M4 positive allosteric modulators

Abstract

M4 positive allosteric modulators of compounds having the formula: wherein R1 is a 4- or 5-membered heterocycle, each heterocycle can be unsubstituted or substituted with one or more substituents, and the ring contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R2 is a C1-C6 alkyl; A is a 4- or 5-membered heterocycle, each heterocycle can be unsubstituted or substituted with one or more substituents, and the ring contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R3 is a hydrogen atom or a C1-C6 alkyl; and Ar is a 5-10 membered heterocyclic, aromatic, or heteroaromatic monocyclic or bicyclic ring.

Description

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 607,385, filed December 7, 2023, the contents of which are incorporated herein by reference.

[0002] field This invention relates to compounds used as M4-positive allosteric modulators and their manufacture. These compounds can be used as medicines for the therapeutic and / or preventative treatment of M4-mediated diseases or conditions such as Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, and Huntington's disease.

[0003] background Muscarinic acetylcholine receptors are G protein-coupled receptors (GPCRs) composed of five subtypes called M1, M2, M3, M4, and M5. The M4 receptor is coupled to Gi and is primarily expressed in the cerebral cortex, striatum, hypothalamus, and hippocampus (Lebois et al.). 神经药理学 , 136, 362-373 (2018)).

[0004] A genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) identified a single nucleotide polymorphism (SNP) significantly associated with the disease, located at locus rs7951870, which includes the M4 gene (Pardinas et al.). 自然遗传学 ,50,381-389 (2018)).

[0005] Cholinergic neurotransmission is known to play a crucial role in cognitive function, as evidenced by the fact that cholinergic receptor antagonists can cause severe memory impairment, while acetylcholinesterase inhibitors such as donequazil exhibit a pro-cognitive effect in Alzheimer's disease. In schizophrenia, a high dopaminergic state in the striatum and nucleus accumbens is associated with psychosis and is currently the target of antipsychotic drugs that block dopamine D2 receptors.

[0006] A recently developed M4-specific positive allosteric modulator (“PAM”) enhances the effect of the endogenous agonist acetylcholine, revealing the role of these receptors in controlling dopamine release in the striatum and key synapses known to be cognitively important in the hippocampus.

[0007] A recent study demonstrated that M4 PAM reduced striatal dopamine release in wild-type mice treated with amphetamines, but did not reduce M4 knockout (Byun et al.). 神经精神药理学, 39, 1578 (2014)). Another study showed that M4 PAM induces inhibition of glutamate excitatory synaptic transmission at the CA1 synapse of the Schaeffer collateral in the hippocampus (Thom et al., 39, 1578 (2014)). 海马体 , 27, 794-810 (2017)).

[0008] Further in vivo rodent studies showed that M4 PAM VU0467154 improved associative learning impairment in touchscreen paired visual discrimination tasks induced by the non-competitive NMDA receptor antagonist MK-801. These effects were absent in M4 knockout mice, demonstrating the specificity of this phenotype for the M4 receptor (Bubser et al., 美国化学学会化学 神经科学 ,5,920-942 (2014)).

[0009] By using specific PAM to activate striatal and hippocampal M4 receptors, the hyperdopaminergic state in the striatum and hyperstimulation of the hippocampus can be reduced, thereby providing a treatment for psychosis and cognitive impairment in schizophrenia.

[0010] A clinical study of 345 Alzheimer's patients showed that the M1 / M4 agonist xanomeline, by activating muscarinic receptors, improved cognitive and psychiatric symptoms such as hallucinations, delusions, and vocal outbursts (Bodick et al.). 《神经病学文献》 , 54, 465-73 (1997). Therefore, M4 PAM can improve cognitive deficits and alleviate psychiatric symptoms in Alzheimer's patients.

[0011] It is known that the M4 receptor controls dopamine release in the striatum (Tzavara et al., 《美国实验生物学会联合会杂志》 , 18, 1410-1412 (2004)), this region is important for reward and addiction. It was shown that M4 knockout mice had a higher rate of cocaine self-administration in performance behavior tests (Schmidt et al., 18, 1410-1412 (2004)). 精神药理学 , 216, 367-378 (2011)), while conversely, M4 PAM tool compounds reduced cocaine self-administration in mice (Dencker et al., , 216, 367-378 (2011)). 精神药理学 These results suggest that activation of the M4 receptor may reduce addiction.

[0012] Huntington's disease is caused by the triplet duplication of the glutamine-encoding gene in the Huntington gene, which leads to neurodegeneration, resulting in motor abnormalities, cognitive impairment, and eventually dementia and death.

[0013] Long-term treatment with M4 PAM has been shown to improve motor and synaptic deficits in a mouse model of Huntington's disease (YAC128 mice) (Pancani et al.). 美国国家科学院院刊 , 112, 14078-14083 (2015)). M4 PAM can normalize early changes in corticostellar transmission, thereby slowing the progression of Huntington's disease.

[0014] Parkinson's disease is caused by the degeneration of dopamine-producing neurons in the substantia nigra. Dopamine deficiency leads to motor dysfunction, which can be treated with L-DOPA supplementation for a period of time. However, this treatment loses its effectiveness over time, requiring higher doses of L-DOPA to control symptoms; higher doses can also induce motor dysfunction.

[0015] In a mouse model of 6-hydroxydopamine-induced Parkinson's disease, M4 PAM treatment reduced L-DOPA-induced motor dysfunction. These findings were replicated in a monkey model of MPTP-induced Parkinson's disease (Shen et al.). 神经元 Therefore, M4 PAM can be used as a symptomatic treatment for L-DOPA-induced motor disorders in Parkinson's disease.

[0016] This demonstrates that M4 antagonists block the nociceptive effects of spinal cord electrical stimulation in a rat model of neuropathic pain (Schechtmann et al.). 疼痛 , 139, 136-145 (2008)), and knockdown of M4 in the rat spinal cord has also been shown to increase thermal nociceptiveness in rats (Cai et al., 139, 136-145 (2008)). 神经化学杂志 , 111, 1000-1010 (2009)). Therefore, M4 activation can reduce pain.

[0017] Modulating M4 receptor activity is a promising therapeutic strategy for treating or preventing M4-mediated diseases or conditions such as Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, and Huntington's disease. Examples of compounds suggested for such uses are disclosed and / or claimed in WO2018 / 066718, WO2018 / 002760A1, WO2018 / 234953A1, WO2021 / 099527A1, and US 2023 / 0348490.

[0018] However, new compounds, formulations, treatments, and therapies are still needed to treat or prevent M4-mediated diseases or conditions. Therefore, the object of this invention is to provide compounds that can be used to treat, prevent, or improve such diseases and conditions and have improved therapeutic properties.

[0019] Overview The first embodiment relates to a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: in R1 is a 4- or 5-membered heterocycle, each of which may be unsubstituted or substituted by one or more substituents, and the heterocycle contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur; R2 is a C1-C6 alkyl group; A is a 4- or 5-membered heterocycle, each of which may be unsubstituted or substituted by one or more substituents, and the heterocycle contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur; R3 is a hydrogen atom or a C1-C6 alkyl group; and Ar is a 5-10 membered heterocycle, aromatic ring, or heteroaromatic ring, each ring may be unsubstituted or substituted with one or more substituents, and each heterocycle or heteroaromatic ring contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0020] Another embodiment involves a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: R1, R2, R3, A, and Ar have the meanings described above.

[0021] Another embodiment involves a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: R2, R3, A, and Ar have the meanings described above, and R 4a and R 4b Each is independently selected from hydrogen atoms, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, and hydroxyl groups.

[0022] Another embodiment involves a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: Where R1, R2, R3, R 4a R 4b And Ar has the meaning described above.

[0023] Detailed description Definition 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. All patents, applications, published applications, and other publications cited herein are incorporated in their entirety by reference. Where a term in this document has multiple possible definitions, the definition in this section shall prevail unless otherwise stated.

[0024] The term "alkyl" refers to a monovalent or polyvalent, such as monovalent or divalent, straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms ("C1-C6-alkyl"), such as 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl (Me), ethyl (Et), propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Preferred alkyl groups have 1 to 4 carbon atoms ("C1-C6-alkyl"). 1-4 Alkyl group). A particularly preferred, but not limiting, example of an alkyl group is methyl.

[0025] The term "alkoxy" refers to an alkyl group as defined above, which is attached to a parent molecule portion via an oxygen atom. Unless otherwise stated, an alkoxy group contains 1 to 6 carbon atoms ("C1-C6 alkoxy"). In some preferred embodiments, an alkoxy group contains 1 to 4 carbon atoms. In other embodiments, an alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of an alkoxy group is methoxy.

[0026] The term "aromatic ring" refers to a monocyclic or bicyclic carbocyclic system, wherein a monocyclic system has a conjugated π-electron system and a total of 6 ring atoms, and a bicyclic system has a total of 10 to 12 ring atoms with conjugated π-electron systems. When the term "aromatic ring" is used to refer to a bicyclic carbocyclic system, at least one or two of the carbon rings have conjugated π-electron systems. A particularly preferred but non-limiting example of an aromatic ring is the phenyl group. A "bicyclic aromatic ring" refers to an aromatic moiety consisting of two rings, wherein the two rings share two common ring atoms.

[0027] The terms "asymmetric carbon atom" and "asymmetric center" refer to a carbon atom with four different atoms and / or groups bonded to it. According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can be either an "R" or "S" configuration.

[0028] The term "substituent" refers to an atom or group that replaces a hydrogen atom.

[0029] The term "halogen atom" or "halogenated," alone or in combination, refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and particularly a fluorine atom or a chlorine atom. The term "halogenated" in combination with another group indicates that the group is substituted by at least one halogen atom, particularly by one to five halogens, and even more particularly by one to four halogen atoms, i.e., one, two, three, or four halogens.

[0030] The term "haloalkyl" refers to an alkyl group as defined above, wherein at least one hydrogen atom of the alkyl group has been substituted with a halogen atom, preferably a fluorine atom. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms have been substituted with a halogen atom, most preferably fluorine. Particularly preferred, but not limiting, examples of haloalkyl groups are trifluoromethyl and trifluoroethyl.

[0031] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom, preferably a fluorine atom. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms are replaced by a halogen atom, most preferably a fluorine atom. Particularly preferred, but not limiting, examples of haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0032] The term "heteroaromatic ring" refers to a monocyclic or bicyclic ring, either monovalent or polyvalent, having a total of 5 to 10 ring atoms, wherein at least one ring in the system has a conjugated π-electron system, and at least one ring in the system contains one or more heteroatoms. Preferably, a "heteroaromatic ring" refers to a 5- to 10-membered monocyclic or bicyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, sulfur, and nitrogen. Most preferably, a "heteroaromatic ring" refers to a 5- to 10-membered monocyclic or bicyclic ring containing 1 to 2 heteroatoms independently selected from oxygen and nitrogen.

[0033] Some non-limiting examples of heteroaromatic rings include 2-pyridyl, 3-pyridyl, 4-pyridyl, indole-1-yl, 1 H -Indole-2-yl, 1 H -Indole-3-yl, 1 H -Indole-4-yl, 1 H -Indole-5-yl, 1 H -Indole-6-yl, 1 H -Indole-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1 H -Indazole-3-yl, 1 H -Indazole-4-yl, 1 H -Indazole-5-yl, 1 H -Indazole-6-yl, 1 H -Indazole-7-yl, Pyrazole-1-yl, 1 H-pyrazole-3-yl, 1 H -pyrazole-4-yl, 1 H -pyrazole-5-yl, imidazole-1-yl, 1 H -imidazol-2-yl, 1 H -imidazol-4-yl, 1 H -Imidazol-5-yl, Oxazo-2-yl, Oxazo-4-yl, Oxazo-5-yl, Thiazol-4-yl and 1,2,4-oxadiazol-3-yl.

[0034] The term "heterocyclic" refers to a saturated or partially unsaturated monocyclic or bicyclic system, preferably a monocyclic system, having 3 to 10 ring atoms, more preferably 3 to 8, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclic" refers to a heterocyclic portion consisting of two rings having two common ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms; and two spirocyclic portions, i.e., the two rings are connected by a common ring atom. Some non-limiting examples of heterocycles include azirrobut-3-yl, azirrobut-2-yl, oxacyclobut-3-yl, oxacyclobut-2-yl, 2-oxopyrrolidine-1-yl, 2-oxopyrrolidine-3-yl, 5-oxopyrrolidine-2-yl, 5-oxopyrrolidine-3-yl, 2-oxo-1-piperidinyl, 2-oxo-3-piperidinyl, 2-oxo-4-piperidinyl, 6-oxo-2-piperidinyl, 6-oxo-3-piperidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholino-2-yl, morpholino-3-yl, pyrrolylalkyl (e.g., pyrrolidine-3-yl), 3-azabicyclo[3.1.0]hex-6-yl, or 2,5-diazabicyclo[2.2.1]hept-2-yl.

[0035] Other non-limiting examples of 5-membered monocyclic heteroaromatic rings or heterocycles include: .

[0036] Other non-limiting examples of 5-membered monocyclic heteroaromatic rings include: .

[0037] Other non-limiting examples of a 6-membered monocyclic heteroaromatic ring or heterocycle include: .

[0038] Non-limiting examples of bicyclic heteroaromatic rings with nitrogen as the only heteroatom include: .

[0039] The term "hydroxyl group" refers to the -OH group.

[0040] The term "cyano" refers to the -CN group.

[0041] As used herein, “tautomer” and “tautomerism” refer to alternative forms of the compounds disclosed herein that differ in the position of their protons. Non-limiting examples include enol-ketone and imine-enamine tautomers, or heteroaryl forms containing a ring atom attached to a ring-NH- moiety and a ring=N- moiety (such as pyrazole, imidazole, benzimidazole, triazole, and tetraazole).

[0042] It should be understood that isotopes can be present in the compounds described herein. Each chemical element represented in the compound structure may include any isotope of that element. For example, in the compounds described herein, a hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, references to the compounds herein cover all potential isotopic forms unless the context clearly specifies otherwise.

[0043] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound that does not eliminate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting the compounds disclosed herein with acids or bases. Salts formed by bases include, but are not limited to, ammonium salts (NH4+). + Alkali metal salts, such as, but not limited to, sodium or potassium salts; alkaline earth metal salts, such as, but not limited to, calcium or magnesium salts; salts of organic bases, such as, but not limited to, dicyclohexylamine, guanidine, guanidine, methylguanidine, etc. N 1,3-methyl-D-glucosamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts formed with the amino groups of amino acids, such as, but not limited to, arginine and lysine. Useful acid-based salts include, but are not limited to, acetates, adipates, aspartates, ascorbic acid salts, benzoates, butyrates, decanoates, caproate, hexanoate, camphor sulfonates, citrates, decanoates, formates, fumarates, gluconates, glutarate, glycolates, hexanoate, laurates, lactates, maleates, nitrates, oleates, oxalates, octanoate, propionates, palmitates, phosphates, sebate, succinates, stearates, sulfates, sulfonates (e.g., methanesulfonate, ethanesulfonate, p-toluenesulfonate), salicylates, tartrates, and toluenesulfonates.

[0044] Acid addition salts can be formed by mixing with a solution of a pharmaceutically acceptable, non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, etc. Basic salts can be formed by mixing with a solution of a pharmaceutically acceptable, non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc. Suitable pharmaceutically acceptable salts may include compounds having one or more counterions, such as dichlorides; or having a portion of a counterion, such as hemitartaric acid salts.

[0045] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules or a portion thereof, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, 3 or 4 solvent or water molecules, or alternatively, ¼ to ½ solvent or water molecules.

[0046] As used herein, “regulating” receptor activity means activating it, that is, increasing its cellular function above a baseline measured in its specific environment; or inactivating it, that is, decreasing its cellular function below a baseline measured in its environment and / or rendering it unable to perform its cellular function at all, even in the presence of a natural binding partner. A natural binding partner is an endogenous molecule that acts as a receptor agonist.

[0047] As used herein, “subject” means an animal that is the object of treatment, observation and / or experimentation. “Animal” includes cold-blooded and warm-blooded vertebrates and invertebrates, such as birds, fish, shellfish, reptiles, and especially mammals. “Mammals” include, but are not limited to, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cattle; horses; primates such as monkeys, chimpanzees and apes, and especially humans.

[0048] As used in this article, "patient" refers to a subject who is being treated by a medical specialist (e.g., MD or DVM) in an attempt to cure or at least alleviate the effects of a particular disease or condition or, in the best of all, prevent its occurrence.

[0049] As used herein, "pharmaceuticalally acceptable excipient" refers to an inert substance added to a pharmaceutical composition to provide (but not limited to) volume, consistency, stability, binding capacity, lubrication, disintegration capacity, etc., without eliminating the biological activity and biological properties of the active ingredient.

[0050] As used herein, “receptor” is intended to include any molecule present inside or on the cell surface that may affect cell physiology when inhibited or stimulated by a ligand. Typically, a receptor includes an extracellular domain with ligand-binding properties, a transmembrane domain anchoring the receptor to the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding (“signal transduction”). Receptors also include any intracellular molecule that generates a signal in response to binding. Receptors also include any molecule that has the characteristic structure of a receptor but does not recognize a ligand. Furthermore, receptors include truncated, modified, mutated receptors, or any molecule containing part or all of the receptor sequence.

[0051] When used herein, “prevention / avoidance” should not be construed as meaning that, after using a compound or pharmaceutical composition according to the embodiments disclosed herein to achieve prevention, the condition and / or disease will never recur. Furthermore, the term should not be construed as meaning that, after using this medicine to prevent the condition, the condition will at least partially not occur. Rather, “prevention / avoidance” is intended to indicate that, if the condition to be prevented still occurs despite the use of this medicine, its severity will be less than if the medicine were not used.

[0052] As used herein, the term “about” includes the number plus or minus 0.5 of its last digit. Thus, “about 1” means 0.5 to 1.5, and “about 0.1” means 0.05 to 0.15.

[0053] Compound The first embodiment relates to a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: in R1 is a 4- or 5-membered heterocycle, each of which may be unsubstituted or substituted by one or more substituents, and the heterocycle contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur; R2 is a C1-C6 alkyl group; A is a 4- or 5-membered heterocycle, each of which may be unsubstituted or substituted by one or more substituents, and the heterocycle contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur; R3 is a hydrogen atom or a C1-C6 alkyl group; and Ar is a 5-10 membered heterocycle, aromatic ring, or heteroaromatic ring, each ring may be unsubstituted or substituted with one or more substituents, and each heterocycle or heteroaromatic ring contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0054] Another embodiment involves a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: R1, R2, R3, A, and Ar have the meanings described above.

[0055] Another embodiment involves a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: R2, R3, A, and Ar have the meanings described above, and R 4a and R 4b Each is independently selected from hydrogen atoms, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, and hydroxyl groups; Another embodiment involves a compound of the following formula, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof: Where R1, R2, R3, R 4a R 4b And Ar has the meaning described above.

[0056] According to some implementations, R1 is a four-membered heterocycle that is either unsubstituted or substituted with one or more substituents.

[0057] According to some implementations, R1 is a 4-membered heterocycle substituted with one or more substituents.

[0058] According to some embodiments, R1 is a 4-membered heterocycle substituted with one or more substituents selected from halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, and hydroxyl groups.

[0059] According to some implementations, R1 is a azirrocyclobutyl group.

[0060] According to some implementations, R1 is an unsubstituted nitrogen-containing heterocyclic butyl group.

[0061] According to some embodiments, R1 is an azacyclobutyl group substituted with one or more substituents. According to some embodiments, the substituents are selected from halogen atoms, methyl, ethyl, hydroxyl, methoxy, and ethoxy groups.

[0062] According to some embodiments, R1 is an azacyclobutyl group substituted with two substituents, which may be the same or different. According to some embodiments, the substituents are selected from halogen atoms, methyl, ethyl, hydroxyl, methoxy, and ethoxy groups. According to some embodiments, the substituents are selected from fluorine atoms, methyl, hydroxyl, and methoxy groups.

[0063] According to some implementations, R1 is a azirrobutyl group, which is bonded to a pyrimidinyl ring via the N atom of the azirrobutyl group.

[0064] According to some embodiments, R2 is a C1-C6 alkyl group. According to some embodiments, R2 is a C1-C4 alkyl group, such as methyl or ethyl.

[0065] According to some embodiments, A is a 5-membered heterocycle that is either unsubstituted or substituted by one or more substituents other than Ar, and contains one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

[0066] According to some implementations, A is a 5-membered heterocycle that is substituted only with Ar and contains one or two heteroatoms selected from nitrogen, oxygen and sulfur.

[0067] According to some embodiments, A is a 5-membered heterocycle substituted only with Ar, and it contains only one heteroatom. According to some embodiments, the heteroatom is nitrogen.

[0068] According to some embodiments, A is a pyrrolidinyl group. According to some embodiments, A is a pyrrolidinyl group in which the nitrogen atom of the pyrrolidinyl group is bonded to Ar. According to other embodiments, A is a pyrrolidinyl group in which the nitrogen atom of the pyrrolidinyl group is bonded to the carbon atom of the carbonyl group.

[0069] According to some embodiments, R3 is a C1-C6 alkyl group. According to some embodiments, R3 is a C1-C4 alkyl group. According to some embodiments, R3 is a methyl group.

[0070] According to some embodiments, Ar is a 5-10 membered heterocyclic ring that is unsubstituted or substituted with one or more substituents, and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur.

[0071] According to some embodiments, Ar is substituted by at least one substituent selected from halogen atoms, C1-C6 alkyl groups (one or more hydrogen atoms may be substituted by halogen atoms), C1-C6 alkoxy groups (one or more hydrogen atoms may be substituted by halogen atoms), and cyano groups.

[0072] In some embodiments, Ar is not substituted. In other embodiments, Ar is substituted by one substituent. In other embodiments, Ar is substituted by two substituents.

[0073] According to some embodiments, Ar is a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. According to some embodiments, Ar is a 5- or 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0074] According to some embodiments, Ar is a six-membered heterocyclic ring containing one, two, or three nitrogen atoms.

[0075] According to some implementations, the only heteroatom is nitrogen, and Ar is selected from: as well as , Each of them is either unreplaced or replaced.

[0076] According to some embodiments, Ar has one of the following structures as shown below: , , , , , , or , Each of them is either unreplaced or replaced.

[0077] According to some embodiments, Ar is a 6-membered heteroaromatic ring having a single heteroatom. According to some embodiments, Ar is a 6-membered heteroaromatic ring containing a nitrogen atom. According to some embodiments, Ar is a 6-membered heterocycle having a single heteroatom. According to some embodiments, Ar is a 6-membered heterocycle containing a nitrogen atom.

[0078] According to some embodiments, Ar is a 6-membered heterocyclic ring having two heteroatoms. According to some embodiments, both heteroatoms are nitrogen atoms. According to some embodiments, Ar is a 6-membered heterocyclic ring having two heteroatoms. According to some embodiments, both heteroatoms are nitrogen atoms.

[0079] According to some implementations, Ar has the following structure: in n is an integer from 0 to 2, inclusive; and X1, X2, X3, X4, and X5 are each independently a heteroatom selected from nitrogen, oxygen, and sulfur, or each is independently a carbon atom, with each carbon atom being either unsubstituted or substituted.

[0080] In some implementations, n equals 0. In other implementations, n equals 1. In other implementations, n equals 2.

[0081] According to some implementations, at least one of X1, X2, X3, and X4 is a carbon atom substituted by a substituent.

[0082] According to some implementations, Ar is selected from the following 5-membered heterocyclic aromatic rings or heterocycles: , Each ring is either unsubstituted or substituted by one or more substituents.

[0083] According to some implementations, Ar is selected from the following 5-membered heterocyclic aromatic rings or heterocycles: , Each of them was either replaced or not replaced.

[0084] According to some implementations, Ar is selected from the following 6-membered heteroaromatic rings or heterocycles: , Each ring is either unsubstituted or substituted by one or more substituents.

[0085] According to some implementations, Ar has the following structure: in m and n are each integers from 0 to 2, inclusive; and X1, X2, X3, X4, X5, X6, X7, X8, and X9 are each independently a heteroatom selected from nitrogen, oxygen, and sulfur, or each is independently a carbon atom, with each carbon atom being either unsubstituted or substituted.

[0086] In some implementations, n and m are both equal to 0. In other implementations, n is equal to 1 and m is equal to 0. In other implementations, n is equal to 0 and m is equal to 1. In other implementations, n and m are both equal to 1. In other implementations, n is equal to 2 and m is equal to 0. In other implementations, n is equal to 0 and m is equal to 2. In other implementations, n is equal to 1 and m is equal to 2. In other implementations, n is equal to 2 and m is equal to 1.

[0087] According to some implementations, the only heteroatom is nitrogen, and Ar is selected from: Each of these structures is either unsubstituted or substituted with one or more substituents. Similar structures with other heteroatoms (e.g., oxygen and / or sulfur) have also been considered.

[0088] According to some embodiments, Ar is a 9-membered bicyclic heteroaromatic ring, which is unsubstituted or substituted with one or more substituents. According to some embodiments, Ar is a 9-membered heteroaromatic ring having at least two heteroatoms selected from nitrogen, oxygen, and sulfur. According to some embodiments, Ar is an unsubstituted 9-membered heteroaromatic ring. According to other embodiments, Ar is a 9-membered heteroaromatic ring substituted with one substituent. According to other embodiments, Ar is a 9-membered heteroaromatic ring substituted with two substituents.

[0089] In some embodiments of the compound, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, Ar is a 5-membered heterocycle selected from the group consisting of: .

[0090] In some embodiments of the compound, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, Ar is a 6-membered heterocycle selected from the group consisting of: .

[0091] In some embodiments of the compound, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, the pharmaceutically acceptable salt is selected from the group consisting of maleate, fumarate and tartrate.

[0092] In some embodiments, the compound has the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0093] In some embodiments, the compound has the following structure: , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0094] In some embodiments, the compound has the following structure: , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0095] In some embodiments, the compound has the following structure: , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0096] In some embodiments, the compound has the following structure: , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0097] In some embodiments, the compound has the following structure: , Or its deuterated counterpart.

[0098] In some embodiments, the compound has the following structure: , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0099] In some embodiments, the compound has the following structure: , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0100] In some embodiments, the compound has the following structure: , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0101] In some embodiments, the compound has the following structure: , , ,or , Or it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0102] In some embodiments, Ar is an unsubstituted 9-membered heteroaromatic ring. In other embodiments, Ar is a 9-membered heteroaromatic ring substituted with one substituent. In other embodiments, Ar is a 9-membered heteroaromatic ring substituted with two substituents.

[0103] The compounds of this invention include all hydrates, solvates, and complexes of the compounds used in this invention. If the compounds of this invention contain a chiral center or another form of isomerism, this document aims to cover all forms of such one or more isomers, including enantiomers and diastereomers. Compounds containing a chiral center can be used as racemic mixtures, enantiomer-enriched mixtures, or racemic mixtures can be separated using well-known techniques, and a single enantiomer can be used alone. The compounds described in this invention are in racemic form or as a single enantiomer. Enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469-1474, (1997) IUPAC. In the case of compounds having unsaturated carbon-carbon double bonds, both cis (Z) and trans (E) isomers are within the scope of this invention. In the case where compounds can exist in tautomeric forms, such as keto-enol tautomeric forms, each tautomeric form is considered to be included in this invention, whether present in equilibrium form or predominantly in one form.

[0104] When the structure of the compounds of this invention includes asymmetric carbon atoms, such compounds can occur as racemates, racemic mixtures, and isolated single enantiomers. All such isomers of these compounds are explicitly included in this invention. Each stereogenic carbon can be either R or S configuration. Therefore, it should be understood that isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention unless otherwise stated. These isomers can be obtained substantially in pure form by classical separation techniques and stereochemically controlled synthesis, such as those described in J. Jacques, A. Collet, and S. Wilen, “Enantiomers, Racemates and Resolutions” (published by John Wiley & Sons, New York, 1981). For example, resolution can be performed by preparative chromatography on a chiral column.

[0105] This invention also aims to include all isotopes of atoms appearing in the compounds disclosed herein. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include carbon-13 and carbon-14.

[0106] It should be noted that any carbon symbol in the structure of this application, when used without further symbols, is intended to represent all isotopes of carbon, such as 12 C 13 C or 14 C. In addition, any containing 13 C or 14 Compounds of C can specifically have the structure of any compound disclosed herein.

[0107] It should also be noted that any hydrogen symbol in the structure of this application, when used without further notation, is intended to represent all isotopes of hydrogen, such as 1 H, 2 H or 3 H. Furthermore, any containing 2 H or 3 Compounds containing H can specifically have the structure of any of the compounds disclosed herein. These symbols for hydrogen isotopes include H, D, and T, which respectively refer to… 1 H, 2 H and 3 H, and these corresponding tags are considered equivalent.

[0108] Isotope-labeled compounds can typically be prepared using conventional techniques known to those skilled in the art or methods similar to those described in the examples disclosed herein, using an appropriate isotope-labeled reagent instead of the unlabeled reagent used.

[0109] The term "substitution" refers to a functional group as described above, in which one or more bonds connected to hydrogen atoms are replaced by bonds connected to non-hydrogen or non-carbon atoms, provided that the normal valence is maintained and the substitution produces a stable compound. Substituent groups also include groups in which one or more bonds connected to carbon or hydrogen atoms are replaced by one or more bonds connected to heteroatoms (including double or triple bonds). Examples of substituent groups include the functional groups described above, and in particular halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl groups; alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropoxy; aryloxy groups, such as phenoxy; arylalkoxy groups, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; thiol groups, such as methylthio, ethylthio, and propylthio; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently substituted by one or more of the disclosed or claimed substituent moieties, either singly or in multiples. Independent substitution means that (two or more) substituents can be the same or different.

[0110] It should be understood that those skilled in the art can select the substituents and substitution modes on the compounds of this invention to provide chemically stable compounds, which can be readily synthesized from readily available starting materials using techniques known in the art and the methods described below. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups can be located on the same carbon or different carbons, as long as a stable structure is produced.

[0111] When selecting compounds for this invention, those skilled in the art will recognize that various substituents, i.e., R1, R2, etc., should be selected based on well-known principles of chemical structure linkage. Furthermore, if no hydrogen is shown in the carbon-based structure herein, the implied hydrogen should be understood as fulfilling the required valence. In the carbon-based molecules herein, it should be understood that when R3, R... 4a and / or R 4bWhen hydrogen is present, all implied hydrogen atoms remain on the molecule to achieve valence as needed. Furthermore, hydrogen atoms not shown on atoms other than carbon should also be understood as present to achieve valence as needed. The drawn groups are assumed to contain these implied hydrogen atoms and, if necessary, allow for connection points on carbon or non-carbon atoms (if permitted) and any tautomerism.

[0112] Various R groups attached to the aromatic ring of the compounds disclosed herein can be added to the ring using standard procedures, such as those described in Advanced Organic Chemistry: Part B: Reactions and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th Edition (2007), the contents of which are incorporated herein by reference.

[0113] Methods of treating or alleviating symptoms of neurological or neuropsychiatric disorders include administering the compounds described herein or compositions comprising the compounds described herein in an amount sufficient to treat or alleviate the symptoms of the neurological or neuropsychiatric disorder.

[0114] In some embodiments, the neurological or neuropsychiatric disorders involve psychosis or psychotic symptoms. In some embodiments, the neurological or neuropsychiatric disorders are Alzheimer's disease, schizophrenia, psychosis, or Parkinson's disease. In some embodiments, the neurological or neuropsychiatric disorders are pain, chemical addiction, or Huntington's disease. In some embodiments, the neurological or neuropsychiatric disorders are related to or mediated by M4 receptor activity.

[0115] A method for activating an M4 receptor or enhancing the response of an M4 receptor to its ligand comprises contacting an M4 receptor with an amount of the compound described herein to activate the M4 receptor or enhance the response of the M4 receptor to the ligand.

[0116] A method for enhancing the response of an M4 receptor to a ligand in a subject includes administering to the subject an amount of the compound described herein to enhance the response of the M4 receptor to the ligand.

[0117] In this implementation, the ligand is acetylcholine.

[0118] Synthesis and Examples The compounds of the various embodiments described above can be prepared using commercially available starting materials and / or reagents, and using methods and techniques known and available to those skilled in the art.

[0119] Materials and methods: CDCl3 or DMSO were recorded on Bruker AVANCE-300 (300 MHz) and Bruker AVANCE-400 (400 MHz) instruments.d 6 Proton nuclear magnetic resonance in solution ( 1 ¹H NMR spectra. Chemical shifts are given in parts per million (ppm), with tetramethylsilane as an internal standard.

[0120] Using Shimadzu UFLC / MS (Prominence UFLC High Pressure Gradient System / LCMS-2020) in electrospray ionization mode (ESI) + Under the following conditions, purity and low-resolution mass spectrometry (MS) measurements can be performed using one or more of the following LC conditions.

[0121] LC conditions 1: The column used was an L-column 2 ODS (3.0 mm × 50 mm id, 3 μm, CERI), the temperature was 40°C, and the flow rate was 1.5 mL / min. Under acidic conditions, mobile phases A and B were 0.05% aqueous solution of TFA and 0.05% MeCN solution of TFA, respectively. The proportion of mobile phase B increased linearly from 5% to 90% within 0.9 min and remained at 90% for the next 1.1 min.

[0122] LC conditions 2: The column used was an L-column 2 ODS (3.0 mm × 50 mm id, 3 μm, CERI), the temperature was 40°C, and the flow rate was 1.5 mL / min. Mobile phases A and B under neutral conditions were a mixture of 5 mmol / L AcONH4 and MeCN (9 / 1, v / v) and a mixture of 5 mmol / L AcONH4 and MeCN (1 / 9, v / v), respectively. The proportion of mobile phase B increased linearly from 5% to 90% within 0.9 min and remained at 90% for the next 1.1 min.

[0123] LC Condition 3: A Zorbax Ext C18 column (50 × 4.6 mm, 5 μm) was used, with a flow rate of 1.5 mL / min. Mobile phases A and B consisted of a 10 mM aqueous solution of NH4OAc and MeCN. The proportion of mobile phase B increased linearly from 10% to 30% within 1.5 min, then from 30% to 90% within the next 3.0 min. This mobile phase composition was maintained for 4 min, and finally returned to its initial state within 5 min.

[0124] LC Condition 4: A YMC Triart C18 column (33 × 2.1 mm, 3 μm) was used, with a flow rate of 1.5 mL / min. Mobile phases A and B consisted of 0.05% formic acid aqueous solution and MeCN. The proportion of mobile phase B was 2%, held for 0.75 min, then reached 10% within 1.0 min, further reached 98% within 2.0 min, held for 2.25 min, and finally returned to the initial state within 3.0 min.

[0125] The reaction progress was determined by thin-layer chromatography (TLC) analysis on Merck Kieselgel 60 F254 plates or Fuji Silysia NH plates. Chromatographic purification was performed on silica gel columns (Merck Kieselgel 60, 70-230 mesh, Merck; Chromatorex NH-DM 1020, 100-200 mesh, Fuji Silysia Chemical; Inject and Universal columns, YAMAZEN, or Purif-Pack Si or NH, Shoko Scientific). Preparative HPLC was obtained using a Gilson preparative HPLC system with a UV detector (220 nm) or a YMC preparative HPLC system. All commercially available solvents and reagents were used without further purification. Yields were not optimized.

[0126] Abbreviations used: THF, tetrahydrofuran; EtOAc, ethyl acetate; MeOH, methanol; DMSO, dimethyl sulfoxide; EtOH, ethanol; MeCN, acetonitrile; DMF N,N - Dimethylformamide; TFA, trifluoroacetic acid; Xantphos, (5-diphenylphosphino-9,9-dimethylbenzyl-4-yl)diphenylphosphine; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); DME, 1,2-dimethoxyethane; DIPEA, N, N -Diisopropylethylamine; DMA N,N -Dimethylacetamide.

[0127] Intermediate 1 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]Pyrimidin-6-yl)(pyrrolidine-3-yl)methyl ketone dihydrochloride Step 1 (R)-3-(4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate At room temperature, to (R) A solution of 1-(tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid (992 mg, 4.61 mmol) in THF (5 mL) was added with oxalyl chloride (669 μL, 97.6 mmol) and DMF (30 μL, 0.39 mmol). After stirring at the same temperature for 2 hours, the mixture was concentrated under vacuum. The residue was dissolved in THF (5 mL), and the solution was added to 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5-pyrrolidinecarboxylic acid at room temperature. H -pyrrolo[3,4- d The mixture was prepared in a solution of pyrimidine dihydrochloride (1.00 g, 3.80 mmol), THF (5 mL), and a saturated aqueous solution of NaHCO3 (4 mL). The mixture was stirred at room temperature for 2 days. Brine was added to the mixture, and the mixture was extracted five times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 10%–40% MeOH in EtOAc) to give the title compound (148 mg) as a pale yellow oil.

[0128] 1 H NMR (300 MHz, CDCl3, 300 K) δ 1.46 (9H, s), 2.06-2.30 (2H, m), 2.36-2.54 (5H, m), 3.04-3.82 (5H, m), 4.19-4.31 (4H, m), 4.56-4.67 (2H, m),4.71-4.87 (2H, m).

[0129] m / z 388.4 [M+H] + .

[0130] Step 2 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]Pyrimidin-6-yl)(pyrrolidine-3-yl)methyl ketone dihydrochloride At room temperature, to (R) -3-(4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- d780 mg (2.01 mmol) of tert-butyl pyrimidine-6-carbonylpyrrolidine-1-carboxylate was added to a solution of EtOAc (3 mL) in 4 M HCl in EtOAc (7 mL) / MeOH (2 mL). The mixture was stirred at the same temperature for 5 hours. The mixture was concentrated under vacuum to give the title compound (759 mg) as a pale yellow gel.

[0131] 1 H NMR (300 MHz, DMSO- d 6 , 300 K) δ 1.91-2.04 (1H, m), 2.23-2.46 (3H,m), 3.07-3.69 (8H, m), 4.26-4.76 (6H, m), 4.76-5.13 (2H, m), 8.81-9.51 (2H,m).

[0132] m / z 288.3 [M+H] + .

[0133] Intermediate 2 4-(azacyclobut-1-yl)-2-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine ditrifluoroacetate Step 1 2-Ethyl-4-hydroxy-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate At room temperature, propionimidamide hydrochloride (21.76 g, 200.4 mmol) was added fractionally to a solution of 1-(tert-butyl)-3-ethyl-4-oxopyrrolidine-1,3-dicarboxylate (21.5 g, 83.5 mmol) and Et3N (29.1 mL, 209 mmol) in t-BuOH (50 mL). The mixture was stirred at 80°C for 5 hours under N2 and concentrated under vacuum. THF and water were added to the residue, and the mixture was extracted with EtOAc. The organic layer was separated, washed with 10% citric acid aqueous solution and brine, dried over Na2SO4, and concentrated under vacuum. The residue was added to tert-butyl methyl ether and stirred for 30 minutes. The precipitate was collected by filtration, washed with tert-butyl methyl ether, and dried to give the title compound (6.82 g) as a white solid.

[0134] 1H NMR (300 MHz, CDCl3, 300 K) δ 1.35 (3H, td, J = 7.6, 2.3 Hz), 1.51(9H, s), 2.75 (2H, q, J = 7.6 Hz), 4.49-4.60 (4H, m), 12.16 (1H, br s).

[0135] m / z 266.1 [M+H] + .

[0136] Step 2 4-((1 H -benzo[ d [1,2,3]triazol-1-yl)oxy)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate At room temperature, to 2-ethyl-4-hydroxy-5,7-dihydro-6 H -pyrrolo[3,4- d ]Tertiary butyl pyrimidine-6-carboxylate (6.824 g, 25.72 mmol) was added to a solution of DMF (50 mL) ((1 H -benzo[ d [1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate (V) (14.79 g, 33.44 mmol) and DBU (5.815 mL, 38.58 mmol). The mixture was stirred under N2 at the same temperature for 30 min. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 5%–35% EtOAc in n-hexane) to give the title compound (8.98 g) as a white amorphous solid.

[0137] 1 H NMR (300 MHz, CDCl3, 300 K) δ 0.95 (3H, t, J = 7.6 Hz), 1.54 (9H,s), 2.67 (2H, q, J = 7.6 Hz), 4.68-4.86 (4H, m), 7.41-7.59 (3H, m), 8.13 (1H,d, J = 8.3 Hz).

[0138] m / z 383.2 [M+H] + .

[0139] Step 3 4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate At room temperature, towards 4-((1 H -benzo[ d [1,2,3]triazol-1-yl)oxy)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate (8.98 g, 23.5 mmol) was added to a solution of aziridine butane hydrochloride (3.30 g, 35.2 mmol) and DBU (10.6 mL, 70.4 mmol) in DMF (30 mL). The mixture was stirred under N2 at the same temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 5%–40% EtOAc in n-hexane) to give the title compound (6.43 g) as a white solid.

[0140] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.28 (3H, t, J = 7.6 Hz), 1.50 (9H,s), 2.40 (2H, quin, J = 7.6 Hz), 2.70-2.77 (2H, m), 4.19-4.25 (4H, m), 4.41-4.50 (2H, m), 4.57-4.65 (2H, m).

[0141] m / z 305.1 [M+H] + .

[0142] Step 4 4-(azacyclobut-1-yl)-2-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine ditrifluoroacetate At room temperature, 4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- dA mixture of tert-butyl pyrimidine-6-carboxylate (6.421 g, 21.09 mmol) and TFA (13.0 mL) was stirred for 4 hours. The reaction mixture was concentrated under vacuum (azeotropically with toluene) to give the title compound (14.21 g) as a pale yellow solid.

[0143] 1 H NMR (300 MHz, DMSO- d 6 , 300 K) δ 1.22 (3H, t, J = 7.6 Hz), 2.30-2.45(2H, m), 2.72 (2H, q, J = 7.6 Hz), 4.27-4.48 (6H, m), 4.60 (2H, s), 9.94-10.17 (2H, m).

[0144] m / z 205.1 [M+H] + .

[0145] Example 5 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl) methyl ketone Under microwave irradiation, (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- dA mixture of pyrimidin-6-yl)(pyrrolidine-3-yl)methyl ketone dihydrochloride (28.8 mg, 79.9 μmol), 4-bromo-2-(difluoromethoxy)pyridine (35.8 mg, 160 μmol), Xantphos (4.63 mg, 7.99 μmol), Pd2(dba)3 (7.32 mg, 7.99 μmol), and Cs2CO3 (78.1 mg, 240 μmol) in DME (1 mL) was stirred at 120°C for 1 hour. The mixture was diluted with water (0.5 mL) and extracted with EtOAc (1 mL). Insoluble substances were filtered off, and the solvent was concentrated by blowing away air at 60°C. The residue was purified by preparative HPLC (YMC-TriartC18, eluted with MeCN / 10 mM NH4HCO3 aqueous solution). The desired fraction was evaporated by blowing air at 60°C to give the title compound (8.2 mg).

[0146] m / z 431.3 [M+H] + .

[0147] Example 12-1 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl) methyl ketone Under microwave irradiation, (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- dA mixture of pyrimidin-6-yl)(pyrrolidine-3-yl)methyl ketone dihydrochloride (28.8 mg, 79.9 μmol), 4-bromo-2-(difluoromethoxy)pyridine (35.8 mg, 160 μmol), Xantphos (4.63 mg, 7.99 μmol), Pd2(dba)3 (7.32 mg, 7.99 μmol), and Cs2CO3 (78.1 mg, 240 μmol) in DME (1 mL) was stirred at 120°C for 1 hour. The mixture was diluted with water (0.5 mL) and extracted with EtOAc (1 mL). Insoluble substances were filtered off, and the solvent was concentrated by blowing away air at 60°C. The residue was purified by preparative HPLC (YMC-TriartC18, eluted with MeCN / 10 mM NH4HCO3 aqueous solution). The desired fraction was evaporated by blowing air at 60°C to give the title compound (8.3 mg).

[0148] m / z 399.2 [M+H] + .

[0149] Example 12-2 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl) methyl ketone Step 1 (R) ethyl 1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylate At room temperature, to (R) Ethyl pyrrolidine-3-carboxylate hydrochloride (1.50 g, 8.35 mmol) was added to a solution of 2-chloro-4-fluoropyridine (1000 μL, 10.8 mmol) and DIPEA (3.50 mL, 20 mmol) in DMSO (7 mL). The mixture was stirred at 100°C for 1 hour. The mixture was cooled to room temperature. Water was added to the mixture, and the mixture was extracted three times with EtOAc. The combined organic layers were washed twice with water and then with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 10%–30% EtOAc in n-hexane) to give the title compound (2.10 g) as a colorless oil.

[0150] 1H NMR (300 MHz, CDCl3, 301 K) δ 1.29 (3H, t, J = 7.2 Hz), 2.27-2.37(2H, m), 3.16-3.28 (1H, m), 3.31-3.51 (2H, m), 3.56 (2H, d, J = 7.2 Hz), 4.19(2H, q, J = 7.2 Hz), 6.31 (1H, dd, J = 6.0, 2.3 Hz), 6.39 (1H, d, J = 2.3Hz), 7.97 (1H, d, J = 6.0 Hz).

[0151] m / z 255.2 [M+H] + Step 2 (R) -1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylic acid At room temperature, to (R) Ethyl 1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylate (2.10 g, 8.24 mmol) was added to a solution of EtOH (6 mL) in which 8 M NaOH aqueous solution (2.00 mL, 16.0 mmol) was added. After stirring at the same temperature for 30 minutes, 4 M HCl aqueous solution (4.00 mL, 16.0 mmol) was added to the reaction mixture. The mixture was stirred overnight at the same temperature. The precipitate was collected by filtration and the solid was washed with water and iPr₂O. The solid was dried under vacuum to give the title compound (1.80 g) as a white powder.

[0152] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.08-2.28 (2H, m), 3.15-3.25 (1H,m), 3.31-3.39 (2H, m), 3.41-3.55 (2H, m), 6.46-6.52 (2H, m), 7.85-7.91 (1H,m), 12.52 (1H, br s).

[0153] m / z 227.2 [M+H] + .

[0154] Step 3 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl) methyl ketone At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine (121 mg, 637 μmol), ( R 1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylic acid (1467 mg, 646 μmol) and 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b DIPEA (83 mg, 0.64 mmol) was added to a solution of pyridinium 3-oxide hexafluorophosphate (307 mg, 807 μmol) in DMF (1.5 mL). The mixture was stirred at the same temperature for 1 hour. Water was added to the mixture, and the mixture was extracted five times with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under vacuum to give residue A. The aqueous layer was concentrated under vacuum, and EtOH was added to the residue. Insoluble substances were removed by filtration, and the filtrate was concentrated under vacuum. THF was added to the residue, and insoluble substances were removed by filtration. The filtrate was concentrated under vacuum to give residue B. Residues A and B were combined. The combined residue was purified by preparative HPLC (YMC-Triart C18, eluted with acetonitrile solution containing 10 mM ammonium bicarbonate in H2O). The desired fraction was concentrated under vacuum and azeotropically mixed with MeCN to give the title compound (167 mg) as a white powder.

[0155] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.26-2.49 (4H, m), 2.51 (3H, br s), 3.26-3.47 (2H, m), 3.48-3.72 (3H, m), 4.14-4.40 (4H, m), 4.55-4.97 (4H, m),6.31 (1H, br d, J = 5.4 Hz), 6.39 (1H, br s), 7.97 (1H, d, J = 5.4 Hz).

[0156] m / z 399.3 [M+H] + .

[0157] Example 13 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate At room temperature, to (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl)-methyl ketone (174 mg, 437 μmol) was dissolved in MeCN (1 mL) with fumaric acid (50.6 mg, 436 μmol). EtOH (6 mL) was added to the mixture, and the mixture was stirred at 50°C to obtain a clear solution. The solution was concentrated under vacuum, and the residue was dissolved in EtOH (0.5 mL). The solution was diluted with MeCN (10 mL) and sonicated. A precipitate appeared. The suspension was stirred at 50°C for 30 min, cooled to room temperature, and left overnight at the same temperature. The precipitate was collected by filtration and washed with MeCN, and dried under vacuum to give the title compound (181 mg) as a white powder.

[0158] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.08-2.20 (1H, m), 2.21-2.40 (6H,m), 3.36-3.56 (4H, m), 3.57-3.68 (1H, m), 4.09-4.27 (4H, m), 4.34-4.66 (2H,m), 4.67-5.03 (2H, m), 6.46-6.53 (2H, m), 6.63 (2H, s), 7.86-7.92 (1H, m), 13.06 (2H, br s).

[0159] m / z 399.1 [M+H] + .

[0160] Example 16 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d]pyrimidin-6-yl)(1-(2,5-dichloropyridin-4-yl)pyrrolidine-3-yl) methyl ketone Will (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A mixture of pyrimidin-6-yl)(pyrrolidine-3-yl) methyl ketone dihydrochloride (28.8 mg, 79.9 μmol), 2,5-dichloro-4-fluoropyridine (26.6 mg, 160 μmol), and DIPEA (41.3 mg, 320 μmol) in DMA (1 mL) was stirred overnight at 100°C. The mixture was concentrated by evaporation with air at 60°C. The residue was purified by preparative HPLC (YMC-Triart C18, eluted with MeCN / 10 mMNH4HCO3 aqueous solution). The desired fraction was evaporated by evaporation with air at 60°C to give the title compound (14.2 mg).

[0161] m / z 433.1 [M+H] + .

[0162] Example 32 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone Step 1 (R) -3-( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate At room temperature, to (R) A solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (633 mg, 2.94 mmol) in THF (6 mL) was mixed with oxalyl dichloride (522 μL, 5.94 mmol) and DMF (30.0 μL, 384 μmol). After stirring at the same temperature for 2 h, the mixture was concentrated under vacuum. The residue was dissolved in THF (5 mL), and the solution was added to the solution at room temperature.(R) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine hemispheres 2R,3R The mixture was prepared by stirring 2,3-bis((4-methylbenzoyl)oxy)succinate (see WO2018066718) (1.00 g, 2.52 mmol), saturated aqueous NaHCO3 solution (5 mL), and THF (5 mL) at room temperature for 2 days. The saturated aqueous NaHCO3 solution was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 0%–30% MeOH in EtOAc) to give the title compound (812 mg) as a colorless foam.

[0163] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.39 (3H, d, J = 6.3 Hz), 1.42-1.48(9H, m), 2.07-2.30 (2H, m), 2.37-2.48 (2H, m), 2.49-2.55 (3H, m), 3.02-3.19(1H, m), 3.33-3.43 (1H, m), 3.44-3.74 (3H, m), 4.07-4.18 (2H, m), 4.24-4.34(2H, m), 4.60 (2H, s), 5.35 (1H, q, J = 6.3 Hz).

[0164] m / z 402.4 [M+H] + .

[0165] Step 2 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidine-6-yl)(( R )-Pyrrolidine-3-yl)methyl ketone dihydrochloride At room temperature, 4 M HCl (5 mL, 0.02 mol) from EtOAc was added to... (R) -3- ((R) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H-pyrrolo[3,4- d 812 mg (2.02 mmol) of tert-butyl pyrimidine-6-carbonylpyrrolidine-1-carboxylate was dissolved in MeOH (2 mL). After stirring at the same temperature for 1 hour, the mixture was concentrated under vacuum to give a crude title compound (861 mg) as a yellow oil. This substance could be used in the next reaction without further purification.

[0166] 1 H NMR (300 MHz, CD3OD, 300 K) δ 1.45-1.59 (3H, m), 2.07-2.23 (1H, m), 2.39-2.67 (6H, m), 3.37-3.87 (5H, m), 4.31-4.78 (4H, m), 4.86-5.15 (2H, m),5.30-5.54 (1H, m).

[0167] m / z 302.3 [M+H] + .

[0168] Step 3 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidine-6-yl)(( R )-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone Under microwave irradiation, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (15.4 mg, 18.1 μmol), ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R)A mixture of pyrrolidine-3-yl)methyl ketone dihydrochloride (67.8 mg, 181 μmol), 4-bromo-2-(difluoromethoxy)pyridine (81.1 mg, 362 μmol), Cs₂CO₃ (177 mg, 543 μmol), and DMF (1.5 mL) was heated at 120°C for 1 hour. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum. The residue was purified by column chromatography (NH₄ silica gel, eluted with 0%–30% EtOAc in n-hexane) to obtain a crude product. The crude product was purified by preparative HPLC (YMC-Triart C18, eluted with acetonitrile solution containing 10 mM ammonium bicarbonate in H₂O). The desired fraction was lyophilized to give the title compound (27.1 mg) as a white solid.

[0169] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.39-1.49 (3H, m), 2.31-2.49 (4H, m), 2.51-2.54 (3H, m), 3.25-3.47 (2H, m), 3.52-3.68 (3H, m), 4.13 (2H, q, J = 7.9Hz), 4.29 (2H, q, J = 7.8 Hz), 4.64 (2H, s), 5.37 (1H, q, J = 6.0 Hz), 5.91(1H, d, J = 2.0 Hz), 6.24 (1H, dd, J = 5.9, 2.2 Hz), 7.43 (1H, t, J = 73.8Hz), 7.81 (1H, d, J = 5.9 Hz).

[0170] m / z 445.3 [M+H] + .

[0171] Example 33-1 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate Will( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) 1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone (1.17 g, 2.63 mmol) and fumaric acid (300 mg, 2.58 mmol) were dissolved in EtOH (15 mL) at 60°C. MeCN (30 mL) was added to the solution, and the entire stirred solution was cooled to room temperature. The solution was concentrated under vacuum until a precipitate appeared, and the suspension was then stirred at room temperature for 1 hour and diluted with MeCN. The precipitate was filtered, washed with MeCN, and dried to give the title compound (938 mg) as a colorless powder.

[0172] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.26-1.41 (3H, m), 2.02-2.42 (7H,m), 3.32-3.68 (5H, m), 4.03-4.27 (4H, m), 4.27-4.83 (2H, m), 5.18-5.45 (1H,m), 6.00-6.06 (1H, m), 6.38-6.45 (1H, m), 6.63 (2H, s), 7.43-7.84 (2H, m), 13.11 (2H, br s).

[0173] m / z 445.2 [M+H] + .

[0174] Example 33-2 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate At 0°C, (R) -3-( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d4.20 g (10.5 mmol) of tert-butyl pyrimidine-6-carbonylpyrrolidine-1-carboxylate was dissolved in TFA (15 mL, 0.20 mol) and stirred at room temperature for 20 minutes. The mixture was concentrated under vacuum, diluted with toluene (10 mL), and concentrated under vacuum. A mixture of the residue, 4-bromo-2-(difluoromethoxy)pyridine (3.05 g, 13.6 mmol), Pd2(dba)3 (287 mg, 314 μmol), Xantphos (363 mg, 628 μmol), Cs2CO3 (13.6 g, 41.8 mmol), and DME (50 mL) was stirred overnight at 80°C under N2. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under vacuum, passed through an NH silica gel pad, and eluted with THF. The eluent was concentrated under vacuum and purified by column chromatography (silica gel, eluted with 0%-10% MeOH in EtOAc) to obtain a pale yellow gel. (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone (3.62 g).

[0175] A pale yellow gel and fumaric acid (0.95 g, 8.2 mmol) were dissolved in EtOH (10 mL) and MeCN (20 mL) at 60°C. The solution was concentrated under vacuum to half its volume, and the stirred mixture was cooled to room temperature to produce a precipitate. MeCN (20 mL) was added dropwise to the stirred suspension, and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered, washed with MeCN, and dried to give the title compound (3.22 g) as a colorless powder.

[0176] 1 H NMR (300 MHz, DMSO- d 6 , 301 K) δ 1.24-1.42 (3H, m), 2.02-2.43 (7H,m), 3.32-3.67 (5H, m), 4.02-4.25 (4H, m), 4.26-4.85 (2H, m), 5.17-5.46 (1H,m), 6.00-6.06 (1H, m), 6.38-6.46 (1H, m), 6.63 (2H, s), 7.36-7.90 (2H, m), 13.09 (2H, br s).

[0177] m / z 445.0 [M+H] + .

[0178] Example 33-3 – Synthesis of the compound of Example 33 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate Step 1 (R) Methyl 1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-carboxylate At room temperature, tripotassium phosphate (419 g, 1.98 mol) was added to 4-bromo-2-(difluoromethoxy)pyridine (177 g, 790 mmol) and (R) 3-pyrrolidine-3-carboxylic acid (100 g, 869 mmol) was added to a mixture in DMSO (600 mL). The mixture was stirred at 50°C over a period of time. The mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to below 10°C, and methyl iodine (168 g, 1.19 mol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The mixture was quenched at 0°C with water (2000 mL) and extracted twice with TBME (1000 mL). The organic layers were combined, washed with water and brine, dried over MgSO4, and concentrated under vacuum. The residues were combined and recrystallized from TBME-n-hexane (1:5, v / v, 600 mL, dissolved at 70°C and then cooled to 0°C) to give the title compound (170.3 g) as a white solid.

[0179] 1 H NMR (300 MHz, DMSO- d 6 , 301 K) δ 2.06-2.32 (2H, m), 3.23-3.59 (5H,m), 3.65 (3H, s), 6.02 (1H, d, J = 1.9 Hz), 6.42 (1H, dd, J = 6.0, 2.3 Hz),7.29-7.93 (1H, m), 7.79 (1H, d, J = 6.0 Hz).

[0180] m / z 273.1 [M+H] + .

[0181] The optical purity was determined to be 98.6% ee by chiral HPLC (column: CHIRALPAK IH (CP029) 4.6 mm ID * 250 mm L, 5 μm. Mobile phase: CO2 / 0.5% diethylamine in 2-propanol = 860 / 140 (v / v)).

[0182] Step 2 (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-carboxylate salt At 50°C, (R) A mixture of methyl 1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-carboxylate (168 g, 616 mmol) and 3N HCl in water (1800 mL, 5.40 mol) was stirred for 3 hours. The mixture was concentrated under vacuum. MeCN was added to the residue. The mixture was concentrated under vacuum (almost all the water should be removed by azeotropic extraction). The residue was ground with MeCN (900 mL) and THF (900 mL), and the precipitate was collected by filtration to give the title compound (144 g) as a grayish-white solid. The mother liquor was concentrated under vacuum and ground with MeCN (300 mL) and THF (300 mL), and the precipitate was collected by filtration to give the title compound (29 g) as a grayish-white solid.

[0183] 1 H NMR (400 MHz, DMSO- d 6 δ 2.10–2.30 (2H, m), 3.24 (1H, quin, J = 7.1 Hz), 3.35–3.46 (2H, m), 3.48–3.64 (2H, m), 6.18 (1H, br s), 6.43–6.62 (1H, m), 7.43–7.92 (2H, m). 2H was not clearly observed.

[0184] m / z 259.0 [M+H] + .

[0185] The optical purity was determined to be 97.6% ee and 99.8% ee by chiral HPLC (column: CHIRALPAK IH (CP029) 4.6 mm ID * 250 mmL, 5 μm. Mobile phase: CO2 / 0.5% diethylamine in 2-propanol = 860 / 140 (v / v)).

[0186] Step 3 (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone At room temperature, to (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-carboxylate (9.79 g, 33.2 mmol) and triethylamine (4.63 mL, 33.2 mmol) were added in portions to a suspension in MeCN (512 mL) of di(1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-carboxylate (9.79 g, 33.2 mmol) and triethylamine (4.63 mL, 33.2 mmol) in MeCN (512 mL). H (-Imidazol-1-yl)methyl ketone (5.63 g, 34.7 mmol) was added, and the mixture was stirred at room temperature for 60 minutes. The mixture was cooled to 0°C, and triethylamine (6.11 g, 60.4 mmol) was added. The mixture was then heated at 0°C. (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine hemispheres (2R,3R) -2,3-bis((4-methylbenzoyl)oxy)succinate (12.0 g, 15.1 mmol) was added in portions to the mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated NaHCO3 solution (500 mL) and extracted twice with EtOAc (500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under vacuum. The residue was passed through a silica gel pad (300 g of NH silica gel, eluted with 50% EtOAc in n-hexane) to give a white amorphous title compound (12.7 g).

[0187] 1 H NMR (400 MHz, DMSO- d 6 , 303 K) δ 1.26-1.43 (3H, m), 2.04-2.43 (7H,m), 3.33-3.70 (5H, m), 3.97-4.24 (4H, m), 4.27-4.87 (2H, m), 5.13-5.53 (1H,m), 6.02 (1H, d, J = 1.9 Hz), 6.41 (1H, dd, J= 6.0, 1.9 Hz), 7.25-7.96 (2H,m). m / z 445.1 [M+H] + .

[0188] Step 4 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate At room temperature, to ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone (2.24 g, 5.04 mmol) was added to a solution of EtOH (26 mL) with fumaric acid (526 mg, 4.54 mmol), and the mixture was stirred at 78°C for 1 hour. Insoluble substances were filtered off, and the filtrate was concentrated under vacuum to remove EtOH. MeCN (26 mL) was added to the residue, and the mixture was stirred at room temperature for 3 hours. The precipitate was filtered and washed with MeCN (20 mL) to give a crude product of a grayish-white solid. (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate (2.10 g). The resulting crude product ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) 1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate (263 mg, 469 μmol) was dissolved in EtOH (4 mL) at 75°C. Heptane (6 mL) was added dropwise to this solution over 30 minutes at 70°C. The mixture was stirred at 45–50°C for 5 hours and then overnight at room temperature. The resulting precipitate was collected by filtration to give the title compound (178 mg) as colorless crystals.

[0189] 1 H NMR (400 MHz, DMSO- d 6 , 298 K) δ 1.18-1.51 (3H, m), 2.04-2.42 (7H,m), 3.38-3.68 (5H, m), 4.03-4.25 (4H, m), 4.26-4.85 (2H, m), 5.13-5.48 (1H,m), 5.97-6.09 (1H, m), 6.41 (1H, br d, J = 5.9 Hz), 6.63 (2H, s), 7.33-7.95(2H, m), 12.54-13.72 (2H, br s).

[0190] m / z 445.1 [M+H] + .

[0191] The ratio of enantiomers to diastereomers was determined by chiral HPLC (column: CHIRALPAK IF(TK009) 4.6 mm ID * 250 mmL, 5 μm. Mobile phase: n-hexane / ethyl acetate / diethylamine = 100 / 900 / 1 (v / v / v)). The ratio was 100.00:ND:ND.

[0192] Example 37 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(5-chloropyridin-3-yl)pyrrolidine-3-yl) methyl ketone Step 1 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]Pyrimidin-6-yl)(pyrrolidine-3-yl)methyl ketone ditrifluoroacetate Add trifluoroacetic acid (2 mL) to room temperature. (R) -3-(4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4-d The mixture was added to tert-butyl pyrimidine-6-carbonyl)-pyrrolidine-1-carboxylate (1478 mg, 381 μmol). The mixture was stirred at the same temperature for 10 minutes. The mixture was concentrated under vacuum to give a crude title compound (233 mg) as an orange oil. This product was ready for the next reaction without further purification.

[0193] m / z 288.1 [M+H] + .

[0194] Step 2 (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(5-chloropyridin-3-yl)pyrrolidine-3-yl) methyl ketone Under microwave irradiation, the crude product (R) -(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A mixture of pyrimidin-6-yl)(pyrrolidine-3-yl) methyl ketone ditrifluoroacetate (48.6 mg), 5-bromo-3-chloropyridine (22.8 mg, 118 μmol), RuPhos Pd G4 (10.0 mg, 11.8 μmol), Cs2CO3 (144 mg, 442 μmol), and DME (2 mL) was heated at 120°C for 2 hours. The mixture was purified by column chromatography (silica gel, eluted with 0%–40% MeOH in EtOAc), followed by column chromatography (NH silica gel, eluted with 50%–100% EtOAc in n-hexane) to give the title compound (21.0 mg) as a white powder.

[0195] 1 H NMR (300 MHz, CDCl3, 301 K) δ 2.28-2.55 (7H, m), 3.27-3.57 (3H, m), 3.57-3.64 (2H, m), 4.20-4.31 (4H, m), 4.58-4.94 (4H, m), 6.80 (1H, dd, J =2.6, 1.9 Hz), 7.86 (1H, d, J = 2.6 Hz), 7.90 (1H, d, J = 1.9 Hz).

[0196] m / z 399.3 [M+H]+.

[0197] Example 38 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(5-chloropyridin-3-yl)pyrrolidine-3-yl)methyl ketone Under microwave irradiation, the crude product ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) A mixture of 3-pyrrolidine-3-yl)methyl ketone dihydrochloride (38.5 mg), 5-bromo-3-chloropyridine (31.4 mg, 163 μmol), RuPhos Pd G4 (7.4 mg, 8.7 μmol), Cs2CO3 (137 mg, 422 μmol), DME (1.5 mL), and DMF (0.5 mL) was heated at 120°C for 2 hours. The mixture was purified by column chromatography (silica gel, eluted with 0%–25% MeOH in EtOAc), followed by column chromatography (NH silica gel, eluted with 50%–100% EtOAc in n-hexane) to give the title compound (10.9 mg) as a colorless foam.

[0198] 1 H NMR (300 MHz, CDCl3, 300 K) δ 1.37-1.52 (3H, m), 2.29-2.64 (7H, m), 3.24-3.73 (5H, m), 4.07-4.21 (2H, m), 4.24-4.36 (2H, m), 4.40-4.84 (2H, m), 5.17-5.42 (1H, m), 6.76-6.83 (1H, m), 7.84-7.88 (1H, m), 7.88-7.92 (1H, m).

[0199] m / z 413.3 [M+H] + .

[0200] Example 39 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d]pyrimidin-6-yl)( (R) -1-(2-methoxypyridin-4-yl)pyrrolidine-3-yl)methyl ketone Under microwave irradiation, the crude product ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) A mixture of pyrrolidine-3-yl)methyl ketone dihydrochloride (65.4 mg), 4-iodo-2-methoxypyridine (72.2 mg, 307 μmol), Cs₂CO₃ (200 mg, 614 μmol), RuPhos Pd G₄ (13.1 mg, 15.4 μmol), and DME (1 mL) was heated at 120°C for 1 hour. The residue was purified by preparative HPLC (YMC-Triart C18, eluting with acetonitrile solution containing 10 mM ammonium bicarbonate and H₂O). The desired fraction was lyophilized to give the title compound (18.9 mg) as a white solid.

[0201] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.37-1.48 (3H, m), 2.28-2.37 (2H, m), 2.37-2.50 (2H, m), 2.51-2.54 (3H, m), 3.22-3.44 (2H, m), 3.48-3.65 (3H, m),3.86-3.92 (3H, m), 4.10-4.19 (2H, m), 4.25-4.33 (2H, m), 4.65 (2H, s), 5.37(1H, q, J = 6.3 Hz), 5.77 (1H, d, J = 2.2 Hz), 6.13 (1H, dd, J = 6.0, 2.1Hz), 7.84 (1H, d, J = 5.9 Hz).

[0202] m / z 409.2 [M+H] + .

[0203] Example 41 (R) -(4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate Step 1 (R) ethyl 1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylate At room temperature, to (R) Ethyl pyrrolidine-3-carboxylate hydrochloride (1.50 g, 8.35 mmol) was added to a solution of 2-chloro-4-fluoropyridine (1000 μL, 10.8 mmol) and DIPEA (3.50 mL, 20 mmol) in DMSO (7 mL). The mixture was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature. Water was added to the mixture, and the mixture was extracted three times with EtOAc. The combined organic layers were washed twice with water and then with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 10%–30% EtOAc in n-hexane) to give the title compound (2.10 g) as a colorless oil.

[0204] 1 H NMR (300 MHz, CDCl3, 301 K) δ 1.29 (3H, t, J = 7.2 Hz), 2.27-2.37(2H, m), 3.16-3.28 (1H, m), 3.31-3.51 (2H, m), 3.56 (2H, d, J = 7.2 Hz), 4.19(2H, q, J = 7.2 Hz), 6.31 (1H, dd, J = 6.0, 2.3 Hz), 6.39 (1H, d, J = 2.3Hz), 7.97 (1H, d, J = 6.0 Hz).

[0205] m / z 255.2 [M+H] + .

[0206] Step 2 (R) -1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylic acid At room temperature, to (R)Ethyl 1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylate (2.10 g, 8.24 mmol) was added to a solution of EtOH (6 mL) in which 8 M NaOH aqueous solution (2.00 mL, 16.0 mmol) was added. After stirring at the same temperature for 30 minutes, 4 M HCl aqueous solution (4.00 mL, 16.0 mmol) was added to the reaction mixture. The mixture was stirred overnight at the same temperature. The precipitate was collected by filtration and the solid was washed with water and iPr₂O. The solid was dried under vacuum to give the title compound (1.80 g) as a white powder.

[0207] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.08-2.28 (2H, m), 3.15-3.25 (1H,m), 3.31-3.39 (2H, m), 3.41-3.55 (2H, m), 6.46-6.52 (2H, m), 7.85-7.91 (1H,m), 12.52 (1H, br s).

[0208] m / z 227.2 [M+H] + .

[0209] Step 3 (R) -(4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl) methyl ketone At room temperature, 4-(azacyclobut-1-yl)-2-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine bis(trifluoroacetate) (650 mg, 964.9 μmol) was added to a solution of DMF (8 mL). (R) -1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylic acid (219 mg, 965 μmol), 2-(3 H -[1,2,3]triazolo[4,5- bPyridin-3-yl)-1,1,3,3-tetramethylisourea-1,1,3,3-tetramethylisourea-1,447 mmol (V) and DIPEA (499 mg, 3.86 mmol). The mixture was stirred under N2 at the same temperature for 16 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The aqueous layer was concentrated under vacuum. The residue was purified by preparative HPLC (YMC-Triart C18, eluting with acetonitrile solution containing 10 mM ammonium bicarbonate in H2O). The desired fraction was lyophilized to give the title compound (183 mg) as a white solid.

[0210] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.29 (3H, t, J = 7.6 Hz), 2.29-2.49(4H, m), 2.71-2.79 (2H, m), 3.29-3.44 (2H, m), 3.52-3.66 (3H, m), 4.21-4.30(4H, m), 4.60-4.90 (4H, m), 6.31 (1H,dd, J = 5.9, 2.2 Hz), 6.39 (1H, d, J =2.2 Hz), 7.96 (1H, d, J = 5.9 Hz).

[0211] m / z 413.2 [M+H] + .

[0212] Step 4 (R) -(4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidine-3-yl)methyl ketone fumarate Add EtOH (5 mL) to room temperature (R) -(4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- dA mixture of pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)-pyrrolidine-3-yl) methyl ketone (161 mg, 389 μmol) and fumaric acid (45.1 mg, 389 μmol) was prepared. The mixture was stirred at 50°C for 5 minutes to obtain a clear solution. The solution was concentrated under vacuum, and the residue was dissolved in EtOH (3 mL). The solution was diluted with MeCN (10 mL) and sonicated. A precipitate appeared. The suspension was stirred at 50°C for 20 minutes, cooled to room temperature, and left to stand at the same temperature for a weekend. The precipitate was collected by filtration and washed with a small amount of MeCN, and dried under vacuum to obtain a white powder (116 mg, powder A). The filtrate was concentrated under vacuum to obtain a residue (88 mg). MeCN (2 mL) and EtOAc (2 mL) were added to the residue, and the solution was sonicated. A precipitate appeared. iPr2O (3 mL) and powder A were added to the suspension. The suspension was sonicated, stirred at 50°C for 20 minutes, cooled to room temperature, and placed in a refrigerator for 20 minutes. The precipitate was collected by filtration, and the solid was washed with a small amount of EtOAc and dried under vacuum to give the title compound (181 mg) as a white powder.

[0213] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.14-1.24 (3H, m), 2.08-2.40 (4H,m), 2.58-2.67 (2H, m), 3.33-3.54 (4H, m), 3.56-3.68 (1H, m), 4.10-4.29 (4H,m), 4.34-4.67 (2H, m), 4.68-5.04 (2H, m), 6.44-6.54 (2H, m), 6.63 (2H, s), 7.84-7.94 (1H, m), 13.10 (2H, br s).

[0214] m / z 413.1 [M+H] + .

[0215] Example 43 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2,5-dichloropyridin-4-yl)pyrrolidine-3-yl)methyl ketone Step 1 (R) -3-((R)-4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate At room temperature, to (R) 1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (1.1 g, 5.1 mmol) was added to a solution of 1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid in THF (11 mL) and DMF (77 mg, 1.1 mmol) with oxalyl dichloride (1.3 g, 11 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and dissolved in THF (10 mL). This mixture was then added to... (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine hemispheres 2R,3R 1.2 g (3.0 mmol) of 2,3-bis((4-methylbenzoyl)oxy)succinate and 15 mL of saturated NaHCO3 aqueous solution were stirred in THF (10 mL) and the mixture was stirred at room temperature for 2 days. The mixture was partitioned between EtOAc and water, and the EtOAc layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 50%–100% EtOAc in n-hexane) to give the title compound (1.20 g) as a colorless gel.

[0216] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.39 (3H, d, J = 6.1 Hz), 1.46 (9H,s), 2.06-2.22 (2H, m), 2.37-2.49 (2H, m), 2.51 (3H, s), 3.04-3.17 (1H, m), 3.32-3.43 (1H, m), 3.44-3.67 (3H, m), 4.12-4.17 (2H, m), 4.23-4.34 (2H, m), 4.60 (2H, s), 5.31-5.39 (1H, m).

[0217] m / z 402.2 [M+H] + .

[0218] Step 2 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidine-6-yl)(( R )-Pyrrolidine-3-yl)methyl ketone ditrifluoroacetate At room temperature, (R) -3-( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d A mixture of tert-butyl pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate (1.2 g, 3.0 mmol) and TFA (10 mL) was stirred for 1 hour. After removing the solvent under vacuum, the resulting residue was suspended in toluene and the mixture was concentrated under vacuum at 70°C to give a crude title compound (2.20 g) as a colorless gel. This substance could be used for the next reaction without further purification.

[0219] m / z 302.1 [M+H] + .

[0220] Step 3 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(2,5-dichloropyridin-4-yl)pyrrolidine-3-yl)methyl ketone Will(( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidine-6-yl)(( R A mixture of 3-pyrrolidine-3-yl)methyl ketone ditrifluoroacetate (50 mg, 94 μmol), 2,5-dichloro-4-fluoropyridine (31 mg, 0.19 mmol), and DIPEA (66 μL, 0.38 mmol) in DMA (5 mL) was stirred overnight at 100°C. After removing the solvent under vacuum, the residue was partitioned between EtOAc and water. The EtOAc layer was washed five times with water, washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (NH4 silica gel, eluted with 50%–100% EtOAc in n-hexane) to give the title compound (19 mg) as a colorless gel.

[0221] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.41 (3H, d, J = 6.1 Hz), 2.23-2.32(2H, m), 2.38-2.49 (2H, m), 2.52 (3H, s), 3.14-3.28 (1H, m), 3.67-3.81 (2H,m), 3.83-3.99 (2H, m), 4.06-4.20 (2H, m), 4.24-4.38 (2H, m), 4.64 (2H, d, J =0.7 Hz), 5.30-5.43 (1H, m), 6.52 (1H, s), 8.00 (1H, s).

[0222] m / z 447.1 [M+H] + .

[0223] Example 45 ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (R) -1-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-3-yl)methyl ketone Under microwave irradiation, ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- dA mixture of pyrimidin-6-yl)((R)-pyrrolidine-3-yl) methyl ketone ditrifluoroacetate (100 mg, 189 μmol), 2-bromo-5-chloro-3-fluoropyridine (71.5 mg, 340 μmol), Cs₂CO₃ (308 mg, 944 μmol), and methanesulfonic acid (2-dicyclohexylphosphine-2',6'-di-isopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (16.1 mg, 18.9 μmol) in DMF (1 mL) and DME (3 mL) was heated at 120°C for 2 hours. At room temperature, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 30%-90% EtOAc in n-hexane) to give the title compound (40 mg) as a colorless gel.

[0224] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.41 (3H, d, J = 6.4 Hz), 2.18-2.36(2H, m), 2.38-2.49 (2H, m), 2.52 (3H, s), 3.14-3.26 (1H, m), 3.64-3.76 (1H,m), 3.79-3.95 (3H, m), 4.09-4.16 (2H, m), 4.22-4.34 (2H, m), 4.61-4.69 (2H,m), 5.29-5.42 (1H, m), 7.18 (1H, dd, J = 12.3, 2.1 Hz), 7.86-7.89 (1H, m).

[0225] m / z 431.2 [M+H] + .

[0226] Example 50 ( (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)((S)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone (S,S) -Isomer) Step 1 (R)-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate 4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d The racemic mixture of tert-butyl pyrimidine-6-carboxylate (240 g, 788 mmol) was separated by chiral separation (column: DAICL CHIRALPAK AD (250 mm * 50 mm, 10 μm), mobile phase: CO2-EtOH (0.1% NH4OH)) to obtain a brown solid. (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ] tert-butyl pyrimidine-6-carboxylate (109 g, tR1) and brown solid ( S )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d 110 g of tert-butyl pyrimidine-6-carboxylate (tR2). The optical purity of tR1 was determined to be 100% ee by analysis using a chiral SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, mobile phase: phase A is CO2 and phase B is EtOH (0.05% diethylamine)). The optical purity of tR2 was 98.7% ee.

[0227] tR1 analysis data: 1 H NMR (400 MHz, DMSO- d 6 ) δ 1.25-1.34 (3H, m), 1.40-1.50 (9H, m), 2.27-2.40 (5H, m), 4.04-4.21 (4H, m), 4.24-4.39 (2H, m), 4.92-5.10 (1H, m).

[0228] m / z 305.2 [M+H] + .

[0229] tR2 analysis data: 1 H NMR (400 MHz, DMSO- d 6 ) δ 1.21-1.34 (3H, m), 1.40-1.50 (9H, m), 2.25-2.40 (5H, m), 4.00-4.42 (6H, m), 4.89-5.09 (1H, m).

[0230] m / z 305.2 [M+H] + .

[0231] Step 2 (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dimethylsulfonate At room temperature, to (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d 2.00 g (6.57 mmol) of tert-butyl pyrimidine-6-carboxylate was added to a solution of methanesulfonic acid (1.58 g, 16.4 mmol) in CH3CN (20 mL). The mixture was stirred at room temperature for 5 days and then stirred overnight at 60°C. The reaction mixture was concentrated under vacuum to give a crude product as a brown oil. (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dimethylsulfonate (3.27 g).

[0232] 1 H NMR (300 MHz, DMSO- d 6 , 300 K) δ 1.48 (3H, d, J = 6.4 Hz), 2.36(7.5H, s), 2.37-2.45 (2H, m), 2.48 (3H, s), 4.19-5.20 (7H, m), 9.41-10.07(2H, m).

[0233] m / z 205.1 [M+H] + .

[0234] Step 3 (S) -3-(( S )-4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate At room temperature, to (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dimethylsulfonate (995 mg, 89 Wt%, 2.23 mmol), (3 S HATU (1.27 g, 3.35 mmol) was added to a solution of 1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (578 mg, 2.69 mmol) and DIPEA (2.00 mL, 11.5 mmol) in DMF (10 mL). The mixture was stirred at the same temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 20%–80% EtOAc in n-hexane) to give a colorless foam. (S) -3-( (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d 608 mg) pyrimidine-6-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0235] 1 H NMR (300 MHz, CDCl3, 301 K) δ 1.36-1.51 (12H, m), 2.06-2.32 (2H,m), 2.35-2.57 (5H, m), 3.01-3.24 (1H, m), 3.30-3.45 (1H, m), 3.46-3.81 (3H,m), 4.04-4.20 (2H,m), 4.21-4.35 (2H,m), 4.37-4.83 (2H,m), 5.10-5.42 (1H,m).

[0236] m / z 402.2 [M+H] + .

[0237] Step 4 ( (S)-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (S) -1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone At room temperature, ( S )-3-( (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d A mixture of tert-butyl pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate (608 mg, 1.51 mmol) and TFA (8 mL, 0.1 mol) was stirred for 1 hour. The mixture was concentrated under vacuum. Toluene and MeCN were added to the residue, and the mixture was concentrated under vacuum. This process was repeated 3 times. At room temperature, 4-bromo-2-(difluoromethoxy)pyridine (441 mg, 1.97 mmol), Pd2(dba)3 (68 mg, 75.7 μmol), Xanthos (88 mg, 151 μmol), and Cs2CO3 (2.47 g, 7.57 mmol) were added to a solution of the residue in DME (16 mL). The mixture was stirred at 80°C under Ar for 16 hours. The mixture was cooled to room temperature, filtered, and washed with EtOAc. The filtrate was concentrated under vacuum, passed through an NH-SiO2 pad, and eluted with THF. The eluent was concentrated under vacuum, and the residue was purified by column chromatography (silica gel, eluted with 0%-10% MeOH in EtOAc) to obtain a pale yellow amorphous powder. (S) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidin-6-yl)((S)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3-yl) methyl ketone (536 mg).

[0238] 1 H NMR (400 MHz, DMSO- d 6 , 296 K) δ 1.21-1.48 (3H, m), 1.70-2.44 (7H,m), 3.35-3.70 (5H, m), 3.97-4.87 (6H, m), 5.15-5.47 (1H, m), 6.03 (1H, br s), 6.36-6.50 (1H, m), 7.41-7.89 (2H, m).

[0239] m / z 445.2 [M+H] + .

[0240] Examples 51 and 52: Diastereomers of the compound in Example 33 were prepared in a manner similar to that in Example 50.

[0241] 51 is (( S )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidine-6-yl)(( R )-1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone.

[0242] m / z 445.2 [M+H] + .

[0243] 1 H NMR (400 MHz, DMSO- d 6 , 296 K) δ 1.25-1.41 (3H, m), 2.04-2.43 (7H,m), 3.27-3.70 (5H, m), 4.04-4.24 (4H, m), 4.28-4.79 (2H, m), 5.19-5.48 (1H,m), 6.00-6.07 (1H, m), 6.39-6.46 (1H, m), 7.64 (1H, t, J = 73.7 Hz), 7.79(1H, d, J = 5.9 Hz).

[0244] 52 is ( (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)( (S) -1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)pyrrolidine-3-yl)methyl ketone.

[0245] m / z 445.3 [M+H] + .

[0246] 1 H NMR (300 MHz, DMSO- d 6, 301 K) δ 1.21-1.48 (3H, m), 2.01-2.42 (7H,m), 3.27-3.74 (5H, m), 3.96-4.79 (6H, m), 5.12-5.50 (1H, m), 5.96-6.09 (1H,m), 6.30-6.52 (1H, m), 7.63 (1H, t, J = 73.8 Hz), 7.79 (1H, d, J = 6.0 Hz).

[0247] Table 1. Chemical structures, compound names, preparation methods, and physicochemical data of Examples 1-49. Bioassay In vitro M4 and M2 function assays The functional activity of compounds at M4 and M2 receptors was determined by measuring changes in intracellular calcium ion levels induced by receptor-mediated signaling cascades. Intracellular calcium levels were measured using the calcium-sensitive fluorescent dye “Calcium Kit II – iCellux” (DOJINDO). Fluorescence changes were monitored using a fluorescence imager FDSS μCELL (Hamamatsu Photonics K.K.). Increased intracellular calcium was readily detectable when the muscarinic receptor agonist acetylcholine activated both receptors.

[0248] Stable CHO-K1 / M4 / Gα15 cell lines (M00238, GenScript) or CHO-K1 / M2 / Gα15 cell lines (M00258, GenScript) were routinely grown as monolayers in Ham's F-12K medium (FUJIFILM Wako PureChemical Corporation) at 37°C in 5% CO2, supplemented with 10% fetal bovine serum (FBS) (Corning), 200 μg / ml Zeocin (Invitrogen), and 100 μg / ml hygromycin B (FUJIFILM Wako PureChemical Corporation). Once confluent, cells were cryopreserved at -186°C in CELLBANKER 1plus (NIPPON ZENYAKU KOGYOCO., LTD.). 24 hours prior to testing, cells were thawed and the frozen medium was removed by centrifugation. Cells were then seeded at a density of 8,000 cells / 20 μl / well in 384-well (Greiner) plates with black walls and clear bottoms in Ham's F-12K medium supplemented with 10% FBS. On the day of assay, 20 μl of Calcium Kit II-iCellux dye solution was added to the cells, and the cells were incubated at 37°C. 0 C. Incubate at 5% CO2 for 45 minutes.

[0249] Accomplishment assay: 10 µL of the test compound diluted in HBSS, 20 mM HEPES, 0.1% BSA, or 0.5% (finally 0.1%) DMSO was added to each well and the fluorescence intensity was measured using FDSS μCELL for 3 minutes.

[0250] Positive allosteric modulator (PAM) assay: 10 µL of the test compound diluted in HBSS, 20 mM HEPES, 0.1% BSA, or 0.5% (final 0.1%) DMSO containing 15 nM (final 3 nM) to 45 nM (final 9 nM) acetylcholine (M2) or 75 nM (final 15 nM) acetylcholine (M4) was added to each well, and fluorescence intensity was measured using an FDSS μCELL for 3 minutes. The concentration of acetylcholine used was expected to induce a 20% maximal cellular response to acetylcholine (i.e., EC20). Acetylcholine EC20 in each plate was evaluated and used to recalibrate EC20 (if necessary) for subsequent experiments.

[0251] Data Analysis: In the agonist and PAM assays, cellular response data generated using serial dilutions of the test compound (or acetylcholine) up to 10 µM were fitted to a four-parameter logistic equation using CDD Vault (Collaborative Drug Discovery, Burlingame, CA). The fitted maximum response of all compounds relative to 10 µM acetylcholine (relative efficacy, RE) is reported. The concentrations of the test compound that produced a half-maximum response (EC50) for all compounds with an RE equal to or greater than 50% are reported. “ND” (“Undetermined”) indicates an RE less than 50%. Results are shown in tables.

[0252] Table 2. Bioassay Results Determination of in vitro clearance rate Oxidative metabolic clearance using microsomes Liver microsomes were obtained from Sekisui XenoTech, LLC. (Kansas City, Kansas). Microsomes (0.2 mg protein / mL) and compounds (1 μmol / L) were mixed in phosphate-buffered saline (pH 7.4). The reaction was initiated by adding an NADPH-generating system (a mixture of MgCl2, β-NADP+, glucose-6-phosphate, and glucose-6-phosphate dehydrogenase) to the mixture. Incubation was performed at 37°C and terminated by adding acetonitrile at 15 min and 30 min. As a control, zero-time incubation was performed, terminated by adding acetonitrile before adding the NADPH-generating system. After mixing and centrifuging, the concentration of compounds in the supernatant fraction was measured using LC-MS / MS with a Unison UK-C18 HT column (3.0 μm, 2.0 × 20 mm).

[0253] The clearance rate (μL / min / mg protein) is calculated as follows: {1000 × rate constant (calculated as an exponential function of the residual rate versus time curve, assuming it is first-order elimination) / microsomal protein (mg / mL)} WO 2018 / 066718 discloses reference compounds T1 as Example 29, T2 as Example 111 and T3 as Example 176. The activity of the reference compound against the M4 receptor and the in vitro clearance rates of the reference compound and Example 33 were also determined. The results are shown in Table 2. Example 33 showed a significantly lower clearance rate compared to Examples T1, T2 and T3.

[0254] METH-induced hyperkinesis assay from J Jackson Laboratory J apan Inc. (Kanagawa, Japan) purchased seven-week-old male Wistar rats for METH-induced hyperactivity assays. All animals were maintained on a 12-hour light / dark cycle with free access to food and water. Room temperature and humidity ranged from 20°C to 26°C and 40% to 70%, respectively. All procedures were performed in accordance with animal testing guidelines and approved by the Institutional Animal Care and Use Committee of Shonan Health Innovation Park. The facility is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0255] Motor activity was measured using a SUPERMEX spontaneous movement analyzer (Muromachi Kikai, Japan). Animals were placed in exercise rooms (L×W×H: 24 cm×37 cm×30 cm) for habituation the afternoon of the day prior to testing. On the day of testing, they were removed from each room and treated with an oral administration of a medium (0.5 w / v % methylcellulose 400 solution), Example 33, or CVL-231, and then quickly returned to the room. Thirty minutes after drug treatment, the animals were again removed from the room and treated with a medium (saline) or METH (0.25 mg / kg subcutaneously, Sumitomo Dainippon Pharma, Japan), and then quickly transferred to the test room. Activity counts were recorded in consecutive 1-minute intervals (bins), and then counts were recorded for every 5-minute interval, as well as cumulative counts at 30, 60, 90, and 120 minutes after METH administration. The results are shown in Table 3.

[0256] Table 3 As can be seen from Table 3, Example 33 is more effective than the prior art compound CVL-231 in reversing METH-induced hypermotility, with a MED of 10 mg / kg (relative to 60 mg / kg).

[0257] Cardiovascular remote sensing research in monkeys The cardiovascular (CV) effects of the test compound can be assessed in suitable test subjects, such as male cynomolgus monkeys (n=3 or 4), using telemetry studies. The test compound can be administered orally once daily via a Latin square crossover design, with intervals of 6 or 7 days or longer. Heart rate, blood pressure, and ECG can be monitored within 24 hours of administration, and the CV effect between the test compound and the mediator control group can be qualitatively and quantitatively assessed at each measurement point. Pharmacokinetics (PK) can be analyzed to examine the dose-response relationship before or after CV measurements. Plasma concentrations of the test compound in all animals can be measured 4 hours after administration for comparison with the PK profile. The compounds of the present invention (including Example 33) can be compared with prior art compounds. Examples of dose levels include 5 mg / kg, 10 mg / kg, 20 mg / kg, and 30 mg / kg. Measurable parameters include systolic blood pressure, diastolic blood pressure, and HR, as well as ECG parameters (RR interval, PR interval, QRS duration, QT interval, and individually corrected QT interval [QTci interval]).

[0258] Compared to the prior art M4 PAM, the compounds of the present invention are expected to show less severe effects on at least one of systolic blood pressure, diastolic blood pressure and HR in terms of duration and / or extent.

[0259] The foregoing description is intended to provide a complete overview and description of how to manufacture and use the various embodiments claimed below to those skilled in the art, and is not intended to limit the scope of the disclosure herein. Obvious modifications to those skilled in the art are intended to fall within the scope of the appended claims. All publications, patents, and patent applications referenced in this specification are incorporated herein by reference, as if each such publication, patent, or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

1. A compound having the following formula, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or deuterated analogue thereof: in R1 is a 4- or 5-membered heterocycle, each of which can be unsubstituted or substituted by one or more substituents, and the 4- or 5-membered heterocycle contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. R2 is a C1-C6 alkyl group; A is a 4- or 5-membered heterocycle, each of which can be unsubstituted or substituted by one or more substituents, and the 4- or 5-membered heterocycle contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. R3 is a hydrogen atom or a C1-C6 alkyl group; and Ar is a 5-10 membered heterocycle, an aromatic or heteroaromatic monocyclic or bicyclic ring, each of which can be unsubstituted or substituted with one or more substituents, and each heterocycle or heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein the compound has the following formula: 。 3. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein the compound has the following formula: in R 4a and R 4b Each is independently selected from the group consisting of hydrogen atoms, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, and hydroxyl groups.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein the compound has the following formula: in R 4a and R 4b Each is independently selected from the group consisting of hydrogen atoms, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, and hydroxyl groups.

5. The compound according to claim 1 or 2, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein R1 is an unsubstituted or substituted four-membered heterocycle.

6. The compound according to claim 1 or 2, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein R1 is a 4-membered heterocycle substituted with one or more substituents.

7. The compound of claim 6, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy and hydroxyl.

8. The compound according to any one of claims 1, 2, 5, 6 or 7, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein R1 is azacyclobutyl.

9. The compound according to any one of claims 1, 2, 3, 5 or 8, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analog thereof, wherein R1 is an unsubstituted azacyclobutyl group.

10. The compound of any one of claims 1, 2, 5, 6, 7 or 8, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analog thereof, wherein R1 is an azacyclobutyl group substituted with one or more substituents.

11. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1, 2, 5, 6, 7, 8 or 10, wherein R1 is an azacyclobutyl group substituted with two substituents, which may be the same or different.

12. The compound according to any one of claims 8-11, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the azahexabutyl group is linked to the pyrimidinyl ring via the nitrogen of the azahexabutyl group.

13. The compound according to any one of claims 10-12, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is selected from the group consisting of halogen, methyl, ethyl, hydroxy, methoxy and ethoxy.

14. The compound according to any one of claims 10-12, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is selected from the group consisting of fluorine, methyl, hydroxyl and methoxy.

15. The compound according to any one of claims 1-14, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein A is a 5-membered heterocycle, said 5-membered heterocycle may be unsubstituted or substituted with one or more substituents other than Ar, and said 5-membered heterocycle contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

16. The compound according to any one of claims 1-15, a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof, or a deuterated analogue thereof, wherein A is selected from the group consisting of: ， Each ring is either unsubstituted or substituted.

17. The compound according to any one of claims 1-15, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein A is a 5-membered heteroatom ring having a single heteroatom.

18. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-15 and 17, wherein the heteroatom of A is nitrogen.

19. The compound according to any one of claims 1-15, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein A is a 5-membered heteroatom ring having two heteroatoms.

20. The compound of claim 19, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein both heteroatoms are nitrogen.

21. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-15 and 17-20, wherein A is an unsubstituted 5-membered heterocycle.

22. The compound according to any one of claims 1-18, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein A is an unsubstituted or substituted pyrrolidinyl group.

23. The compound of claim 22, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the pyrrolidinium is bound to Ar by the nitrogen of the pyrrolidinium.

24. The compound of claim 22, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the pyrrolidinyl group is bonded to the carbonyl group via the nitrogen of the pyrrolidinyl group.

25. The compound according to any one of claims 1-24, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein R3 is methyl.

26. The compound according to any one of claims 1-25, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is an unsubstituted or substituted 5-10 membered heteroaromatic ring, and said 5-10 membered heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

27. The compound according to any one of claims 1-26, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is substituted by at least one substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy and cyano, optionally, one or more hydrogens of the C1-C6 alkyl group can be substituted by halogen; optionally, one or more hydrogens of the C1-C6 alkoxy group can be substituted by halogen.

28. The compound according to any one of claims 1-26, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is unsubstituted.

29. The compound according to any one of claims 1-27, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is substituted by a substituent.

30. The compound according to any one of claims 1-27, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is substituted by two substituents.

31. The compound according to any one of claims 1-30, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

32. The compound according to any one of claims 1-31, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms.

33. The compound according to any one of claims 1-32, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is selected from the group consisting of: as well as , Each of them is either unreplaced or replaced.

34. The compound according to any one of claims 1-33, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heteroaromatic ring having a single heteroatom.

35. The compound of claim 34, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the heteroatom is nitrogen.

36. The compound according to any one of claims 1-33, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heteroaromatic ring having two heteroatoms.

37. The compound of claim 36, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein both of the heteroatoms are nitrogen.

38. The compound according to any one of claims 1-37, wherein Ar has the following structure: in n is an integer from 0 to 2, inclusive; and X1, X2, X3, X4 and X5 are each independently selected from the following groups: (i) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and (ii) carbon, each of which is either unsubstituted or substituted.

39. The compound of claim 38, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein n equals 0.

40. The compound of claim 38, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein n equals 1.

41. The compound of claim 38, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein n equals 2.

42. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 is a heteroatom.

43. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 is a heteroatom.

44. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X3 is a heteroatom.

45. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X4 is a heteroatom.

46. ​​The compound of claim 40, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 is a heteroatom.

47. The compound of claim 41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein each X5 is a heteroatom.

48. The compound of claim 41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to X4 is a heteroatom.

49. The compound of claim 41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to the carbon bound to A is a heteroatom.

50. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X2 are heteroatoms.

51. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X3 are heteroatoms.

52. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X4 are heteroatoms.

53. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 and X3 are heteroatoms.

54. The compound according to any one of claims 39-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 and X4 are heteroatoms.

55. The compound of claim 40, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X5 are heteroatoms.

56. The compound of claim 40, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 and X5 are both heteroatoms.

57. The compound of claim 40, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X3 and X5 are heteroatoms.

58. The compound of claim 40, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X4 and X5 are heteroatoms.

59. The compound according to any one of claims 38-58, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein one of X1, X2, X3 and X4 is a carbon substituted by a substituent.

60. The compound of claim 59, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X1.

61. The compound of claim 59, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X2.

62. The compound of claim 59, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X3.

63. The compound of claim 59, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X4.

64. The compound according to any one of claims 40 or 42-45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 is a carbon substituted by a substituent.

65. The compound according to any one of claims 41-45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to X4 is a carbon substituted by a substituent.

66. The compound according to any one of claims 41-45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to the carbon atom bound to A is a carbon substituted by a substituent.

67. The compound according to any one of claims 38-58, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein two of X1, X2, X3 and X4 are each carbons substituted by a substituent.

68. The compound of claim 67, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein one substituent is bound to X1 and the other substituent is bound to X2.

69. The compound of claim 67, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein one substituent is bound to X1 and the other substituent is bound to X3.

70. The compound of claim 67, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein one substituent is bound to X1 and the other substituent is bound to X4.

71. The compound of claim 67, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein one substituent is bound to X2 and the other substituent is bound to X3.

72. The compound of claim 67, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein one substituent is bound to X2 and the other substituent is bound to X4.

73. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 40 or 42-45, wherein X5, and one of X1, X2, X3 and X4 are each a carbon substituted by a substituent.

74. The compound according to any one of claims 41-45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to X4, and one of X1, X2, X3 and X4 are each a carbon substituted by a substituent.

75. The compound according to any one of claims 41-45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5, and one of X1, X2, X3 and X4 are each a carbon atom substituted by a substituent.

76. The compound according to any one of claims 73-75, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 is substituted with a substituent.

77. The compound according to any one of claims 73-75, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 is substituted with a substituent.

78. The compound according to any one of claims 73-75, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X3 is substituted with a substituent.

79. The compound according to any one of claims 73-75, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X4 is substituted with a substituent.

80. The compound of claim 41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein both X5 are carbon atoms substituted by substituents.

81. The compound according to any one of claims 1-37, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 5-membered heteroaromatic ring or heterocycle selected from the group consisting of: ， Each ring is either unsubstituted or substituted with one or more substituents.

82. The compound according to any one of claims 1-37, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heterocyclic or heteroaromatic ring selected from the group consisting of: ， Each ring is either unsubstituted or substituted with one or more substituents.

83. The compound according to any one of claims 1-37, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar has the following structure: in m and n are each integers from 0 to 2, inclusive, where at least one of m and n is 0 or 1; and X1, X2, X3, X4, X5, X6, X7, X8, and X9 are each independently selected from the following groups: heteroatoms in the group consisting of nitrogen, oxygen, and sulfur, and carbon, each carbon being either unsubstituted or substituted.

84. The compound of claim 83, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is selected from the group consisting of: ， Each of them is either unsubstituted or substituted by one or more substituents.

85. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-37, 83 or 84, wherein Ar is an unsubstituted or substituted 9-membered bicyclic heteroaromatic ring.

86. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-37 or 83-85, wherein Ar is a 9-membered bicyclic heteroaromatic ring having at least two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

87. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-37 or 83-85, wherein Ar is an unsubstituted 9-membered bicyclic heteroaromatic ring.

88. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-37 or 83-85, wherein Ar is a 9-membered bicyclic heteroaromatic ring substituted with one substituent.

89. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-37 or 83-85, wherein Ar is a 9-membered bicyclic heteroaromatic ring substituted with two substituents.

90. The compound of claim 38, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 5-membered heterocycle selected from the group consisting of: 。 91. The compound of claim 38, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heterocycle selected from the group consisting of: 。 92. The compound of claim 1, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the pharmaceutically acceptable salt is selected from the group consisting of maleate, fumarate and tartrate.

93. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, having the following structure: ， ， ， , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or 。 94. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein the compound has the following structure: 。 95. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, wherein the compound has the following structure: 。 96. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein the compound has the following structure: 。 97. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, wherein the compound has the following structure: 。 98. The pharmaceutically acceptable salt or its deuterated analogue according to claim 1, wherein the pharmaceutically acceptable salt has the following structure: 。 99. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, wherein the compound has the following structure: 。 100. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein the compound has the following structure: 。 101. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, wherein the compound has the following structure: 。 102. The compound according to claim 100, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, wherein the compound has the following structure: ， ， ,or 。 103. A method for activating an M4 receptor or enhancing the response of an M4 receptor to a ligand, comprising contacting the M4 receptor with an amount of a compound according to any one of claims 1-102, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, thereby activating the M4 receptor or enhancing the response of the M4 receptor to the ligand.

104. A method for enhancing the response of an M4 receptor to a ligand in a subject, comprising administering to the subject an amount of a compound according to any one of claims 1-102, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, thereby enhancing the response of the M4 receptor to the ligand.

Images