / z: 415.1.

[0203] Step 3. Synthesis of 6-(2-trifluoromethyl-4-hydroxyphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound C12)

[0204] Potassium carbonate (0.68 g, 5.00 eq) was added to a methanol (8 mL) solution of compound C11 (0.41 g, 1.00 eq), and the mixture was stirred at 30–35 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was diluted with water (8 mL), and 0.40 mL of concentrated hydrochloric acid was added dropwise under ice bath conditions until the pH reached approximately 7. Then, 0.15 mL of ethyl acetate was added, and the mixture was stirred for 0.5 hours. The product was collected by filtration and washed with water. Yield: 0.21 g, 70%. LCMS m / z: 301.1.

[0205] Step 4. Synthesis of 6-[4-(furano[2,3-d]pyrimidin-4-oxy)-2-trifluoromethylphenyl]-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 5)

[0206] Compound C12 (0.21 g, 1.0 eq) was added to a solution of cesium carbonate (0.46 g, 2.0 eq) in dimethyl sulfoxide (3 mL), followed by 4-chlorofurano[2,3-d]pyrimidine (0.13 g, 1.2 eq). The reaction mixture was stirred at 45–50 °C for 1.5 h. After the reaction was complete, the mixture was cooled to room temperature, and water (6 mL) was added. 0.50 mL of concentrated hydrochloric acid was added dropwise until the pH reached approximately 7. The mixture was collected by filtration, washed with water, and dried at 65 °C for 12 h to obtain the crude product. The crude product was then slurried with ethyl acetate (2.0 mL), stirred at room temperature for 1 h, filtered, and washed with ethyl acetate to obtain the product. Yield: 0.19 g, 68%.

[0207] LCMS m / z: 406.1. 1H-NMR (400 MHz, CDCl3): 9.09 (s, 1H), 8.56 (s, 1H), 7.43 – 7.35 (m, 4H), 3.13 (s, 3H), 2.71 (s, 3H), 1.77 (s, 3H).

[0208] Example 6:

[0209] 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-(methyl- d 3) Synthesis of phenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound 6)

[0210]

[0211] It was prepared according to the method used to synthesize compound 1 in Example 1. LCMS m / z: 368.1.

[0212] Example 7:

[0213] Synthesis of 6-(2-(fluoromethyl)-4-(furano[2,3-d]pyrimidin-4-yloxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 7)

[0214]

[0215] It was prepared according to the method used to synthesize compound 5 in Example 5. LCMS m / z: 383.1.

[0216] Example 8:

[0217] Synthesis of 6-(2-(difluoromethyl)-4-(furano[2,3-d]pyrimidin-4-yloxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 8)

[0218]

[0219] It was prepared according to the method used to synthesize compound 5 in Example 5. LCMS m / z: 401.1.

[0220] Example 9:

[0221] Synthesis of 6-(2-ethyl-4-(furano[2,3-d]pyrimidin-4-yloxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 9)

[0222]

[0223] It was prepared according to the method used to synthesize compound 1 in Example 1. LCMS m / z: 379.1.

[0224] Example 10:

[0225] Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-propylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 10)

[0226]

[0227] It was prepared according to the method used to synthesize compound 1 in Example 1. LCMS m / z: 393.2.

[0228] Example 11:

[0229] Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-yloxy)-2-isopropylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 11)

[0230]

[0231] It was prepared according to the method used to synthesize compound 1 in Example 1. LCMS m / z: 393.2.

[0232] Example 12:

[0233] Synthesis of 6-(2-cyclopropyl-4-(furano[2,3-d]pyrimidin-4-yloxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 12)

[0234]

[0235] It was prepared according to the method used to synthesize compound 1 in Example 1. LCMS m / z: 391.1.

[0236] Example 13:

[0237] Synthesis of 6-(2-bromo-4-(furano[2,3-d]pyrimidin-4-ylmethyl)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 13)

[0238]

[0239] It was prepared according to the method used to synthesize compound 3 in Example 3. LCMS m / z: 429.1.

[0240] Example 14:

[0241] Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-ylmethyl)-2-methoxyphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 14)

[0242]

[0243] It was prepared according to the method used to synthesize compound 1 in Example 1. LCMS m / z: 381.1.

[0244] Example 15:

[0245] Synthesis of 6-(3-fluoro-4-(furano[2,3-d]pyrimidin-4-oxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 15)

[0246]

[0247]

[0248] Step 1. Synthesis of methyl neopentanoate (4-(4-(benzyloxy)phenyl)-3-fluorophenyl)3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)neopentaate (compound C13)

[0249] (4-(benzyloxy)-3-fluorophenyl)boronic acid (0.89 g, 1.2 eq) was added to a toluene (8 mL) solution of C3 (1.00 g, 1.0 eq), followed by a cesium carbonate (2.94 g, 3.00 eq) solution in purified water (4 mL), and then tris(dibenzylacetone)dipalladium (0) (0.10 g, 0.03 eq). The reaction mixture was stirred at 84 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, separated, and the organic layer was concentrated under vacuum. The product was purified by silica gel chromatography (gradient: 0%–14.4% ethyl acetate in petroleum ether solution) to obtain the product. Yield: 1.19 g, 87%. LCMS m / z: 455.2.

[0250] Step 2. Synthesis of methyl neopentanoate (4-(3-fluoro-4-hydroxyphenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) (compound C14)

[0251] Compound C13 (1.19 g) was added to a 10% palladium hydroxide solution on carbon (0.12 g) in methanol (15 mL) and dichloromethane (10 mL). The mixture was stirred at 30–35 °C for 5 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product. Yield: 0.69 g, 73%. LCMS m / z: 365.1.

[0252] Step 3. Synthesis of 6-(3-fluoro-4-hydroxyphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound C15)

[0253] Potassium carbonate (1.31 g, 5.00 eq) was added to a methanol (25 mL) solution of compound C14 (0.69 g, 1.00 eq), and the mixture was stirred at 30–35 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was diluted with water (20 mL), and 2.50 mL of concentrated hydrochloric acid was added dropwise under ice bath conditions until the pH reached approximately 7. Then, 0.50 mL of ethyl acetate was added, and the mixture was stirred for 0.5 hours. The product was collected by filtration and washed with water. Yield: 0.35 g, 73%. LCMS m / z: 251.1.

[0254] Step 4. Synthesis of 6-(3-fluoro-4-(furano[2,3-d]pyrimidin-4-oxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 15)

[0255] Compound C15 (0.35 g, 1.0 eq) was added to a solution of cesium carbonate (0.90 g, 2.0 eq) in dimethyl sulfoxide (8 mL), followed by 4-chlorofurano[2,3-d]pyrimidine (0.26 g, 1.2 eq). The reaction mixture was stirred at 45–50 °C for 1.5 h. After the reaction was complete, the mixture was cooled to room temperature, and water (16 mL) was added. 0.60 mL of concentrated hydrochloric acid was added dropwise until the pH reached approximately 7. The mixture was collected by filtration, washed with water, and dried at 65 °C for 12 h to obtain the crude product. The crude product was then slurried with ethyl acetate (2 mL), stirred at room temperature for 1 h, filtered, and washed with ethyl acetate to obtain the product. Yield: 0.38 g, 75%.

[0256] LCMS m / z: 369.1. 1 H-NMR (400 MHz, DMSO-d6): 11.49 (s, 1H), 8.59 (s,1H), 8.26 (d, J = 2.6 Hz, 1H), 7.62 (dd, J = 10.8, 2.0 Hz, 1H), 7.39 – 7.32 (m,1H), 7.26 (d, J = 2.6 Hz, 1H), 2.96 (s, 3H), 1.56 (s, 3H).

[0257] Example 16:

[0258] Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-oxy)-3-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 16)

[0259]

[0260]

[0261] Step 1. Synthesis of methyl neopentanoate (4-(4-(benzyloxy)phenyl)-3-methylphenyl)3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)neopentaate (compound C16)

[0262] (4-(benzyloxy)-3-methylphenyl)boronic acid (0.87 g, 1.2 eq) was added to a toluene (8 mL) solution of compound C3 (1.00 g, 1.0 eq), followed by a cesium carbonate (2.94 g, 3.00 eq) solution in purified water (4 mL), and tris(dibenzylacetone)dipalladium(0) (0.10 g, 0.03 eq). The reaction mixture was stirred at 84 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, separated, and the organic layer was concentrated under vacuum. The product was purified by silica gel chromatography (gradient: 0%–16.1% ethyl acetate in petroleum ether solution) to obtain the product. Yield: 0.63 g, 47%. LCMS m / z: 451.2.

[0263] Step 2. Synthesis of methyl neopentanoate (compound C17) of (4-(3-methyl-4-hydroxyphenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0264] Compound C16 (0.63 g) was added to a solution of 10% palladium hydroxide on carbon (0.06 g) in methanol (15 mL) and dichloromethane (10 mL), and the mixture was stirred at 30–35 °C for 5 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product. Yield: 0.46 g, 90%. LCMS m / z: 361.2.

[0265] Step 3. Synthesis of 6-(3-methyl-4-hydroxyphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound C18)

[0266] Potassium carbonate (0.88 g, 5.00 eq) was added to a methanol (15 mL) solution of compound C17 (0.46 g, 1.00 eq), and the mixture was stirred at 30–35 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was diluted with water (20 mL), and 1.60 mL of concentrated hydrochloric acid was added dropwise under ice bath conditions until the pH reached approximately 7. Then, 0.30 mL of ethyl acetate was added, and the mixture was stirred for 0.5 hours. The product was collected by filtration and washed with water. Yield: 0.27 g, 86%. LCMS m / z: 247.1.

[0267] Step 4. Synthesis of 6-(4-(furano[2,3-d]pyrimidin-4-oxy)-3-methylphenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 16)

[0268] Compound C18 (0.27 g, 1.0 eq) was added to a solution of cesium carbonate (0.72 g, 2.0 eq) in dimethyl sulfoxide (10 mL), followed by 4-chlorofurano[2,3-d]pyrimidine (0.20 g, 1.2 eq). The reaction mixture was stirred at 45–50 °C for 1.5 h. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added. 0.50 mL of concentrated hydrochloric acid was added dropwise until the pH reached approximately 7. The mixture was collected by filtration, washed with water, and dried at 65 °C for 12 h to obtain the crude product. The crude product was then slurried in ethyl acetate (2.0 mL), stirred at room temperature for 1 h, filtered, and washed with ethyl acetate to obtain the product. Yield: 0.36 g, 89%.

[0269] LCMS m / z: 365.1. 1 H-NMR (400 MHz, DMSO-d6): 11.45 (s, 1H), 8.56 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.42 – 7.40 (m, 1H), 7.31(dd, J = 8.2, 2.2 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 2.95 (s, 3H), 2.17 (s, 3H), 1.56 (s, 3H).

[0270] Example 17:

[0271] Synthesis of 6-(2,3-difluoro-4-(furano[2,3-d]pyrimidin-4-oxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 17)

[0272]

[0273]

[0274] Step 1. Synthesis of methyl neopentanoate (4-(4-(benzyloxy)phenyl)-2,3-difluorophenyl)3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)neopentaate (compound C19)

[0275] (4-(benzyloxy)-2,3-difluorophenyl)boronic acid (0.48 g, 1.2 eq) was added to a toluene (4 mL) solution of compound C3 (0.50 g, 1.0 eq), followed by a cesium carbonate (1.47 g, 3.00 eq) solution in purified water (2 mL), and tris(dibenzylacetone)dipalladium(0) (0.05 g, 0.03 eq). The reaction mixture was stirred at 84 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, separated, and the organic layer was concentrated under vacuum. The product was purified by silica gel chromatography (gradient: 0%–18.1% ethyl acetate in petroleum ether solution) to obtain the product. Yield: 0.46 g, 65%. LCMS m / z: 473.2.

[0276] Step 2. Synthesis of methyl neopentanoate (compound C20) of (4-(2,3-difluoro-4-hydroxyphenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0277] Compound C19 (0.46 g) was added to a solution of 10% palladium hydroxide on carbon (0.05 g) in methanol (9 mL) and dichloromethane (5 mL), and the mixture was stirred at 30–35 °C for 5 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product. Yield: 0.30 g, 81%. LCMS m / z: 383.1.

[0278] Step 3. Synthesis of 6-(2,3-difluoro-4-hydroxyphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound C21)

[0279] Potassium carbonate (0.54 g, 5.00 eq) was added to a methanol (10 mL) solution of compound C20 (0.30 g, 1.00 eq), and the mixture was stirred at 30–35 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was diluted with water (8 mL), and 0.40 mL of concentrated hydrochloric acid was added dropwise under ice bath conditions until the pH reached approximately 6. Then, 0.50 mL of ethyl acetate was added, and the mixture was stirred for 0.5 hours. The product was collected by filtration and washed with water. Yield: 0.13 g, 60%. LCMS m / z: 269.1.

[0280] Step 4. Synthesis of 6-(2,3-difluoro-4-(furano[2,3-d]pyrimidin-4-oxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 17)

[0281] Compound C21 (0.13 g, 1.0 eq) was added to a solution of cesium carbonate (0.31 g, 2.0 eq) in dimethyl sulfoxide (2 mL), followed by 4-chlorofurano[2,3-d]pyrimidine (0.09 g, 1.2 eq). The reaction mixture was stirred at 50-55 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (4 mL) was added. 0.30 mL of concentrated hydrochloric acid was added dropwise until the pH reached approximately 7. The mixture was collected by filtration, washed with water, and dried at 65 °C for 12 hours to obtain the crude product. The crude product was then slurried with ethyl acetate (1 mL), stirred at room temperature for 1 hour, filtered, and washed with ethyl acetate to obtain the product. Yield: 0.15 g, 79%.

[0282] LCMS m / z: 387.1. 1 H-NMR (400 MHz, CDCl3): 9.07 (s, 1H), 8.53 (s, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.32 (ddd, J = 8.5, 6.5, 1.9 Hz, 1H), 7.09 (ddd, J = 8.9,6.8, 2.2 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 3.18 (s, 3H), 1.78 (s, 3H).

[0283] Example 18:

[0284] Synthesis of 6-(3,5-difluoro-4-(furano[2,3-d]pyrimidin-4-oxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 18)

[0285]

[0286]

[0287] Step 1. Synthesis of methyl neopentanoate (4-(4-(benzyloxy)phenyl)-3,5-difluorophenyl)3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)neopentaate (compound C22)

[0288] (4-(benzyloxy)-3,5-difluorophenyl)boronic acid (0.48 g, 1.2 eq) was added to a toluene (4 mL) solution of compound C3 (0.50 g, 1.0 eq), followed by a cesium carbonate (1.47 g, 3.00 eq) solution in purified water (2 mL), and tris(dibenzylacetone)dipalladium(0) (0.05 g, 0.03 eq). The reaction mixture was stirred at 84 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, separated, and the organic layer was concentrated under vacuum. The product was purified by silica gel chromatography (gradient: 0%–18.1% ethyl acetate in petroleum ether solution) to obtain the product. Yield: 0.30 g, 42%. LCMS m / z: 473.2.

[0289] Step 2. Synthesis of methyl neopentanoate (compound C23) of (4-(3,5-difluoro-4-hydroxyphenyl)-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)

[0290] Compound C22 (0.30 g) was added to a solution of 10% palladium hydroxide on carbon (0.03 g) in methanol (4 mL) and dichloromethane (3 mL), and the mixture was stirred at 25–30 °C for 5 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product. Yield: 0.22 g, 92%. LCMS m / z: 383.1.

[0291] Step 3. Synthesis of 6-(3,5-difluoro-4-hydroxyphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (compound C24)

[0292] Potassium carbonate (0.40 g, 5.00 eq) was added to a methanol (7 mL) solution of compound C23 (0.22 g, 1.00 eq), and the mixture was stirred at 25–30 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was diluted with water (8 mL), and 0.60 mL of concentrated hydrochloric acid was added dropwise under ice bath conditions until the pH reached approximately 5. Then, 0.50 mL of ethyl acetate was added, and the mixture was stirred for 0.5 hours. The product was collected by filtration and washed with water. Yield: 0.03 g, 20%. LCMS m / z: 269.1.

[0293] Step 4. Synthesis of 6-(3,5-difluoro-4-(furano[2,3-d]pyrimidin-4-oxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 18)

[0294] Compound C24 (0.03 g, 1.0 eq) was added to a solution of cesium carbonate (0.07 g, 2.0 eq) in dimethyl sulfoxide (1 mL), followed by 4-chlorofurano[2,3-d]pyrimidine (0.02 g, 1.2 eq). The reaction mixture was stirred at 50-55 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (2 mL) was added. 0.05 mL of concentrated hydrochloric acid was added dropwise until the pH reached approximately 6. The mixture was collected by filtration, washed with water, and dried at 65 °C for 12 hours to obtain the crude product. The crude product was then slurried with ethyl acetate (1 mL), stirred at room temperature for 1 hour, filtered, and washed with ethyl acetate to obtain the product. Yield: 0.03 g, 67%.

[0295] LCMS m / z: 387.1. 1 H-NMR (400 MHz, DMSO-d6): 11.53 (s, 1H), 8.62 (s, 1H), 8.30 (d, J = 2.5 Hz, 1H), 7.59 – 7.51 (m, 2H), 7.34 (d, J = 2.5 Hz, 1H), 2.97 (s, 3H), 1.58 (s, 3H).

[0296] Example 19:

[0297] Synthesis of 6-(2,6-difluoro-4-(furano[2,3-d]pyrimidin-4-yloxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 19)

[0298]

[0299] It was prepared according to the method used to synthesize compound 18 in Example 18. LCMS m / z: 387.1.

[0300] Example 20:

[0301] Synthesis of 6-(2,6-dimethyl-4-(furano[2,3-d]pyrimidin-4-oxy)phenyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione (compound 20)

[0302]

[0303] It was prepared according to the method used to synthesize compound 18 in Example 18. LCMS m / z: 379.1.

[0304] Biological testing evaluation

[0305] The present invention is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0306] The chemical structure of Comparative Example 1 of the present invention is shown below, and it was prepared according to the method of Example 9 in International Patent Application WO2015162518A1.

[0307] .

[0308] Test Example 1: The compound of the present invention and its interaction with the D1 / D5 receptor function EC 50 Measurement

[0309] 1. Experimental objective:

[0310] The study investigated the functional activity of the compounds of this invention with D1 / D5 receptors.

[0311] 2. Test materials:

[0312] (1) Test sample: The compound of the present invention was prepared in-house.

[0313] (2) Experimental materials: CHO-K1 / D1 cells, self-constructed CHO-K1 / D1 cells; CHO-K1 / D5 cells (purchased from Genscript Biotech (M00322)).

[0314] Main reagent information

[0315]

[0316] (3) Information on main testing instruments

[0317]

[0318] 3. Experimental methods:

[0319] (1) Cells were cultured using CHO-K1 / D1 and CHO-K1 / D5 / Gα15. The cell suspension was added to a centrifuge tube containing 10 mL of HBSS buffer and centrifuged at 750 rpm for 5 minutes.

[0320] (2) Discard the supernatant, resuspend the precipitate in an appropriate amount of experimental buffer, and count 20 μL of the precipitate using a cell counter.

[0321] (3) Take an appropriate amount of cell suspension and dilute it. Add 10 μL of cell suspension to each well of the cell plate and centrifuge at 1000 rpm for 1 minute.

[0322] (4) Add the compound to the cell plate using Tecan-D3000, centrifuge at 1000 rpm for 1 minute, seal the cell plate and incubate at room temperature for 45 minutes.

[0323] (5) Take an appropriate amount of cAMP-d2 stock solution and Anti-cAMP-Cryptate stock solution and dilute them with lysis buffer at a ratio of 1:20. Then mix the two solutions by inverting them at a ratio of 1:1. Do not vortex.

[0324] (6) Add 10 μL of the prepared test reagent to the cell plate and centrifuge at 1000 rpm for 1 minute. Incubate the cell plate at room temperature in the dark for 1 hour.

[0325] (7) After centrifuging the cell plate at 1000 rpm for 1 minute, read the plate using Envision. Excitation light was 340 nm, and emission light was 620 nm and 665 nm.

[0326] (8) Data analysis: Multiply the ratio of the two channel signals (665 nm / 620 nm) by 10000 to obtain the final raw data for analysis.

[0327] Formula for calculating compound activation rate in agonist testing:

[0328] Activity%=100-(Readout-LC) / (HC-LC) 100

[0329] HC (High Control): Average readings from 200 μM Dopamine wells

[0330] LC (Low Control): Average reading of the DMSO orifice

[0331] Readout: Compound readings

[0332] Curve fitting model (four-parameter fitting): log(agonist) vs. response-variable slope

[0333] 4. Experimental Results:

[0334] The results obtained through the above methods are shown in Table 1.

[0335] Table 1. The compounds of this invention and their interaction with D1 / D5 receptor function (ECG) 50 Measurement data table

[0336]

[0337] 5. Experimental Conclusions

[0338] The results show that the representative compounds of this invention have a significant activating effect on the D1 / D5 receptor.

[0339] Test Example 2: Test on the binding ability of the compound of the present invention to the D1 receptor

[0340] 1. Experimental objective:

[0341] The in vitro D1 receptor binding strength of the compounds of this invention was investigated to assess their binding affinity to the target.

[0342] 2. Test methods:

[0343] 2.1 Preparation of Buffer and Compound

[0344] A: D1 buffer: Weigh 2.98 g HEPES, 0.73 g NaCl, 119 mg MgCl2, and 46.53 mg EDTA-2Na, add 250 mL of ultrapure water, and adjust the pH to 7.4. The final concentrations are 50 mM HEPES, 50 mM NaCl, 5 mM MgCl2, 0.5 mM EDTA, and pH 7.4.

[0345] B: Test sample (compound of this invention): The theoretical sample weight is calculated based on the designed concentration and required volume. Generally 5.0 × 10⁻⁶. -3 M is the initial dosage, dissolved in DMSO, and then sequentially diluted with DMSO to 5.0 × 10⁻⁶. -4 M~5.0×10 -9 M, dilute the diluted DMSO solution with buffer to the working concentration, 5.0 × 10⁻⁶. -5 M~5.0×10 -11 M, the final concentration of DMSO in the working solution is 1% (the final concentration of DMSO in the reaction system is 0.2%). The test sample should be stored at 4 ℃ after preparation and discarded after the test.

[0346] 2.2 Preparation of receptor membrane

[0347] CHO-D1 cells were removed from the -80 ℃ freezer and thawed naturally. They were then centrifuged at 2000 g at 4 ℃ for 10 min, the supernatant was discarded, and the pellet was collected. Buffer was added to the pellet, and the mixture was homogenized for 20-30 s. The pellet was then centrifuged at 48000 g at 4 ℃ for 25 min, the supernatant was discarded, and the mixture was again homogenized for 20-30 s. The pellet was then centrifuged at 48000 g at 4 ℃ for 25 min, the supernatant was discarded, and the pellet was stored at -80 ℃.

[0348] 2.3 Receptor competition binding assay

[0349] 2.3.1 Combined with experimental conditions

[0350]

[0351] 2.3.2 Receptor Binding Assay Procedure

[0352] (1) Add 50 μL of solvent (1% DMSO) to the total bound well (TB) and 50 μL of non-specific bound well (NB) with a final concentration of 1.0 × 10⁻⁶. -5 M), add 50 μL of the test compound to each well (CB).

[0353] (2) Add 100 μL of buffer solution to each reaction well.

[0354] (3) First, prepare the prepared membrane into a suspension of membrane of the corresponding concentration using a homogenizing solution for later use.

[0355] (4) Add 50 μL of radioactive ligand to each reaction well.

[0356] (5) Add 50 μL of membrane suspension to each reaction well.

[0357] (6) Incubate each reaction well at 25 °C for 90 min. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. The UniFilter-96 GF / C plate is soaked in 0.5% PEI for more than 1 h in advance. After filtration, the filter membrane is dried in an oven at 60 °C. After attaching the bottom membrane, add 40 µL of scintillation solution, seal the membrane, and let it stand.

[0358] (7) Place the filter plate into the liquid scintillation counter for counting.

[0359] 2.4 Data Analysis

[0360] Based on the effect values ​​at different concentration test points of the compound samples, the interaction curves of the compound samples with the receptors were fitted using GraphPad Prism software, and the Ki values ​​were calculated, as shown in Table 2.

[0361] Table 2. Results of the test on the binding affinity of the compounds of the present invention to the D1 receptor.

[0362]

[0363] 3. Experimental Conclusions

[0364] The results show that, compared with Comparative Example 1, the representative compound of the present invention has a stronger binding ability to the D1 receptor and exhibits a stronger affinity for the D1 receptor.

[0365] Test Example 3: In vitro liver microsomal stability determination of the compound of the present invention

[0366] 1. Experimental objective:

[0367] The stability of the compound of this invention in liver microsomes of four species: rat, dog, cynomolgus monkey, and human.

[0368] 2. Test materials:

[0369] (1) Test sample: The compound of the present invention was prepared in-house.

[0370] (2) Test materials:

[0371] Liver microsomal information:

[0372]

[0373] Reagent Information:

[0374]

[0375] (3) Main experimental instruments:

[0376]

[0377] 3. Experimental methods:

[0378] A) Prepare eight 96-well incubation plates, named T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The reaction time points for the first six incubation plates are 0, 5, 15, 30, 45, and 60 minutes, respectively. Do not add the test or control compound to the Blank60 plate; sample after 60 minutes of incubation. Incubate the NCF60 plate with potassium phosphate buffer instead of the NADPH regeneration solution for 60 minutes. Samples at all time points are in triplicate.

[0379] B) Add 100 μL of microsomal working solution (liver microsomal protein concentration of 1 mg / mL) and 2 μL of test or control working solution to T0, T5, T15, T30, T45, T60, and NCF60 plates, respectively. Add only microsomal working solution to Blank60 plates. Then, except for T0 and NCF60, incubate the Blank60, T5, T15, T30, T45, and T60 plates in a 37°C water bath for about 10 minutes. For T0 plates, add 600 μL of stop solution (acetonitrile solution containing 500 ng / mL verapamil) before adding the NADPH regeneration system working solution.

[0380] C) Add 98 μL of potassium phosphate buffer to each well of the NCF60 plate and incubate for 60 minutes.

[0381] D) After pre-incubation at Blank 60, T5, T15, T30, T45, and T60, 98 μL of NADPH regeneration working solution was added to each sample well to initiate the reaction. Therefore, for sample wells containing the working solution of the test sample or control, the final reaction concentration of the analyte and positive control testosterone was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0382] E) After incubation for an appropriate time (e.g., 5, 15, 30, 45 and 60 minutes), 600 μL of stop solution was added to each sample well of the test sample and the control sample well of the Blank60, T5, T15, T30, T45, T60 and NCF60 plates to terminate the reaction.

[0383] F) Shake all sample plates well and centrifuge at 4000×g for 15 minutes. Take a certain amount of the supernatant of the test sample and the reference sample and dilute it in pure water for LC-MS / MS analysis.

[0384] 4. Experimental Results:

[0385] The results obtained through the above methods are shown in Table 3.

[0386] Table 3. Stability results of the compounds of the present invention in liver microsomes of different species.

[0387]

[0388] Note: The classification criteria for clearance rate are shown in the table below:

[0389]

[0390] 5. Experimental Conclusions

[0391] The representative compounds of this invention exhibit good stability in liver microsomes of different species, especially in human liver microsomes.

[0392] Test Example 4: Pharmacokinetic Experiment of the Compound of the Present Invention in Cynomolgus Monkeys

[0393] 1. Experimental objective:

[0394] Male cynomolgus monkeys were administered the compound of the present invention via intravenous and oral gavage. The blood concentration of the compound after administration was determined in the cynomolgus monkeys, and the pharmacokinetic parameters were calculated to evaluate the pharmacokinetic properties of the compound of the present invention.

[0395] 2. Test materials:

[0396] (1) Test sample: The compound of the present invention was prepared in-house.

[0397] (2) Experimental animals: Crab-eating macaques, male, Suzhou Tuowei Biotechnology Co., Ltd.

[0398] (3) Main experimental instruments:

[0399]

[0400] 3. Test Procedure:

[0401] (1) Dosage information:

[0402] Drug preparation: Calculate the preparation volume based on the weight of the sample to be tested, add 5% DMSO, and after the sample is fully dissolved, add 40% PEG400, then add 55% 20% β-cyclodextrin aqueous solution, and mix thoroughly for later use.

[0403] Route of administration: 2 mg / kg orally by gavage.

[0404] Dosage frequency and duration: Single dose.

[0405] (2) Test method:

[0406] After stratifying by body weight, the cynomolgus monkeys were randomly divided into groups of three, with each group fasted overnight. The drugs were administered orally by gavage. At 0, 0.1667, 0.33, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours, 0.4 mL of blood was collected from the forelimb vein of the monkeys into sample tubes containing the anticoagulant sodium heparin and placed on wet ice. The tubes were then incubated at 4000 r·min. -1 Centrifuge for 10 min to separate the plasma, and freeze it in a -80℃ freezer until analysis.

[0407] 4. Experimental Results and Analysis:

[0408] The concentration of the compound in the plasma samples was determined using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). In this embodiment of the invention, the plasma concentration of the compound was detected after administration, and relevant pharmacokinetic parameters were calculated. The retention times of the compound and internal standard, chromatographic acquisition, and chromatographic integration were processed using Chromeleon 7.2.10 ES software (Thermo, USA), and the data were statistically processed using Microsoft Office software. The non-compartmental model of the WinNonlin™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma concentration, and the linear logarithmic trapezoidal method was used to calculate the pharmacokinetic parameters. Specific results are shown in Table 4.

[0409] Table 4. Pharmacokinetic results of the compounds of this invention in cynomolgus monkeys after administration.

[0410]

[0411] 5. Experimental Conclusion:

[0412] As can be seen from the experimental results in Table 4, the representative compounds of this invention exhibit suitable half-life and good exposure after oral administration, and have good pharmacokinetic properties.

[0413] Test Example 5: Pharmacodynamic Experiment of the Compound of the Present Invention in a Reserpine-Induced Parkinson's Model

[0414] 1. Experimental objective:

[0415] Reserpine-induced male C57BL / 6J Parkinson's disease model mice were administered the compound by oral gavage. The performance of the compound in spontaneous activity of the mice was measured, the movement distance of the mice was calculated, and the pharmacodynamic evaluation of the compound was performed.

[0416] 2. Test materials:

[0417] (1) Test sample: The compound of the present invention was prepared in-house.

[0418] (2) Experimental animals: C57BL / 6J mice, SPF grade, male, Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0419] (3) Main experimental instruments:

[0420]

[0421] 3. Test Procedure:

[0422] (1) Dosage information:

[0423] Drug preparation: Calculate the preparation volume based on the weight of the modeling drug reserpine and the sample to be tested. Add 5% DMSO. After the sample is fully dissolved, add 40% PEG400 and then add 55% 20% β-cyclodextrin aqueous solution. Mix thoroughly and set aside.

[0424] Administration routes: The modeling drug reserpine was administered subcutaneously at 10 mL / kg, and the test compound was administered orally at 10 mL / kg.

[0425] Dosage frequency and duration: Single dose.

[0426] (2) Test method:

[0427] C57BL / 6J mice were stratified by body weight and randomly divided into groups of 10 mice each. The model group received a subcutaneous injection of reserpine (0.5 mg / kg body weight), and 24 hours later, the mice were administered the drug orally and then subjected to a spontaneous activity test. One hour before the spontaneous activity test, the mice were placed in the test chamber to acclimatize. During the spontaneous activity test, the mice were placed in an activity box and recorded for 30 minutes, followed by another 120 minutes after the oral administration of the drug. The distance the mice traveled in the spontaneous activity box was evaluated.

[0428] 4. Experimental Results and Analysis:

[0429] Following administration of the compound in this embodiment of the invention, the animal movement distance was recorded using Anymaze software. Experimental data were analyzed using one-way ANOVA, and pairwise comparisons were performed using Dunnett's multiple comparisons tests. Specific results are shown in Table 5.

[0430] Table 5. Test results of the compounds of the present invention in a reserpine-induced mouse Parkinson's disease model.

[0431]

[0432] Note: ED 50 It is half of the effective amount.

[0433] 5. Experimental Conclusion:

[0434] As shown in Table 5, in the reserpine-induced Parkinson's model, the representative compound of this invention significantly increased spontaneous activity in mice after oral administration. Moreover, compared with Comparative Example 1, the compound of this invention had a significantly lower half-maximal effective dose and a stronger pharmacological effect.

[0435] Although specific embodiments of the present invention have been described in detail, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention based on all the teachings disclosed, and all such modifications and substitutions are within the scope of protection of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A compound as shown in Formula II, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof: in: X3 is either O or S; When present, R1 can be hydrogen, deuterium, or C independently. 1-6 Alkyl or C 1-6 Deuterated alkyl groups; R2 is a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups; R 3a R 3b R4 and R4 are independently hydrogen, deuterium, and C. 1-6 Alkyl or C 1-6 Deuterated alkyl groups; m is an integer between 0 and 3.

2. The compound of formula II as claimed in claim 1, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts, characterized in that, One or more of the following conditions must be met: (1) When present, R1 is independently hydrogen, deuterium, methyl, ethyl, n-propyl or isopropyl; (2) R2 is fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, -CD3, -CHF2 or -CH2F; (3) R 3a R 3b R4 and R4 are each independently hydrogen, methyl, or ethyl; (4) m is 0, 1 or 2.

3. The compound of formula II as claimed in claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Equation II is further shown as in Equation II-A or II-B: or in: X3, R1, R2, R 3a R 3b R4 and m are as described in claim 1.

4. The compound of formula II as claimed in claim 1, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts, characterized in that, Equation II is further shown in Equation III: in: X3 is either O or S; R2 is a halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups.

5. The compound of formula II as claimed in claim 4, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Equation III is further shown as Equation III-A or III-B: or in: X3 and R2 are as described in claim 4.

6. The compound of formula II as claimed in claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Equation II is further shown in Equation IV: in: R2 is a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups.

7. The compound of formula II as claimed in claim 6, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R2 can be fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, -CD3, -CHF2, or -CH2F.

8. The compound of formula II as claimed in claim 6, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Formula IV is further illustrated as in Formula IV-A or IV-B: or in: R2 is as described in claim 6.

9. The compound of formula II as claimed in any one of claims 1-8, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 。 10. A method for preparing the compound of formula II as claimed in claim 1, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, characterized in that, Includes the following steps: in: LG is halogen; X3, R1, R2, R 3a R 3b R4 and m are as described in claim 1.

11. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula II as claimed in any one of claims 1-9, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. Use of the compound of Formula I, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-9, in the preparation of a medicament for the prevention and / or treatment of dopamine D1-like receptor-mediated diseases.

13. Use of the compound of Formula I as claimed in any one of claims 1-9, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 11 in the preparation of a medicament for the prevention and / or treatment of neurological diseases.

14. The use as described in claim 12 or 13, characterized in that, The relevant diseases are selected from one or more of the following: schizophrenia, impulsivity, compulsive gambling, overeating, autism spectrum disorder, restless legs syndrome, Parkinson's disease, mild cognitive impairment, age-related cognitive decline, major depressive disorder, treatment-resistant depression, postpartum depression, Alzheimer's disease, Huntington's disease, bipolar disorder, chronic emotional blunting, loss of interest, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, serotonin syndrome, substance abuse and drug dependence, relapse of substance abuse, Tourette syndrome, tardive dyskinesia, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction, migraine, systemic lupus erythematosus, hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, refractory edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, and pain.

15. The use as described in claim 12 or 13, characterized in that, The relevant diseases are selected from one or more of the following: cognitive impairment, attention deficit hyperactivity disorder, dementia, anxiety, depression, and hypersomnia.

16. The use as described in claim 14, characterized in that, The relevant diseases are selected from one or more of the following: schizophrenia, Parkinson's disease, mild cognitive impairment, age-related cognitive decline, major depressive disorder, treatment-resistant depression, postpartum depression, and Alzheimer's disease.

17. The use as described in claim 15, characterized in that, The relevant diseases are selected from one or both of cognitive impairment and dementia.

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