M4 positive allosteric modulators

Abstract

M4 positive allosteric modulators are disclosed which having a formula or a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof. These compounds may be used for the therapeutic and / or prophylactic treatment of N14mediated diseases or disorders, such as Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction and Huntington's disease.

Description

M4 POSITIVE ALLOSTERIC MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No.63 / 607,351, filed December 7, 2023, the contents of which are hereby incorporated by reference. FIELD

[0002] The present invention relates to compounds useful as M4 positiveallosteric modulators and their manufacture. These compounds may be useful as medicaments for 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. BACKGROUND

[0003] Muscarinic acetylcholine receptors are G-protein-coupled receptors(GPCRs) and consist of five subtypes termed Ml, M2, M3, M4 and M5. The M4 receptor is coupled to Gi and is mainly 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 and24,542 controls) identified a single nucleotide polymorphism significantly linked to disease at locus rs7951870, which includes the M4 gene (Pardinas et al., Nature Genetics, 50, 381-389 (2018)).

[0005] Cholinergic neurotransmission is known to have an important role incognitive functions as evidenced by the fact that cholinergic receptor antagonists cause profound memory impairments and acetylcholinesterase inhibitors like donepezil show pro-cognitive effects in Alzheimer’s disease. In schizophrenia, a hyper-dopaminergic state in the striatum and nucleus accumbens has been associated with psychosis and is the target of current antipsychotic drugs blocking the dopamine D2 receptor.

[0006] Recent development of M4 specific positive allosteric modulators(“PAMs”), that potentiate the effects of the endogenous agonist acetylcholine, has uncovered a role for these receptors in the control of dopamine release in the striatum and in key synapses known to be important for cognition in the hippocampus.

[0007] In a recent study, it was demonstrated that M4 PAMs reduce striataldopamine release after amphetamine treatment in wild-type mice but not M4 knock-outs (Byun et al., Neuropsychopharmacology, 39, 1578 (2014)). Another study showed that M4 PAM induced inhibition of glutamate excitatory synaptic transmission at the Schaeffer collateral-CA1 synapse in the hippocampus (Thom et al., Hippocampus, 27, 794-810 (2017)).

[0008] Further rodent in vivo studies showed that the M4 PAM VU0467154ameliorated the associative learning impairments in the touch screen pair- wise visual discrimination task induced by MK- 801, a non-competitive NMDA receptor antagonist. These effects were absent in the M4 knockout mice, demonstrating the specificity of this phenotype to the M4 receptor (Bubser et al., ACS Chemical Neuroscience, 5, 920-942 (2014)).

[0009] Activating the striatal and hippocampal M4 receptors by using aspecific PAM can reduce the hyperdopaminergic state in the striatum and the excessive stimulation of the hippocampus, providing a treatment of psychosis and cognitive impairment in schizophrenia.

[0010] Activation of muscarinic receptors by the M1 / M4 agonist xanomelinehas been shown to improve cognition and psychiatric symptoms like hallucinations, delusions and vocal outbursts in a clinical study with 345 Alzheimer patients (Bodick et al., Arch Neurol, 54, 465-73 (1997)). An M4 PAM could therefore improve cognitive deficiencies in Alzheimer patients and reduce psychiatric symptoms.

[0011] M4 receptors are known to control dopamine release in the striatum(Tzavara et al., The FASEB Journal, 18, 1410-1412 (2004)), a region important for reward and addiction. It was shown that M4 knock-out mice have higher cocaine self-administration in an operant behavior test (Schmidt et al., Psychopharmacology, 216, 367-378 (2011)) and conversely that a M4 PAM tool compound is reducing cocaine self-administration in mice (Dencker et al., Psychopharmacology, 224, 277-287 (2012)). These results indicate that activation of the M4 receptor may reduce addiction.

[0012] Huntington’s disease is caused by a triplet repeat expansion coding forGlutamine in the Huntington gene, which cause neurodegeneration, leading to movement abnormalities, cognitive impairments evolving to dementia and death.

[0013] It was shown that chronic treatment with a M4 PAM can improve themotor and synaptic defects in a mouse model of Huntington (Y AC128 mice)(Pancani et al., Proceedings of the National Academy of Sciences, 112, 14078-14083 (2015)). An M4 PAM may normalize early changes in corticostriatal transmission and thereby reduce the progression of Huntington’s disease.

[0014] Parkinson’s disease is caused by a degeneration of dopamineproducing neurons in the substantia nigra. The lack of dopamine is causing movement disorders that can be treated for a certain period by L-DOPA supplementation. This treatment losses its efficacy overtime and higher doses of L-DOPA are needed to control the symptoms, higher doses are also inducing dyskinesia.

[0015] It was shown in a mouse 6-hydroxydopamine lesion model ofParkinson, that M4 PAM treatment can reduce the L-DOPA induced dyskinesia, these findings were reproduced in a monkey MPTP model of Parkinson (Shen et al., Neuron, 88, 762-773 (2015)). An M4 PAM could therefore be used as a symptomatic treatment of L-DOPA induced dyskinesia in Parkinson’s disease.

[0016] An M4 antagonist was shown to block the antinociceptive effect ofelectrical spinal cord stimulation in a rat neuropathic pain model (Schechtmann et al., Pain, 139, 136-145 (2008)), also M4 knock-down in the rat spinal cord has been shown to increase heat nociception in rats (Cai et al., Journal of Neurochemistry, 111, 1000-1010 (2009)). Therefore, M4 activation could reduce pain sensation.

[0017] Modulating M4 receptor activity is a promising therapeutic strategyfor the treatment or prevention of M4-mediated diseases or disorders, suchas Alzheimer’s disease, schizophrenia, psychosis, Parkinson’s disease, pain, addiction and Huntington’s disease. Examples of compounds that have been suggested for such use(s) are disclosed and / or claimed in WO2018 / 066718, WO2018 / 002760A1, WO2018 / 234953A1, WO2021 / 099527A1, and US 2023 / 0348490.

[0018] There nevertheless remains a need for new compounds, formulations,treatments and therapies to treat or prevent M4-mediated diseases or disorders. Accordingly, it is an object of this invention to provide compounds useful for the treatment or prevention or amelioration of such diseases and disorders with improved therapeutic properties. SUMMARY

[0017] A first embodiment relates to compounds of the formula:

[0018] wherein

[0019] R1 is a 4- or 5-membered heterocyclic ring, each of which mayunsubstituted or substituted by one or more substituents and which ring contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

[0020] R2 is a C1-C6 alkyl group;

[0021] L is O, NRx, or CRyRz, where Rx is a hydrogen atom or a C1-C6 alkylgroup and Ryand Rzare each independently a hydrogen atom or a C1-C6alkyl group;

[0022] A is a 4- or 5-membered heterocyclic ring, each of which may beunsubstituted or substituted by one or more substituents and which ring contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

[0023] R3 is a hydrogen atom or a C1-C6 alkyl group; and

[0024] Ar is a 5-10 membered heterocyclic, aromatic or heteroaromatic ring,each of which may be unsubstituted or substituted by one or more substituents and the heterocyclic or heteroaromatic ring(s) of which each contain 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; or

[0025] a pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof.

[0026] Another embodiment relates to compounds having the formula:

[0027] wherein R1, R2, R3, L, A, and Ar have the meanings above,

[0028] or a pharmaceutically acceptable salt or pharmaceutically acceptablesalt hydrate or deuterated analog thereof.

[0029] Another embodiment relates to compounds having the formula:

[0030] wherein R2, R3, L, A, and Ar have the meanings above, and

[0031] R4a and R4b are each individually selected from a hydrogen atom, ahalogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group; or

[0032] a pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof.

[0033] Another embodiment relates to compounds having the formula:

[0034] wherein R1, R2, R3, L, and Ar have the meanings above,

[0035] or a pharmaceutically acceptable salt or pharmaceutically acceptablesalt hydrate or deuterated analog thereof. DETAILED DESCRIPTION Definitions

[0036] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there are multiple possible definitions for a term herein, those in this section prevail unless stated otherwise.

[0037] The term “alkyl group” refers to a mono- or multivalent, e.g., a mono-or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-C6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl (Me), ethyl (Et), propyl, 2- propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert- butyl, and 2,2-dimethylpropyl. Preferred alkyl groups have 1 to 4 carbon atoms (“C1-4alkyl”). A particularly preferred, yet non-limiting example of an alkyl group is methyl.

[0038] The term “alkoxy group” refers to an alkyl group, as previouslydefined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C1-C6alkoxy”). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the 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, yet non-limiting example of an alkoxy group is methoxy.

[0039] The term “aromatic ring” refers to a monocyclic or bicycliccarbocyclic ring system wherein the monocyclic ring system has a conjugated π-electron system and a total of 6 ring atoms, wherein the bicyclic ring system has a total of 10 to 12 ring atoms having a conjugated π-electron system. When the term “aromatic ring” is used to refer to a bicyclic carbocyclic system, at least one or both of the constituent carbocyclic rings has a conjugated π-electron system. A particularly preferred, yet non-limiting example of an aromatic ring is a phenyl group. “Bicyclic aromatic ring” refers to aromatic moieties consisting of two cycles having two ring atoms in common.

[0040] The terms “asymmetric carbon atom” and “asymmetric center” meana carbon atom with four different atoms and / or groups bound thereto. According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be of the “R” or “S” configuration.

[0041] The term “substituent” means an atom or group that replaces ahydrogen atom.

[0042] The terms “halogen atom” or “halo”, alone or in combination, denotea fluorine atom, a chlorine atom, a bromine atom, or an iodine and particularly a fluorine atom or a chlorine atom. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen atom, particularly substituted with one to five halogens, more particularly one to four halogen atoms, i.e., one, two, three, or four halogens.

[0043] The term “haloalkyl” refers to an alkyl group, as previously defined,wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably a fluorine atom. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2, or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl and trifluoroethyl.

[0044] The term “haloalkoxy” refers to an alkoxy group, wherein at least oneof the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably a fluorine atom. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2, or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably a fluorine atom. Particularly preferred, yet non-limiting examples of haloalkoxy are difluoromethoxy and trifluoromethoxy.

[0045] The term “heteroaromatic ring” refers to a mono- or multivalent,monocyclic or bicyclic ring, 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, “heteroaromatic ring” refers to a 5-10 membered monocyclic or bicyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, sulfur, and nitrogen. Most preferably, “heteroaromatic ring” refers to a 5-10 membered monocyclic or bicyclic ring containing 1 to 2 heteroatoms independently selected from oxygen and nitrogen.

[0046] Some non-limiting examples of heteroaromatic rings include 2-pyridyl, 3-pyridyl, 4-pyridyl, indol-l-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H- indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-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, 1H-indazol-3-yl, 1H-indazol-4-yl, lH-indazol-5-yl, 1H- indazol-6-yl, 1H-indazol-7-yl, pyrazol-l-yl, 1H-pyrazol-3-yl, 1H- pyrazol-4- yl, 1H-pyrazol-5-yl, imidazol-l-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H- imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, and 1,2,4- oxadiazol-3-yl.

[0047] The term “heterocyclic ring” refers to a saturated or partly unsaturatedmono- or bicyclic, preferably monocyclic ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O, and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. “Bicyclic heterocyclic ring” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclic rings include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan- 2-yl, 2-oxopyrrolidin-1-yl, 2- oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5- oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3- piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6 -oxo-3-piperidyl, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl,pyrrolidinyl (e.g., pyrrolidin-3-yl), 3-azabicyclo[3.1.0]hexan-6-yl, or 2, 5- diazabicyclo[2.2.1]heptan-2-yl.

[0048] Other non-limiting examples of 5-membered monocyclicheteroaromatic rings include:

[0049] Other non-limiting examples of 5-membered monocyclicheteroaromatic rings include:.

[0050] Other non-limiting examples of 6-membered monocyclicheteroaromatic or heterocyclic rings include:

[0051] Non-limiting examples of bicyclic heteroaromatic rings in whichnitrogen is the only heteroatom include:

[0052] .

[0053] The term “hydroxy group” refers to an -OH group.

[0054] The term “cyano group” refers to an -CN group.

[0055] As used herein, “tautomer” and “tautomeric” refer to alternate formsof a compound disclosed herein that differ in the position of a proton. Non- limiting examples include enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0056] It is understood that isotopes may be present in the compoundsdescribed herein. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound described herein a hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0057] As used herein, “pharmaceutically acceptable salt” refers to a salt of acompound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt (NH4+); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)- methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine. Useful acid-based salts include, without limitation, acetates, adipates, aspartates, ascorbates, benzoates, butyrates, caprate, caproate, caprylate, camsylates, citrates, decanoates, formates, fumarates, gluconates, glutarate, glycolates, hexanoates, laurates, lactates, maleates, nitrates, oleates, oxalates, octanoates, propanoates, palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfonates, such as methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, tartrates, and tosylates.

[0058] Acid addition salts can be formed by mixing with a solution of apharmaceutically 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, or the like. 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 and the like. Suitable pharmaceutically acceptable salts can be composed of a compound with one or more counterions, e.g., a dichloride, or with a fraction of a counterion, e.g., a hemitartrate.

[0059] Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or a fraction thereof, for example from 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 of a solvent or water molecule.

[0060] As used herein, to “modulate” the activity of a receptor means eitherto activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and / or render 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 is an agonist for the receptor.

[0061] As used herein, a “subject” refers to an animal that is the object oftreatment, observation and / or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as birds, fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.

[0062] As used herein, a “patient” refers to a subject that is being treated bya medical professional such as an M.D. or a D.V.M. to attempt to cure, or at least ameliorate the effects of, a particular disease or condition or to prevent the disease or condition from occurring in the first place.

[0063] As used herein, a “pharmaceutically acceptable excipient” refers to aninert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication,disintegrating ability, etc., to the composition and that does not abrogate the biological activity and properties of the active ingredient.

[0064] As used herein, a “receptor” is intended to include any moleculepresent inside or on the surface of a cell that may affect cellular physiology when it is inhibited or stimulated by a ligand. Typically, a receptor comprises an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding (“signal transduction”). A receptor also includes any intracellular molecule that in response to ligation generates a signal. A receptor also includes any molecule having the characteristic structure of a receptor, but with no identifiable ligand. In addition, a receptor includes a truncated, modified, mutated receptor, or any molecule comprising partial or all of the sequences of a receptor.

[0065] When used herein, “prevent / preventing” should not be construed tomean that a condition and / or a disease never might occur again after use of a compound or pharmaceutical composition according to embodiments disclosed herein to achieve prevention. Further, the term should neither be construed to mean that a condition not might occur, at least to some extent, after such use to prevent said condition. Rather, “prevent / preventing” is intended to mean that the condition to be prevented, if occurring despite such use, will be less severe than without such use.

[0066] As used herein, the term “about” includes the recited number ±0.5 ofthe last digit thereof. Thus, “about 1” means 0.5 to 1.5 and “about 0.1” means 0.05 to 0.15.

[0067] Compounds

[0068] A first embodiment relates to compounds of the formula:

[0069] wherein

[0070] R1 is a 4- or 5-membered heterocyclic ring, each of which mayunsubstituted or substituted by one or more substituents and which ring contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

[0071] R2 is a C1-C6 alkyl group;

[0072] L is O, NRx, or CRyRz, where Rx is a hydrogen atom or a C1-C6 alkylgroup and Ryand Rzare each independently a hydrogen atom or a C1-C6alkyl group;

[0073] A is a 4- or 5-membered heterocyclic ring, each of which may beunsubstituted or substituted by one or more substituents and which ring contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

[0074] R3 is a hydrogen atom or a C1-C6 alkyl group; and

[0075] Ar is a 5-10 membered heterocyclic, aromatic or heteroaromatic ring,each of which may be unsubstituted or substituted by one or moresubstituents and the heterocyclic or heteroaromatic ring(s) of which each contain 1, 2, or 3 heteroatoms selected nitrogen, oxygen, and sulfur; or

[0076] a pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof.

[0077] Another embodiment relates to compounds having the formula:

[0078] wherein R1, R2, R3, L, A, and Ar have the meanings above,

[0079] or a pharmaceutically acceptable salt or pharmaceutically acceptablesalt hydrate or deuterated analog thereof.

[0080] Another embodiment relates to compounds having the formula:

[0081] wherein R2, R3, L, A, and Ar have the meanings above, and

[0082] R4a and R4b are each individually selected from a hydrogen atom, ahalogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group; or

[0083] a pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof.

[0084] Another embodiment relates to compounds having the formula:

[0085] wherein R1, R2, R3, L, and Ar have the meanings above,

[0086] or a pharmaceutically acceptable salt or pharmaceutically acceptablesalt hydrate or deuterated analog thereof.

[0087] According to some embodiments, R1 is a 4-membered heterocyclicring which is unsubstituted or substituted by one or more substituents.

[0088] According to some embodiments, R1 is a 4-membered heterocyclicring substituted by one or more substituents.

[0089] According to some embodiments, R1 is a 4-membered heterocyclicring substituted by one or more substituents selected from a halogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group.

[0090] According to some embodiments, R1 is an azetidinyl group.

[0091] According to some embodiments, R1 is an unsubstituted azetidinylgroup.

[0092] According to some embodiments, R1 is an azetidinyl groupsubstituted by one or more substituents. According to some embodiments,the substituent is selected from a halogen atom, a methyl group, an ethyl group, a hydroxy group, a methoxy group, and an ethoxy group.

[0093] According to some embodiments, R1 is an azetidinyl group substitutedby two substituents, which may be the same or different. According to some embodiments, the substituent is selected from a halogen atom, a methyl group, an ethyl group, a hydroxy group, a methoxy group, and an ethoxy group. According to some embodiments, the substituent is selected from a fluorine atom, a methyl group, a hydroxy group, and a methoxy group.

[0094] According to some embodiments, R1 is an azetidinyl group which isbound to the pyrimidinyl ring through the N atom of the azetidinyl group.

[0095] According to some embodiments, R2 is a C1-C6 alkyl group.According to some embodiments, R2is a C1-C4alkyl group, such as a methyl group or an ethyl group.

[0096] According to some embodiments, L is an oxygen atom.

[0097] According to some embodiments, L is an amino group of the formulaNRx. In certain embodiments, Rxis a hydrogen atom or a C1-C6alkyl group. In certain embodiments, Rxis a hydrogen atom or a methyl group.

[0098] According to some embodiments, L is CRyRz. In certain embodimentsRyand Rzare each independently a hydrogen atom or a C1-C6alkyl group. In certain embodiments, Ryand Rzare each a hydrogen atom.

[0099] According to some embodiments, wherein A is a 4-memberedheterocyclic ring, which is unsubstituted or substituted by one or more substituents in addition to Ar and which contains 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0100] According to some embodiments, A is a 4-memberedheterocyclic ring substituted by Ar only and which contains 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0101] According to some embodiments, A is an azetidinyl group.According to some embodiments, A is an azetidinyl group which is bound to Ar through the nitrogen atom of the azetidinyl group. According to other embodiments, A is an azetidinyl group. which is bound to L through the nitrogen atom of the azetidinyl group.

[0102] According to some embodiments, A is a 5-membered heterocyclicring, which is unsubstituted or substituted by one or more substituents in addition to Ar and which contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0103] According to some embodiments, A is an unsubstituted 5-memberedheterocyclic ring which contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0104] According to some embodiments, A is a pyrrolidinyl group.According to some embodiments, A is a pyrrolidinyl group that is bound to Ar through the nitrogen atom of the pyrrolidinyl group. According to other embodiments, A is a pyrrolidinyl group that is bound to Ar through the nitrogen atom of the pyrrolidinyl group. According to other embodiments, the pyrrolidinyl group is bound to L through the nitrogen atom of the pyrrolidinyl group.

[0105] According to some embodiments, R3 is a C1-C6 alkyl group.According to some embodiments, R3is a C1-C4alkyl group. According to some embodiments, R3is methyl.

[0106] According to some embodiments, Ar is a 5-10 memberedheteroaromatic ring, which is unsubstituted or substituted by one or more substituents and which contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur. According to some embodiments, Ar is a 5-10 membered heterocyclic ring, which is unsubstituted or substituted by one or more substituents and which contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0107] According to some embodiments, Ar is substituted by at least onesubstituent selected from a halogen atom, a C1-C6alkyl group in which one or more of the hydrogen atoms may be replaced by a halogen atom, a C1-C6alkoxy group in which one or more of the hydrogen atoms may be replaced by a halogen atom, and a cyano group.

[0108] According to some embodiments, Ar is unsubstituted. According toother embodiments, Ar is substituted by one substituent. According to other embodiments, Ar is substituted by two substituents.

[0109] According to some embodiments, Ar is a 5- or 6-memberedheteroaromatic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. According to some embodiments, Ar is a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0110] According to some embodiments, Ar is a 6-memberedheteroaromatic ring containing 1, 2 or 3 nitrogen atom(s). According to some embodiments, Ar is a 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atom(s).

[00111] According to some embodiments, where the only heteroatom isnitrogen, Ar is selected from:each of which is unsubstituted or substituted.

[00112] According to some embodiments, Ar has one of the followingstructures and is attached as follows:, , ,oreach of which is unsubstituted or substituted.

[00113] According to some embodiments, Ar is a 6-memberedheteroaromatic 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 heterocyclicring having a single heteroatom. According to some embodiments, Ar is a 6- membered heterocyclic ring containing a nitrogen atom.

[0114] According to some embodiments, Ar is a 6-memberedheteroaromatic ring having two heteroatoms. According to some embodiments, both of the heteroatoms are nitrogen atoms. According to some embodiments, Ar is a 6-membered heterocyclic ring having two heteroatoms. According to some embodiments, both of the heteroatoms are nitrogen atoms.

[0115] According to some embodiments, Ar has the structure:

[0116] wherein

[0117] n is an integer from 0 to 2, inclusive; and

[0118] each X1, X2, X3, X4, and X5 is individually a heteroatom selectedfrom nitrogen, oxygen, and sulfur, or a carbon atom, each of which is unsubstituted or substituted by a substituent.

[0119] According to some embodiments, n equals 0. According to otherembodiments, n equals 1. According to still other embodiments, n equals 2.

[0120] According to some embodiments, at least one of X1, X2, X3, and X4is a carbon atom that is substituted by a substituent.

[0121] According to some embodiments, Ar is a 5-memberedheteroaromatic or heterocyclic ring selected from:each of which is unsubstituted or substituted by one or more substituents.

[0122] According to some embodiments, Ar is a 5-memberedheteroaromatic ring selected from, each of which is substituted or unsubstituted.

[0123] According to some embodiments, Ar is a 6-memberedheteroaromatic or heterocyclic ring selected from:each of which is unsubstituted or substituted by one or more substituents.

[0124] According to some embodiments, Ar has the structure:

[0125] wherein

[0126] m and n are each an integer from 0 to 2, inclusive; and

[0127] each X1, X2, X3, X4, X5 X6, X7, X8, and X9 is individually aheteroatom selected from nitrogen, oxygen, and sulfur, or a carbon atom, each of which is unsubstituted or substituted by a substituent.

[0128] According to some embodiments, both n and m equal 0. Accordingto other embodiments, n equals 1 and m equals 0. According to still other embodiments, n equals 0 and m equals 1. According to still other embodiments, both n and m equal 1. According to still other embodiments, n equals 2 and m equals 0. According to still other embodiments, n equals 0 and m equals 2. According to still other embodiments, n equals 1 and m equals 2. According to still other embodiments, n equals 2 and m equals 1.

[0129] According to some embodiments, where the only heteroatom isnitrogen, Ar is selected from:each of which is unsubstituted or substituted by one or more substituents. Similar structures with other heteroatoms, such as oxygen and / or sulfur, are also contemplated.

[0130] According to some embodiments, Ar is a 9-membered bicyclicheteroaromatic ring which is unsubstituted or substituted by one or more substituents.

[00131] According to some embodiments, Ar is a 9-membered heteroaromaticring having at least 2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[00132] According to some embodiments, Ar is an unsubstituted 9-memberedheteroaromatic ring. According to other embodiments, Ar is a 9-membered heteroaromatic ring substituted by one substituent. According to still other embodiments, Ar is a 9-membered heteroaromatic ring substituted by two substituents.

[00133] According to some embodiments, Ar is an unsubstituted 9-memberedheteroaromatic ring. According to other embodiments, Ar is a 9-membered heteroaromatic ring by one substituent. According to still other embodiments, Ar is a 9-membered heteroaromatic ring by two substituents.

[00134] In some embodiments of the compound, pharmaceuticallyacceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, Ar is a 5-membered heterocyclic ring selected from the group consisting of:

[0135] In some embodiments of the compound, pharmaceuticallyacceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, Ar is a 6-membered heterocyclic ring selected from the group consisting of:and

[00136] In some embodiments of the compound, pharmaceuticallyacceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, said pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a fumarate salt, and a tartrate salt.

[00137] In some embodiments, the compound or pharmaceuticallyacceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, has the structure:, ,

[00138] In some embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0139] In some embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0140] In some embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0141] In some embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0142] In some embodiments, the compound has the structure:, or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0143] In some embodiments, the compound has the structure:oror is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0144] In some embodiments, the pharmaceutically acceptable salt is.

[0145] The compounds of the present invention include all hydrates,solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containinga chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469- 1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon- carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

[0146] When the structure of the compounds of this invention includesan asymmetric carbon atom such compound can occur as racemates, racemic mixtures, and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons,NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

[0147] The subject invention is also intended to include all isotopes ofatoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include carbon-13 and carbon-14.

[0148] It will be noted that any notation of a carbon in structuresthroughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C may specifically have the structure of any of the compounds disclosed herein.

[0149] It will also be noted that any notation of a hydrogen in structuresthroughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H, or3H. Furthermore, any compounds containing2H or3H may specifically have the structure of any of the compounds disclosed herein. This notation of hydrogen isotopes includes H, D, and T to refer to1H,2H, and3H, respectively, and these corresponding labels are treated as being equivalent.

[0150] Isotopically-labeled compounds can generally be prepared byconventional techniques known to those skilled in the art or by processes analogous to those described in the Examples disclosed herein using an appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.

[0151] The term "substituted" refers to a functional group as describedabove in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms, provided that normal valences are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon (s) or hydrogen (s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. 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; alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and cyclopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4- trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p- toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl . Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0152] It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0153] In choosing the compounds of the present invention, one ofordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. Moreover, where hydrogens are not shown in the carbon-based structures herein, implicit hydrogens are understood to complete valences as required. In the carbon-based molecules herein, it is understood that when R3, R4a, and / or R4bare hydrogen, all implicit hydrogens are nevertheless present on the molecule to complete valences as required. Furthermore, hydrogens not shown on atoms other than carbon are also understood to be present to complete valences as required. Groups as drawn are taken to contain these implicit hydrogens, and as needed to allow for attachment points on carbon or non-carbon atoms, where permitted, and for any tautomeric structures.

[0154] The various R groups attached to the aromatic rings of thecompounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: PartB: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

[0155] A method of treating, or reducing a symptom of, a neurologicalor neuropsychiatric disorder comprising administering a compound as described herein, or a composition comprising a compound as described herein, in an amount sufficient to treat or reduce a symptom of a neurological or neuropsychiatric disorder.

[0156] In embodiments, the neurological or neuropsychiatric disorderinvolves a psychosis or a psychosis symptom. In embodiments, the neurological or neuropsychiatric disorder is an Alzheimer’s disease, schizophrenia, psychosis, or Parkinson’s disease. In embodiments, the neurological or neuropsychiatric disorder is pain, a chemical addiction or a Huntington’s disease. In embodiments, the neurological or neuropsychiatric disorder is associated with an M4 receptor activity or is M4-mediated.

[0157] A method of activating an M4 receptor, or potentiating aresponse of an M4 receptor to a ligand thereof, comprising contacting the M4 receptor with an amount of a compound as described herein so as to activate the M4 receptor or potentiate a response of an M4 receptor to a ligand.

[0158] A method of potentiating a response of an M4 receptor to aligand in a subject comprising administering to the subject an amount of a compound as described herein so as to potentiate a response of an M4 receptor to a ligand.

[0159] In embodiments the ligand is acetylcholine.

[0160] Synthesis and Examples

[0161] The compounds of the various embodiments above can be madeusing commercially available starting materials and / or reagents using methods and techniques known and available to those skilled in the art.

[0129] Materials and method:

[0130] Proton nuclear magnetic resonance (1H NMR) spectra were recordedon Bruker AVANCE-300 (300 MHz) and Bruker AVANCE-400 (400 MHz) instruments. Chemical shifts are given in parts per million (ppm) with tetramethylsilane as an internal standard.

[0131] Purity and low-resolution mass spectra (MS) were measured using aShimadzu UFLC / MS (Prominence UFLC high pressure gradient system / LCMS-2020) operating in an electron spray ionization mode (ESI+) with one or more LC conditions below.

[0132] LC condition 1: The column used was an L-column 2 ODS (3.0 mm× 50 mm i.d., 3 μm, CERI) with a temperature of 40 °C and a flow rate of 1.5 mL / min. Mobile phases A and B under acidic conditions were 0.05% TFA in water and 0.05% TFA in MeCN, respectively. The ratio of mobile phase B was increased linearly from 5% to 90% over 0.9 min, 90% over the next 1.1 min.

[0133] LC condition 2: The column used was an L-column 2 ODS (3.0 mm× 50 mm i.d., 3 μm, CERI) with a temperature of 40 °C and a flow rate of 1.5 mL / min. Mobile phases A and B under a neutral condition were a mixture of 5 mmol / L AcONH4and MeCN (9 / 1, v / v) and a mixture of 5 mmol / LAcONH4and MeCN (1 / 9, v / v), respectively. The ratio of mobile phase B was increased linearly from 5% to 90% over 0.9 min, 90% over the next 1.1 min.

[0134] LC condition 3: The column used was an Zorbax Ext C18 (50 x 4.6mm, 5µm) with a flow rate of 1.5 mL / min. Mobile phase A and B were 10 mM NH4OAc in water and MeCN. The ratio of mobile phase B was increased linearly from 10% to 30% over 1.5 min, 30% to 90% over the next 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min.

[0135] LC condition 4: The column used was an YMC Triart C18 (33 x2.1mm, 3µm) with a flow rate of 1.5 mL / min. Mobile phases A and B were 0.05% formic acid in water and MeCN. The ratio of mobile phase B was 2%held for 0.75 min, then to 10% in 1.0 min, further to 98% in 2.0 min, held this mobile phase composition to 2.25 min and finally back to initial condition in 3.0 min.

[0136] Reaction progress was determined by thin layer chromatography(TLC) analysis on Merck Kieselgel 60 F254 plates or Fuji Silysia NH plates or above mentioned UFLC / MS analysis. Chromatographic purification was carried out on silica gel columns (Merck Kieselgel 60, 70−230 mesh, Merck; Chromatorex NH-DM 1020, 100−200 mesh, Fuji Silysia Chemical; Inject column and Universal column, YAMAZEN, or Purif-Pack Si or NH, Shoko Scientific). Preparative HPLC was performed using a Gilson preparative HPLC system or YMC preparative HPLC system with UV detector (220 nm).

[0137] All commercially available solvents and reagents were used withoutfurther purification.

[0138] Abbreviations used:

[0139] THF, tetrahydrofuran; EtOAc, ethyl acetate; MeOH, methanol;DMSO, dimethyl sulfoxide; EtOH, ethanol; MeCN, acetonitrile; DMF, N,N- dimethylformamide; HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; TFA, trifluoro- acetic acid; Xantphos, (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)- diphenylphosphane; DBU, 1,8-diazabicyclo [5.4.0] undec-7-ene; Pd2(dba)3, Tris(dibenzylidene-acetone)dipalladium(0); DME, 1,2-di-methoxyethane; DIPEA, N,N-diisopropylethylamine; DMA, N,N-dimethylacetamide; DMAP, N,N-dimethyl-4-aminopyridine.

[0140] Example 1

[0141] 1-(4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)ethan- 1-one

[0142] Step 1

[0143] 4-(Azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]-pyrimidine dimethanesulfonate

[0144] To a solution of tert-butyl 4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (4.40 g, 14.5 mmol) in MeCN (40 mL) was added MsOH (3.47 g, 36.1 mmol) at room temperature. Themixture was stirred at 60 °C overnight and concentrated in vacuo. To a stirring mixture of the residue in EtOH (1 mL) was dropwise added EtOAc (10 mL). The resulting suspension was stirred for 1 h at room temperature. The precipitate was filtered, washed with EtOAc, and dried to give the titled compound (4.70 g) as a pale brown solid.

[0145] 1H NMR (300 MHz, DMSO-d6, 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).

[0146] m / z 205.1 [M+H]+

[0147] Step 2

[0148] 1-(4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)ethan- 1-one

[0149] To a solution of 4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dimethanesulfonate (170 mg, 430 μmol) in DMF (8 mL) was added 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetic acid (178 mg, 430 μmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (11.7 mg, 86.0 μmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1- amine hydrochloride (107 mg, 559 μmol) and Et3N (174 mg, 1.72 mmol) at room temperature. The mixture was stirred at the same temperature under N2for 16 h. 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 Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 50% MeOH in EtOAc) to givethe titled compound (159 mg) as a light brown solid.

[0150] 1H 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).

[0151] m / z 447.3 [M+H]+

[0152] Example 2

[0153] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0154] Step 1

[0155] 4-Nitrophenyl 4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0156] To a solution of 4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dimethanesulfonate (111 mg, 281 μmol) in DMF (2 mL) was added p-nitrophenyl chloroformate (84.8 mg, 421 μmol) and DIPEA (145.0 mg, 1.12 mmol) at room temperature. The mixture was stirred at the same temperature for 1 h. 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 Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%- 10% MeOH in EtOAc) to give the titled compound (75.6 mg) as a white amorphous solid.

[0157] 1H 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).

[0158] m / z 370.1 [M+H]+

[0159] Step 2

[0160] To a solution of 4-nitrophenyl 4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (74.6 mg, 202 μmol) in MeCN (2 mL) was added 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol (48.5 mg , 222 μmol) and DIPEA (78.3 mg, 606 μmol) at room temperature. The mixture was stirred at 50 °C under N2for 30 min. After being stirred at 70 °C for further 30 min, DMAP (4.93 mg, 40.4 μmol) was added to the reaction mixture. The mixture was stirred at room temperature under N2for 16 h. Then the reaction mixture was heated at 100 °C for 30 min under microwave irradiation and concentrated in vacuo. To the residue was added DIPEA (39.2 mg, 303 μmol) and DMF (2 mL) at room temperature. The mixture was stirred at 80 °C under N2for 1 h. After being stirred at 100 °C for further 1 h, 55% NaH (13.2 mg, 303 μmol) was added to the reaction mixture at 0 °C. The mixture was stirred at room temperature under N2for 30 min. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 100% MeOH in EtOAc) to givethe titled compound (42.5 mg) as a pale yellow amorphous solid.

[0161] 1H 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).

[0162] m / z 449.2 [M+H]+

[0163] Example 4

[0164] 4-(Azetidin-1-yl)-2,5-dimethyl-N-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

[0165] Step 1

[0166] 4-(Aetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carbonyl chloride

[0167] To a solution of 4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dimethanesulfonate (50.0 mg, 126 μmol) in THF (1 mL) was added Et3N (51.0 mg, 504 μmol) and triphosgene (44.9 mg, 151 μmol) at room temperature. The mixture was stirred at the same temperature for 10 min. The mixture was concentrated in vacuo to give the titled compound (119 mg) as a brown solid. This product was subjected to the next reaction without further purification.

[0168] m / z 267.1 [M+H]+

[0169] Step 2

[0170] 4-(Azetidin-1-yl)-2,5-dimethyl-N-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

[0171] To a solution of 4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carbonyl chloride (33.6 mg, 1126 μmol) in THF (2 mL) was added 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine bistrifluoroacetate (58.8 mg, 132 μmol) and Et3N (127 mg, 1.26 mmol) at room temperature. After being stirred at the same temperature for 2 h, MeCN (0.5 mL) and DMF (0.5 mL) was added to the reaction mixture. The mixture was stirred at the same temperature under N2for 16 h. 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 Na2SO4and concentrated in vacuo. 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 titled compound (20.3 mg) as a white amorphous solid.

[0172] 1H 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 = 5.6 Hz).

[0173] m / z 448.2 [M+H]+

[0174] Example 8-1

[0175] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0176] Step 1

[0177] tert-Butyl 4-hydroxy-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0178] To a suspension of 1-(tert-butyl) 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (8.26 g, 32.1 mmol) and Et3N (11.2 mL, 80.2 mmol) in t-BuOH (45 mL) was added portionwise acetimidamide hydrochloride (7.28 g, 77.0 mmol), and the mixture was stirred at 80 ⁰C for 5 h. The solvent was evaporated, and the residue was partitioned between a solution of EtOAc (30 mL) and THF (10mL) and 10 % aqueous citric acid solution (40 mL). The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water, brine, dried over Na2SO4and concentrated to give an orange paste. t-butyl methyl ether (15 mL) was added to the residue and stirred at room temperature for 60 min. The precipitate was collected by filtration, washed with iPr2O and dried to afford the titled compound (3.71 g) as a white powder.

[0179] 1H 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).

[0180] m / z 252.2 [M+H]+

[0181] Step 2

[0182] tert-Butyl 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0183] To a suspension of tert-butyl 4-hydroxy-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (5.32 g, 21.2 mmol) in DMF (50 mL) was added DBU (4.75 mL, 31.8 mmol) at room temperature. After being stirred at the same temperature for 5 min, ((1H-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 h. Water was added to the mixture and the mixture was extracted with EtOAc three times. The organic layer was separated, washed with water twice and brine, dried over Na2SO4and concentrated in vacuo. EtOAc was added to the residue, and the insoluble material was collected by filtration and dried in vacuo to afford the titled compound (5.18 g) as a white powder. The filtrate was concentrated in vacuo. EtOAc was added to the residue, and the insoluble material was collected by filtration and dried in vacuo to afford the additional titled compound (1.23 g) as a white powder. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, eluted with 5% - 35% EtOAc in n-hexane) to afford the additional titled compound (0.56 g) as a white powder.

[0184] 1H 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).

[0185] m / z 369.3 [M+H]+

[0186] Step 3

[0187] tert-Butyl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0188] To a suspension of tert-butyl 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (6.41 g, 17.4 mmol) and azetidine hydrochloride (2.45 g, 26.2 mmol) in DMF (30 mL) was added DBU (7.81 mL, 3 Eq, 52.2 mmol) at room temperature. The mixture was stirred at the same temperature for 4 h. Water was added to the mixture, and the mixture was extracted with EtOAc-THF four times. The combined organic layers were washed with saturated NaHCO3aq. and brine, dried over Na2SO4and concentrated in vacuo. The residue was azeotroped with toluene. The residue was purified by column chromatography (NH silica gel, eluted with 5% - 40% EtOAc in n-hexane) to afford the titled compound (1.98 g) as a white powder.

[0189] 1H 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).

[0190] m / z 291.3 [M+H]+

[0191] Step 4

[0192] 4-(Azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dihydrochloride

[0193] To a suspension of tert-butyl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.98 g, 6.82 mmol) in MeOH (20 mL) was added 4 M HCl in EtOAc (30 mL, r, 0.12 mol) at room temperature. The mixture was stirred at the same temperature for 1 h. The mixture was concentrated in vacuo, and MeCN was added to the residue. Theprecipitate was collected by filtration, washed with MeCN and dried in vacuo to afford the titled compound (1.73 g) as an off-white powder.

[0194] 1H NMR (300 MHz, DMSO-d6, 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).

[0195] m / z 191.3 [M+H]+

[0196] Step 5

[0197] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0198] To a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol (174mg, 796 μmol) in THF (3 mL) were added 4-nitrophenyl chloroformate (160 mg, 794 μmol) and Et3N (654 mg, 6.46 mmol) at room temperature. After being stirred at the same temperature for 2 h, 4-(azetidin-1-yl)-2-methyl-6,7- dihydro-5H-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 h. Water was added to the mixture, and the mixture was extracted with EtOAc twice. The organic layer was separated, washed with saturated NaHCO3aq. three times and brine twice, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 30% - 70% EtOAc in n-hexane) to give impure product as a white powder. The powder was washed with EtOAc-MeOH-iPr2O, dried in vacuo to afford the titled compound (115 mg) as a white powder.

[0199] 1H 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).

[0200] m / z 435.3 [M+H]+

[0201] Example 8-2

[0202] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0203] Step 1

[0204] 1-(tert-Butoxycarbonyl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0205] 4-Nitrophenyl chloroformate (919 mg, 4.56 mmol) was added to amixture of Et3N (2.65 mL, 19.0 mmol) and tert-butyl 3-hydroxyazetidine-1- carboxylate (790 mg, 4.56 mmol) in THF (8 mL) at room temperature. The mixture was stirred at room temperature for 1h.4-(azetidin-1-yl)-2-methyl- 6,7-dihydro-5H-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 h. The mixture was poured into saturated NaHCO3aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo.The residue was purified by column chromatography (silica gel, eluted with 0% - 10% MeOH in EtOAc) to afford the titled compound (758 mg) as white amorphous solid.

[0206] 1H NMR (300 MHz, DMSO-d6, 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).

[0207] m / z 390.4 [M+H]+

[0208] Step 2

[0209] Azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidine-6-carboxylate

[0210] A mixture of 1-(tert-butoxycarbonyl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (756 mg, 1.94 mmol) and TFA (2.99 mL, 38.8 mmol) was stirred at room temperature for 16 h. The mixture was poured into saturated NaHCO3aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 15% MeOH in EtOAc) to afford crude titled compound (1.77 g) as a pale yellow oil.

[0211] 1H NMR (400 MHz, DMSO-d6, 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).

[0212] m / z 290.3 [M+H]+

[0213] Step 3

[0214] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0215] A mixture of crude azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (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 with EtOAc twice. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10% - 100% EtOAc in n-hexane) and triturated with EtOAc and n-hexane to afford the titled compound (106 mg) as white powder.

[0216] 1H 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).

[0217] m / z 435.3 [M+H]+

[0218] Example 8-3

[0219] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0220] Step 1

[0221] 4-Nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)carbonate

[0222] To a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol (1.89g, 8.66 mmol) and Et3N (3.62 mL, 26.0 mmol) in THF (70 mL) was added 4-nitrophenyl chloroformate (3.49 g, 17.3 mmol) at room temperature. 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 MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 85% EtOAc in n-hexane) and recrystallized from EtOAc-pentane to afford the titled compound (2.41 g) as a white solid.

[0223] 1H 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, 2.2 Hz), 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).

[0224] m / z 384.1 [M+H]+

[0225] Step 2

[0226] 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0227] To a solution of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (1.20 g, 6.29 mmol) and 4-nitrophenyl (1-(2- (trifluoromethyl)pyridin-4-yl)azetidin-3-yl) carbonate (2.41 g 6.29 mmol) in THF (70 mL) was added Et3N (3.51 mL, 25.2 mmol) at room temperature.The mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10% - 100% EtOAc in n-hexane) to give white solid. The solid was recrystallized from EtOAc-heptane to afford the titled compound (2.32 g) as a white powder.

[0228] 1H 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).

[0229] m / z 435.1 [M+H]+

[0230] Example 8-4

[0231] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0232] tert-Butyl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (12.8 g, 44.12 mmol) was added portionwise to TFA (100 mL) at 0 ⁰C, and the mixture was stirred at 0 ⁰C for 60 min and concentrated in vacuo. EtOAc (200 mL) was added to the residue and concentrated in vacuo twice. To a solution of the residue in THF (300 mL) was added portionwise Et3N (30.7 mL, 221 mmol) at 0 ⁰C and stirred for 15min. 4-Nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl) carbonate (16.9 g, 44.1 mmol) was added portionwise at 0 ⁰C, and the mixture was stirred at room temperature for 16 h. Water (300 mL) and EtOAc (300 mL) were added to the mixture and partitioned. Aqueous layer was extracted with EtOAc-THF (1:1, 100 mL) twice. The combined organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was passed through glass filter column (NH silica gel, eluted with EtOAc to give crude 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4- (azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (19.0 g, 99%) as a white powder. The obtained compound (18.0 g) was dissolved in EtOAc (750 mL) at 75 ⁰C. After filtration, heptane (750 mL) was added dropwise to the mixture at 70 ⁰C and allowed to cool to room temperature. The mixture was stirred at room temperature for 16 h. The precipitate was collected by filtration and washed with a solution of EtOAc- heptane (1:1, v / v), dried in vacuo at 65 ⁰C for 16 h to afford the titled compound (16.1 g%) as a white powder.

[0233] 1H 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).

[0234] m / z 435.1 [M+H]+

[0235] Example 9

[0236] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate maleate

[0237] Maleic acid (26.7 mg, 230 μmol) and 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidine-6-carboxylate (100 mg, 230 μmol) was dissolved in EtOH (3 mL) under heating with warm oil bath. EtOAc (3 mL) was slowly added to the mixture. The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with EtOAc to afford the titled compound (106 mg) as a white solid.

[0238] 1H NMR (300 MHz, DMSO-d6, 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, br s).

[0239] m / z 435.2 [M+H]+

[0240] Example 10

[0241] 1-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2-(difluoromethoxy)pyridin-4-yl)azetidin-3- yl)ethan-1-one

[0242] To a solution of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dihydrochloride (28.1 mg, 107 μmol) in DMF (1.5mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (59.5 mg, 427 μmol) and ethyl 2-(1-(2-(difluoromethoxy)pyridin-4-yl)azetidin-3-yl)acetate (36.1 mg, 126 μmol) at room temperature. The mixture was stirred at 80 °C under N2for 19 h. 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 Na2SO4and concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Triart C18, eluted with H2O in acetonitrile containing 10 mM ammonium bicarbonate). The desired fraction was lyophilized to give the titled compound (15.3 mg) as white solid.

[0243] 1H 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).

[0244] m / z 431.2 [M+H]+

[0245] Example 13-1

[0246] 1-(2-(Difluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0247] Step 1

[0248] Azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate

[0249] 1-(tert-Butoxycarbonyl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (168 mg, 431 μmol)was dissolved in TFA (3 mL) at room temperature. The mixture was stirred for 1 h at room temperature. The mixture was concentrated in vacuo and azeotroped with toluene to afford the crude titled compound (230 mg) as a crude product. This product was subjected to the next reaction without further purification.

[0250] m / z 290.2 [M+H]+

[0251] Step 2

[0252] 1-(2-(Difluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0253] A mixture of Pd2(dba)3 (8.85 mg, 9.66 μmol), Cs2CO3 (315 mg, 966μmol), Xantphos (11.2 mg, 19.3 μmol), 4-bromo-2-(difluoromethyl)pyridine (80.4 mg, 387 μmol), crude azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7- dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (100 mg, 193 μmol) and DME (4 mL) was heated at 130 °C for 1 h under microwave irradiation. The mixture was poured into saturated NaHCO3aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Triart C18, eluted with H2O in acetonitrile containing 10 mM ammonium bicarbonate) to afford the titled compound (24 mg) as a pale yellow gum.

[0254] 1H 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).

[0255] m / z 417.2 [M+H]+

[0256] Example 13-2

[0257] 1-(2-(Difluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0258] Step 1

[0259] 1-(2-(difluoromethyl)pyridin-4-yl)azetidin-3-ol

[0260] A mixture of azetidin-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 at 80 °C under N2 overnight. The mixture was filtered and washed with EtOAc. The filtrate was concentrated in vacuo, 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 afford the titled compound (1.65 g) as a pale yellow solid.

[0261] 1H 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).

[0262] m / z 200.9 [M+H]+

[0263] Step 2

[0264] 1-(2-(Difluoromethyl)pyridin-4-yl)azetidin-3-yl (4-nitrophenyl)carbonate

[0265] To a solution of 4-nitrophenyl chloroformate (3.32 g, 16.5 mmol) inTHF (10 mL) was added dropwise a solution of 1-(2- (difluoromethyl)pyridin-4-yl)azetidin-3-ol (1.65 g, 8.24 mmol) and Et3N (1.72 mL, 12.4 mmol) in THF (2 mL) at 0 °C. To a mixture was further added Et3N (1.72 mL, 12.4 mmol), then stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3aq. and brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 60% EtOAc in n-hexane) to afford the titled compound (2.54 g) as an off-white solid.

[0266] 1H 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).

[0267] m / z 365.9 [M+H]+

[0268] Step 3

[0269] 1-(2-(Difluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0270] To a solution of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (1.22 g, 6.41 mmol) and 1-(2- (difluoromethyl)pyridin-4-yl)azetidin-3-yl (4-nitrophenyl)carbonate (2.54 g,6.95 mmol) in THF (20 mL) was added Et3N (3.58 mL, 25.7 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was passed through a NH silica gel pad and eluted with THF. The eluent was concentrated in vacuo and purified by column chromatography (NH silica gel, eluted with 20% - 100% EtOAc in n-hexane) and crystallized from EtOAc-heptane to afford the titled compound (2.41 g) as a white powder.

[0271] 1H NMR (400 MHz, DMSO-d6, 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).

[0272] m / z 417.0 [M+H]+

[0273] Example 14

[0274] 1-(2-(Difluoromethoxy)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0275] Step 1

[0276] 1-(2-(Difluoromethoxy)pyridin-4-yl)azetidin-3-ol

[0277] A mixture of azetidin-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 at 80 °C under N2overnight. The mixture was filtered and washed with EtOAc. The filtrate was concentrated in vacuo, purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in n- hexane) to afford the titled compound (3.3 g) as a pale yellow solid.

[0278] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 3.65 (2H, dd, J = 9.5, 4.6Hz), 4.05-4.21 (2H, m), 4.59 (1H, qt,= 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).

[0279] m / z 217.1 [M+H]+

[0280] Step 2

[0281] 1-(2-(Difluoromethoxy)pyridin-4-yl)azetidin-3-yl (4-nitrophenyl)carbonate

[0282] To a solution of 4-nitrophenyl chloroformate (4.5 g, 22 mmol) in THF(48 mL) was added dropwise a solution of 1-(2-(difluoromethoxy)pyridin-4- yl)azetidin-3-ol (2.4 g, 11 mmol) and Et3N (4.6 mL, 33 mmol) in THF (48 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 aq. and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 40% EtOAc in n-hexane) to afford the titled compound (4.5 g) as a yellow oil.

[0283] 1H 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).

[0284] m / z 382.0 [M+H]+

[0285] Step 3

[0286] 1-(2-(Difluoromethoxy)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0287] A mixture of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (1.5 g, 7.9 mmol), 1-(2-(difluoromethoxy)pyridin-4- yl)azetidin-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 at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc twice. The organic layer was separated, washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was crystallized from EtOAc to give crude titled compound (2.1 g, 62 %) as a white solid. The mother liquid was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc and NH silica gel, eluted with EtOAc) and triturated with EtOAc to give further crude titled compound (0.3 g, 9 %) as a white solid.

[0288] Obtained crude titled compound (2.4 g) was dissolved in EtOH (432mL) at 75 °C. The insoluble material was removed by filtration. To the filtrate was added n-heptane (240 mL) 60 °C. The mixture was stirred at 40 °C for 2 h and at room temperature over weekend. The resultingprecipitate was corrected by filtration to afford the titled compound (2.1 g) as a white solid.

[0289] 1H NMR (400 MHz, DMSO-d6, 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).

[0290] m / z 433.1 [M+H]+

[0291] Example 15

[0292] 1-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidin-6-yl)-2-(1-(2-methylpyridin-4-yl)azetidin-3-yl)ethan-1-one

[0293] Step 1

[0294] Ethyl 2-(1-(2-methylpyridin-4-yl)azetidin-3-yl)acetate

[0295] A mixture of ethyl 2-(azetidin-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 h under microwave irradiation. The mixture was diluted with water (0.5 mL) and extracted with EtOAc (1 mL). The insoluble material was filtered off, and the solvent was concentrated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (YMC-TriartC18, eluted withMeCN / 10 mM NH4HCO3aq). The desired fraction was evaporated by blowing away with the air at 60 °C to give the titled compound. The obtained product was subjected to the next reaction.

[0296] Step 2

[0297] 2-(1-(2-Methylpyridin-4-yl)azetidin-3-yl)acetic acid

[0298] A mixture of the above-obtained ethyl 2-(1-(2-methylpyridin-4-yl)azetidin-3-yl)acetate, 2 M NaOH (100 μL, 200 μmol) and EtOH (1 mL) was stirred at room temperature for 3 h. The mixture was acidified by 2 M HCl and concentrated by blowing away with the air at 60 °C to give the crude titled compound. This product was subjected to the next reaction without the further purification.

[0299] Step 3

[0300] 1-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2-methylpyridin-4-yl)azetidin-3-yl)ethan-1-one

[0301] A mixture of the above-obtained 2-(1-(2-methylpyridin-4-yl)azetidin-3-yl)acetic acid, 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4- d]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 at room temperature overnight. The mixture was acidified by 2 M HCl and concentrated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (YMC-TriartC18, eluted with MeCN / 10 mM NH4HCO3aq). The desired fraction was evaporated by blowing away with the air at 60 °C to give the titled compound (29 mg).

[0302] m / z 379.2 [M+H]+

[0303] Example 20

[0304] 1-(4-Cyano-3-(trifluoromethyl)phenyl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0305] A mixture of azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (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 h under microwave irradiation. The mixture was diluted with water (0.5 mL) and extracted with EtOAc (1 mL). The insoluble material was filtered off, and the solvent was concentrated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (YMC- TriartC18, eluted with MeCN / 10 mM NH4HCO3aq). The desired fraction was evaporated by blowing away with the air at 60 °C to give the titled compound.

[0306] m / z 459.1 [M+H]+

[0307] Example 21

[0308] 1-(2,5-Dichloropyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0309] A mixture of azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (38.8 mg, 79.9 μmol), 2,5-dichloro-4-fluoropyridine (26.6 mg, 160 μmol), 2,5- dichloro-4-fluoropyridine (26.6 mg, 160 μmol), DIPEA (41.3 mg, 320 μmol) in DMA (1 mL) was stirred at 100 °C overnight. The mixture was concentrated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (YMC-TriartC18, eluted with MeCN / 10 mM NH4HCO3aq). The desired fraction was evaporated by blowing away with the air at 60 °C to give the titled compound.

[0310] m / z 435.1 [M+H]+

[0311] Example 23-1

[0312] 1-(2-(Trifluoromethyl)pyrimidin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0313] Step 1

[0314] 1-(2-(Trifluoromethyl)pyrimidin-4-yl)azetidin-3-ol

[0315] A mixture of azetidin-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 h. The residue was purified by preparative HPLC (CERI L-Column 2 ODS, eluted with H2O in acetonitrile containing 10 mM ammonium bicarbonate) to afford the titled compound (651 mg) as a white solid.

[0316] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 3.71-3.90 (2H, m), 4.30 (2H,ddd, J = 9.8, 6.8, 1.2 Hz), 4.62 (1H, qt, J = 6.6, 4.4 Hz), 5.83 (1H, d, J = 6.6 Hz), 6.59 (1H, d, J = 6.1 Hz), 8.28 (1H, d, J = 6.1 Hz).

[0317] m / z 220.2 [M+H]+

[0318] Step 2

[0319] 4-Nitrophenyl (1-(2-(trifluoromethyl)pyrimidin-4-yl)azetidin-3-yl)carbonate

[0320] To a solution of 1-(2-(trifluoromethyl)pyrimidin-4-yl)azetidin-3-ol(645 mg, 2.94 mmol) and Et3N (1.23 mL, 8.83 mmol) in THF (20 mL) was added 4-nitrophenyl chloroformate (1.19 g, 5.89 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated NaHCO3aq. and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 60% EtOAc in n-hexane) to afford the titled compound (1.12 g) as a white solid.

[0321] m / z 385.2 [M+H]+

[0322] Step 3

[0323] 1-(2-(Trifluoromethyl)pyrimidin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0324] To a solution of 4-nitrophenyl (1-(2-(trifluoromethyl)pyrimidin-4-yl)azetidin-3-yl) carbonate (482 mg, 1.25 mmol) and 4-(azetidin-1-yl)-2- methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dihydrochloride (300 mg, 1.14 mmol) in THF (20 mL) was added Et3N (636 μL, 4.56 mmol) at room temperature. The mixture was stirred at room temperature for 16 h, then diluted with water and extracted with EtOAc. The organic layer was washed with brine and water, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) and crystallized from EtOAc - heptane to afford the titled compound (395 mg) as a white powder.

[0325] 1H NMR (400 MHz, DMSO-d6, 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).

[0326] m / z 436.3 [M+H]+

[0327] Example 23-2

[0328] 1-(2-(Trifluoromethyl)pyrimidin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0329] Parallel synthesis

[0330] A mixture of azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (38.8 mg, 79.9 μmol), 4-chloro-2-(trifluoromethyl)pyrimidine (0.16 g, 160 μmol), DIPEA (55.7 μL, 320 μmol) in DMA (1 mL) was stirred at 100 °C overnight. The mixture was concentrated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (YMCTriartC18, eluted with MeCN / 10 mM NH4HCO3aq.). The desired fraction was evaporated by blowing away with the air at 60 °C to afford the titled compound (15.3 mg).

[0331] m / z 436.1 [M+H]+

[0332] Example 36

[0333] 1-(2-Methoxypyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0334] Step 1

[0335] 1-(2-Methoxypyridin-4-yl)azetidin-3-ol

[0336] To a solution of azetidin-3-ol hydrochloride (1 g, 9 mmol) in DME (50mL) was added 4-bromo-2-methoxypyridine (2 g, 0.01 mol), Cs2CO3(7 g, 0.02 mol), methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy- 1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (0.4 g, 0.5mmol) at room temperature. The mixture was stirred at 100 °C under N2for 15 h. The resulting mixture was filtrated through a Celite pad. The filtrate was concentrated in vacuo. The residue was crystallized from EtOAc to afford the titled compound (1.09 g) as a light brown solid.

[0337] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 3.58 (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 = 2.0 Hz), 5.69 (1H, d, J = 6.4 Hz), 6.05 (1H, dd, J = 5.6, 2.0 Hz), 7.75 (1H, d, J = 5.6 Hz).

[0338] m / z 181.1 [M+H]+

[0339] Step 2

[0340] 1-(2-Methoxypyridin-4-yl)azetidin-3-yl (4-nitrophenyl) carbonate

[0341] To a solution of 1-(2-methoxypyridin-4-yl)azetidin-3-ol (1.09 g, 6.05mmol) and Et3N (2.53 mL, 18.1 mmol) in THF (40 mL) was added 4- nitrophenyl chloroformate (2.44 g, 12.1 mmol) at room temperature. 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 MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 85% EtOAc in n-hexane) to afford the titled compound (1.5 g) as a white solid.

[0342] 1H NMR (300 MHz, CDCl3, 300 K) δ 3.90 (3H, s), 4.01-4.08 (2H, m),4.30-4.38 (2H, m), 5.44 (1H, tt, J = 6.5, 4.1 Hz), 5.71 (1H, d, J = 1.9 Hz), 6.04 (1H, dd, J = 5.9, 2.1 Hz), 7.37-7.43 (2H, m), 7.89 (1H, d, J = 6.0 Hz), 8.27-8.33 (2H, m).

[0343] m / z 346.1 [M+H]+

[0344] Step 3

[0345] 1-(2-Methoxypyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0346] To a solution of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (200 mg, 1.05 mmol) and 1-(2-methoxypyridin-4- yl)azetidin-3-yl (4-nitrophenyl) carbonate (399 mg, 1.16 mmol) in THF (20 mL) was added Et3N (586 μL, 4.20 mmol) at room temperature. The mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10% - 90% EtOAc in n-hexane) to give white solid. The solid was crystallized from EtOAc-heptane to afford the titled compound (250 mg) as a colorless crystals.

[0347] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.28-2.36 (5H, m), 3.76 (3H,s), 3.87 (2H, dd, J = 9.3, 3.9 Hz), 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, 1.8 Hz), 7.78 (1H, d, J = 5.6 Hz).

[0348] m / z 397.2 [M+H]+

[0349] Example 37

[0350] 1-(2-Chloropyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0351] Step 1

[0352] 1-(2-Chloropyridin-4-yl)azetidin-3-ol

[0353] A mixture of azetidin-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 at 100 °C overnight in a sealed tube. The reaction mixture was poured into K2CO3aq. and extracted with EtOAc three times. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo to give crude titled compound (1.94 g) as a beige powder.

[0354] m / z 185.0 [M+H]+

[0355] Step 2

[0356] 1-(2-Chloropyridin-4-yl)azetidin-3-yl (4-nitrophenyl) carbonate

[0357] To a solution of crude 1-(2-chloropyridin-4-yl)azetidin-3-ol (1.94 g)and 4-nitrophenyl chloroformate (2.76 g, 13.7 mmol) in THF (50 mL) was added Et3N (3.82 mL, 27.4 mmol) at room temperature. The mixture was stirred at room temperature for 1 h.4-Nitrophenyl chloroformate (920 mg, 4.56 mmol) was added and the mixture was stirred at room temperature for1 h. The reaction mixture was poured into saturated NaHCO3aq. and extracted with EtOAc twice. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in n-hexane) to afford the titled compound (2.92 g) as a pale yellow powder.

[0358] 1H NMR (400 MHz, CDCl3, 300 K) δ 4.05-4.15 (2H, m), 4.39 (2H,ddd, J = 9.5, 6.5, 1.1 Hz), 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 = 2.2 Hz), 7.36-7.44 (2H, m), 8.04 (1H, d, J = 5.9 Hz), 8.28-8.34 (2H, m).

[0359] m / z 350.2 [M+H]+

[0360] Step 3

[0361] 1-(2-Chloropyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0362] A mixture of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (1.20 g, 6.31 mmol), 1-(2-chloropyridin-4-yl)azetidin-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 at room temperature overnight. The reaction mixture was diluted with water. The precipitate was collected by filtration, washed with water to give a crude titled compound (1.79 g) as a pale yellow powder. The filtrate was extracted with EtOAc three times. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give additional crude titled compound (0.71 g) as a yellow powder. The obtained crude titled compounds were combined and purified by column chromatography (NH silica gel, eluted with 30% - 100% EtOAc in n-hexane)and triturated with EtOAc to give the solid (2.09 g). The solid was recrystallized from EtOH-heptane to afford the titled compound (1.99 g) as a white powder.

[0363] 1H 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).

[0364] m / z 401.2 [M+H]+

[0365] Example 40-1

[0366] 1-(2-Methyl-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate

[0367] Step 1

[0368] 1-(2-Chloro-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol

[0369] A mixture of azetidin-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 h. Thereaction mixture was poured into saturated NaHCO3aq. and extracted with EtOAc twice. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 30% - 70% EtOAc in n-hexane) to afford the titled compound (4.13 g) as a colorless powder.

[0370] 1H 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).

[0371] m / z 253.0 [M+H]+

[0372] Step 2

[0373] 1-(2-Methyl-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol

[0374] A mixture of 1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol (1.01 g, 4.00 mmol), trimethylboroxine (ca.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 h under N2under microwave irradiation. The reaction was repeated and combined, which totally 16.67 mmol of 1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol was used. The reaction mixture was diluted with EtOAc and water, and then filtered through a celite pad. The filtrate was extracted with EtOAc twice. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 70% EtOAc in n-hexane) and triturated with EtOAc-n- hexane to afford the titled compound (3.50 g) as a colorless powder.

[0375] 1H NMR (400 MHz, CDCl3, 300 K) δ 2.48 (3H, s), 2.57 (1H, d, J =6.1 Hz), 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).

[0376] m / z 233.0 [M+H]+

[0377] Step 3

[0378] 1-(2-Methyl-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl (4-nitrophenyl) carbonate

[0379] To a solution of 1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)azetidin-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) was added Et3N (6.28 mL, 45.1 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was poured into saturated NaHCO3aq. and extracted with EtOAc twice. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 60% EtOAc in n-hexane) to afford the titled compound (5.27 g) as a pale yellow powder.

[0380] 1H 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).

[0381] m / z 398.0 [M+H]+

[0382] Step 4

[0383] 1-(2-Methyl-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate

[0384] A mixture of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (2.50 g, 13.1 mmol), 1-(2-methyl-6-(trifluoromethyl)pyridin- 4-yl)azetidin-3-yl (4-nitrophenyl) carbonate (5.27 g, 13.3 mmol), Et3N (2.20 mL, 15.8 mmol) and THF (80 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 30% - 80% EtOAc in n-hexane). This product (5.01 g) was recrystallized from EtOH-heptane to afford the titled compound (4.50 g) as a colorless powder.

[0385] 1H 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).

[0386] m / z 449.2 [M+H]+

[0387] Example 40-2

[0388] 1-(2-Methyl-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidine-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate

[0389] A mixture of azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (34.1 mg, 65.9 μmol), 4-bromo-2-methyl-6-(trifluoromethyl)pyridine (31.6 mg, 132 μmol), methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-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 h under microwave irradiation. The mixture was purified by column chromatography (NH silica gel, eluted with 20% - 70% EtOAc in n-hexane) to afford the titled compound (14.8 mg) as a white amorphous solid.

[0390] 1H 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 = 1.7 Hz), 6.49 (1H, d, J = 2.2 Hz).

[0391] m / z 449.3 [M+H]+

[0392] Example 50

[0393] (S)-1-(2-(Trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0394] Triphosgene (8.9 mg, 30 μmol) was added to a mixture of DMAP (11mg, 86 μmol), triethylamine (35 mg, 0.34 mmol) and (S)-1-(2- (trifluoromethyl)pyridin-4-yl)pyrrolidin-3-ol (20 mg, 86 μmol) in THF (3 mL) at 0 °C. The mixture was stirred at room temperature for 30 min. 4- (Azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (23 mg, 0.10 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was poured into saturated NaHCO3aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4andconcentrated in vacuo. The residue was purified by preparative HPLC (YMC-Triart C18, eluted with H2O in acetonitrile containing 10 mM ammonium bicarbonate) to give the titled compound (7.9 mg) as a white solid.

[0395] 1H 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).

[0396] m / z 449.4 [M+H]+

[0397] Example 70

[0398] (R)-1-(4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2-chloropyridin-4-yl)azetidin-3-yl)ethan-1-one

[0399] Step 1

[0400] Ethyl 2-(azetidin-3-yl)acetate trifluoroacetate

[0401] To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (300 mg, 1.23 mmol) was added TFA (703 mg, 6.17 mmol) atroom temperature. The mixture was stirred at the same temperature for 16 h and concentrated in vacuo (azeotroped with toluene) to give the titled compound (395 mg) as a colorless oil.

[0402] 1H 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).

[0403] m / z 144.1 [M+H]+

[0404] Step 2

[0405] Ethyl 2-(1-(2-chloropyridin-4-yl)azetidin-3-yl)acetate

[0406] To a solution of ethyl 2-(azetidine-3-yl)acetate trifluoroacetate (228mg, 713 μmol) in DMSO (3 mL) was added 2-chloro-4-fluoropyridine (141 mg, 1.07 mmol) and DIPEA (373 μL, 2.14 mmol) at room temperature. The mixture was stirred at 100 °C for 16 h. 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 MgSO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 2% - 30% EtOAc in n-hexane) to give ethyl the titled compound (152 mg) as a white solid.

[0407] 1H NMR (400 MHz, DMSO-d6, 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).

[0408] m / z 255.0 [M+H]+

[0409] Step 3

[0410] Sodium 2-(1-(2-chloropyridin-4-yl)azetidin-3-yl)acetate

[0411] A mixture of ethyl 2-(1-(2-chloropyridin-4-yl)azetidin-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 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give the crude titled compound (169 mg) as a white solid. This material was used in the next reaction without further purification.

[0412] Step 4

[0413] (R)-1-(4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2-chloropyridin-4-yl)azetidin-3-yl)ethan-1-one

[0414] To a solution of sodium 2-(1-(2-chloropyridin-4-yl)azetidin-3-yl)acetate (45.6 mg) in THF (2 mL) was added oxalyl chloride (91.7 mg, 722 μmol) and N,N-dimethylformamide (1.12 μL, 14.4 μmol) at room temperature. After being stirred at room temperature for 1 h, oxalyl chloride (91.7 mg, 722 μmol) was added to the reaction mixture. The mixture was stirred at the same temperature under N2for 3 h. The mixture was concentrated in vacuo and azeotroped with toluene. To the residue was added (R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidine hemi(2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate (93.9 mg, 159 μmol) and THF (1 mL). After being stirred at 0 °C for 5 min, saturated NaHCO3aq. (1 mL) was added slowly to the reaction mixture. The mixture was stirred at room temperature under N2 for 16 h. 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 Na2SO4and concentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0% - 50% EtOAc in n-hexane) to give the titled compound (17.0 mg) as a white solid.

[0415] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.33 (3H, dd, J = 10.5, 6.1Hz), 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).

[0416] m / z 413.2 [M+H]+

[0417] Example 57-1

[0418] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0419] Step 1

[0420] 4-(Azetidin-1-yl)-2-ethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinebistrifluoroacetate

[0421] A mixture of tert-butyl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (6.42 g, 21.1 mmol) and TFA (13.0 mL, 169 mmol) was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give crude titled compound (14.2 g) as a pale yellow solid.

[0422] m / z 205.1 [M+H]+

[0423] Step 2

[0424] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate

[0425] To a solution of crude 4-(azetidin-1-yl)-2-ethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine bistrifluoroacetate (375 mg,) in THF (6 mL) was added 4-nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl) carbonate (213 mg, 556.1 μmol) and Et3N (310 μL, 2.22 mmol) at room temperature. The mixture was stirred at the same temperature under N2for 16 h. 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 Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) and (silica gel, eluted with 0% - 20% MeOH in EtOAc) to afford the titled compound (143 mg) as a white powder.

[0426] 1H 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).

[0427] m / z 449.2 [M+H]+

[0428] Example 57-2

[0429] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate

[0430] To a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-ol (30.0mg, 138 μmol) in THF (1.5 mL) was added 4-nitrophenyl chloroformate (36.0 mg, 179 μmol) and Et3N (38.3 μL, 275 μmol) at room temperature. After being stirred at the same temperature for 2 h, crude 4-(azetidin-1-yl)- 2-ethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine bistrifluoroacetate (79.6 mg) and Et3N (95.8 μL, 688 μmol) was added to the reaction mixture. The mixture was stirred at the same temperature under N2for 16 h. 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 in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 30% EtOAc in n-hexane) to afford the titled compound (32.5 mg) as a white amorphous solid.

[0431] 1H 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).

[0432] m / z 449.2 [M+H]+

[0433] Example 58-1

[0434] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate hemifumarate

[0435] To a solution of 4-nitrophenyl (1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl) carbonate (517 mg, 1.349 mmol) and crude 4-(azetidin-1- yl)-2-ethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine bistrifluoroacetate (910.0 mg) in THF (5 mL) was added Et3N (1.00 mL, 7.17 mmol) at room temperature. The mixture was stirred at the same temperature overnight. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc. saturated NaHCO3aq. was added to the solution and the mixture was extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 aq. four times and brine twice, dried over Na2SO4 and concentrated in vacuo. 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 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2- ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (312 mg) as a colorless oil. The oil was dissolved in THF (5 mL) and fumaric acid (40.4 mg, 0.348 mmol) was added thereto. The mixture was stirred at 50 °C for 5 min. The solution was concentrated in vacuo. To the residue were added EtOH (1.5 mL) and MeCN (10 mL). The suspension was stirred at 50 °C for 10 min, cooled to room temperature for 20 min. The precipitate was collected by filtration and washed with MeCN, dried in vacuo to give a white powder. To the powder were added EtOH (10 mL) and MeCN (10 mL). Thesuspension was stirred at 50 °C for 10 min. The solution was concentrated in vacuo. To the residue were added EtOH (1.5 mL) and MeCN (10 mL). The solution was sonicated to give a suspension and the suspension was concentrated in vacuo to afford the titled compound (295 mg) as a white powder.

[0436] 1H NMR (400 MHz, DMSO-d6, 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).

[0437] m / z 449.2 [M+H]+

[0438] Example 58-2

[0439] 1-(2-(Trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate hemifumarate

[0440] MeOH (10 mL) and THF (5 mL) were added to a mixture of 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-ethyl-5,7- dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (127 mg, 283 μmol) and fumaric acid (33.0 mg, 284 μmol) at room temperature. The mixture was stirred at 50 °C for 10 min. The solution was concentrated in vacuo and the residue was dissolved in EtOH (0.5 mL). The solution was diluted with MeCN (10 mL) and resulting suspension was stirred at 50 °C for 30 min,cooled to room temperature and leaved at the same temperature for 3 h. The precipitate was collected by filtration and washed with MeCN, dried in vacuo to afford the titled compound (91.6 mg) as a white powder.

[0441] 1H NMR (400 MHz, DMSO-d6, 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).

[0442] m / z 449.1 [M+H]+

[0443] Example 65-1

[0444] 1-(2-Chloro-6-methylpyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0445] To a suspension of azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2200 mg, 7.61 mmol), Cs2CO3 (3.72 g, 11.4 mmol), and 4-bromo-6-chloropicoline (1.88 g, 9.12 mmol) in toluene (88 mL) was added RuPhos Pd G4 (647 mg, 760 μmol) at room temperature. The mixture was stirred at 110 °C under Ar overnight. The another batch, which 500 mg of azetidin-3-yl 4-(azetidin-1-yl)-2- methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate was used, was combined. 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 Na2SO4and concentrated in vacuo. The residuewas purified by column chromatography (NH silica gel and silica gel, eluted with 0% - 30% MeOH in EtOAc) and triturated with EtOAc. The residue (2.5 g) was dissolved with THF (95 mL) at 60 °C. To the mixture was added heptane (40 mL) at 60 °C. After being stirred at 60 °C for 1 h, heptane (55 mL) was added to the reaction mixture. The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration to afford the titled compound (2.3 g) as a white solid.

[0446] 1H NMR (400 MHz, DMSO-d6, 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 = 7.9 Hz), 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).

[0447] m / z 415.1 [M+H]+

[0448] Example 65-2

[0449] 1-(2-Chloro-6-methylpyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0450] A mixture of crude azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (1.5 g, 1.8 mmol), 4-bromo-2-chloro-6-methylpyridine (0.52 g, 2.5 mmol), methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-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 °Cfor 2 h under microwave irradiation. The mixture was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc) followed by column chromatography (NH silica gel, eluted with 40% - 90% EtOAc in n-hexane). The residue was triturated with EtOAc-n-hexane to afford the titled compound (266 mg) as a white solid.

[0451] 1H NMR (400 MHz, DMSO-d6, 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 = 7.9 Hz), 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).

[0452] m / z 415.3 [M+H]+

[0453] Example 65-3

[0454] 1-(2-Chloro-6-methylpyridin-4-yl)azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate

[0455] A mixture of crude azetidin-3-yl 4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (39.4 mg), 4-bromo-6-chloropicoline (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 h under microwave irradiation. The mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) and then further purified by column chromatography (silica gel, eluted with 0% - 20% MeOHin EtOAc) to afford the titled compound (11.8 mg) as a white powder.

[0456] 1H 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).

[0457] m / z 415.3 [M+H]+

[0458] Example 67

[0459] 1-(2-Chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate

[0460] Step 1

[0461] 1-(tert-Butoxycarbonyl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate

[0462] To a solution of tert-butyl3-hydroxyazetidine-1-carboxylate (447 mg,2.579 mmol) and 4-nitrophenol chloroformate (525 mg, 2.602 mmol) in THF (20 mL) was added Et3N (1.18 mL, 8.49 mmol) at room temperature. After being stirred at the same temperature for 2 h, saturated NaHCO3aq. (10 mL) and (R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidine hemi(2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate (1000 mg, 1.70 mmol) were added to the reaction mixture. The mixture was stirredat room temperature for 2 days. Saturated NaHCO3aq. was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3aq. three times and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 30% MeOH in EtOAc) to afford the titled compound (654 mg) as a colorless foam.

[0463] 1H 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).

[0464] m / z 404.4 [M+H]+

[0465] Step 2

[0466] Azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo [3,4-d]pyrimidine-6-carboxylate bis-trifluoroacetate

[0467] TFA (5 mL) was added to 1-(tert-butoxycarbonyl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (654 mg, 1.620 mmol) at room temperature. The mixture was stirred at the same temperature for 20 min. The mixture was concentrated in vacuo to afford the crude titled compound (1216 mg) as a brown oil. This product was subjected to the next reaction without further purification.

[0468] 1H 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).

[0469] m / z 304.3 [M+H]+

[0470] Step 3

[0471] 1-(2-Chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate

[0472] To a solution of azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate bistrifluoroacetate (48.3 mg, 90.9 μmol) in DMSO (0.5 mL) was added 2-chloro-4- fluoropyridine (17.9 mg, 136 μmol) and DIPEA (47.5 μL, 273 μmol) at room temperature. The mixture was stirred at 100 °C under N2for 16 h. 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 in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) to afford the titled compound (19.7 mg) as a pale yellow oil.

[0473] 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).

[0474] m / z 415.2 [M+H]+

[0475] Example 68-1

[0476] 1-(2-Chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]-pyrimidine-6-carboxylate fumarate

[0477] Step 1-1

[0478] 1-(2-Chloropyridin-4-yl)azetidin-3-ol

[0479] A mixture of azetidin-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 at 100 °C overnight in a sealed tube. The reaction mixture was poured into K2CO3aq. and extracted with EtOAc three times. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in n-hexane) to afford the titled compound (166 mg) as a colorless powder.

[0480] 1H 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).

[0481] m / z 185.2 [M+H]+

[0482] Step 1-2

[0483] 1-(2-Chloropyridin-4-yl)azetidin-3-ol

[0484] The reaction mixture was poured into K2CO3 aq. and extracted withEtOAc three times. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo to give crude titled compound (542 mg)as a pale yellow powder.

[0485] m / z 185.2 [M+H]+

[0486] Step 2

[0487] 1-(2-chloropyridin-4-yl)azetidin-3-yl (4-nitrophenyl) carbonate

[0488] To a solution of crude 1-(2-chloropyridin-4-yl)azetidin-3-ol (542 mg)and Et3N (1.15 mL, 8.22 mmol) in THF (20 mL) was added 4-nitrophenyl chloroformate (1.10 g, 5.48 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO3aq. and extracted with EtOAc twice. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in n-hexane) to afford the titled compound (825 mg) as a pale yellow powder.

[0489] 1H 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).

[0490] m / z 350.2 [M+H]+

[0491] Step 3

[0492] 1-(2-Chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0493] To a solution of (R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hemi((2R,3R)-2,3-bis((4-methylbenzoyl)oxy)- succinate) (refer to WO2018066718) (255 mg, 321 μmol), NaHCO3(200 mg,2.38 mmol), water (2 mL), and THF (6 mL) was added 1-(2-chloropyridin- 4-yl)azetidin-3-yl (4-nitrophenyl) carbonate (269 mg, 770 μmol) at room temperature. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3aq. and brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 100% EtOAc in n-hexane) to give crude titled compound (303 mg) as a colorless gum.

[0494] This product was subjected to the next reaction without furtherpurification.

[0495] m / z 415.1 [M+H]+

[0496] Step 4

[0497] 1-(2-Chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate fumarate

[0498] A mixture of crude 1-(2-chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (295 mg) and fumaric acid (74 mg, 0.64 mmol) in 2-propanol (1 mL) was stirred at 50 °C. To the resulting solution was added dropwise MeCN (10 mL) at 50 °C. The whole mixture was allowed to cool to rt overnight. The precipitate was filtered, washed with MeCN, and dried to give 1-(2-chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl- 5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate fumarate (162 mg) as a colorless solid. The mother liquor was concentrated in vacuo, diluted in MeCN (4 mL), and statically leaved overnight. The formed precipitate was filtered, washed with MeCN, and dried to afford the titled compound (83 mg)as a colorless solid.

[0499] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.33 (3H, dd, J = 10.5, 6.1Hz), 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).

[0500] m / z 415.2 [M+H]+

[0501] Example 68-2

[0502] 1-(2-Chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate fumarate l

[0503] To a solution of (R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hemi((2R,3R)-2,3-bis((4-methylbenzoyl)oxy)- succinate) (120 mg, 151 μmol), NaHCO3(127 mg, 1.51 mmol), H2O (5 mL), and THF (10 mL) was added 1-(2-chloropyridin-4-yl)azetidin-3-yl (4- nitrophenyl) carbonate (116 mg, 332 μmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3aq. and brine, dried over MgSO4and concentrated in vacuo. The residue was passed through a NH silica gel padand eluted with THF. The eluent was concentrated in vacuo and purified by column chromatography (silica gel, eluted with 0% - 15% MeOH in EtOAc) to give 1-(2-chloropyridin-4-yl)azetidin-3-yl (R)-4-(azetidin-1-yl)-2,5- dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (78 mg, 0.188 mmol) as a colorless gum. The mixture of the product and fumaric acid (22 mg, 0.19 mmol) was dissolved in EtOH. The solution was concentrated in vacuo, diluted in MeCN (4 mL), and statically leaved overnight. The formed precipitate was filtered, washed with MeCN, and dried to afford the titled compound (50 mg) as a colorless solid.

[0504] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.33 (3H, dd, J = 10.5, 6.1Hz), 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).

[0505] m / z 415.1 [M+H]+

[0506] Example 92

[0507] 1-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(3-(2-methylpyridin-4-yl)azetidin-1-yl)ethan-1-one[

[0509] tert-Butyl 3-(2-methylpyridin-4-yl)azetidine-1-carboxylate

[0510] A mixture of anhydrous DMA (10 mL) and zinc (3.2 g, 49 mmol) wasstirred 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 to maintain the temperature below 65 °C. The resulting slurry was aged for 15 min. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (9.1 g, 32 mmol) in DMA (20 mL) was added dropwise over 1 h at a rate to maintain the temperature below 65 °C, and the milky suspension was stirred for 30 min while slowly cooling to 20 °C to give the 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 with alternate vacuum / N2purges to the mixture B. The above prepared mixture A was added to the mixture B. The mixture was degassed with vacuum / N2twice and then heated to 80 °C for 2 h. The mixture was filtered over celite, and the filtrate was diluted with EtOAc. The organic mixture was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and evaporated to brown oil. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 60% EtOAc in n-hexane) to give the titled compound (1.23 g) as a yellow oil.

[0511] 1H NMR (400 MHz, DMSO-d6, 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).

[0512] m / z 249.3 [M+H]+

[0513] Step 2

[0514] Benzyl 2-(3-(2-methylpyridin-4-yl)azetidin-1-yl)acetate

[0515] A mixture of tert-butyl 3-(2-methylpyridin-4-yl)azetidine-1-carboxylate (3.00 g, 12.1 mmol) and 4 M HCl in EtOAc (15.1 mL, 60.4 mmol) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo 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 at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine and water, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 30% - 100% EtOAc in n-hexane, then silica gel, eluted with 0% - 20% MeOH in EtOAc) to give 6the titled compound (437 mg) as a colorless oil.

[0516] 1H NMR (400 MHz, DMSO-d6, 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 = 4.9 Hz).

[0517] m / z 297.3 [M+H]+

[0518] Step 3

[0519] 2-(3-(2-Methylpyridin-4-yl)azetidin-1-yl)acetic acid

[0520] To a solution of benzyl 2-(3-(2-methylpyridin-4-yl)azetidin-1-yl)acetate (430 mg, 1.45 mmol) in EtOH (10 mL) was added 10% Pd-C (77.2 mg), and the mixture was stirred under H2atmosphere at room temperaturefor 18 h. The insoluble materials were filtered off. The filtrate was concentrated in vacuo to give the titled compound (305 mg) as colorless oil.

[0521] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.45 (3H, s), 3.44 (2H, q, J= 7.1 Hz), 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 was not found.

[0522] m / z 207.1 [M+H]+

[0523] Step 4

[0524] 1-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(3-(2-methylpyridin-4-yl)azetidin-1-yl)ethan-1-one

[0525] To a solution of 2-(3-(2-methylpyridin-4-yl)azetidin-1-yl)acetic acid(50 mg, 0.24 mmol) in DMF (3 mL) were added 4-(azetidin-1-yl)-2-methyl- 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dihydrochloride (77 mg, 0.29 mmol), DIPEA (0.13 g, 0.97 mmol) and HATU (0.12 g, 0.32 mmol), and the mixture was stirred at room temperature for 16 h. 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 in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 100% EtOAc in n-hexane, then 0% - 20% MeOH in EtOAc) and preparative HPLC (CERI L-Column 2 ODS, eluted with H2O in acetonitrile containing 10 mM ammonium bicarbonate), then crystallized from EtOAc- n-heptane to give the titled compound (17 mg) as a white powder.

[0526] 1H 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).

[0527] m / z 379.3 [M+H]+

[0528] Table 1. Compound structure, compound name, preparation methodand physicochemical data for Examples 1-95.5000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600mER H A H 631 1.v491 8-0 696-41945000 / 08600ER A 731 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A H H H 041 m 1.v491 8-0 696-41945000 / 08600ER A m H 141 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 341 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600E4R A m H 444 541 1.v491 8-0 696-41945000 / 08600ER A 641 1.v491 8-0 696-41945000 / 0m860H04ER A44m H 741 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 051 1.v491 8-0 696-41945000 / 08600ER A 151 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-4194ER A0000600ER A5000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 08600ER A 851 1.v491 8-0 696-41945000 / 08600ER A 1.v491 8-0 696-41945000 / 0s860H0E(R 6 A34m H4(6 24 061 1.v491 8-0 696-41945000 / 086 3003E5R 9 A5m H2(3 74 161 1.v491 8-0 696-41941.v491 8-0 696-4194

[0529] Biological Assay

[0530] In Vitro M4 &M2 Functional Assay

[0531] The functional activity of compounds at the M4 and M2 receptors wasdetermined by measuring changes in the level of intracellular calcium ions caused by signaling cascades mediated by the receptor. Intracellular calcium levels weremeasured using a calcium sensitive fluorescent dye, 'Calcium Kit II - iCellux'(DOJINDO). The changes in fluorescence were monitored by a fluorescent imager,FDSS μCELL (Hamamatsu Photonics K.K.). Increases in intracellular calcium were readily detected upon activation of both receptors by the muscarinic receptor agonist acetylcholine.

[0532] CHO-K1 / M4 / Gα15 Stable Cell Line (M00238, GenScript) or CHO-K1 / M2 / Gα15 Stable Cell Line (M00258, GenScript) was routinely grown as monolayers in Ham's F-12K medium (FUJIFILM Wako Pure Chemical Corporation) supplemented with 10% fetal bovine serum (FBS) (Corning), 200μg / ml Zeocin (Invitrogen), 100μg / ml Hygromycin B (FUJIFILM Wako Pure Chemical Corporation) in 5% CO2at 37 °C. Once confluent, cells were cryopreserved by freezing at -186 °C in CELLBANKER 1plus (NIPPON ZENYAKU KOGYO CO.,LTD.). Twenty-four hours prior to testing, cells were resuscitated and the freezing media was removed via centrifugation. Cells were then seeded in black-walled clear bottom 384-well plates (Greiner) at a density of 8,000 cells / 20μl / well in Ham's F-12K medium supplemented with 10% FBS. On the day of assay, 20μl of Calcium Kit II - iCellux dye solution was added to the cells, and the cells were incubated for 45 minutes at 37 ⁰C, 5% CO2.

[0533] Agonist Assays: 10 µL test compound diluted in HBSS, 20mMHEPES, 0.1% BSA, 0.5% (final 0.1%) DMSO was added to each well and fluorescence intensity was measured for 3 minutes using the FDSS μCELL.

[0534] Positive allosteric modulator (PAM) assays: 10 µL test compounddiluted in HBSS, 20mM HEPES, 0.1% BSA, 0.5% (final 0.1%) DMSO containing between 15 nM (final 3 nM) and 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 for 3 minutes using the FDSS μCELL. The concentration of acetylcholine used was that expected to induce 20% of the maximal cellular response to acetylcholine (i.e. the EC20). The EC20 of acetylcholine was evaluated in every plate and used to recalibrate the EC20 (if necessary) for subsequent experiments.

[0535] Data analysis: In both Agonist assay and PAM assay, cellularresponse data generated using serial dilutions of test compound (or acetylcholine) up to 10 µM was fitted to a four-parameter logistic equation using CDD Vault (Collaborative Drug Discovery, Burlingame, CA). The fitted maximum response relative to 10 µM acetylcholine (Relative Efficacy, RE) was reported for all compounds. The concentration of test compound giving a half-maximal response (EC50) was reported for all compounds where RE was equal to or greater than 50%. "ND” (“Not Determined") denotes that RE was less than 50%. The results are set out in the tables.

[0536] Table 2. Results of Biological Assay.ND – means not determined; NT – means not tested.

[0537] Determination of the in vitro clearance

[0538] Oxidative metabolic clearance with microsomes

[0539] Liver microsomes were obtained from Sekisui XenoTech, LLC.(Kansas City, KS). The microsomes (0.2 mg protein / mL) and the compound (1 μmol / L) were mixed in phosphate buffer (pH7.4). 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 mixtures. Incubation was conducted at 37°C and terminated at 15 and 30 min by adding acetonitrile. The zero-time incubation, which served as the control, was terminated by adding acetonitrile before adding an NADPH generating system. After the samples were mixed and centrifuged, the compound concentrations in the supernatant fractions were measured by LC-MS / MS and a Unison UK-C18 HT column (3.0 μm, 2.0 × 20 mm).

[0540] The clearance (μL / min / mg protein) was calculated to the following:

[0541] {1000 × rate constant (calculated based on the exponential function ofthe remaining rate vs time curve on the assumption that it is the first order elimination) / microsomal protein (mg / mL)}

[0542] WO 2018 / 066718 discloses reference compounds T1 as example 4, T2as example 7 and T3 as example 11.

[0543] Activity of the reference compounds towards the M4 receptor, as wellas in vitro clearance of the reference compounds and example 8 were also determined. The results are shown in table 2.

[0544] Table 2

[0545] Examples 8 exhibit clearance values reduced significantly compared toclearance values of examples T1, T2 and T3.

[0546] METH-induced hyperlocomotion assays

[0547] Seven-week-old male Wistar rats were purchased from JacksonLaboratory Japan Inc. (Kanagawa, Japan) for METH-induced hyperlocomotion assays. All animals were maintained under a 12-hour light / dark cycle and given free access to food and water. The room temperature and humidity were 20°C-26°C and 40%-70%, respectively. All procedures were conducted in accordance with the guidelines for animal experiments and approved by the Institutional Animal Care and Use Committee of Shonan Health Innovation Park. This facility has acquired the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) international certification.

[0548] Locomotion activity was measured using a SUPERMEX spontaneousmotor analyzer (Muromachi Kikai, Japan). Animals were placed in locomotor chambers (length x width x height: 24 x 37 x 30 cm) in the afternoon of the day before the test for habituation. On the test day, they were removed from each chamber and treated with either vehicle (0.5w / v% methyl cellulose 400 Solution), Example 8 or CVL-231 via oral administration and then quickly returned to the chamber. 30 min after the drug treatment, animals were again removed from the chambers and treated with either vehicle (saline) or METH (0.25 mg / kg s.c. administration, Sumitomo Dainippon Pharma, Japan) and then quickly transferred to the test chamber. Activity counts were recorded in successive 1-minute bins and then number of counts per 5-minute bins and cumulative counts during 30, 60, 90 and 120 minutes after METH administration. The results are shown in table 3.

[0549] Table 3

[0529] As can be seen from Table 3, Example 8 was significantly more effective atreversing METH-induced hyperlocomotion than prior art compound CVL-231 with an MED of 30mg / kg v 60 mg / kg.

[0530] Cardiovascular Telemetry Study in Monkeys

[0531] The cardiovascular (CV) effects of test compounds can be assessed in asuitable test subject such as male cynomolgus monkeys (n=3 or 4) using a telemetry study. The test compound can be administered orally once a day at an interval of 6 or 7 days or more by a latin square crossover design. Heart rate, blood pressure and ECG can be monitored for 24 hours post dose and the CV effects evaluated qualitatively and quantitatively between test-article and vehicle control group at eachassay point. The pharmacokinetics (PK) can be analyzed to examine the dose- response relation before or after the CV assay. Plasma concentrations of the test article can be measured at 4 hours post-dose in all animals to compare with the PK profile. Compounds of the invention, including Example 8, can be compared to prior art compounds. Dosage levels examples include 5, 10, 20 and 30 mg / kg. Measurable assay parameters: Systolic BP, Diastolic BP, and HR, and ECG parameters (RR interval, PR interval, QRS duration, QT interval, and QT interval corrected individually [QTci interval])

[0532] The compounds of the invention are expected to show less severe effects induration and / or extent in at least one of Systolic BP, Diastolic BP and HR than prior art M4 PAMs.

[0550] The description set forth above is provided to give those of ordinary skill inthe art with a complete disclosure and description of how to make and use the various embodiments claimed below and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited 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

WHAT IS CLAIMED IS:

1. A compound of the formula:wherein R1is a 4- or 5-membered heterocyclic ring, each of which may unsubstituted or substituted by one or more substituents and which ring contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R2is a C1-C6alkyl group; L is O, NRx, or CRyRz, where Rxis a hydrogen atom or a C1-C6alkyl group and Ryand Rzare each independently a hydrogen atom or a C1-C6alkyl group; A is a 4- or 5-membered heterocyclic ring, each of which may be unsubstituted or substituted by one or more substituents and which ring contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R3is a hydrogen atom or a C1-C6alkyl group; and Ar is a 5-10 membered heterocyclic, aromatic or heteroaromatic monocyclic or bicyclic ring, each of which may be unsubstituted or substituted by one or more substituents and the heterocyclic or heteroaromatic ring(s) of which each contain 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

2. The compound of claim 1 having the formulaor a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

3. The compound of claim 1 or 2 having the formulawherein R4aand R4bare each individually selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group; or a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

4. The compound of claim 1 or 2 having the formulaor a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

5. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1, 2, or 4, wherein R1is a 4-membered heterocyclic ring which is unsubstituted or substituted by one or more substituents.

6. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 1, 2 or 4, wherein R1is a 4-membered heterocyclic ring substituted by one or more substituents.

7. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 6, wherein said substituent is selected from the group consisting of a halogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group.

8. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1, 2, 4, 5, 6, or 7, wherein R1is an azetidinyl group.

9. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1, 2, 3, 4, 5, or 8, wherein R1is an unsubstituted azetidinyl group.

10. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1, 2, 4, 5, 6, 7, or 8, wherein R1is an azetidinyl group substituted by one or more substituents.

11. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1, 2, 4, 5, 6, 7, 8, or 10, wherein R1is an azetidinyl group substituted by two substituents, which may be the same or different.

12. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 8-11, wherein said azetidinyl group is bound to the pyrimidinyl ring through the N atom of the azetidinyl group.

13. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 10-12, wherein said substituent is selected from the group consisting of a halogen atom, a methyl group, an ethyl group, a hydroxy group, a methoxy group, and an ethoxy group.

14. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 10-12,wherein said substituent is selected from the group consisting of a fluorine atom, a methyl group, a hydroxy group, and a methoxy group.

15. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-14, wherein L is O.

16. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-14, wherein L is NRx.

17. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-14 or 16, wherein Rxis a hydrogen atom or a C1-C6alkyl group.

18. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-14, 16, or 17, wherein Rxis a hydrogen atom or a methyl group.

19. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-14, wherein L is CRyRz.

20. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-14 or 19, wherein Ryand Rzare each independently a hydrogen atom or a C1-C6alkyl group.

21. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-14, 19, or 20, wherein Ryand Rzare each a hydrogen atom.

22. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-21, wherein A is a 4-membered heterocyclic ring, which is unsubstituted or substituted by one or more substituents in addition to Ar and which contains 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

23. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-22, wherein A is a 4-membered heterocyclic ring substituted by Ar only and which contains 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

24. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-23, wherein A is an azetidinyl group.

25. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 24, wherein said azetidinyl group is bound to Ar through the nitrogen atom of the azetidinyl group.

26. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 24, wherein said azetidinyl group is bound to L through the nitrogen atom of the azetidinyl group.

127. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-21, wherein A is a 5-membered heterocyclic ring, which is unsubstituted or substituted by one or more substituents in addition to Ar and which contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

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

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

30. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 29, wherein said pyrrolidinyl group is bound to Ar through the nitrogen atom of the pyrrolidinyl group.

31. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 29, wherein said pyrrolidinyl group is bound to L through the nitrogen atom of the pyrrolidinyl group.

32. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-31, wherein R3is methyl.

33. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-32, wherein Ar is a 5-10 membered heteroaromatic ring, which is unsubstituted or substituted by one or more substituents and which ring contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

34. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-33, wherein Ar is substituted by at least one substituent selected from the group consisting of a halogen atom, a C1-C6alkyl group, optionally in which one or more of the hydrogen atoms may be replaced by a halogen atom, a C1-C6alkoxy group, optionally in which one or more of the hydrogen atoms may be replaced by a halogen atom, and a cyano group.

35. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-33, wherein Ar is unsubstituted.

36. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-34, wherein Ar is substituted by one substituent.

137. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-34, wherein Ar is substituted by two substituents.

38. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-37, 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, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-38, wherein Ar is a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom(s).

40. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-39, wherein Ar is selected from the group consisting ofeach of which is unsubstituted or substituted.

41. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-39, wherein Ar is a 6-membered heteroaromatic ring having a single heteroatom. 1 142. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 41, wherein said heteroatom is a nitrogen atom.

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

44. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 43, wherein both of said heteroatoms are nitrogen atoms.

45. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-44, wherein Ar has the structurewherein n is an integer from 0 to 2, inclusive; and each X1, X2, X3, X4, and X5is individually selected from the group consisting of (i) a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and (ii) a carbon atom, each of which is unsubstituted or substituted by a substituent.

46. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 45, wherein n equals 0.

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

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

49. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X1is a heteroatom.

50. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X2is a heteroatom.

51. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X3is a heteroatom.

52. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X4is a heteroatom.

53. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 47, wherein X5is a heteroatom.

154. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 48, wherein each X5is a heteroatom.

55. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 48, wherein the X5adjacent to X4is a heteroatom.

56. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 48, wherein the X5adjacent to the carbon atom bound to A is a heteroatom.

57. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X1and X2are both heteroatoms.

58. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X1and X3are both heteroatoms.

59. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X1and X4are both heteroatoms.

60. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X2and X3are both heteroatoms.

61. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 46-48, wherein X2and X4are both heteroatoms.

62. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 47, wherein X1and X5are both heteroatoms.

63. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 47, wherein X2and X5are both heteroatoms.

64. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 47, wherein X3and X5are both heteroatoms.

65. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 47, wherein X4and X5are both heteroatoms.

66. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 45-65, wherein one of X1, X2, X3, and X4is a carbon atom that is substituted by a substituent.

67. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 66, wherein said substituent is bound to X1.

68. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 66, wherein said substituent is bound to X2.

69. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 66, wherein said substituent is bound to X3.

70. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 66, wherein said substituent is bound to X4.

71. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 47 or 49- 52, wherein X5is a carbon atom that is substituted by a substituent.

72. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 48-52, wherein the X5adjacent to X4is a carbon atom that is substituted by a substituent.

73. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 48-52, 1wherein the X5adjacent to the carbon atom bound to A is a carbon atom that is substituted by a substituent.

74. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 45-65, wherein two of X1, X2, X3, and X4are each a carbon atom that is substituted by a substituent.

75. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 74, wherein one substituent is bound to X1and one substituent is bound to X2.

76. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 74, wherein one substituent is bound to X1and one substituent is bound to X3.

77. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 74, wherein one substituent is bound to X1and one substituent is bound to X4.

78. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 74, wherein one substituent is bound to X2and one substituent is bound to X3.

79. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 74, wherein one substituent is bound to X2and one substituent is bound to X4.

80. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 47 or 49- 52, wherein X5and one of X1, X2, X3, and X4are each a carbon atom that is substituted by a substituent.

81. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 48-52, wherein the X5 adjacent to X4 and one of X1, X2, X3, and X4 are each a carbon atom that is substituted by a substituent.

82. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 48-52, wherein the X5adjacent and one of X1, X2, X3, and X4are each a carbon atom that is substituted by a substituent.

83. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 80-82, wherein X1is substituted by a substituent.

84. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 80-82, wherein X2is substituted by a substituent.

85. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 80-82, wherein X3is substituted by a substituent.

86. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 80-82, wherein X4is substituted by a substituent.

87. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 48, wherein both X5are each a carbon atom that is substituted by a substituent.

88. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-49, wherein Ar is a 5-membered heterocyclic or heteroaromatic ring selected from the group consisting of:each of which is unsubstituted or substituted by one or more substituents.

89. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-49, wherein Ar is a 6-membered heterocyclic or heteroaromatic ring selected from the group consisting of:each of which is unsubstituted or substituted by one or more substituents.

90. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-38, wherein Ar has the structurewherein m and n are each an integer from 0 to 2, inclusive; and each X1, X2, X3, X4, X5X6, X7, X8, and X9is individually selected from the group consisting of a heteroatom selected from the group consisting of nitrogen, 1 1oxygen, and sulfur, and a carbon atom, each of which is unsubstituted or substituted by a substituent.

91. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 90, wherein Ar is selected from the group consisting ofeach of which is unsubstituted or substituted by one or more substituents.

92. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-38, 90, or 91 wherein Ar is a 9-membered bicyclic heteroaromatic ring which is unsubstituted or substituted by one or more substituents.

93. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-38 or 90- 92 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, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-38 or 90- 93, wherein Ar is an unsubstituted 9-membered bicyclic heteroaromatic ring.

95. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-38 or 90- 193, wherein Ar is a 9-membered bicyclic heteroaromatic ring substituted by one substituent.

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

97. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 45, wherein Ar is a 5- membered heterocyclic ring selected from the group consisting of:.

98. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 45, wherein Ar is a 6- membered heterocyclic ring selected from the group consisting of:and99. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a fumarate salt, and a tartrate salt.

100. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 1, having the structure:

101. The compound of claim 1, having the structureor pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

102. The compound of claim 1, having the structureor pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

103. The compound of claim 1, having the structureor pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

104. The compound of claim 1, having the structureor pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

105. The compound of claim 1, having the structure, oror pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

106. The compound of claim 1, having the structure.

107. The pharmaceutically acceptable salt of claim 1 ,which is.

108. A method of activating an M4 receptor, or potentiating a response of an M4 receptor to a ligand thereof, comprising contacting the M4 receptor with an amountof a compound of any one of claims 1-107 or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, so as to activate the M4 receptor or potentiate a response of an M4 receptor to a ligand.

109. A method of potentiating a response of an M4 receptor to a ligand in a subject comprising administering to the subject an amount of a compound of a compound of any one of claims 1-107 or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, so as to potentiate a response of an M4 receptor to a ligand.

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