M4 positive allosteric modulators

Abstract

Disclosed are M4 positive allosteric modulators having a formula or a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof. These compounds can be used in the therapeutic and / or prophylactic treatment of M4 mediated diseases or disorders, such as Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, and Huntington's disease.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 607,351, 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.). Neuropharmacology , 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.). Nature Genetics ,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.). Neuropsychopharmacology, 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)). Hippocampus , 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., ACS Chemical Neuroscience ,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.). Arch Neurol , 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., FASEB Journal , 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)). Psychopharmacology , 216, 367-378 (2011)), while conversely, M4 PAM tool compounds reduced cocaine self-administration in mice (Dencker et al., , 216, 367-378 (2011)). Psychopharmacology 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.). Proceedings of the National Academy of Sciences , 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.). Neuron 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.). Pain , 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)). Journal of Neurochemistry , 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; L represents O, NR x or CR y R z , where R x It is a hydrogen atom or a C1-C6 alkyl group, and R y and R z Each is independently a hydrogen atom or 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, L, 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, L, 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: R1, R2, R3, L, and Ar have the meanings described above.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] The term "substituent" refers to an atom or group that replaces a hydrogen atom.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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 refers to a spirocyclic portion, 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.

[0034] Other non-limiting examples of 5-membered monocyclic heteroaromatic rings include: .

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

[0036] Other non-limiting examples of a 6-membered monocyclic heteroaromatic ring or heterocycle include: .

[0037] Non-limiting examples of bicyclic heteroaromatic rings with nitrogen as the only heteroatom include: .

[0038] The term "hydroxyl group" refers to the -OH group.

[0039] The term "cyano" refers to the -CN group.

[0040] 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).

[0041] 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.

[0042] 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, caprylate, 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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; L represents O, NR x or CR y R z , where R x It is a hydrogen atom or a C1-C6 alkyl group, and R y and R z Each is independently a hydrogen atom or 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.

[0053] 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, L, A, and Ar have the meanings described above.

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

[0055] According to some implementations, R1 is a four-membered heterocycle that is either unsubstituted or substituted with one or more substituents.

[0056] According to some implementations, R1 is a 4-membered heterocycle substituted with one or more substituents.

[0057] 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.

[0058] According to some implementations, R1 is a azirrocyclobutyl group.

[0059] According to some implementations, R1 is an unsubstituted nitrogen-containing heterocyclic butyl group.

[0060] 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.

[0061] 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.

[0062] According to some implementations, R1 is an azahexacyclic butyl group, which is bonded to a pyrimidinyl ring via the N atom of the azahexacyclic butyl group.

[0063] 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.

[0064] According to some implementation methods, L represents an oxygen atom.

[0065] According to some implementations, L is a variable having the formula NR x The amino group. In some embodiments, R x It is a hydrogen atom or a C1-C6 alkyl group. In some embodiments, R x It is a hydrogen atom or a methyl group.

[0066] According to some implementation methods, L is CR y R z In some implementations, R y and R z Each is independently a hydrogen atom or a C1-C6 alkyl group. In some embodiments, R y and R z Each is a hydrogen atom.

[0067] According to some embodiments, A is a 4-membered heterocycle that is unsubstituted or substituted by one or more substituents other than Ar, and contains one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

[0068] According to some implementations, A is a 4-membered heterocycle that is substituted only with Ar and contains one or two heteroatoms selected from nitrogen, oxygen and sulfur.

[0069] According to some embodiments, A is an azirrocyclobutyl group. According to some embodiments, A is an azirrocyclobutyl group bonded to Ar via the nitrogen atom of the azirrocyclobutyl group. According to other embodiments, A is an azirrocyclobutyl group bonded to L via the nitrogen atom of the azirrocyclobutyl group.

[0070] 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 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0071] According to some implementations, A is an unsubstituted 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0072] 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 Ar. According to other embodiments, the pyrrolidinyl group is in which the nitrogen atom of the pyrrolidinyl group is bonded to L.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] According to some embodiments, Ar is a six-membered heterocyclic ring containing one, two, or three nitrogen atoms.

[0079] 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.

[0080] According to some embodiments, Ar has one of the following structures as shown below: , , , , , , or , Each of them is either unreplaced or replaced.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] In some implementations, n equals 0. In other implementations, n equals 1. In other implementations, n equals 2.

[0085] According to some implementations, at least one of X1, X2, X3, and X4 is a carbon atom substituted by a substituent.

[0086] According to some implementations, Ar is selected from the following 5-membered heterocyclic aromatic rings or heterocycles: , Each of them is either unsubstituted or substituted by one or more substituents.

[0087] According to some implementations, Ar is selected from the following 5-membered heteroaromatic rings: , Each of them was either replaced or not replaced.

[0088] 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.

[0089] According to some implementations, Ar has the following structure: in m and n are 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.

[0090] 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.

[0091] 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.

[0092] According to some implementations, Ar is a 9-membered bicyclic heteroaromatic ring that is either unsubstituted or substituted with one or more substituents.

[0093] According to some implementations, Ar is a 9-membered heteroaromatic ring having at least two heteroatoms selected from nitrogen, oxygen and sulfur.

[0094] 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.

[0095] 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.

[0096] 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: .

[0097] 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: .

[0098] 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.

[0099] In some embodiments, the compound or its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue has the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， , , , , , , , , , , , , , , , , , .

[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 it could be a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] In some embodiments, the pharmaceutically acceptable salt is .

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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 4b When 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] In this implementation, the ligand is acetylcholine.

[0122] 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.

[0123] Materials and methods: Proton nuclear magnetic resonance (NMR) was recorded on Bruker AVANCE-300 (300 MHz) and Bruker AVANCE-400 (400 MHz) instruments. 1 ¹H NMR spectra. Chemical shifts are given in parts per million (ppm), with tetramethylsilane as an internal standard.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] The reaction progress was determined by thin-layer chromatography (TLC) on Merck Kieselgel 60 F254 plates or Fuji Silysia NH plates, or by UFLC / MS analysis as described above. Chromatographic purification was performed on silica 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 performed using a Gilson preparative HPLC system with a UV detector (220 nm) or a YMC preparative HPLC system.

[0130] All commercially available solvents and reagents can be used without further purification.

[0131] Abbreviations used: THF, tetrahydrofuran; EtOAc, ethyl acetate; MeOH, methanol; DMSO, dimethyl sulfoxide; EtOH, ethanol; MeCN, acetonitrile; DMF N,N -Dimethylformamide; HATU, 1-[bis(dimethylamino)methylene]-1 H -1,2,3-Triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; TFA, trifluoroacetic acid; Xantphos, (5-diphenylphosphino-9,9-dimethylbenzanton-4-yl)diphenylphosphine; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); DME, 1,2-dimethoxyethane; DIPEA, N , N -Diisopropylethylamine; DMA N , N -Dimethylacetamide; DMAP, N , N -Dimethyl-4-aminopyridine.

[0132] Example 1 1-(4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl)ethyl-1-one Step 1 4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dimethylsulfonate At room temperature, 4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d MsOH (3.47 g, 36.1 mmol) was added to a solution of tert-butyl pyrimidine-6-carboxylate (4.40 g, 14.5 mmol) in MeCN (40 mL). The mixture was stirred overnight at 60°C and concentrated under vacuum. EtOAc (10 mL) was added dropwise to the stirred mixture of the residue in EtOH (1 mL). The resulting suspension was stirred at room temperature for 1 hour. The precipitate was filtered, washed with EtOAc, and dried to give the title compound (4.70 g) as a pale brown solid.

[0133] 1 H NMR (300 MHz, DMSO- d 6 , 299 K) δ 1.49 (3H, d, J = 6.8 Hz), 2.34-2.50(11H, m), 4.22-4.54 (5H, m), 4.69 (1H, br d, J = 15.9 Hz), 5.12 (1H, q, J =6.4 Hz), 9.41-10.28 (3H, m).

[0134] m / z 205.1 [M+H] + Step 2 1-(4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl)ethyl-1-one At room temperature, to 4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dimethanesulfonate (170 mg, 430 μmol) was added to a solution of DMF (8 mL) with 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl)acetic acid (178 mg, 430 μmol) and 3 H-[1,2,3]triazolo[4,5- b Pyridine-3-ol (11.7 mg, 86.0 μmol), 3-(((ethylimino)methylene)amino)- N,N -Dimethylpropyl-1-amine hydrochloride (107 mg, 559 μmol) and Et3N (174 mg, 1.72 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 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 0%–50% MeOH in EtOAc) to give the title compound (159 mg) as a light brown solid.

[0135] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.37-1.45 (3H, m), 2.41-2.49 (2H, m), 2.49-2.54 (3H, m), 2.69-2.79 (2H, m), 3.22-3.35 (1H, m), 3.74 (2H, dt, J =8.2, 5.3 Hz), 4.12 (2H, q, J = 7.7 Hz), 4.23-4.34 (4H, m), 4.52-4.56 (2H, m), 5.34 (1H, q, J = 6.1 Hz), 6.32 (1H, dd, J = 5.6, 2.2 Hz), 6.57 (1H, d, J =2.2 Hz), 8.27 (1H, d, J = 5.9 Hz).

[0136] m / z 447.3 [M+H] + Example 2 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 4-Nitrophenyl 4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H-pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dimethylsulfonate (111 mg, 281 μmol) was added to a solution of p-nitrobenzene chloroformate (84.8 mg, 421 μmol) and DIPEA (145.0 mg, 1.12 mmol) in DMF (2 mL). The mixture was stirred for 1 hour at the same temperature. 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 0%–10% MeOH in EtOAc) to give the title compound (75.6 mg) as a white amorphous solid.

[0137] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.47-1.53 ​​(3H, m), 2.40-2.49 (2H, m), 2.52-2.56 (3H, m), 4.09-4.18 (2H, m), 4.27-4.35 (2H, m), 4.51-4.80 (2H, m), 5.20-5.32 (1H, m), 7.35-7.40 (2H, m), 8.24-8.31 (2H, m).

[0138] m / z 370.1 [M+H] + Step 2 At room temperature, 4-nitrophenyl 4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- dPyrimidine-6-carboxylate (74.6 mg, 202 μmol) was added to a solution in MeCN (2 mL) along with 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol (48.5 mg, 222 μmol) and DIPEA (78.3 mg, 606 μmol). The mixture was stirred at 50°C for 30 min under N2. After stirring for another 30 min at 70°C, DMAP (4.93 mg, 40.4 μmol) was added to the reaction mixture. The mixture was stirred at room temperature under N2 for 16 h. The reaction mixture was then heated at 100°C for 30 min under microwave irradiation and concentrated under vacuum. DIPEA (39.2 mg, 303 μmol) and DMF (2 mL) were added to the residue at room temperature. The mixture was stirred at 80°C for 1 h under N2. After stirring at 100°C for 1 hour, 55% NaH (13.2 mg, 303 μmol) was added to the reaction mixture at 0°C. The mixture was stirred at room temperature under N2 for 30 minutes. 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 0%–100% MeOH in EtOAc) to give the title compound (42.5 mg) as a pale yellow amorphous solid.

[0139] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.38-1.45 (3H, m), 2.43 (2H, quin, J = 7.6 Hz), 2.48-2.53 (3H, m), 4.00-4.15 (4H, m), 4.24-4.33 (2H, m), 4.35-4.64(4H, m), 5.05-5.19 (1H, m), 5.38-5.53 (1H, m), 6.36-6.40 (1H, m), 6.61-6.64(1H, m), 8.30-8.34 (1H, m).

[0140] m / z 449.2 [M+H] + Example 4 4-(azacyclobut-1-yl)-2,5-dimethyl- N -(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl)-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxamide Step 1 4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbonyl chloride At room temperature, 4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dimethanesulfonate (50.0 mg, 126 μmol) was added to a solution of Et3N (51.0 mg, 504 μmol) and triphosgene (44.9 mg, 151 μmol) in THF (1 mL). The mixture was stirred at the same temperature for 10 minutes. The mixture was concentrated under vacuum to give the title compound (119 mg) as a brown solid. This product was ready for the next reaction without further purification.

[0141] m / z 267.1 [M+H] + Step 2 4-(azacyclobut-1-yl)-2,5-dimethyl- N -(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl)-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxamide At room temperature, 4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbonyl chloride (33.6 mg, 1126 μmol) was added to a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-amine bis(trifluoroacetate) (58.8 mg, 132 μmol) and Et3N (127 mg, 1.26 mmol) in THF (2 mL). After stirring at the same temperature for 2 hours, MeCN (0.5 mL) and DMF (0.5 mL) were added to the reaction mixture. The mixture was stirred at the same temperature under N2 for 16 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 0%–50% EtOAc in n-hexane) and (silica gel, eluted with 0%–80% MeOH in EtOAc) to give the title compound (20.3 mg) as a white amorphous solid.

[0142] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.41 (3H, d, J = 6.1 Hz), 2.41 (2H,quin, J = 7.6 Hz), 2.51 (3H, s), 3.79-3.87 (2H, m), 4.09-4.13 (2H, m), 4.25-4.38 (4H, m), 4.41-4.50 (2H, m), 4.84-4.92 (1H, m), 5.21-5.32 (2H, m), 6.28(1H, dd, J = 5.6, 2.0 Hz), 6.54 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 5.6Hz).

[0143] m / z 448.2 [M+H] + Example 8-1 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 4-Hydroxy-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate 1-(tert-butyl)-3-ethyl-4-oxopyrrolidine-1,3-dicarboxylate (8.26 g, 32.1 mmol) and Et3N (11.2 mL, 80.2 mmol) were subjected to [a specific reaction / treatment]. t Ethamidin hydrochloride (7.28 g, 77.0 mmol) was added in portions to the suspension of -BuOH (45 mL), and the mixture was incubated at 80 °C. 0Stirred at C for 5 hours. Evaporate the solvent and partition the residue between EtOAc (30 mL) and THF (10 mL) solutions and 10% citric acid aqueous solution (40 mL). Extract the aqueous layer with EtOAc. Wash the combined organic layers with water and brine, dry over Na2SO4 and concentrate to give an orange paste. Add tert-butyl methyl ether (15 mL) to the residue and stir at room temperature for 60 minutes. Collect the precipitate by filtration and use... i Pr2O was washed and dried to give the title compound (3.71 g) as a white powder.

[0144] 1 H NMR (300 MHz, CDCl3, 300 K) δ 1.51 (9H, s), 2.52 (3H, s), 4.48-4.59 (4H, m), 12.77 (1H, br s).

[0145] m / z 252.2 [M+H] + Step 2 4-((1 H -benzo[ d [1,2,3]triazol-1-yl)oxy)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d tert-butyl pyrimidine-6-carboxylate At room temperature, to 4-hydroxy-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d DBU (4.75 mL, 31.8 mmol) was added to a suspension of tert-butyl pyrimidine-6-carboxylate (5.32 g, 21.2 mmol) in DMF (50 mL). After stirring for 5 minutes at the same temperature, ((1) H -benzo[ d[1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate (12.2 g, 27.5 mmol) was added to the reaction mixture. The mixture was stirred at the same temperature for 1 hour. Water was added to the mixture, and the mixture was extracted three times with EtOAc. The organic layer was separated, washed twice with water and then with brine, dried over Na2SO4, and concentrated under vacuum. EtOAc was added to the residue, and the insoluble matter was collected by filtration and dried under vacuum to give the title compound (5.18 g) as a white powder. The filtrate was concentrated under vacuum. EtOAc was added to the residue, and the insoluble matter was collected by filtration and dried under vacuum to give another title compound (1.23 g) as a white powder. The filtrate was concentrated under vacuum, and the residue was purified by column chromatography (silica gel, eluted with 5%–35% EtOAc in n-hexane) to give an additional title compound (0.56 g) as a white powder.

[0146] 1 H NMR (300 MHz, CDCl3, 300 K) δ 1.54 (9H, s), 2.43 (3H, s), 4.65-4.87(4H, m), 7.40-7.62 (3H, m), 8.13 (1H, d, J = 7.9 Hz).

[0147] m / z 369.3 [M+H] + Step 3 4-(azacyclobut-1-yl)-2-methyl-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-methyl-5,7-dihydro-6 H -pyrrolo[3,4- dDBU (7.81 mL, 3 Eq, 52.2 mmol) was added to a DMF (30 mL) suspension of tert-butyl pyrimidine-6-carboxylate (6.41 g, 17.4 mmol) and azacyclobutane hydrochloride (2.45 g, 26.2 mmol). The mixture was stirred at the same temperature for 4 hours. Water was added to the mixture, and the mixture was extracted four times with EtOAc-THF. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, and concentrated under vacuum. The residue was azeotropically reacted with toluene. The residue was purified by column chromatography (NH4 silica gel, eluted with 5%–40% EtOAc in n-hexane) to give the title compound (1.98 g) as a white powder.

[0148] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.50 (9H, s), 2.35-2.46 (2H, m), 2.47-2.53 (3H, m), 4.17-4.27 (4H, m), 4.39-4.51 (2H, m), 4.56-4.68 (2H, m).

[0149] m / z 291.3 [M+H] + Step 4 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dihydrochloride At room temperature, 4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A suspension of tert-butyl pyrimidine-6-carboxylate (1.98 g, 6.82 mmol) in MeOH (20 mL) was added to a solution of EtOAc (30 mL, 0.12 mol) in 4 M HCl. The mixture was stirred at the same temperature for 1 hour. The mixture was concentrated under vacuum, and MeCN was added to the residue. The precipitate was collected by filtration, washed with MeCN, and dried under vacuum to give the title compound (1.73 g) as a grayish-white powder.

[0150] 1 H NMR (300 MHz, DMSO- d 6, 301 K) δ 2.32-2.46 (2H, m), 2.49 (3H, s), 4.28-4.65 (9H, m), 10.27-10.82 (2H, m).

[0151] m / z 191.3 [M+H] + Step 5 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-nitrophenyl chloroformate (160 mg, 794 μmol) and Et3N (654 mg, 6.46 mmol) were added to a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol (174 mg, 796 μmol) in THF (3 mL). After stirring at the same temperature for 2 hours, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5- H -pyrrolo[3,4- d Pyrimidine dihydrochloride (170 mg, 646 μmol), THF (2 mL), and DMF (2 mL) were added to the reaction mixture. The mixture was stirred at the same temperature for 2 hours. Water was added to the mixture, and the mixture was extracted twice with EtOAc. The organic layer was separated, washed three times with saturated NaHCO3 aqueous solution, washed twice with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (NH4 silica gel, eluted with 30%-70% EtOAc in n-hexane) to give an impure product as a white powder. The solution was then purified with EtOAc-MeOH- i Pr2O was washed and dried under vacuum to give the title compound as a white powder (115 mg).

[0152] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.37-2.48 (2H, m), 2.48-2.53 (3H, m), 3.99-4.07 (2H, m), 4.19-4.28 (4H, m), 4.35-4.44 (2H, m), 4.47-4.56 (2H, m),4.70 (2H, br s), 5.38-5.50 (1H, m), 6.38 (1H, dd, J= 5.7, 2.3 Hz), 6.63 (1H,d, J = 2.3 Hz), 8.32 (1H, d, J = 5.7 Hz).

[0153] m / z 435.3 [M+H] + Example 8-2 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 1-(tert-butoxycarbonyl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-nitrophenyl chloroformate (919 mg, 4.56 mmol) was added to a mixture of Et3N (2.65 mL, 19.0 mmol) and tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (790 mg, 4.56 mmol) in THF (8 mL). The mixture was stirred at room temperature for 1 hour. 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5- H -pyrrolo[3,4- d Pyrimidine dihydrochloride (1.00 g, 3.80 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The mixture was poured into a saturated aqueous solution of NaHCO3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 0%–10% MeOH in EtOAc) to give the title compound (758 mg) as a white amorphous solid.

[0154] 1 H NMR (300 MHz, DMSO- d 6 , 300 K) δ 1.38 (9H, s), 2.26-2.41 (5H, m), 3.81 (2H, br dd, J= 9.6, 3.2 Hz), 4.11-4.22 (6H, m), 4.33 (1H, s), 4.43 (1H,s), 4.61 (1H, s), 4.70 (1H, s), 5.06-5.13 (1H, m).

[0155] m / z 390.4 [M+H] + Step 2 Azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 1-(tert-butoxycarbonyl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylate (756 mg, 1.94 mmol) and TFA (2.99 mL, 38.8 mmol) was stirred for 16 hours. The mixture was poured into a saturated aqueous solution of NaHCO3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 0%–15% MeOH in EtOAc) to give a crude, pale yellow oil containing the title compound (1.77 g).

[0156] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.36-2.46 (2H, m), 2.49-2.50 (3H,m), 4.00-4.08 (2H, m), 4.26-4.50 (6H, m), 4.56 (1H, br s), 4.64 (1H, br s), 4.70 (1H, br s), 4.77 (1H, br s), 5.19-5.26 (1H, m), 8.79-8.91 (1H, m), 9.07-9.21 (1H, m).

[0157] m / z 290.3 [M+H] + Step 3 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H-pyrrolo[3,4- d Pyrimidine-6-carbamate The crude product was aziridine-3-yl-4-(aziridine-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylate bis(trifluoroacetate) (350 mg), 4-chloro-2-trifluoromethylpyridine (105 mg, 576 μmol), CsF (58.4 mg, 384 μmol), Et3N (268 μL, 1.92 mmol), and DMSO (2 mL) was stirred at 80°C for 2 days. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 10%–100% EtOAc in n-hexane) and ground with EtOAc and n-hexane to give the title compound (106 mg) as a white powder.

[0158] 1 H NMR (300 MHz, CDCl3, 300 K) δ 2.33-2.57 (5H, m), 3.99-4.09 (2H, m), 4.24 (4H, t, J = 7.6 Hz), 4.34-4.44 (2H, m), 4.52 (2H, dt, J = 7.2, 2.1 Hz),4.67-4.74 (2H, m), 5.37-5.51 (1H, m), 6.38 (1H, dd, J = 5.5, 2.5 Hz), 6.63 (1H, d, J = 2.3 Hz), 8.32 (1H, d, J = 5.7 Hz).

[0159] m / z 435.3 [M+H] + Example 8-3 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 4-Nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl) carbonate At room temperature, 4-nitrophenyl chloroformate (3.49 g, 17.3 mmol) was added to a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol (1.89 g, 8.66 mmol) and Et3N (3.62 mL, 26.0 mmol) in THF (70 mL). The mixture was stirred at room temperature for 2.5 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 5%–85% EtOAc in n-hexane) and recrystallized from EtOAc-pentane to give the title compound (2.41 g) as a white solid.

[0160] 1 H NMR (400 MHz, CDCl3, 300 K) δ 4.12-4.19 (2H, m), 4.45 (2H, ddd, J =9.5, 6.7, 1.0 Hz), 5.50 (1H, tt, J = 6.5, 4.1 Hz), 6.41 (1H, dd, J = 5.6, 2.2Hz), 6.65 (1H, d, J = 2.4 Hz), 7.37-7.43 (2H, m), 8.28-8.33 (2H, m), 8.35(1H, d, J = 5.6 Hz).

[0161] m / z 384.1 [M+H] + Step 2 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- dPyrimidine (1.20 g, 6.29 mmol) and 4-nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl) carbonate (2.41 g, 6.29 mmol) in a solution of THF (70 mL) were added to Et3N (3.51 mL, 25.2 mmol). The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 10%–100% EtOAc in n-hexane) to give a white solid. The solid was recrystallized from EtOAc-heptane to give the title compound (2.32 g) as a white powder.

[0162] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.38-2.52 (5H, m), 4.01-4.08 (2H, m), 4.24 (4H, t, J = 7.6 Hz), 4.34-4.44 (2H, m), 4.47-4.56 (2H, m), 4.70 (2H, s), 5.39-5.48 (1H, m), 6.38 (1H, dd, J = 5.6, 2.2 Hz), 6.63 (1H, d, J = 2.2 Hz), 8.32 (1H, d, J = 5.6 Hz).

[0163] m / z 435.1 [M+H] + Example 8-4 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate In 0 0 At C, 4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d 12.8 g (44.12 mmol) of tert-butyl pyrimidine-6-carboxylate was added in portions to TFA (100 mL) and kept at 0°C. 0The mixture was stirred at C for 60 minutes and concentrated under vacuum. EtOAc (200 mL) was added to the residue, and the mixture was concentrated twice under vacuum. At 0°C... 0 At C, Et3N (30.7 mL, 221 mmol) was added in portions to the solution of the residue in THF (300 mL), and the mixture was stirred for 15 minutes. 0 4-Nitrophenyl(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl) carbonate (16.9 g, 44.1 mmol) was added in portions at C, and the mixture was stirred at room temperature for 16 hours. Water (300 mL) and EtOAc (300 mL) were added to the mixture and partitioned. The aqueous layer was extracted twice with EtOAc-THF (1:1, 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was filtered through a glass filter column (NH silica gel, eluted with EtOAc) to give a crude white powder of 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -Pyrrolo[3,4-d]pyrimidine-6-carboxylate (19.0 g, 99%). The resulting compound (18.0 g) was heated at 75 °C. 0 Dissolved in EtOAc (750 mL) at C. After filtration, dissolved in 70 mL. 0 Heptane (750 mL) was added dropwise to the mixture at C and cooled to room temperature. The mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with EtOAc-heptane (1:1, v / v) solution. 0 Vacuum drying at C for 16 hours yielded the title compound as a white powder (16.1 g%).

[0164] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.38-2.47 (2H, m), 2.48-2.53 (3H, m), 4.00-4.10 (2H, m), 4.24 (4H, t, J = 7.6 Hz), 4.35-4.45 (2H, m), 4.47-4.57 (2H,m), 4.70 (2H, s), 5.38-5.51 (1H, m), 6.38 (1H, dd, J = 5.6, 2.4 Hz), 6.63 (1H, d, J = 2.2 Hz), 8.32 (1H, d, J = 5.6 Hz).

[0165] m / z 435.1 [M+H] + Example 9 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate maleate Maleic acid (26.7 mg, 230 μmol) and 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6-yl were heated in a warm oil bath. H -pyrrolo[3,4- d Pyrimidine-6-carboxylate (100 mg, 230 μmol) was dissolved in EtOH (3 mL). EtOAc (3 mL) was slowly added to the mixture. The mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration and washed with EtOAc to give the title compound (106 mg) as a white solid.

[0166] 1 H NMR (300 MHz, DMSO- d 6 , 301 K) δ 2.25-2.36 (2H, m), 2.38 (3H, s), 4.01 (2H, dd, J = 9.6, 3.6 Hz), 4.23 (4H, br s), 4.34-4.53 (4H, m), 4.70 (2H, br d, J = 24.9 Hz), 5.23-5.41 (1H, m), 6.21 (2H, s), 6.61 (1H, dd, J = 5.7, 2.3 Hz), 6.82 (1H, d, J = 2.3 Hz), 8.26 (1H, d, J = 5.7 Hz), 13.70 (2H, brs).

[0167] m / z 435.2 [M+H] + Example 10 1-(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6H -pyrrolo[3,4- d ]pyrimidin-6-yl)-2-(1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-yl)ethyl-1-one At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine dihydrochloride (28.1 mg, 107 μmol) was added to a solution of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (59.5 mg, 427 μmol) and ethyl acetate of 2-(1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-yl) (36.1 mg, 126 μmol) in DMF (1.5 mL). The mixture was stirred at 80°C under N2 for 19 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 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 (15.3 mg) as a white solid.

[0168] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.39-2.49 (2H, m), 2.50 (3H, s), 2.72-2.77 (2H, m), 3.20-3.31 (1H, m), 3.64-3.71 (2H, m), 4.17-4.27 (6H, m),4.52-4.58 (2H, m), 4.71-4.77 (2H, m), 5.75 (1H, d, J = 2.0 Hz), 6.08 (1H, dd, J = 5.9, 2.0 Hz), 7.22-7.61 (1H, m), 7.80 (1H, d, J = 5.9 Hz).

[0169] m / z 431.2 [M+H] + Example 13-1 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 Azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate bis(trifluoroacetate) At room temperature, 1-(tert-butoxycarbonyl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate (168 mg, 431 μmol) was dissolved in TFA (3 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and azeotropically reacted with toluene to give the crude title compound (230 mg) as the crude product. This product could be used for the next reaction without further purification.

[0170] m / z 290.2 [M+H] + Step 2 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate The following substances were added: Pd2(dba)3 (8.85 mg, 9.66 μmol), Cs2CO3 (315 mg, 966 μmol), Xantphos (11.2 mg, 19.3 μmol), 4-bromo-2-(difluoromethyl)pyridine (80.4 mg, 387 μmol), and crude aziridine-3-yl-4-(aziridine-1-yl)-2-methyl-5,7-dihydro-6 ... H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylate bis(trifluoroacetate) (100 mg, 193 μmol) and DME (4 mL) was heated at 130°C for 1 hour under microwave irradiation. The mixture was poured into a saturated aqueous solution of NaHCO3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by preparative HPLC (YMC-Triart C18, eluting with acetonitrile solution containing 10 mM ammonium bicarbonate and H2O) to give the title compound (24 mg) as a pale yellow gel.

[0171] 1 H NMR (300 MHz, CDCl3, 300 K) δ 2.35-2.47 (2H, m), 2.48-2.53 (3H, m), 3.97-4.08 (2H, m), 4.24 (4H, t, J = 7.6 Hz), 4.34-4.44 (2H, m), 4.48-4.55(2H, m), 4.70 (2H, s), 5.35-5.51 (1H, m), 6.31-6.73 (3H, m), 8.26 (1H, d, J =5.7 Hz).

[0172] m / z 417.2 [M+H] + Example 13-2 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-ol A mixture of aziridine-3-ol hydrochloride (1.90 g, 17.3 mmol), 4-bromo-2-(difluoromethyl)pyridine (3.00 g, 14.4 mmol), Pd2(dba)3 (396 mg, 433 μmol), Xantphos (501 mg, 865 μmol), Cs2CO3 (14.1 g, 43.3 mmol), and DME (80 mL) was stirred overnight at 80°C under N2. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under vacuum, purified by column chromatography (silica gel, eluted with 30%–100% EtOAc in n-hexane), and solidified with EtOAc-n-hexane (1:2, v / v) to give the title compound (1.65 g) as a pale yellow solid.

[0173] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.71 (1H, br s), 3.81-3.90 (2H, m), 4.22-4.31 (2H, m), 4.85 (1H, br s), 6.30 (1H, dd, J= 5.6, 2.4 Hz), 6.35-6.66(2H, m), 8.21 (1H, d, J = 5.6 Hz).

[0174] m / z 200.9 [M+H] + Step 2 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate At 0°C, a solution of 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-ol (1.65 g, 8.24 mmol) and Et3N (1.72 mL, 12.4 mmol) in THF (2 mL) were added dropwise to a solution of 4-nitrophenylchloroformate (3.32 g, 16.5 mmol) in THF (10 mL). Et3N (1.72 mL, 12.4 mmol) was then added to the mixture, and the mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 10%–60% EtOAc in n-hexane) to give the title compound (2.54 g) as a grayish-white solid.

[0175] 1 H NMR (400 MHz, CDCl3, 300 K) δ 4.10-4.18 (2H, m), 4.43 (2H, ddd, J =9.5, 6.6, 1.0 Hz), 5.49 (1H, tt, J = 6.5, 4.1 Hz), 6.34-6.69 (3H, m), 7.37-7.44 (2H, m), 8.27-8.34 (3H, m).

[0176] m / z 365.9 [M+H] + Step 3 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4-d Pyrimidine (1.22 g, 6.41 mmol) and 1-(2-(difluoromethyl)pyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl) carbonate (2.54 g, 6.95 mmol) were added to a solution of Et3N (3.58 mL, 25.7 mmol) in THF (20 mL). The mixture was stirred for 2 hours at room temperature and concentrated under vacuum. The residue was passed through an NH silica gel pad and eluted with THF. The eluent was concentrated under vacuum and purified by column chromatography (NH silica gel, eluted with 20%–100% EtOAc in n-hexane) and crystallized from EtOAc-heptane to give the title compound (2.41 g) as a white powder.

[0177] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.25-2.39 (5H, m), 3.98 (2H, dd, J = 9.7, 3.8 Hz), 4.10-4.24 (4H, m), 4.29-4.49 (4H, m), 4.68 (2H, br d, J =33.7 Hz), 5.31 (1H, dt, J = 6.5, 3.4 Hz), 6.52 (1H, dd, J = 5.5, 1.6 Hz),6.58-6.90 (2H, m), 8.20 (1H, d, J = 5.6 Hz).

[0178] m / z 417.0 [M+H] + Example 14 1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-ol A mixture of aziridine-3-ol hydrochloride (2.7 g, 25 mmol), 4-bromo-2-(difluoromethoxy)pyridine (4.0 g, 18 mmol), Cs₂CO₃ (17 g, 54 mmol), Xantphos (0.62 g, 1.1 mmol), Pd₂(dba)₃ (0.49 g, 0.54 mmol), and DME (75 mL) was stirred overnight at 80°C under N₂. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under vacuum and purified by column chromatography (silica gel, eluted with 10%–50% EtOAc in n-hexane) to give the title compound (3.3 g) as a pale yellow solid.

[0179] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 3.65 (2H, dd, J = 9.5, 4.6 Hz),4.05-4.21 (2H, m), 4.59 (1H, qt, J = 6.5, 4.6 Hz), 5.74 (1H, d, J = 6.4 Hz), 5.88 (1H, d, J = 2.0 Hz), 6.24 (1H, dd, J = 5.9, 2.2 Hz), 7.42-7.82 (2H, m).

[0180] m / z 217.1 [M+H] + Step 2 1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate At 0°C, a solution of 1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-ol (2.4 g, 11 mmol) and Et3N (4.6 mL, 33 mmol) in THF (48 mL) were added dropwise to a solution of 4-nitrophenylchloroformate (4.5 g, 22 mmol) in THF (48 mL). The mixture was stirred at 0°C for 2 hours. The mixture was poured into water and 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 20%–40% EtOAc in n-hexane) to give the title compound (4.5 g) as a yellow oil.

[0181] 1 H NMR (400 MHz, CDCl3, 300 K) δ 4.06-4.11 (2H, m), 4.38 (2H, ddd, J =9.4, 6.5, 1.0 Hz), 5.46 (1H, tt, J = 6.5, 4.1 Hz), 5.84 (1H, d, J = 2.0 Hz), 6.15 (1H, dd, J = 5.7, 2.1 Hz), 7.37-7.65 (3H, m), 7.87 (1H, d, J = 5.6 Hz),8.28-8.33 (2H, m).

[0182] m / z 382.0 [M+H] + Step 3 1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- d A mixture of pyrimidine (1.5 g, 7.9 mmol), 1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl) carbonate (3.6 g, 9.5 mmol), NaHCO3 (3.3 g, 39 mmol), THF (80 mL), and water (50 mL) was stirred overnight. The mixture was quenched with water at room temperature and extracted twice with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was crystallized from EtOAc to give the crude title compound (2.1 g, 62%) as a white solid. The mother liquor was purified by column chromatography (silica gel, eluted with 0%–20% MeOH in EtOAc; and NH4 silica gel, eluted with EtOAc) and ground with EtOAc to further give the crude title compound (0.3 g, 9%) as a white solid.

[0183] The crude title compound (2.4 g) was dissolved in EtOH (432 mL) at 75 °C. Insoluble substances were removed by filtration. Heptane (240 mL) was added to the filtrate at 60 °C. The mixture was stirred at 40 °C for 2 hours and then stirred at room temperature for a period of time. The precipitate was collected by filtration to give the title compound (2.1 g) as a white solid.

[0184] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.25-2.38 (5H, m), 3.94 (2H, dd, J = 9.8, 3.7 Hz), 4.16 (4H, br s), 4.26-4.33 (2H, m), 4.34-4.46 (2H, m), 4.60-4.77 (2H, m), 5.29 (1H, td, J = 6.4, 2.6 Hz), 5.98 (1H, s), 6.32 (1H, dd, J =5.9, 2.0 Hz), 7.42-7.81 (1H, m), 7.82 (1H, d, J = 5.9 Hz).

[0185] m / z 433.1 [M+H] + Example 15 1-(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d]pyrimidine (-6-yl)-2-(1-(2-methylpyridin-4-yl)azacyclobut-3-yl)ethyl-1-one Step 1 2-(1-(2-methylpyridin-4-yl)azacyclobut-3-yl)ethyl acetate A mixture of ethyl 2-(azacyclobut-3-yl)acetate (28.6 mg, 200 μmol), 4-chloro-2-methylpyridine (10.4 mg, 200 μmol), RuPhos Pd G3 (16.7 mg, 20.0 μmol), and Cs₂CO₃ (130 mg, 399 μmol) in DME (1 mL) was stirred at 120°C for 2 hours under microwave irradiation. 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 air evaporation 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 air evaporation at 60°C to give the title compound. The resulting product was used for the next reaction.

[0186] Step 2 2-(1-(2-methylpyridin-4-yl)azacyclobut-3-yl)acetic acid The mixture of ethyl 2-(1-(2-methylpyridin-4-yl)azacyclobut-3-yl)acetate, 2 M NaOH (100 μL, 200 μmol), and EtOH (1 mL) was stirred for 3 hours at room temperature. The mixture was acidified with 2 M HCl and concentrated by blowing away air at 60°C to give the crude title compound. This product can be used for the next reaction without further purification.

[0187] Step 3 1-(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)-2-(1-(2-methylpyridin-4-yl)azacyclobut-3-yl)ethyl-1-one At room temperature, the above-obtained 2-(1-(2-methylpyridin-4-yl)azacyclobut-3-yl)acetic acid and 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5-acetic acid are... H -pyrrolo[3,4- dA mixture of pyrimidine dihydrochloride (52.6 mg, 200 μmol), HATU (75.9 mg, 200 μmol), and DIPEA (103 mg, 799 μmol) in DMA (1 mL) was stirred overnight. The mixture was acidified with 2 M HCl and concentrated by air evaporation at 60°C. The residue was purified by preparative HPLC (YMC-Triart C18, eluted with MeCN / 10 mM NH4HCO3 aqueous solution). The desired fraction was evaporated by air evaporation at 60°C to give the title compound (29 mg).

[0188] m / z 379.2 [M+H] + Example 20 1-(4-cyano-3-(trifluoromethyl)phenyl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Azacyclobut-3-yl4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylic acid bis(trifluoroacetate) (38.8 mg, 79.9 μmol), 4-bromo-2-(trifluoromethyl)benzonitrile (40.0 mg, 160 μmol), 4-bromo-2-(trifluoromethyl)benzonitrile (40.0 mg, 160 μmol), RuPhos Pd G4 (6.80 mg, 7.99 μmol), and Cs2CO3 (78.1 mg, 240 μmol) in DME (1 mL) was stirred at 120°C for 1 hour under microwave irradiation. 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 it away with air at 60 °C to obtain the title compound.

[0189] m / z 459.1 [M+H] + Example 21 1-(2,5-Dichloropyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6H -pyrrolo[3,4- d Pyrimidine-6-carbamate Azacyclobut-3-yl4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylate bis(trifluoroacetate) (38.8 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 air evaporation at 60°C. The residue was purified by preparative HPLC (YMC-Triart C18, eluted with MeCN / 10 mM NH4HCO3 aqueous solution). The desired fraction was evaporated by air evaporation at 60°C to give the title compound.

[0190] m / z 435.1 [M+H] + Example 23-1 1-(2-(trifluoromethyl)pyrimidin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 1-(2-(trifluoromethyl)pyrimidin-4-yl)azacyclobut-3-ol A mixture of aziridine-3-ol hydrochloride (380 mg, 3.47 mmol), 4-chloro-2-(trifluoromethyl)pyrimidine (1.01 g, 5.55 mmol), and DIPEA (2.42 mL, 13.9 mmol) in DMA (10 mL) was stirred at 80°C for 16 hours. The residue was purified by preparative HPLC (CERI L-column 2 ODS, eluted with acetonitrile solution containing 10 mM ammonium bicarbonate and H2O) to give the title compound (651 mg) as a white solid.

[0191] 1 H NMR (400MHz, DMSO-) d 6, 300K) δ3.71-3.90 (2H, m), 4.30 (2H, ddd, J = 9.8, 6.8, 1.2Hz), 4.62 (1H, qt, J = 6.6, 4.4Hz), 5.83 (1H, d, J = 6.6Hz), 6.59 (1H, d, J = 6.1Hz), 8.28 (1H, d, J = 6.1Hz).

[0192] m / z 220.2 [M+H] + Step 2 4-Nitrophenyl(1-(2-(trifluoromethyl)pyrimidin-4-yl)azacyclobut-3-yl) carbonate At room temperature, 4-nitrophenyl chloroformate (1.19 g, 5.89 mmol) was added to a solution of 1-(2-(trifluoromethyl)pyrimidin-4-yl)azacyclobut-3-ol (645 mg, 2.94 mmol) and Et3N (1.23 mL, 8.83 mmol) in THF (20 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding a saturated aqueous solution of NaHCO3, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 0%–60% EtOAc in n-hexane) to give the title compound (1.12 g) as a white solid.

[0193] m / z 385.2 [M+H] + Step 3 1-(2-(trifluoromethyl)pyrimidin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-nitrophenyl (1-(2-(trifluoromethyl)pyrimidin-4-yl)azacyclobut-3-yl) carbonate (482 mg, 1.25 mmol) and 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5- H -pyrrolo[3,4- dPyrimidine dihydrochloride (300 mg, 1.14 mmol) was added to a solution of Et3N (636 μL, 4.56 mmol) in THF (20 mL). The mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with EtOAc. The organic layer was washed with brine and water, filtered, and concentrated under vacuum. The residue was purified by column chromatography (NH4 silica gel, eluted with 50%–100% EtOAc in n-hexane) and crystallized from EtOAc-heptane to give the title compound (395 mg) as a white powder.

[0194] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.23-2.39 (5H, m), 4.05-4.25 (6H,m), 4.31-4.52 (4H, m), 4.59-4.78 (2H, m), 5.31 (1H, br dd, J = 6.2, 4.0 Hz), 6.68 (1H, d, J = 5.9 Hz), 8.33 (1H, d, J = 6.1 Hz).

[0195] m / z 436.3 [M+H] + Example 23-2 1-(2-(trifluoromethyl)pyrimidin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate parallel synthesis Azacyclobut-3-yl4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylate bis(trifluoroacetate) (38.8 mg, 79.9 μmol), 4-chloro-2-(trifluoromethyl)pyrimidine (0.16 g, 160 μmol), and DIPEA (55.7 μL, 320 μmol) in DMA (1 mL) was stirred overnight at 100°C. The mixture was concentrated by air evaporation at 60°C. The residue was purified by preparative HPLC (YMCTriart C18, eluted with MeCN / 10 mM NH4HCO3 aqueous solution). The desired fraction was evaporated by air evaporation at 60°C to give the title compound (15.3 mg).

[0196] m / z 436.1 [M+H] + Example 36 1-(2-methoxypyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 1-(2-Methoxypyridin-4-yl)azacyclobut-3-ol At room temperature, 4-bromo-2-methoxypyridine (2 g, 0.01 mol), Cs₂CO₃ (7 g, 0.02 mol), and methanesulfonic acid-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (0.4 g, 0.5 mmol) were added to a solution of azirmonobutyl-3-ol hydrochloride (1 g, 9 mmol) in DME (50 mL). The mixture was stirred at 100°C under N₂ for 15 hours. The resulting mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum. The residue was crystallized from EtOAc to give the title compound (1.09 g) as a light brown solid.

[0197] 1 H NMR (400MHz, DMSO-) d 6 ,300K) δ3.58(1H, dd, J=8.6, 4.6Hz), 3.55-3.56(1H, m), 3.75(3H, s), 4.04-4.11(2H, m), 4.49-4.63(1H, m ), 5.63 (1H, d, J=2.0Hz), 5.69 (1H, d, J=6.4Hz), 6.05 (1H, dd, J=5.6, 2.0Hz), 7.75 (1H, d, J=5.6Hz).

[0198] m / z 181.1 [M+H] + Step 2 1-(2-methoxypyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate At room temperature, 4-nitrophenyl chloroformate (2.44 g, 12.1 mmol) was added to a solution of 1-(2-methoxypyridin-4-yl)azacyclobut-3-ol (1.09 g, 6.05 mmol) and Et3N (2.53 mL, 18.1 mmol) in THF (40 mL). The mixture was stirred at room temperature for 2.5 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 5%–85% EtOAc in n-hexane) to give the title compound (1.5 g) as a white solid.

[0199] 1 H NMR (300MHz, CDCl3, 300K) δ3.90 (3H, s), 4.01-4.08 (2H, m), 4.30-4.38 (2H, m), 5.44 (1H, tt, J = 6.5, 4.1Hz), 5.71 (1H, d, J = 1.9Hz), 6.04 (1H, dd, J = 5.9, 2.1Hz), 7.37-7.43 (2H, m), 7.89 (1H, d, J = 6.0Hz), 8.27-8.33 (2H, m).

[0200] m / z 346.1 [M+H] + Step 3 1-(2-methoxypyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine (200 mg, 1.05 mmol) and 1-(2-methoxypyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl) carbonate (399 mg, 1.16 mmol) were added to a solution of Et3N (586 μL, 4.20 mmol) in THF (20 mL). The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (NH4 silica gel, eluted with 10%–90% EtOAc in n-hexane) to give a white solid. The solid was crystallized from EtOAc-heptane to give colorless crystals of the title compound (250 mg).

[0201] 1 H NMR (400MHz, DMSO-) d 6 , 300K) δ2.28-2.36 (5H, m), 3.76 (3H, s), 3.87 (2H, dd, J =9.3, 3.9Hz), 4.10-4.27 (6H, m), 4.35 (1H, s), 4.43 (1H, s), 4.63 (1H, br s), 4.71 (1H, br s), 5.22-5.34 (1H, m), 5.72 (1H, s), 6.12 (1H, dd, J = 5.7, 1.8Hz), 7.78 (1H, d, J = 5.6Hz).

[0202] m / z 397.2 [M+H] + Example 37 1-(2-chloropyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 1-(2-chloropyridin-4-yl)azacyclobut-3-ol In a sealed tube, a mixture of aziridine-3-ol hydrochloride (1.00 g, 9.13 mmol), 2-chloro-4-fluoropyridine (1.44 g, 11.0 mmol), DIPEA (4.77 mL, 27.4 mmol), and DMSO (5 mL) was stirred overnight at 100°C. The reaction mixture was poured into an aqueous solution of K₂CO₃ and extracted three times with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated under vacuum to give a crude, beige powder of the title compound (1.94 g).

[0203] m / z 185.0 [M+H] + Step 2 1-(2-chloropyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate At room temperature, Et3N (3.82 mL, 27.4 mmol) was added to a solution of crude 1-(2-chloropyridin-4-yl)azacyclobut-3-ol (1.94 g) and 4-nitrophenyl chloroformate (2.76 g, 13.7 mmol) in THF (50 mL). The mixture was stirred at room temperature for 1 hour. 4-nitrophenyl chloroformate (920 mg, 4.56 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 10%–100% EtOAc in n-hexane) to give the title compound (2.92 g) as a pale yellow powder.

[0204] 1 H NMR (400MHz, CDCl3, 300K) δ4.05-4.15 (2H, m), 4.39 (2H, ddd, J = 9.5, 6.5, 1.1Hz), 5.47 (1H, tt, J = 6.5, 4.1 Hz), 6.23 (1H, dd, J = 5.7, 2.1 Hz), 6.31 (1H, d, J = 2.2Hz), 7.36-7.44 (2H, m), 8.04 (1H, d, J = 5.9 Hz), 8.28-8.34 (2H, m).

[0205] m / z 350.2 [M+H] + Step 3 1-(2-chloropyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 H -pyrrolo[3,4- dA mixture of pyrimidine (1.20 g, 6.31 mmol), 1-(2-chloropyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl) carbonate (2.21 g, 1 Eq, 6.31 mmol), Et3N (1.05 mL, 7.57 mmol), and THF (30 mL) was stirred overnight. The reaction mixture was diluted with water. The precipitate was collected by filtration and washed with water to give a crude title compound (1.79 g) as a pale yellow powder. The filtrate was extracted three times with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum to give another crude title compound (0.71 g) as a yellow powder. The obtained crude title compounds were combined and purified by column chromatography (NH4 silica gel, eluted with 30%–100% EtOAc in n-hexane) and ground with EtOAc to give a solid (2.09 g). Recrystallization of the solid from EtOH-heptane yielded the title compound (1.99 g) as a white powder.

[0206] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.43 (2H, quin, J = 7.6 Hz), 2.48-2.53 (3H, m), 3.95-4.03 (2H, m), 4.24 (4H, t, J = 7.6 Hz), 4.30-4.38 (2H, m), 4.48-4.54 (2H, m), 4.66-4.74 (2H, m), 5.35-5.47 (1H, m), 6.20 (1H, dd, J =5.7, 2.1 Hz), 6.28 (1H, d, J = 2.2 Hz), 8.00 (1H, d, J = 5.9 Hz).

[0207] m / z 401.2 [M+H] + Example 40-1 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -Pyrrolo[3,4-d]pyrimidine-6-carboxylate Step 1 1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol A mixture of aziridine-3-ol hydrochloride (3.42 g, 31.2 mmol), 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (8.00 g, 26.0 mmol), Et3N (10.9 mL, 78.1 mmol), and DMSO (80 mL) was stirred at 60°C for 4 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 30%–70% EtOAc in n-hexane) to give the title compound (4.13 g) as a colorless powder.

[0208] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.27 (1H, d, J = 5.9 Hz), 3.86-3.94(2H, m), 4.25-4.33 (2H, m), 4.89 (1H, qt, J = 6.3, 4.2 Hz), 6.34 (1H, d, J =2.0 Hz), 6.51 (1H, d, J = 2.0 Hz).

[0209] m / z 253.0 [M+H] + Step 2 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol A mixture of 1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol (1.01 g, 4.00 mmol), trimethylcycloboroxane (approximately 50% in THF) (2.3 mL, 8.00 mmol), XPhos Pd G3 (84.6 mg, 100 μmol), Cs₂CO₃ (2.61 g, 8.00 mmol), and DME (18 mL) was heated at 100°C for 1 hour under microwave irradiation in N₂. The reaction was repeated and the mixtures were combined, using a total of 16.67 mmol of 1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol. The reaction mixture was diluted with EtOAc and water and then filtered through a diatomaceous earth mat. The filtrate was extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 20%–70% EtOAc in n-hexane) and ground with EtOAc-n-hexane to give the title compound (3.50 g) as a colorless powder.

[0210] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.48 (3H, s), 2.57 (1H, d, J = 6.1Hz), 3.81-3.87 (2H, m), 4.21-4.29 (2H, m), 4.86 (1H, qt, J = 6.3, 4.2 Hz), 6.21 (1H, d, J = 1.7 Hz), 6.46 (1H, d, J = 2.0 Hz).

[0211] m / z 233.0 [M+H] + Step 3 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate At room temperature, Et3N (6.28 mL, 45.1 mmol) was added to a solution of 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol (3.49 g, 15.0 mmol) and 4-nitrophenyl chloroformate (6.06 g, 30.1 mmol) in THF (50 mL) and CH3CN (50 mL). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The residue was poured into a saturated aqueous solution of NaHCO3 and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 20%–60% EtOAc in n-hexane) to give the title compound (5.27 g) as a pale yellow powder.

[0212] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.51 (3H, s), 4.09-4.16 (2H, m), 4.38-4.46 (2H, m), 5.48 (1H, tt, J = 6.5, 4.0 Hz), 6.27 (1H, d, J = 2.0 Hz), 6.51 (1H, d, J = 2.0 Hz), 7.37-7.44 (2H, m), 8.28-8.34 (2H, m).

[0213] m / z 398.0 [M+H] + Step 4 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate At room temperature, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5 HA mixture of pyrrolo[3,4-d]pyrimidine (2.50 g, 13.1 mmol), 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl) carbonate (5.27 g, 13.3 mmol), Et3N (2.20 mL, 15.8 mmol), and THF (80 mL) was stirred overnight. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (NH4 silica gel, eluted with 30%–80% EtOAc in n-hexane). The product (5.01 g) was recrystallized from EtOH-heptane to give the title compound (4.50 g) as a colorless powder.

[0214] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.37-2.47 (2H, m), 2.47-2.53 (6H, m), 3.97-4.05 (2H, m), 4.24 (4H, t, J = 7.6 Hz), 4.32-4.41 (2H, m), 4.48-4.55(2H, m), 4.67-4.73 (2H, m), 5.37-5.48 (1H, m), 6.24 (1H, d, J = 1.7 Hz), 6.49 (1H, d, J = 2.2 Hz).

[0215] m / z 449.2 [M+H] + Example 40-2 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Azacyclobut-3-yl4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- dA mixture of pyrimidine-6-carboxylate bis(trifluoroacetate) (34.1 mg, 65.9 μmol), 4-bromo-2-methyl-6-(trifluoromethyl)pyridine (31.6 mg, 132 μmol), methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (5.60 mg, 6.59 μmol), Cs₂CO₃ (64.4 mg, 198 μmol), and DME (0.8 mL) was heated at 120°C for 1 hour under microwave irradiation. The mixture was purified by column chromatography (NH₄ silica gel, eluted with 20%–70% EtOAc in n-hexane) to give the title compound (14.8 mg) as a white amorphous solid.

[0216] 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.40-2.48 (2H, m), 2.48-2.52 (6H, m), 3.97-4.04 (2H, m), 4.24 (4H, td, J = 7.6, 3.9 Hz), 4.33-4.40 (2H, m), 4.53(2H, br d, J = 2.2 Hz), 4.70 (2H, s), 5.38-5.47 (1H, m), 6.24 (1H, d, J = 1.7Hz), 6.49 (1H, d, J = 2.2 Hz).

[0217] m / z 449.3 [M+H] + Example 50 (S)-1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidine-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At 0°C, triphosgene (8.9 mg, 30 μmol) was added to a mixture of DMAP (11 mg, 86 μmol), triethylamine (35 mg, 0.34 mmol), and (S)-1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidine-3-ol (20 mg, 86 μmol) in THF (3 mL). The mixture was stirred at room temperature for 30 minutes. At 0°C, 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5- H -pyrrolo[3,4- d Pyrimidine hydrochloride (23 mg, 0.10 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The mixture was poured into a saturated aqueous solution of NaHCO3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by preparative HPLC (YMC-Triart C18, eluting with acetonitrile solution containing 10 mM ammonium bicarbonate in H2O) to give the title compound (7.9 mg) as a white solid.

[0218] 1 H NMR (300 MHz, CDCl3, 300 K) δ 2.28-2.52 (7H, m), 3.48-3.58 (3H, m), 3.67-3.75 (1H, m), 4.21 (4H, dt, J = 9.8, 7.6 Hz), 4.36-4.73 (4H, m), 5.41-5.56 (1H, m), 6.45-6.57 (1H, m), 6.69-6.80 (1H, m), 8.26-8.36 (1H, m).

[0219] m / z 449.4 [M+H] + Example 70 (R)-1-(4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)-2-(1-(2-chloropyridin-4-yl)azacyclobut-3-yl)ethyl-1-one Step 1 2-(azacyclobut-3-yl)ethyl acetate trifluoroacetate At room temperature, TFA (703 mg, 6.17 mmol) was added to a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)azacyclobutane-1-carboxylate (300 mg, 1.23 mmol). The mixture was stirred at the same temperature for 16 hours and concentrated under vacuum (azeotropically with toluene) to give the title compound (395 mg) as a colorless oil.

[0220] 1 H NMR (300 MHz, CDCl3, 300 K) δ 1.27 (3H, t, J = 7.2 Hz), 2.72 (2H,d, J = 7.2 Hz), 3.31 (1H, dt, J = 15.8, 8.2 Hz), 3.92-4.05 (2H, m), 4.16 (2H,q, J = 7.2 Hz), 4.23-4.35 (2H, m), 8.47 (1H, br s), 8.81 (1H, br s).

[0221] m / z 144.1 [M+H] + Step 2 2-(1-(2-chloropyridin-4-yl)azacyclobut-3-yl)ethyl acetate At room temperature, 2-chloro-4-fluoropyridine (141 mg, 1.07 mmol) and DIPEA (373 μL, 2.14 mmol) were added to a solution of 2-(azacyclobut-3-yl)ethyl trifluoroacetate (228 mg, 713 μmol) in DMSO (3 mL). The mixture was stirred at 100°C for 16 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 MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 2%–30% EtOAc in n-hexane) to give the title compound (152 mg) as a white solid.

[0222] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.18 (3H, t, J = 7.1 Hz), 2.71 (2H,d, J= 7.8 Hz), 2.95-3.08 (1H, m), 3.63 (2H, dd, J = 8.4, 5.7 Hz), 4.02-4.10(4H, m), 6.29-6.35 (2H, m), 7.88 (1H, d, J = 5.6 Hz).

[0223] m / z 255.0 [M+H] + Step 3 Sodium 2-(1-(2-chloropyridin-4-yl)azacyclobut-3-yl)acetate A mixture of ethyl 2-(1-(2-chloropyridin-4-yl)azacyclobut-3-yl)acetate (150 mg, 590 μmol), 2 M NaOH (590 μL, 1.18 mmol), and EtOH (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and azeotropically reacted with toluene to give a crude, white solid of the title compound (169 mg). This substance was ready for use in the next reaction without further purification.

[0224] Step 4 (R)-1-(4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)-2-(1-(2-chloropyridin-4-yl)azacyclobut-3-yl)ethyl-1-one At room temperature, oxaloyl chloride (91.7 mg, 722 μmol) was added to a solution of sodium 2-(1-(2-chloropyridin-4-yl)azacyclobut-3-yl)acetate (45.6 mg) in THF (2 mL). N,N - Dimethylformamide (1.12 μL, 14.4 μmol). After stirring at room temperature for 1 hour, oxaloyl chloride (91.7 mg, 722 μmol) was added to the reaction mixture. The mixture was stirred at the same temperature under N2 for 3 hours. The mixture was concentrated under vacuum and azeotropically reacted with toluene. (The remaining mixture was then added to the residue.) R )-4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine hemispheres 2R, 3R2,3-bis((4-methylbenzoyl)oxy)succinate (93.9 mg, 159 μmol) and THF (1 mL). After stirring at 0°C for 5 minutes, a saturated aqueous solution of NaHCO3 (1 mL) was slowly added to the reaction mixture. The mixture was stirred at room temperature under N2 for 16 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 0%–50% EtOAc in n-hexane) to give the title compound (17.0 mg) as a white solid.

[0225] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.33 (3H, dd, J = 10.5, 6.1 Hz),2.26-2.40 (5H, m), 3.91-4.00 (2H, m), 4.08 (2H, q, J = 7.3 Hz), 4.14-4.23(2H, m), 4.26-4.54 (4H, m), 5.04-5.20 (1H, m), 5.24-5.36 (1H, m), 6.41 (1H,dt, J = 5.6, 2.0 Hz), 6.44-6.47 (1H, m), 6.63 (2H, s), 7.93 (1H, dd, J = 5.7,1.6 Hz), 13.10 (2H, br s).

[0226] m / z 413.2 [M+H] + Example 57-1 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Step 1 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- d A mixture of tert-butyl pyrimidine-6-carboxylate (6.42 g, 21.1 mmol) and TFA (13.0 mL, 169 mmol) was stirred for 4 hours. The reaction mixture was concentrated under vacuum and azeotropically reacted with toluene to give a crude, pale yellow solid of the title compound (14.2 g).

[0227] m / z 205.1 [M+H] + Step 2 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, the crude product 4-(azacyclobut-1-yl)-2-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine bis(trifluoroacetate) (375 mg) was added to a solution of 4-nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl carbonate (213 mg, 556.1 μmol) and Et3N (310 μL, 2.22 mmol) in THF (6 mL). The mixture was stirred at the same temperature under N2 for 16 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 (NH4Cl, eluted with 50%–100% EtOAc in n-hexane) and (silica gel, eluted with 0%–20% MeOH in EtOAc) to give the title compound (143 mg) as a white powder.

[0228] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.25-1.31 (3H, m), 2.42 (2H, quind, J = 7.5, 3.2 Hz), 2.70-2.78 (2H, m), 4.04 (2H, br dd, J = 9.2, 3.5 Hz), 4.23(4H, t, J= 7.6 Hz), 4.35-4.43 (2H, m), 4.50-4.56 (2H, m), 4.70 (2H, s), 5.39-5.48 (1H, m), 6.38 (1H, dd, J = 5.6, 2.2 Hz), 6.62 (1H, d, J = 2.2 Hz), 8.32 (1H, d, J = 5.6 Hz).

[0229] m / z 449.2 [M+H] + Example 57-2 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, 4-nitrophenyl chloroformate (36.0 mg, 179 μmol) and Et3N (38.3 μL, 275 μmol) were added to a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-ol (30.0 mg, 138 μmol) in THF (1.5 mL). After stirring at the same temperature for 2 hours, the crude product 4-(azacyclobut-1-yl)-2-ethyl-6,7-dihydro-5-ethyl was added. H -pyrrolo[3,4- d Pyrimidine bis(trifluoroacetate) (79.6 mg) and Et3N (95.8 μL, 688 μmol) were added to the reaction mixture. The mixture was stirred at the same temperature under N2 for 16 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 (NH4 silica gel, eluted with 0%–30% EtOAc in n-hexane) to give the title compound (32.5 mg) as a white amorphous solid.

[0230] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.24-1.32 (3H, m), 2.38-2.47 (2H, m), 2.70-2.78 (2H, m), 4.01-4.07 (2H, m), 4.24 (4H, t, J= 7.6 Hz), 4.35-4.43(2H, m), 4.49-4.56 (2H, m), 4.70 (2H, br s), 5.39-5.48 (1H, m), 6.38 (1H, dd, J = 5.7, 2.3 Hz), 6.63 (1H, d, J = 2.2 Hz), 8.32 (1H, d, J = 5.6 Hz).

[0231] m / z 449.2 [M+H] + Example 58-1 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate hemifumarate At room temperature, 4-nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl) carbonate (517 mg, 1.349 mmol) and crude 4-(azacyclobut-1-yl)-2-ethyl-6,7-dihydro- 5H -pyrrolo[3,4- d Pyrimidine difluoroacetate (910.0 mg) was added to a solution of Et3N (1.00 mL, 7.17 mmol) in THF (5 mL). The mixture was stirred overnight at the same temperature. The mixture was concentrated under vacuum, and the residue was dissolved in EtOAc. A saturated aqueous solution of NaHCO3 was added to the solution, and the mixture was extracted with EtOAc. The organic layer was separated, washed four times with a saturated aqueous solution of NaHCO3 and twice with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 30%-70% EtOAc in n-hexane), followed by column chromatography (silica gel, eluted with 0%-20% MeOH in EtOAc) to give a colorless oily substance, 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro- 6H -pyrrolo[3,4- dPyrimidine-6-carboxylate (312 mg). The oily substance was dissolved in THF (5 mL), and fumaric acid (40.4 mg, 0.348 mmol) was added. The mixture was stirred at 50°C for 5 minutes. The solution was concentrated under vacuum. EtOH (1.5 mL) and MeCN (10 mL) were added to the residue. The suspension was stirred at 50°C for 10 minutes, cooled to room temperature, and held for 20 minutes. The precipitate was collected by filtration and washed with MeCN, and dried under vacuum to obtain a white powder. EtOH (10 mL) and MeCN (10 mL) were added to the powder. The suspension was stirred at 50°C for 10 minutes. The solution was concentrated under vacuum. EtOH (1.5 mL) and MeCN (10 mL) were added to the residue. The solution was sonicated to obtain a suspension, and the suspension was concentrated under vacuum to obtain the title compound (295 mg) as a white powder.

[0232] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.14-1.21 (3H, m), 2.25-2.37 (2H,m), 2.61 (2H, q, J = 7.7 Hz), 4.01 (2H, dd, J = 10.0, 3.9 Hz), 4.12-4.23 (4H,m), 4.32-4.76 (6H, m), 5.24-5.36 (1H, m), 6.57-6.65 (2H, m), 6.81 (1H, d, J =2.0 Hz), 8.25 (1H, d, J = 5.6 Hz), 13.05 (1H, br s).

[0233] m / z 449.2 [M+H] + Example 58-2 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate hemifumarate At room temperature, MeOH (10 mL) and THF (5 mL) were added to 1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-ethyl-5,7-dihydro-6H -pyrrolo[3,4- d The mixture of pyrimidine-6-carboxylate (127 mg, 283 μmol) and fumaric acid (33.0 mg, 284 μmol) was stirred at 50°C for 10 min. 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 the resulting suspension was stirred at 50°C for 30 min, cooled to room temperature, and left to stand at the same temperature for 3 h. The precipitate was collected by filtration and washed with MeCN, and dried under vacuum to give the title compound (91.6 mg) as a white powder.

[0234] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.13-1.22 (3H, m), 2.24-2.39 (2H,m), 2.61 (2H, q, J = 7.6 Hz), 3.95-4.06 (2H, m), 4.09-4.24 (4H, m), 4.31-4.49(4H, m), 4.60-4.75 (2H, m), 5.31 (1H, s), 6.58-6.65 (2H, m), 6.81 (1H, d, J =2.0 Hz), 8.25 (1H, d, J = 5.6 Hz), 13.06 (1H, br s).

[0235] m / z 449.1 [M+H] + Example 65-1 1-(2-chloro-6-methylpyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro- 6H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, to aziridine-3-yl-4-(aziridine-1-yl)-2-methyl-5,7-dihydro- 6H -pyrrolo[3,4- dPyrimidine-6-carboxylate (2200 mg, 7.61 mmol), Cs₂CO₃ (3.72 g, 11.4 mmol), and 4-bromo-6-chloromethylpyridine (1.88 g, 9.12 mmol) in a suspension in toluene (88 mL) were supplemented with RuPhos Pd G4 (647 mg, 760 μmol). The mixture was stirred overnight at 110 °C under Ar conditions. Another batch of compounds was combined, which used 500 mg of aziridine-3-yl-4-(aziridine-1-yl)-2-methyl-5,7-dihydro- 6H -pyrrolo[3,4- d Pyrimidine-6-carboxylate. The mixture was quenched with water at room temperature and 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 (NH4 silica gel and silica gel, eluted with 0%–30% MeOH in EtOAc) and ground with EtOAc. The residue (2.5 g) was dissolved in THF (95 mL) at 60 °C. Heptane (40 mL) was added to the mixture at 60 °C. After stirring at 60 °C for 1 hour, heptane (55 mL) was added to the reaction mixture. The mixture was stirred overnight at room temperature. The precipitate was collected by filtration to give the title compound (2.3 g) as a white solid.

[0236] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.27 (3H, s), 2.29-2.36 (5H, m), 3.92 (2H, dd, J = 9.7, 3.8 Hz), 4.12-4.21 (4H, m), 4.29 (2H, br t, J = 7.9Hz), 4.33-4.47 (2H, m), 4.60-4.76 (2H, m), 5.19-5.36 (1H, m), 6.28 (2H, d, J = 5.1 Hz).

[0237] m / z 415.1 [M+H] + Example 65-2 1-(2-chloro-6-methylpyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro- 6H -pyrrolo[3,4-d Pyrimidine-6-carbamate Crude product: aziridine-3-yl-4-(aziridine-1-yl)-2-methyl-5,7-dihydro- 6H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylate bis(trifluoroacetate) (1.5 g, 1.8 mmol), 4-bromo-2-chloro-6-methylpyridine (0.52 g, 2.5 mmol), methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (0.15 g, 0.18 mmol), Cs₂CO₃ (2.9 g, 9.0 mmol), and DME (15 mL) was heated at 120°C for 2 hours under microwave irradiation. The mixture was purified by column chromatography (silica gel, eluted with 0%–20% MeOH in EtOAc), followed by column chromatography (NH₄ silica gel, eluted with 40%–90% EtOAc in n-hexane). The residue was ground with EtOAc-n-hexane to give the title compound (266 mg) as a white solid.

[0238] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.27 (3H, s), 2.28-2.37 (5H, m), 3.92 (2H, dd, J = 10.0, 3.7 Hz), 4.16 (4H, br s), 4.29 (2H, br t, J = 7.9Hz), 4.34-4.48 (2H, m), 4.59-4.77 (2H, m), 5.20-5.36 (1H, m), 6.28 (2H, d, J = 4.9 Hz).

[0239] m / z 415.3 [M+H] + Example 65-3 1-(2-chloro-6-methylpyridin-4-yl)azacyclobut-3-yl-4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carbamate Crude product: aziridine-3-yl-4-(aziridine-1-yl)-2-methyl-5,7-dihydro- 6H -pyrrolo[3,4- d A mixture of pyrimidine-6-carboxylate bis(trifluoroacetate) (39.4 mg), 4-bromo-6-chloromethylpyridine (17.9 mg, 86.5 μmol), RuPhos Pd G4 (7.5 mg, 8.8 μmol), Cs₂CO₃ (77.4 mg, 238 μmol), and DME (2 mL) was heated at 120°C for 2 hours under microwave irradiation. The mixture was concentrated under vacuum. The residue was purified by column chromatography (NH₄ silica gel, eluted with 50%–100% EtOAc in n-hexane) and then further purified by column chromatography (silica gel, eluted with 0%–20% MeOH in EtOAc) to give the title compound (11.8 mg) as a white powder.

[0240] 1 H NMR (300 MHz, CDCl3, 300 K) δ 2.36-2.48 (5H, m), 2.49-2.53 (3H, m), 3.92-4.01 (2H, m), 4.19-4.28 (4H, m), 4.28-4.36 (2H, m), 4.47-4.55 (2H, m),4.70 (2H, br s), 5.32-5.46 (1H, m), 6.05 (1H, d, J = 1.9 Hz), 6.14 (1H, d, J = 1.9 Hz).

[0241] m / z 415.3 [M+H] + Example 67 1-(2-chloropyridin-4-yl)azacyclobut-3-yl( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro- 6H -pyrrolo[3,4- d]pyrimidine pyridine-6-carboxylate Step 1 1-(tert-butoxycarbonyl)azacyclobut-3-yl ( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro- 6H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, Et3N (1.18 mL, 8.49 mmol) was added to a solution of tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (447 mg, 2.579 mmol) and 4-nitrophenol chloroformate (525 mg, 2.602 mmol) in THF (20 mL). After stirring for 2 hours at the same temperature, saturated NaHCO3 aqueous solution (10 mL) and ( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro- 5H -pyrrolo[3,4- d Pyrimidine hemispheres 2R, 3R 2,3-bis((4-methylbenzoyl)oxy)succinate (1000 mg, 1.70 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 days. A saturated aqueous solution of NaHCO3 was added to the mixture and extracted with EtOAc. The organic layer was separated, washed three times with a saturated aqueous solution of NaHCO3 and then with 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 (654 mg) as a colorless foam.

[0242] 1 H NMR (400 MHz, CDCl3, 300 K) δ 1.37-1.43 (3H, m), 1.45 (9H, s), 2.37-2.48 (2H, m), 2.52 (3H, s), 3.89-4.01 (2H, m), 4.06-4.16 (2H, m), 4.22-4.34 (4H, m), 4.39-4.48 (1H, m), 4.52-4.62 (1H, m), 5.05-5.26 (2H, m).

[0243] m / z 404.4 [M+H] + Step 2 Azacyclobut-3-yl ( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate bis(trifluoroacetate) Add TFA (5 mL) to 1-(tert-butoxycarbonyl)azacyclobut-3-yl ( R)-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro- 6H -pyrrolo[3,4- d The mixture was stirred in pyrimidine-6-carboxylate (654 mg, 1.620 mmol) at the same temperature for 20 minutes. The mixture was then concentrated under vacuum to give the crude title compound (1216 mg) as a brown oil. This product was ready for further reaction without further purification.

[0244] 1 H NMR (300 MHz, CD3OD, 300 K) δ 1.46-1.69 (3H, m), 2.46-2.63 (5H, m), 4.16-4.30 (2H, m), 4.37-4.81 (8H, m), 5.19-5.42 (2H, m).

[0245] m / z 304.3 [M+H] + Step 3 1-(2-chloropyridin-4-yl)azacyclobut-3-yl( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro- 6H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, to the nitrogen-containing heterocyclic butyl-3-yl ( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro- 6H -pyrrolo[3,4- d 2-Chloro-4-fluoropyridine (17.9 mg, 136 μmol) and DIPEA (47.5 μL, 273 μmol) were added to a solution of pyrimidine-6-carboxylate bis(trifluoroacetate) in DMSO (0.5 mL). The mixture was stirred at 100°C for 16 hours under N2. 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 (NH4 silica gel, eluted with 50%–100% EtOAc in n-hexane) to give the title compound (19.7 mg) as a pale yellow oil.

[0246] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.39-1.44 (3H, m), 2.39-2.48 (2H, m), 2.50-2.54 (3H, m), 3.95-4.04 (2H, m), 4.07-4.15 (2H, m), 4.25-4.38 (4H, m),4.42-4.48 (1H, m), 4.53-4.63 (1H, m), 5.07-5.17 (1H, m), 5.35-5.48 (1H, m),6.18-6.22 (1H, m), 6.27-6.29 (1H, m), 7.98-8.02 (1H,m).

[0247] m / z 415.2 [M+H] + Example 68-1 1-(2-chloropyridin-4-yl)azacyclobut-3-yl( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro- 6H -pyrrolo[3,4- d Pyrimidine-6-carboxylate fumarate Step 1-1 1-(2-chloropyridin-4-yl)azacyclobut-3-ol A mixture of aziridine-3-ol hydrochloride (100 mg, 913 μmol), 2-chloro-4-fluoropyridine (180 mg, 1.37 mmol), DIPEA (477 μL, 2.74 mmol), and DMSO (0.5 mL) was stirred overnight at 100°C in a sealed tube. The reaction mixture was poured into an aqueous solution of K₂CO₃ and extracted three times with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 10%–100% EtOAc in n-hexane) to give the title compound (166 mg) as a colorless powder.

[0248] 1 H NMR (300 MHz, CDCl3, 300 K) δ 2.84 (1H, br d, J = 5.3 Hz), 3.77-3.88 (2H, m), 4.17-4.29 (2H, m), 4.76-4.92 (1H, m), 6.16 (1H, dd, J= 5.7, 2.3 Hz), 6.24 (1H, d, J = 1.9 Hz), 7.95 (1H, d, J = 5.7 Hz).

[0249] m / z 185.2 [M+H] + Step 1-2 1-(2-chloropyridin-4-yl)azacyclobut-3-ol The reaction mixture was poured into an aqueous solution of K₂CO₃ and extracted three times with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated under vacuum to give the crude title compound (542 mg) as a pale yellow powder.

[0250] m / z 185.2 [M+H] + Step 2 1-(2-chloropyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate At room temperature, 4-nitrophenyl chloroformate (1.10 g, 5.48 mmol) was added to a solution of crude 1-(2-chloropyridin-4-yl)azacyclobut-3-ol (542 mg) and Et3N (1.15 mL, 8.22 mmol) in THF (20 mL). The mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 10%–100% EtOAc in n-hexane) to give the title compound (825 mg) as a pale yellow powder.

[0251] 1 H NMR (300 MHz, CDCl3, 300 K) δ 4.05-4.16 (2H, m), 4.34-4.45 (2H, m),5.47 (1H, tt, J = 6.5, 4.1 Hz), 6.23 (1H, dd, J = 5.7, 2.3 Hz), 6.31 (1H, d, J = 1.9 Hz), 7.36-7.45 (2H, m), 8.04 (1H, d, J = 5.7 Hz), 8.27-8.35 (2H, m).

[0252] m / z 350.2 [M+H] + Step 3 1-(2-chloropyridin-4-yl)azacyclobut-3-yl( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro- 6H -pyrrolo[3,4- d Pyrimidine-6-carbamate At room temperature, to ( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro- 5H -pyrrolo[3,4- d ]Pyrimidine half(( 2R, 3R 1-(2-chloropyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate (269 mg, 770 μmol) was added to a solution of 2,3-bis((4-methylbenzoyl)oxy)succinate (see WO2018066718) (255 mg, 321 μmol), NaHCO3 (200 mg, 2.38 mmol), water (2 mL), and THF (6 mL). The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 20%–100% EtOAc in n-hexane) to give the crude title compound (303 mg) as a colorless gel.

[0253] The product can be used for the next reaction without further purification.

[0254] m / z 415.1 [M+H] + Step 4 1-(2-chloropyridin-4-yl)azacyclobut-3-yl( R )-4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate fumarate The crude product 1-(2-chloropyridin-4-yl)azacyclobut-3-yl (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- dA mixture of pyrimidine-6-carboxylate (295 mg) and fumaric acid (74 mg, 0.64 mmol) in 2-propanol (1 mL) was stirred at 50°C. MeCN (10 mL) was added dropwise to the resulting solution at 50°C. The mixture was allowed to cool to room temperature overnight. The precipitate was filtered, washed with MeCN, and dried to give a colorless solid of 1-(2-chloropyridin-4-yl)azacyclobut-3-yl (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate fumarate (162 mg). The mother liquor was concentrated under vacuum, diluted with MeCN (4 mL), and allowed to stand overnight. The precipitate formed was filtered, washed with MeCN, and dried to give the title compound (83 mg) as a colorless solid.

[0255] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.33 (3H, dd, J = 10.5, 6.1 Hz),2.26-2.40 (5H, m), 3.91-4.00 (2H, m), 4.08 (2H, q, J = 7.3 Hz), 4.14-4.23(2H, m), 4.26-4.54 (4H, m), 5.04-5.20 (1H, m), 5.24-5.36 (1H, m), 6.41 (1H,dt, J = 5.6, 2.0 Hz), 6.44-6.47 (1H, m), 6.63 (2H, s), 7.93 (1H, dd, J = 5.7,1.6 Hz), 13.10 (2H, br s). m / z 415.2 [M+H] + Example 68-2 1-(2-chloropyridin-4-yl)azacyclobut-3-yl (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate fumarate At room temperature, to (R)-4-(azacyclobut-1-yl)-2,5-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d ]Pyrimidine half(( 2R , 3R 1-(2-chloropyridin-4-yl)azacyclobut-3-yl(4-nitrophenyl)carbonate (116 mg, 332 μmol) was added to a solution of 2,3-bis((4-methylbenzoyl)oxy)succinate (120 mg, 151 μmol), NaHCO3 (127 mg, 1.51 mmol), H2O (5 mL), and THF (10 mL). The mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under vacuum. The residue was 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%-15% MeOH in EtOAc) to give a colorless gel of 1-(2-chloropyridin-4-yl)azacyclobut-3-yl (R) -4-(azacyclobut-1-yl)-2,5-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- d Pyrimidine-6-carboxylate (78 mg, 0.188 mmol). A mixture of the product and fumaric acid (22 mg, 0.19 mmol) was dissolved in EtOH. The solution was concentrated under vacuum, diluted in MeCN (4 mL), and allowed to stand overnight. The precipitate formed was filtered, washed with MeCN, and dried to give the title compound (50 mg) as a colorless solid.

[0256] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 1.33 (3H, dd, J = 10.5, 6.1 Hz),2.26-2.40 (5H, m), 3.91-4.00 (2H, m), 4.08 (2H, q, J = 7.3 Hz), 4.14-4.23(2H, m), 4.26-4.54 (4H, m), 5.04-5.20 (1H, m), 5.24-5.36 (1H, m), 6.41 (1H,dt, J = 5.6, 2.0 Hz), 6.44-6.47 (1H, m), 6.63 (2H, s), 7.93 (1H, dd,J = 5.7,1.6 Hz), 13.10 (2H, br s).

[0257] m / z 415.1 [M+H] + Example 92 1-(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)-2-(3-(2-methylpyridin-4-yl)azacyclobut-1-yl)ethyl-1-one Step 1 3-(2-methylpyridin-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester A mixture of anhydrous DMA (10 mL) and zinc (3.2 g, 49 mmol) was stirred at 20°C while a mixture of 1,2-dibromoethane (0.87 g, 4.7 mmol) and TMS-Cl (0.51 g, 4.7 mmol) was added at a rate maintaining a temperature below 65°C. The resulting slurry was aged for 15 minutes. A solution of tert-butyl 3-iodozacyclobutane-1-carboxylate (9.1 g, 32 mmol) in DMA (20 mL) was added dropwise over 1 hour at a rate maintaining a temperature below 65°C, and the milky suspension was stirred for 30 minutes while being slowly cooled to 20°C to obtain mixture A. A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (1.2 g, 1.5 mmol), CuI (0.28 g, 1.5 mmol), and 4-bromo-2-methylpyridine (5.0 g, 29 mmol) in DMA (10 mL) was placed under N2. The resulting mixture was degassed by alternating vacuum / N2 purging to mixture B. Mixture A prepared above was added to mixture B. The mixture was degassed twice by vacuum / N2 and then heated to 80°C for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was diluted with EtOAc. The organic mixture was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, filtered, and evaporated to a brown oil. The residue was purified by column chromatography (NH silica gel, eluted with 0%-60% EtOAc in n-hexane) to give the title compound (1.23 g) as a yellow oil.

[0258] 1 H NMR (400 MHz, DMSO- d 6, 300 K) δ 1.40 (9H, s), 2.45 (3H, s), 3.69-3.89 (3H, m), 4.16-4.30 (2H, m), 7.13 (1H, dd, J = 5.1, 1.7 Hz), 7.22 (1H,s), 8.38 (1H, d, J = 5.1 Hz).

[0259] m / z 249.3 [M+H] + Step 2 2-(3-(2-methylpyridin-4-yl)azacyclobut-1-yl)benzyl acetate A mixture of tert-butyl 3-(2-methylpyridin-4-yl)azacyclobutane-1-carboxylate (3.00 g, 12.1 mmol) and EtOAc (15.1 mL, 60.4 mmol) in 4 M HCl was stirred for 16 hours at room temperature. The mixture was concentrated under vacuum to give a solid. The solid was dissolved in DMF (4 mL) and Et3N (1.83 g, 18.1 mmol) and benzyl 2-bromoacetate (996 mg, 4.35 mmol) were added. The mixture was stirred for 16 hours at room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine and water, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 30%–100% EtOAc in n-hexane, then with silica gel, eluted with 0%–20% MeOH in EtOAc) to give the title compound (437 mg) as a colorless oil.

[0260] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.44 (3H, s), 3.21-3.28 (2H, m), 3.38 (2H, s), 3.54-3.64 (1H, m), 3.65-3.74 (2H, m), 5.12 (2H, s), 7.14 (1H,dd, J = 4.9, 1.2 Hz), 7.21 (1H, s), 7.29-7.43 (5H, m), 8.35 (1H, d, J = 4.9Hz).

[0261] m / z 297.3 [M+H] + Step 3 2-(3-(2-methylpyridin-4-yl)azacyclobut-1-yl)acetic acid 10% Pd-C (77.2 mg) was added to a solution of 2-(3-(2-methylpyridin-4-yl)azacyclobut-1-yl)benzyl acetate (430 mg, 1.45 mmol) in EtOH (10 mL), and the mixture was stirred at room temperature under H2 atmosphere for 18 hours. Insoluble substances were filtered off. The filtrate was concentrated under vacuum to give the title compound (305 mg) as a colorless oil.

[0262] 1 H NMR (400 MHz, DMSO- d 6 , 300 K) δ 2.45 (3H, s), 3.44 (2H, q, J = 7.1Hz), 3.52-3.62 (2H, m), 3.70-3.83 (1H, m), 3.86-3.98 (2H, m), 7.18 (1H, dd, J = 5.3, 1.6 Hz), 7.26 (1H, s), 8.37 (1H, d, J = 5.1 Hz). 1H does not exist.

[0263] m / z 207.1 [M+H] + Step 4 1-(4-(azacyclobut-1-yl)-2-methyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]pyrimidin-6-yl)-2-(3-(2-methylpyridin-4-yl)azacyclobut-1-yl)ethyl-1-one Add 4-(azacyclobut-1-yl)-2-methyl-6,7-dihydro-5-ethyl to a solution of 2-(3-(2-methylpyridin-4-yl)azacyclobut-1-yl)acetic acid (50 mg, 0.24 mmol) in DMF (3 mL). H -pyrrolo[3,4- dPyrimidine dihydrochloride (77 mg, 0.29 mmol), DIPEA (0.13 g, 0.97 mmol), and HATU (0.12 g, 0.32 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 20%–100% EtOAc in n-hexane, followed by 0%–20% MeOH in EtOAc) and preparative HPLC (CERI L-column 2 ODS, eluted with acetonitrile solution containing 10 mM ammonium bicarbonate in H2O), and then crystallized from EtOAc-n-heptane to give the title compound (17 mg) as a white powder.

[0264] 1 H NMR (400 MHz, CDCl3, 297 K) δ 2.35-2.47 (2H, m), 2.49-2.52 (3H, m), 2.54 (3H, s), 3.30-3.42 (4H, m), 3.71 (1H, quin, J = 7.4 Hz), 3.85-3.95 (2H,m), 4.19-4.31 (4H, m), 4.52-4.64 (2H, m), 4.69-4.84 (2H, m), 7.04 (1H, d, J =5.1 Hz), 7.08 (1H, s), 8.42 (1H, d, J = 5.1 Hz).

[0265] m / z 379.3 [M+H] + Table 1. Compound structures, compound names, preparation methods, and physicochemical data for Examples 1-95. 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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).

[0271] 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 4, T2 as Example 7 and T3 as Example 11. The activity of the reference compound against the M4 receptor and the in vitro clearance rates of the reference compound and Example 8 were also determined. The results are shown in Table 2. The clearance rate value of Example 8 was significantly lower than that of Examples T1, T2 and T3.

[0272] METH-induced hyperkinesis assay from J Jackson Laboratory Japan 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).

[0273] 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 before testing. On the day of testing, they were removed from each room and treated with oral administration of a medium (0.5 w / v % methylcellulose 400 solution), Example 8, 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. As can be seen from Table 3, Example 8 is more effective than the prior art compound CVL-231 in reversing METH-induced hypermotility, with a MED of 30 mg / kg (relative to 60 mg / kg).

[0274] 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 8) 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]).

[0275] 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.

[0276] 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; L represents O, NR x or CR y R z , where R x It is a hydrogen atom or a C1-C6 alkyl group, and R y and R z Each is independently a hydrogen atom or 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 2, or a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analog 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 2, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein the compound has the following formula: 。 5. The compound according to any one of claims 1, 2 or 4, 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, 2 or 4, 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 atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups and hydroxyl groups.

8. The compound according to any one of claims 1, 2, 4, 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, 4, 5 or 8, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analog thereof, wherein R1 is an unsubstituted azacyclobutyl group.

10. The compound of any one of claims 1, 2, 4, 5, 6, 7 or 8, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analog thereof, wherein R1 is an azahexacyclic butyl 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, 4, 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 bonded to the pyrimidinyl ring via the N atom 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 atoms, methyl, ethyl, hydroxyl, 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 atom, 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 L is O.

16. The compound according to any one of claims 1-14, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein L is NR. x .

17. The compound according to any one of claims 1-14 or 16, a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof, or a deuterated analogue, wherein R x It consists of hydrogen atoms or C1-C6 alkyl groups.

18. The compound according to any one of claims 1-14, 16 or 17, a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof or a deuterated analogue thereof, wherein R x It can be a hydrogen atom or a methyl group.

19. The compound according to any one of claims 1-14, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate thereof, or a deuterated analogue thereof, wherein L is a CR y R z .

20. The compound according to any one of claims 1-14 or 19, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate thereof, or a deuterated analogue, wherein R y and R z Each is independently a hydrogen atom or a C1-C6 alkyl group.

21. The compound according to any one of claims 1-14, 19 or 20, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, wherein R y and R z Each is a hydrogen atom.

22. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue thereof, according to any one of claims 1-21, wherein A is an unsubstituted or substituted four-membered heterocycle with one or more substituents other than Ar, and said four-membered heterocycle contains one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

23. The compound according to any one of claims 1-22, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein A is a 4-membered heterocycle substituted only with Ar, and said 4-membered heterocycle contains one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

24. The compound according to any one of claims 1-23, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein A is azacyclobutyl.

25. The compound of claim 24, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the azahexabutyl group is bonded to Ar via the nitrogen atom of the azahexabutyl group.

26. The compound of claim 24, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the azahexabutyl group is bonded to L via the nitrogen atom of the azahexabutyl group.

27. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or a deuterated analogue thereof, according to any one of claims 1-21, wherein A is an unsubstituted or substituted 5-membered heterocycle with one or more substituents other than Ar, and said 5-membered heterocycle contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

28. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue of any one of claims 1-21 or 27, wherein A is an unsubstituted 5-membered heterocycle, and wherein said heterocycle contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

29. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 1-21, 27 or 28, wherein A is a pyrrolidinyl group.

30. The compound of claim 29, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the pyrrolidinyl group is bonded to Ar via the nitrogen atom of the pyrrolidinyl group.

31. The compound of claim 29, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the pyrrolidinyl group is bonded to L via the nitrogen atom of the pyrrolidinyl group.

32. The compound according to any one of claims 1-31, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein R3 is methyl.

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 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.

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 substituted by at least one substituent selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a cyano group; optionally, one or more hydrogen atoms of the C1-C6 alkyl group may be substituted by a halogen atom; optionally, one or more hydrogen atoms of the C1-C6 alkoxy group may be substituted by a halogen atom.

35. The compound according to any one of claims 1-33, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is unsubstituted.

36. The compound according to any one of claims 1-34, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is substituted by a substituent.

37. The compound according to any one of claims 1-34, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is substituted by two substituents.

38. 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- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

39. The compound according to any one of claims 1-38, 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.

40. The compound according to any one of claims 1-39, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is selected from the group consisting of: as well as , Each group is either unsubstituted or substituted.

41. The compound according to any one of claims 1-39, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heteroaromatic ring having a single heteroatom.

42. The compound of claim 41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the heteroatom is a nitrogen atom.

43. The compound according to any one of claims 1-41, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heteroaromatic ring having two heteroatoms.

44. The compound of claim 43, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein both of the heteroatoms are nitrogen atoms.

45. The compound according to any one of claims 1-44, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, 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 atoms, each of which is either unsubstituted or substituted.

46. ​​The compound of claim 45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein n equals 0.

47. The compound of claim 45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein n equals 1.

48. The compound of claim 45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein n equals 2.

49. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 is a heteroatom.

50. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 is a heteroatom.

51. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X3 is a heteroatom.

52. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X4 is a heteroatom.

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

54. The compound of claim 48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein each X5 is a heteroatom.

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

56. The compound of claim 48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to the carbon atom bound to A is a heteroatom.

57. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X2 are both heteroatoms.

58. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X3 are heteroatoms.

59. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X4 are heteroatoms.

60. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 and X3 are heteroatoms.

61. The compound according to any one of claims 46-48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 and X4 are heteroatoms.

62. The compound of claim 47, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 and X5 are heteroatoms.

63. The compound of claim 47, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 and X5 are heteroatoms.

64. The compound of claim 47, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X3 and X5 are heteroatoms.

65. The compound of claim 47, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X4 and X5 are heteroatoms.

66. The compound according to any one of claims 45-65, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein one of X1, X2, X3 and X4 is a carbon atom substituted by a substituent.

67. The compound of claim 66, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X1.

68. The compound of claim 66, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X2.

69. The compound of claim 66, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X3.

70. The compound of claim 66, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the substituent is combined with X4.

71. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 47 or 49-52, wherein X5 is a carbon atom substituted by a substituent.

72. The compound according to any one of claims 48-52, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to X4 is a carbon atom substituted by a substituent.

73. The compound according to any one of claims 48-52, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X5 adjacent to the carbon atom bound to A is a carbon atom substituted by a substituent.

74. The compound according to any one of claims 45-65, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein two of X1, X2, X3 and X4 are each carbon atoms substituted by a substituent.

75. The compound of claim 74, 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.

76. The compound of claim 74, 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.

77. The compound of claim 74, 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.

78. The compound of claim 74, 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.

79. The compound of claim 74, 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.

80. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue thereof, according to any one of claims 47 or 49-52, wherein X5, and one of X1, X2, X3 and X4 are each a carbon atom substituted by a substituent.

81. The compound according to any one of claims 48-52, 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 atom substituted by a substituent.

82. The compound according to any one of claims 48-52, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein the adjacent X5, and one of X1, X2, X3 and X4, is a carbon atom substituted by a substituent.

83. The compound according to any one of claims 80-82, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X1 is substituted with a substituent.

84. The compound according to any one of claims 80-82, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X2 is substituted with a substituent.

85. The compound according to any one of claims 80-82, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X3 is substituted with a substituent.

86. The compound according to any one of claims 80-82, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein X4 is substituted with a substituent.

87. The compound of claim 48, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein both X5 are carbon atoms substituted by substituents.

88. The compound according to any one of claims 1-49, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 5-membered heterocyclic or heteroaromatic ring selected from the group consisting of: ， Each ring is either unsubstituted or substituted with one or more substituents.

89. The compound according to any one of claims 1-49, 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.

90. The compound according to any one of claims 1-38, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar has the following structure: in m and n are integers from 0 to 2, inclusive; 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 atoms, each of which is either unsubstituted or substituted.

91. The compound of claim 90, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is selected from the group consisting of: ， Each ring is either unsubstituted or substituted with one or more substituents.

92. The compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate or deuterated analogue of any one of claims 1-38, 90 or 91, wherein Ar is an unsubstituted or substituted 9-membered bicyclic heteroaromatic ring.

93. The compound according to any one of claims 1-38 or 90-92, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 9-membered bicyclic heteroaromatic ring having at least 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

94. The compound according to any one of claims 1-38 or 90-93, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is an unsubstituted 9-membered bicyclic heteroaromatic ring.

95. The compound according to any one of claims 1-38 or 90-93, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 9-membered bicyclic heteroaromatic ring substituted with one substituent.

96. The compound according to any one of claims 1-38 or 90-93, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 9-membered bicyclic heteroaromatic ring substituted with two substituents.

97. The compound of claim 45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 5-membered heterocycle selected from the group consisting of: 。 98. The compound of claim 45, its pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analogue, wherein Ar is a 6-membered heterocycle selected from the group consisting of: 。 99. 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.

100. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, having 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 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, wherein the compound has the following structure: 。 103. 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: 。 104. 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: 。 105. 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: , or .

106. The compound according to claim 1, having the following structure: 。 107. The pharmaceutically acceptable salt according to claim 1, wherein: 。 108. 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 1-107 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.

109. 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 1-107, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate or deuterated analog thereof, thereby enhancing the response of the M4 receptor to the ligand.

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