M4 positive allosteric modulators

Abstract

M4 positive allosterie modulators of compound of the formula wherein R1 is 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; R2 is a C1-C6 alkyl 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; R3 is a hydrogen atom or a C1-C6 alkyl group; and Ar is a 5-10 membered heterocyclic, aromatic or heteroaromatic monocyclic or bicyclic ring.

Description

M4 POSITIVE ALLOSTERIC MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63 / 607,385, filed December 7, 2023, the contents of which are hereby incorporated by reference. FIELD

[0002] The present invention relates to compounds useful as M4 positive allosteric 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 M1, 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 and 24,542 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 in cognitive 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 striatal dopamine 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 VU0467154 ameliorated 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 a specific 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 xanomeline has 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 for Glutamine 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 the motor 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 dopamine producing 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 of Parkinson, 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 of electrical 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 strategy for 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] 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 nitrogen, oxygen, and sulfur;

[0020] R2is a C1-C6alkyl group;

[0021] 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 nitrogen, oxygen, and sulfur;

[0022] R3is a hydrogen atom or a C1-C6alkyl group; and

[0023] 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

[0024] a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0025] Another embodiment relates to compounds having the formula:

[0026] wherein R1, R2, R3, A, and Ar have the meanings above,

[0027] or a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0028] Another embodiment relates to compounds having the formula:

[0029] wherein R2, R3, A, and Ar have the meanings above, and

[0030] R4aand R4bare each individually selected from a hydrogen atom, a halogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group; or

[0031] a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0032] Another embodiment relates to compounds having the formula:

[0033] wherein R1, R2, R3, R4a, R4b, and Ar have the meanings above,

[0034] or a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof. DETAILED DESCRIPTION Definitions

[0035] Unless defined otherwise, all technical and scientific terms used herein 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.

[0036] 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.

[0037] The term “alkoxy group” refers to an alkyl group, as previously defined, 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.

[0038] The term “aromatic ring” refers to a monocyclic or bicyclic carbocyclic 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 ringshas 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.

[0039] The terms “asymmetric carbon atom” and “asymmetric center” mean a 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.

[0040] The term “substituent” means an atom or group that replaces a hydrogen atom.

[0041] The terms “halogen atom” or “halo”, alone or in combination, denote a 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.

[0042] 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.

[0043] The term “haloalkoxy” refers to an alkoxy group, wherein at least one of 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.

[0044] 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.

[0045] 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.

[0046] The term “heterocyclic ring” refers to a saturated or partly unsaturated mono- 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 two 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.

[0047] Other non-limiting examples of 5-membered monocyclic heteroaromatic or heterocyclic rings include:

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

[0049] Other non-limiting examples of 6-membered monocyclic heteroaromatic or heterocyclic rings include:

[0050] Non-limiting examples of bicyclic heteroaromatic rings in which nitrogen is the only heteroatom include:

[0051] The term “hydroxy group” refers to an -OH group.

[0052] The term “cyano group” refers to an -CN group.

[0053] As used herein, “tautomer” and “tautomeric” refer to alternate forms of 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.

[0054] It is understood that isotopes may be present in the compounds described 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.

[0055] As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound 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.

[0056] Acid addition salts can be formed by mixing with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, 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.

[0057] Pharmaceutically acceptable solvates and hydrates are complexes of a compound 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.

[0058] As used herein, to “modulate” the activity of a receptor means either to 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.

[0059] As used herein, a “subject” refers to an animal that is the object of treatment, 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.

[0060] As used herein, a “patient” refers to a subject that is being treated by a 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.

[0061] As used herein, a “pharmaceutically acceptable excipient” refers to an inert 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.

[0062] As used herein, a “receptor” is intended to include any molecule present 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.

[0063] When used herein, “prevent / preventing” should not be construed to mean 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.

[0064] As used herein, the term “about” includes the recited number ±0.5 of the last digit thereof. Thus, “about 1” means 0.5 to 1.5 and “about 0.1” means 0.05 to 0.15.

[0065] Compounds

[0066] A first embodiment relates to compounds of the formula:

[0067] wherein

[0068] 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 nitrogen, oxygen, and sulfur;

[0069] R2is a C1-C6alkyl group;

[0070] 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 nitrogen, oxygen, and sulfur;

[0071] R3is a hydrogen atom or a C1-C6alkyl group; and

[0072] 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 nitrogen, oxygen, and sulfur; or

[0073] a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0074] Another embodiment relates to compounds having the formula:

[0075] wherein R1, R2, R3, A, and Ar have the meanings above,

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

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

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

[0079] R4aand R4bare each individually selected from a hydrogen atom, a halogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group; or

[0080] a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0081] Another embodiment relates to compounds having the formula:

[0082] wherein R1, R2, R3, R4a, R4b, and Ar have the meanings above,

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

[0084] According to some embodiments, R1is a 4-membered heterocyclic ring which is unsubstituted or substituted by one or more substituents.

[0085] According to some embodiments, R1is a 4-membered heterocyclic ring substituted by one or more substituents.

[0086] According to some embodiments, R1is a 4-membered heterocyclic ring substituted by one or more substituents selected from a halogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, and a hydroxy group.

[0087] According to some embodiments, R1is an azetidinyl group.

[0088] According to some embodiments, R1is an unsubstituted azetidinyl group.

[0089] According to some embodiments, R1is an azetidinyl group substituted 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.

[0090] According to some embodiments, R1is an azetidinyl group substituted by 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.

[0091] According to some embodiments, R1is an azetidinyl group which is bound to the pyrimidinyl ring through the N atom of the azetidinyl group.

[0092] According to some embodiments, R2is a C1-C6alkyl group. According to some embodiments, R2is a C1-C4alkyl group, such as a methyl group or an ethyl group.

[0093] According to some embodiments, 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 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0094] According to some embodiments, A is a 5-membered heterocyclic ring substituted by Ar only and which contains 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0095] According to some embodiments, A is a 5-membered heterocyclic ring substituted by Ar only and which contains only 1 heteroatom. According to some embodiments, that heteroatom is nitrogen.

[0096] According to some embodiments, A is a pyrrolidinyl group. According to some embodiments, A is a pyrrolidinyl group which is bound to Ar through the nitrogen atom of the pyrrolidinyl group. According to otherembodiments, A is a pyrrolidinyl group which is bound to the carbon atom of the carbonyl group through the nitrogen atom of the pyrrolidinyl group.

[0097] According to some embodiments, R3is a C1-C6alkyl group. According to some embodiments, R3is a C1-C4alkyl group. According to some embodiments, R3is methyl.

[0098] According to some embodiments, Ar is a 5-10 membered heteroaromatic 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.

[0099] According to some embodiments, Ar is substituted by at least one substituent 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.

[0100] According to some embodiments, Ar is unsubstituted. According to other embodiments, Ar is substituted by one substituent. According to other embodiments, Ar is substituted by two substituents.

[0101] According to some embodiments, Ar is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. According to some embodiments,Ar is a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0102] According to some embodiments, Ar is a 6-membered heteroaromatic 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).

[0103] According to some embodiments, where the only heteroatom is nitrogen, Ar is selected from:each of which is unsubstituted or substituted.

[0104] According to some embodiments, Ar has one of the following structures and is attached as follows:each of which is unsubstituted or substituted.

[0105] According to some embodiments, Ar is a 6-membered heteroaromatic ring having a single heteroatom. According to someembodiments, Ar is a 6-membered heteroaromatic ring containing a nitrogen atom. According to some embodiments, Ar is a 6-membered heterocyclic ring having a single heteroatom. According to some embodiments, Ar is a 6- membered heterocyclic ring containing a nitrogen atom.

[0106] According to some embodiments, Ar is a 6-membered heteroaromatic 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.

[0107] According to some embodiments, Ar has the structure:

[0108] wherein

[0109] n is an integer from 0 to 2, inclusive; and

[0110] each X1, X2, X3, X4, and X5is individually a heteroatom selected from nitrogen, oxygen, and sulfur, or a carbon atom, each of which is unsubstituted or substituted by a substituent.

[0111] According to some embodiments, n equals 0. According to other embodiments, n equals 1. According to still other embodiments, n equals 2.

[0112] According to some embodiments, at least one of X1, X2, X3, and X4is a carbon atom that is substituted by a substituent.

[0113] According to some embodiments, Ar is a 5-membered heteroaromatic or heterocyclic ring selected from:each of which is unsubstituted or substituted by one or more substituents.

[0114] According to some embodiments, Ar is a 5-membered heteroaromatic or heterocyclic ring selected fromeach of which is substituted or unsubstituted.

[0115] According to some embodiments, Ar is a 6-membered heteroaromatic or heterocyclic ring selected from:each of which is unsubstituted or substituted by one or more substituents.

[0116] According to some embodiments, Ar has the structure:

[0117] wherein

[0118] m and n are each an integer from 0 to 2, inclusive; and

[0119] each X1, X2, X3, X4, X5X6, X7, X8, and X9is individually a heteroatom selected from nitrogen, oxygen, and sulfur, or a carbon atom, each of which is unsubstituted or substituted by a substituent.

[0120] According to some embodiments, both n and m equal 0. According to 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.

[0121] According to some embodiments, where the only heteroatom is nitrogen, Ar is selected from:

[0122] 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.

[0123] According to some embodiments, Ar is a 9-membered bicyclic heteroaromatic ring which is unsubstituted or substituted by one or more substituents. According to some embodiments, Ar is a 9-membered heteroaromatic ring having at least 2 heteroatoms selected from nitrogen, oxygen, and sulfur. According to some embodiments, Ar is an unsubstituted 9-membered heteroaromatic ring. According to other embodiments, Ar is a 9-membered heteroaromatic ring by one substituent. According to still other embodiments, Ar is a 9-membered heteroaromatic ring by two substituents.

[0124] In some embodiments of the compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, Ar is a 5-membered heterocyclic ring selected from the group consisting of:

[0125] In some embodiments of the compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof, Ar is a 6-membered heterocyclic ring selected from the group consisting of:

[0126] In some embodiments of the compound, pharmaceutically acceptable 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.

[0127] In some embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0128] In embodiments, the compound has the structure:or is pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0129] In embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0130] In embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0131] In embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0132] In embodiments, the compound has the structure:or is a deuterated analog thereof.

[0133] In embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0134] In embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0135] In embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0136] In embodiments, the compound has the structure:or is a pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0137] According to some embodiments, Ar is an unsubstituted 9-membered heteroaromatic 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.

[0138] 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 containing a 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 asindividual 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.

[0139] When the structure of the compounds of this invention includes an 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.

[0140] The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By wayof general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include carbon-13 and carbon-14.

[0141] It will be noted that any notation of a carbon in structures throughout 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.

[0142] It will also be noted that any notation of a hydrogen in structures throughout 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.

[0143] Isotopically-labeled compounds can generally be prepared by conventional 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.

[0144] The term "substituted" refers to a functional group as described above 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 morebonds 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.

[0145] It is understood that substituents and substitution patterns on the compounds 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 thesemultiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0146] In choosing the compounds of the present invention, one of ordinary 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.

[0147] The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

[0148] A method of treating, or reducing a symptom of, a neurological or neuropsychiatric disorder comprising administering a compound as described herein, or a composition comprising a compound as describedherein, in an amount sufficient to treat or reduce a symptom of a neurological or neuropsychiatric disorder.

[0149] In embodiments, the neurological or neuropsychiatric disorder involves 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.

[0150] 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 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.

[0151] 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 as described herein so as to potentiate a response of an M4 receptor to a ligand.

[0152] In embodiments the ligand is acetylcholine.

[0153] Synthesis and Examples

[0154] The compounds of the various embodiments above can be made using 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 recorded on Bruker AVANCE-300 (300 MHz) and Bruker AVANCE-400 (400 MHz) instruments in CDCl3or DMSO-d6solution. 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 a Shimadzu UFLC / MS (Prominence UFLC high pressure gradient system / LCMS-2020) operating in an electron spray ionization mode (ESI+) with one or more LC conditions 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 / L AcONH4and 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 4.6 mm, 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 wasincreased 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 x 2.1mm, 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. 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 acquired using a Gilson preparative HPLC system or YMC preparative HPLC system with UV detector (220 nm). All commercially available solvents and reagents were used without further purification. Yields were not optimized.

[0137] Abbreviations used:

[0138] THF, tetrahydrofuran; EtOAc, ethyl acetate; MeOH, methanol; DMSO, dimethyl sulfoxide; EtOH, ethanol; MeCN, acetonitrile; DMF, N,N- dimethylformamide; TFA, trifluoroacetic acid; Xantphos, (5 diphenyl- phosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane; Pd2(dba)3,Tris(dibenzylideneacetone)dipalladium(0); DME, 1,2-dimethoxyethane; DIPEA, N,N-diisopropylethylamine; DMA, N,N-Dimethylacetamide.

[0139] Intermediate 1

[0140] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(pyrrolidin-3-yl)methanone dihydrochloride

[0141] Step 1

[0142] tert-Butyl (R)-3-(4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo- [3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate

[0143] To a solution of (R)-1-(tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid (992 mg, 4.61 mmol) in THF (5 mL) were added oxalyl chloride (669 μL, 97.6 mmol) and DMF (30 μL, 0.39 mmol) at room temperature. After being stirred at the same temperature for 2 h, the mixture was concentrated in vacuo. The residue was dissolved in THF (5 mL), and the solution was added to a mixture of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo- [3,4-d]pyrimidine dihydrochloride (1.00 g, 3.80 mmol), THF (5 mL) and saturated NaHCO3aq. (4 mL) at room temperature. The mixture was stirred at room temperature for 2 days. Brine was added to the mixture, and the mixture was extracted with EtOAc 5 times. The combined organic layer was dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 40% MeOH in EtOAc) to give the titled compound (148 mg) as a pale yellow oil.

[0144] 1H NMR (300 MHz, CDCl3, 300 K) δ 1.46 (9H, s), 2.06-2.30 (2H, m), 2.36-2.54 (5H, m), 3.04-3.82 (5H, m), 4.19-4.31 (4H, m), 4.56-4.67 (2H, m), 4.71-4.87 (2H, m).

[0145] m / z 388.4 [M+H]+

[0146] Step 2

[0147] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(pyrrolidin-3-yl)methanone dihydrochloride

[0148] To a solution of tert-butyl (R)-3-(4-(azetidin-1-yl)-2-methyl-6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate (780 mg 2.01 mmol) in EtOAc (7 mL) / MeOH (2 mL) was added 4M HCl in EtOAc (3 mL) at room temperature. The mixture was stirred at the same temperature for 5 h. The mixture was concentrated in vacuo to give the titled compound (759 mg) as a pale yellow gum.

[0149] 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.91-2.04 (1H, m), 2.23-2.46 (3H, m), 3.07-3.69 (8H, m), 4.26-4.76 (6H, m), 4.76-5.13 (2H, m), 8.81-9.51 (2H, m).

[0150] m / z 288.3 [M+H]+

[0151] Intermediate 2

[0152] 4-(Azetidin-1-yl)-2-ethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine bistrifluoroacetate

[0153] Step 1

[0154] tert-Butyl 2-ethyl-4-hydroxy-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidine-6-carboxylate

[0155] Propionimidamide hydrochloride (21.76 g, 200.4 mmol) was added portionwise to a solution of 1-(tert-butyl) 3-ethyl 4-oxopyrrolidine-1,3- dicarboxylate (21.5 g, 83.5 mmol) and Et3N (29.1 mL, 209 mmol) in t-BuOH (50 mL) at room temperature. The mixture was stirred at 80 °C under N2for 5 h and concentrated in vacuo. THF and water was added to the residue and the mixture was extracted with EtOAc. The organic layer was separated, washed with 10% citric acid aq. and brine, dried over Na2SO4and concentrated in vacuo. The residue was added t-butyl methyl ether and stirred for 30 min. The precipitate was collected by filtration, washed with t- butyl methyl ether, and dried to give the titled compound (6.82 g) as a white solid.

[0156] 1H NMR (300 MHz, CDCl3, 300 K) δ 1.35 (3H, td, J = 7.6, 2.3 Hz), 1.51 (9H, s), 2.75 (2H, q, J = 7.6 Hz), 4.49-4.60 (4H, m), 12.16 (1H, br s).

[0157] m / z 266.1 [M+H]+

[0158] Step 2

[0159] tert-Butyl 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-ethyl-5,7-di- hydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0160] To a solution of tert-butyl 2-ethyl-4-hydroxy-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate (6.824 g, 25.72 mmol) in DMF (50 mL) was added ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethyl- amino)phosphonium hexafluorophosphate(V) (14.79 g, 33.44 mmol) and DBU (5.815 mL, 38.58 mmol) at room temperature. The mixture was stirred at the same 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 5% - 35% EtOAc in n-hexane) to give the titled compound (8.98 g) as a white amorphous solid.

[0161] 1H NMR (300 MHz, CDCl3, 300 K) δ 0.95 (3H, t, J = 7.6 Hz), 1.54 (9H, s), 2.67 (2H, q, J = 7.6 Hz), 4.68-4.86 (4H, m), 7.41-7.59 (3H, m), 8.13 (1H, d, J = 8.3 Hz).

[0162] m / z 383.2 [M+H]+

[0163] Step 3

[0164] tert-Butyl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidine-6-carboxylate

[0165] To a solution of tert-butyl 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2- ethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (8.98 g, 23.5 mmol) in DMF (30 mL) was added azetidine hydrochloride (3.30 g, 35.2mmol) and DBU (10.6 mL, 70.4 mmol) at room temperature. The mixture was stirred at the same temperature under N2for 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 (NH silica gel, eluted with 5% - 40% EtOAc in n-hexane) to give the titled compound (6.43 g) as a white solid.

[0166] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.28 (3H, t, J = 7.6 Hz), 1.50 (9H, s), 2.40 (2H, quin, J = 7.6 Hz), 2.70-2.77 (2H, m), 4.19-4.25 (4H, m), 4.41-4.50 (2H, m), 4.57-4.65 (2H, m).

[0167] m / z 305.1 [M+H]+

[0168] Step 4

[0169] 4-(Azetidin-1-yl)-2-ethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine bistrifluoroacetate

[0170] A mixture of tert-butyl 4-(azetidin-1-yl)-2-ethyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate (6.421 g, 21.09 mmol) and TFA (13.0 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo (azeotroped with toluene) to give the titled compound (14.21 g) as a pale yellow solid.

[0171] 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.22 (3H, t, J = 7.6 Hz), 2.30-2.45 (2H, m), 2.72 (2H, q, J = 7.6 Hz), 4.27-4.48 (6H, m), 4.60 (2H, s), 9.94-10.17 (2H, m).

[0172] m / z 205.1 [M+H]+

[0173] Example 5

[0174] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3-yl)- methanone

[0175] A mixture of (R)-(4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)(pyrrolidin-3-yl)methanone dihydrochloride (28.8 mg, 79.9 μmol), 4-bromo-2-(difluoromethoxy)pyridine (35.8 mg, 160 μmol), Xantphos (4.63 mg, 7.99 μmol), Pd2(dba)3(7.32 mg, 7.99 μmol) and Cs2CO3(78.1 mg, 240 μmol) in DME (1 mL) was stirred at 120 °C for 1 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 / 10mM NH4HCO3aq.). The desired fraction was evaporated by blowing away with the air at 60 °C to give the titled compound (8.2 mg).

[0176] m / z 431.3 [M+H]+

[0177] Example 12-1

[0178] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)methanone

[0179] A mixture of (R)-(4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)(pyrrolidin-3-yl)methanone dihydrochloride (28.8 mg, 79.9 μmol), 4-bromo-2-(difluoromethoxy)pyridine (35.8 mg, 160 μmol), Xantphos (4.63 mg 7.99 μmol), Pd2(dba)3(7.32 mg, 7.99 μmol) and Cs2CO3(78.1 mg, 240 μmol) in DME (1 mL) was stirred at 120 °C for 1 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 (8.3 mg).

[0180] m / z 399.2 [M+H]+

[0181] Example 12-2

[0182] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)methanone

[0183] Step 1

[0184] Ethyl (R)-1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylate

[0185] To a solution of ethyl (R)-pyrrolidine-3-carboxylate hydrochloride (1.50 g, 8.35 mmol) in DMSO (7 mL) were added 2-chloro-4-fluoropyridine (1000 μL, 10.8 mmol) and DIPEA (3.50 mL, 20 mmol) at room temperature. The mixture was stirred at 100 °C for 1 h. The mixture was cooled to room temperature. Water was added to the mixture, and the mixture was extracted with EtOAc three times. The combined organic layer was washed with water twice and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10% - 30% EtOAc in n-hexane) to give the titled compound (2.10 g) as a colorless oil.

[0186] 1H NMR (300 MHz, CDCl3, 301 K) δ 1.29 (3H, t, J = 7.2 Hz), 2.27- 2.37 (2H, m), 3.16-3.28 (1H, m), 3.31-3.51 (2H, m), 3.56 (2H, d, J = 7.2 Hz), 4.19 (2H, q, J = 7.2 Hz), 6.31 (1H, dd, J = 6.0, 2.3 Hz), 6.39 (1H, d, J = 2.3 Hz), 7.97 (1H, d, J = 6.0 Hz).

[0187] m / z 255.2 [M+H]+

[0188] Step 2

[0189] (R)-1-(2-Chloropyridin-4-yl)pyrrolidine-3-carboxylic acid

[0190] To a solution of ethyl (R)-1-(2-chloropyridin-4-yl)pyrrolidine-3- carboxylate (2.10 g, 8.24 mmol) in EtOH (6 mL) was added 8 M NaOH aq. (2.00 mL, 16.0 mmol) at room temperature. After being stirred at the same temperature for 30 min, 4 M HCl aq. (4.00 mL, 16.0 mmol) was added to the reaction mixture. The mixture was stirred at the same temperature overnight. The precipitate was collected by filtration, and the solid was washed withwater and iPr2O. The solid was dried in vacuo to give the titled compound (1.80 g) as a white powder.

[0191] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.08-2.28 (2H, m), 3.15-3.25 (1H, m), 3.31-3.39 (2H, m), 3.41-3.55 (2H, m), 6.46-6.52 (2H, m), 7.85-7.91 (1H, m), 12.52 (1H, br s).

[0192] m / z 227.2 [M+H]+

[0193] Step 3

[0194] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)methanone

[0195] To a solution of 4-(azetidin-1-yl)-2-methyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine (121 mg, 637 μmol), (R)-1-(2-chloropyridin-4- yl)pyrrolidine-3-carboxylic acid (1467 mg, 646 μmol) and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (307 mg, 807 μmol) in DMF (1.5 mL) was added DIPEA (83 mg0.64 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 five times. The organic layer was separated, washed with water and brine, dried over Na2SO4and concentrated in vacuo to give the residue A. The aqueous layer was concentrated in vacuo, and EtOH was added to the residue. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. THF was added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give the residue B. The residue A and B were combined. The combined residue was purified by preparative HPLC (YMC-Triart C18, eluted with H2O in acetonitrile containing 10 mM ammonium bicarbonate). The desired fraction was concentrated in vacuo and azeotroped with MeCN to give the titled compound (167 mg) as white powder.

[0196] 1H NMR (400 MHz, CDCl3, 300 K) δ 2.26-2.49 (4H, m), 2.51 (3H, br s), 3.26-3.47 (2H, m), 3.48-3.72 (3H, m), 4.14-4.40 (4H, m), 4.55-4.97 (4H, m), 6.31 (1H, br d, J = 5.4 Hz), 6.39 (1H, br s), 7.97 (1H, d, J = 5.4 Hz).

[0197] m / z 399.3 [M+H]+

[0198] Example 13

[0199] (R)-(4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)methanone fumarate

[0200] To a solution of (R)-(4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)- methanone (174 mg, 437 μmol) in MeCN (1 mL) was added fumaric acid (50.6 mg, 436 μmol) at room temperature. EtOH (6 mL) was added to the mixture, and the mixture was stirred at 50 °C to give clear solution. 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 sonicated. The precipitate was appeared. The suspension was stirred at 50 °C for 30 min, cooled to room temperature and leaved at the same temperature overnight.The precipitate was collected by filtration and washed with MeCN, dried in vacuo to give the titled compound (181 mg) as a white powder.

[0201] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.08-2.20 (1H, m), 2.21-2.40 (6H, m), 3.36-3.56 (4H, m), 3.57-3.68 (1H, m), 4.09-4.27 (4H, m), 4.34-4.66 (2H, m), 4.67-5.03 (2H, m), 6.46-6.53 (2H, m), 6.63 (2H, s), 7.86-7.92 (1H, m), 13.06 (2H, br s).

[0202] m / z 399.1 [M+H]+

[0203] Example 16

[0204] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)(1-(2,5-dichloropyridin-4-yl)pyrrolidin-3-yl)methanone

[0205] A mixture of (R)-(4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)(pyrrolidin-3-yl)methanone dihydrochloride (28.8 mg, 79.9 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 (14.2 mg).

[0206] m / z 433.1 [M+H]+

[0207] Example 32

[0208] ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3-yl)- methanone

[0209] Step 1

[0210] tert-Butyl (R)-3-((R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate

[0211] To a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (633 mg, 2.94 mmol) in THF (6 mL) were added oxalyl dichloride (522 μL, 5.94 mmol) and DMF (30.0 μL, 384 μmol) at room temperature. After being stirred at the same temperature for 2 h, the mixture was concentrated in vacuo. The residue was dissolved in THF (5 mL) and the solution was added to a mixture 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) (1.00 g, 2.52 mmol), saturated NaHCO3aq. (5 mL) and THF (5 mL) at room temperature. The mixture was stirred at room temperature for 2 days. Saturated NaHCO3aq. was added to the mixture, and the mixture was extracted with EtOAc. The organic layer wasseparated, washed with saturated NaHCO3aq. 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 give the titled compound (812 mg) as a colorless foam.

[0212] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.39 (3H, d, J = 6.3 Hz), 1.42- 1.48 (9H, m), 2.07-2.30 (2H, m), 2.37-2.48 (2H, m), 2.49-2.55 (3H, m), 3.02- 3.19 (1H, m), 3.33-3.43 (1H, m), 3.44-3.74 (3H, m), 4.07-4.18 (2H, m), 4.24- 4.34 (2H, m), 4.60 (2H, s), 5.35 (1H, q, J = 6.3 Hz).

[0213] m / z 402.4 [M+H]+

[0214] Step 2

[0215] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-pyrrolidin-3-yl)methanone dihydrochloride

[0216] 4 M HCl in EtOAc (5 mL, 0.02 mol) was added to a solution of tert- butyl (R)-3-((R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate (812 mg, 2.02 mmol) in MeOH (2 mL) at room temperature. After being stirred at the same temperature for 1 h, the mixture was concentrated in vacuo to give the crude titled compound (861 mg) as a yellow oil. This material was used in the next reaction without further purification.

[0217] 1H NMR (300 MHz, CD3OD, 300 K) δ 1.45-1.59 (3H, m), 2.07-2.23 (1H, m), 2.39-2.67 (6H, m), 3.37-3.87 (5H, m), 4.31-4.78 (4H, m), 4.86-5.15 (2H, m), 5.30-5.54 (1H, m).

[0218] m / z 302.3 [M+H]+

[0219] Step 3

[0220] ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone

[0221] A mixture of methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i- propoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (15.4 mg, 18.1 μmol), ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)((R)-pyrrolidin-3-yl)methanone dihydro- chloride (67.8 mg, 181 μmol), 4-bromo-2-(difluoromethoxy)pyridine (81.1 mg, 362 μmol), Cs2CO3(177 mg, 543 μmol) and DMF (1.5 mL) was heated at 120 °C for 1 h under microwave irradiation. 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 0% - 30% EtOAc in n-hexane) to give crude product. The crude product 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 (27.1 mg) as white solid.

[0222] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.39-1.49 (3H, m), 2.31-2.49 (4H, m), 2.51-2.54 (3H, m), 3.25-3.47 (2H, m), 3.52-3.68 (3H, m), 4.13 (2H, q, J = 7.9 Hz), 4.29 (2H, q, J = 7.8 Hz), 4.64 (2H, s), 5.37 (1H, q, J = 6.0 Hz), 5.91 (1H, d, J = 2.0 Hz), 6.24 (1H, dd, J = 5.9, 2.2 Hz), 7.43 (1H, t, J = 73.8 Hz), 7.81 (1H, d, J = 5.9 Hz).

[0223] m / z 445.3 [M+H]+

[0224] Example 33-1

[0225] ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone fumarate

[0226] ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone (1.17 g, 2.63 mmol) and fumaric acid (300 mg, 2.58 mmol) were dissolved in EtOH (15 mL) at 60 °C. MeCN (30 mL) was added to the solution, and the whole stirred solution was allowed to cool to room temperature. The solution was concentrated in vacuo until precipitates emerged, then the suspension was stirred for 1 h at room temperature and diluted with MeCN. The precipitates were filtered, washed with MeCN, and dried to give the titled compound (938 mg) as a colorless powder.

[0227] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.26-1.41 (3H, m), 2.02-2.42 (7H, m), 3.32-3.68 (5H, m), 4.03-4.27 (4H, m), 4.27-4.83 (2H, m), 5.18-5.45 (1H, m), 6.00-6.06 (1H, m), 6.38-6.45 (1H, m), 6.63 (2H, s), 7.43-7.84 (2H, m), 13.11 (2H, br s).

[0228] m / z 445.2 [M+H]+

[0229] Example 33-2

[0230] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone fumarate

[0231] tert-Butyl (R)-3-((R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate (4.20 g, 10.5 mmol) was dissolved in TFA (15 mL, 0.20 mol) at 0 °C, then stirred for 20 min at room temperature. The mixture was concentrated in vacuo, diluted with toluene (10 mL), and concentrated in vacuo. A mixture of the residue, 4-bromo-2-(difluoromethoxy)pyridine (3.05 g, 13.6 mmol), Pd2(dba)3(287 mg, 314 μmol), Xantphos (363 mg, 628 μmol), Cs2CO3(13.6 g, 41.8 mmol) and DME (50 mL) was stirred at 80 °C under N2overnight. The mixture was filtered and washed with EtOAc. The filtrate was concentrated in vacuo, passed through a NH silica gel pad, and eluted with THF. The eluent was concentrated in vacuo, purified by column chromatography (silica gel, eluted with 0% - 10% MeOH in EtOAc) to give ((R)-4-(azetidin-1-yl)-2,5- dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((R)-1-(2- (difluoromethoxy)pyridin-4-yl)pyrrolidin-3-yl)methanone (3.62 g) as a pale yellow gum.

[0232] The pale yellow gum and fumaric acid (0.95 g, 8.2 mmol) were dissolved in EtOH (10 mL) and MeCN (20 mL) at 60 °C. The solution wasconcentrated in vacuo to half volume, and the stirring mixture was allowed to cool to room temperature to generate precipitates. To the stirring suspension was dropwise added MeCN (20 mL), then the whole mixture was stirred for 2 h at room temperature. The precipitate was filtered, washed with MeCN, and dried to give the titled compound (3.22 g) as a colorless powder.

[0233] 1H NMR (300 MHz, DMSO-d6, 301 K) δ 1.24-1.42 (3H, m), 2.02-2.43 (7H, m), 3.32-3.67 (5H, m), 4.02-4.25 (4H, m), 4.26-4.85 (2H, m), 5.17-5.46 (1H, m), 6.00-6.06 (1H, m), 6.38-6.46 (1H, m), 6.63 (2H, s), 7.36-7.90 (2H, m), 13.09 (2H, br s).

[0234] m / z 445.0 [M+H]+

[0235] Example 33-3 – Synthesis example of the compound of Example 33

[0236] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone fumarate

[0237] Step 1

[0238] Methyl (R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidine-3- carboxylate

[0239] Tripotassium phosphate (419 g, 1.98 mol) was added to a mixture of 4-bromo-2-(difluoromethoxy)pyridine (177 g, 790 mmol) and (R)- pyrrolidine-3-carboxylic acid (100 g, 869 mmol) in DMSO (600 mL) at room temperature. The mixture was stirred at 50 °C over weekend. The mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled below 10 °C, and methyl iodide (168 g, 1.19 mol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (2000 mL) at 0 °C and extracted with TBME (1000 mL) twice. The organic layer was combined, washed with water and brine, dried over MgSO4and concentrated in vacuo. The residue was combined andrecrystallized from TBME-n-hexane (1:5, v / v, 600 mL, dissolved at 70 °C and then, cooled to 0 °C) to give the titled compound (170.3 g,) as a white solid.

[0240] 1H NMR (300 MHz, DMSO-d6, 301 K) δ 2.06-2.32 (2H, m), 3.23-3.59 (5H, m), 3.65 (3H, s), 6.02 (1H, d, J = 1.9 Hz), 6.42 (1H, dd, J = 6.0, 2.3 Hz), 7.29-7.93 (1H, m), 7.79 (1H, d, J = 6.0 Hz).

[0241] m / z 273.1 [M+H]+.

[0242] The optical purity was determined as 98.6%ee by chiral HPLC (Column: CHIRALPAK IH(CP029) 4.6 mmID*250 mmL, 5μm. Mobile phase: CO2 / 0.5% diethylamine in 2-propanol=860 / 140 (v / v)).

[0243] Step 2

[0244] (R)-1-(2-(Difluoromethoxy)pyridin-4-yl)pyrrolidine-3-carboxylic acid hydrochloride

[0245] A mixture of methyl (R)-1-(2-(difluoromethoxy)pyridin-4- yl)pyrrolidine-3-carboxylate (168 g, 616 mmol) and 3N HCl in water (1800 mL, 5.40 mol) was stirred at 50 °C for 3 h. The mixture was concentrated in vacuo. To the residue was added MeCN. The mixture was concentrated in vacuo (almost all of water should be removed by azeotropy). The residue was triturated with MeCN (900 mL) and THF (900 mL), and the precipitate was collected by filtration to give the titled compound (144 g) as an off-white solid. The mother liquor was concentrated in vacuo and triturated with MeCN (300 mL) and THF (300 mL), and the precipitate was collected by filtration to give the titled compound (29 g) as an off-white solid.

[0246] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.10-2.30 (2H, m), 3.24 (1H, quin, J = 7.1 Hz), 3.35-3.46 (2H, m), 3.48-3.64 (2H, m), 6.18 (1H, br s), 6.43-6.62 (1H, m), 7.43-7.92 (2H, m).2H was not observed clearly.

[0247] m / z 259.0 [M+H]+.

[0248] The optical purity was determined as 97.6%ee and 99.8%ee respectively by chiral HPLC (Column: CHIRALPAK IH(CP029) 4.6 mmID*250 mmL, 5μm. Mobile phase: CO2 / 0.5% diethylamine in 2- propanol=860 / 140 (v / v)).

[0249] Step 3

[0250] (R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone

[0251] To a suspension of (R)-1-(2-(difluoromethoxy)pyridin-4- yl)pyrrolidine-3-carboxylic acid hydrochloride (9.79 g, 33.2 mmol) and triethylamine (4.63 mL, 33.2 mmol) in MeCN (512 mL) was added portionwise di(1H-imidazol-1-yl)methanone (5.63 g, 34.7 mmol) at room temperature, and the mixture was stirred at room temperature for 60 min. The mixture was cooled to 0 °C, and triethylamine (6.11 g, 60.4 mmol) was added to the mixture. (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) (12.0 g, 15.1 mmol) was added portionwise to the mixture at 0 °C and stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3solution (500 mL) and extracted with EtOAc (500 mL) twice. The combined organic layer was washed withbrine (500 mL), dried over Na2SO4and concentrated in vacuo. The residue was passed through silica gel pad (NH silica gel 300 g, eluted with 50% EtOAc in n-hexane) to give the titled compound (12.7 g) as a white amorphous.

[0252] 1H NMR (400 MHz, DMSO-d6, 303 K) δ 1.26-1.43 (3H, m), 2.04-2.43 (7H, m), 3.33-3.70 (5H, m), 3.97-4.24 (4H, m), 4.27-4.87 (2H, m), 5.13-5.53 (1H, m), 6.02 (1H, d, J = 1.9 Hz), 6.41 (1H, dd, J = 6.0, 1.9 Hz), 7.25-7.96 (2H, m).

[0253] m / z 445.1 [M+H]+.

[0254] Step 4

[0255] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone fumarate

[0256] To a solution of ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4- yl)pyrrolidin-3-yl)methanone (2.24 g, 5.04 mmol) in EtOH (26 mL) was added fumaric acid (526 mg, 4.54 mmol) at room temperature, and the mixture was stirred at 78 °C for 1 h. Insoluble material was filtered off, and the filtrate was concentrated in vacuo not to remain EtOH. MeCN (26 mL) was added to the residue, and the mixture was stirred at room temperature for 3 h. The precipitate was filtered and washed with MeCN (20 mL) to give crude ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone fumarate (2.10 g) as an off-white solid. The obtained crude((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone fumarate (263 mg, 469 μmol) was dissolved in EtOH (4 mL) at 75 °C. To the solution was added dropwise n-heptane (6 mL) at 70 °C over 30 min. The mixture was stirred at 45-50 °C for 5 h and at room temperature overnight. The resulting precipitate was collected by filtration to give the titled compound (178 mg) as colorless crystals.

[0257] 1H NMR (400 MHz, DMSO-d6, 298 K) δ 1.18-1.51 (3H, m), 2.04-2.42 (7H, m), 3.38-3.68 (5H, m), 4.03-4.25 (4H, m), 4.26-4.85 (2H, m), 5.13-5.48 (1H, m), 5.97-6.09 (1H, m), 6.41 (1H, br d, J = 5.9 Hz), 6.63 (2H, s), 7.33- 7.95 (2H, m), 12.54-13.72 (2H, br s).

[0258] m / z 445.1 [M+H]+.

[0259] The ratio of enantiomers and diastereomers was determined as the titled compound : S,S-isomer (see example 50) : the mixture of R,S-isomer (see example 52) and S,R-isomer (see example 51) = 100.00 : N.D. : N.D.) by chiral HPLC (Column: CHIRALPAK IF(TK009) 4.6 mmID*250 mmL, 5 μm. Mobile phase: n-hexane / ethyl acetate / diethylamine = 100 / 900 / 1 (v / v / v)).

[0260] Example 37

[0261] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(5-chloropyridin-3-yl)pyrrolidin-3-yl)methanone

[0262] Step 1

[0263] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)(pyrrolidin-3-yl)methanone bistrifluoroacetate

[0264] Trifluoroacetic acid (2 mL) was added to tert-butyl (R)-3-(4-(azetidin- 1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)- pyrrolidine-1-carboxylate (1478 mg, 381 μmol) at room temperature. The mixture was stirred at the same temperature for 10 min. The mixture was concentrated in vacuo to give the crude titled compound (233 mg) as an orange oil. This product was subjected to the next reaction without further purification.

[0265] m / z 288.1 [M+H]+

[0266] Step 2

[0267] (R)-(4-(Azetidin-1-yl)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(5-chloropyridin-3-yl)pyrrolidin-3-yl)methanone

[0268] A mixture of crude (R)-(4-(azetidin-1-yl)-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)(pyrrolidin-3-yl)methanone bistrifluoro- acetate (48.6 mg), 5-bromo-3-chloropyridine (22.8 mg, 118 μmol), RuPhos Pd G4 (10.0 mg, 11.8 μmol), Cs2CO3(144 mg, 442 μmol) and DME (2 mL) was heated at 120 °C for 2 h under microwave irradiation. The mixture was purified by column chromatography (silica gel, eluted with 0% - 40% MeOH in EtOAc) followed by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) to give the titled compound (21.0 mg) as a white powder.

[0269] 1H NMR (300 MHz, CDCl3, 301 K) δ 2.28-2.55 (7H, m), 3.27-3.57 (3H, m), 3.57-3.64 (2H, m), 4.20-4.31 (4H, m), 4.58-4.94 (4H, m), 6.80 (1H, dd, J = 2.6, 1.9 Hz), 7.86 (1H, d, J = 2.6 Hz), 7.90 (1H, d, J = 1.9 Hz).

[0270] m / z 399.3 [M+H]+

[0271] Example 38

[0272] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(5-chloropyridin-3-yl)pyrrolidin-3-yl)methanone

[0273] A mixture of crude ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro- 6H-pyrrolo[3,4-d]pyrimidin-6-yl)((R)-pyrrolidin-3-yl)methanone dihydrochloride (38.5 mg), 5-bromo-3-chloropyridine (31.4 mg, 163 μmol), RuPhos Pd G4 (7.4 mg, 8.7 μmol), Cs2CO3(137 mg, 422 μmol), DME (1.5 mL) and DMF (0.5 mL) was heated at 120 °C for 2 h under microwave irradiation. The mixture was purified by column chromatography (silica gel, eluted with 0% - 25% MeOH in EtOAc) followed by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) to give the titled compound (10.9 mg) as a colorless foam.

[0274] 1H NMR (300 MHz, CDCl3, 300 K) δ 1.37-1.52 (3H, m), 2.29-2.64 (7H, m), 3.24-3.73 (5H, m), 4.07-4.21 (2H, m), 4.24-4.36 (2H, m), 4.40-4.84 (2H, m), 5.17-5.42 (1H, m), 6.76-6.83 (1H, m), 7.84-7.88 (1H, m), 7.88-7.92 (1H, m).

[0275] m / z 413.3 [M+H]+

[0276] Example 39

[0277] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)((R)-1-(2-methoxypyridin-4-yl)pyrrolidin-3-yl)methanone

[0278] A mixture of crude ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro- 6H-pyrrolo[3,4-d]pyrimidin-6-yl)((R)-pyrrolidin-3-yl)methanone dihydrochloride (65.4 mg), 4-iodo-2-methoxypyridine (72.2 mg, 307 μmol), Cs2CO3(200 mg, , 614 μmol), RuPhos Pd G4 (13.1 mg, 15.4 μmol) and DME (1 mL) was heated at 120 °C for 1 h under microwave irradiation. 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 (18.9 mg) as white solid.

[0279] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.37-1.48 (3H, m), 2.28-2.37 (2H, m), 2.37-2.50 (2H, m), 2.51-2.54 (3H, m), 3.22-3.44 (2H, m), 3.48-3.65 (3H, m), 3.86-3.92 (3H, m), 4.10-4.19 (2H, m), 4.25-4.33 (2H, m), 4.65 (2H, s), 5.37 (1H, q, J = 6.3 Hz), 5.77 (1H, d, J = 2.2 Hz), 6.13 (1H, dd, J = 6.0, 2.1 Hz), 7.84 (1H, d, J = 5.9 Hz).

[0280] m / z 409.2 [M+H]+

[0281] Example 41

[0282] (R)-(4-(Azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)methanone fumarate

[0283] Step 1

[0284] Ethyl (R)-1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylate

[0285] To a solution of ethyl (R)-pyrrolidine-3-carboxylate hydrochloride (1.50 g, 8.35 mmol) in DMSO (7 mL) were added 2-chloro-4-fluoropyridine (1000 μL, 10.8 mmol) and DIPEA (3.50 mL, 20 mmol) at room temperature. The mixture was stirred at 100 °C for 1 h. The mixture was cooled to room temperature. Water was added to the mixture, and the mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water twice and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10% - 30% EtOAc in n-hexane) to give the titled compound (2.10 g) as a colorless oil.

[0286] 1H NMR (300 MHz, CDCl3, 301 K) δ 1.29 (3H, t, J = 7.2 Hz), 2.27- 2.37 (2H, m), 3.16-3.28 (1H, m), 3.31-3.51 (2H, m), 3.56 (2H, d, J = 7.2 Hz), 4.19 (2H, q, J = 7.2 Hz), 6.31 (1H, dd, J = 6.0, 2.3 Hz), 6.39 (1H, d, J = 2.3 Hz), 7.97 (1H, d, J = 6.0 Hz).

[0287] m / z 255.2 [M+H]+

[0288] Step 2

[0289] (R)-1-(2-Chloropyridin-4-yl)pyrrolidine-3-carboxylic acid

[0290] To a solution of ethyl (R)-1-(2-chloropyridin-4-yl)pyrrolidine-3- carboxylate (2.10 g, 8.24 mmol) in EtOH (6 mL) was added 8 M NaOH aq. (2.00 mL, 16.0 mmol) at room temperature. After being stirred at the same temperature for 30 min, 4 M HCl aq. (4.00 mL, 16.0 mmol) was added to the reaction mixture. The mixture was stirred at the same temperature overnight. The precipitate was collected by filtration, and the solid was washed with water and iPr2O. The solid was dried in vacuo to give the titled compound (1.80 g) as a white powder.

[0291] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.08-2.28 (2H, m), 3.15-3.25 (1H, m), 3.31-3.39 (2H, m), 3.41-3.55 (2H, m), 6.46-6.52 (2H, m), 7.85-7.91 (1H, m), 12.52 (1H, br s).

[0292] m / z 227.2 [M+H]+

[0293] Step 3

[0294] (R)-(4-(Azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)methanone

[0295] To a solution of 4-(azetidin-1-yl)-2-ethyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine, bistrifluoroacetate (650 mg, 964.9 μmol) in DMF (8 mL) was added (R)-1-(2-chloropyridin-4-yl)pyrrolidine-3-carboxylic acid (219 mg, 965 μmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (550 mg, 1.447 mmol) and DIPEA (499 mg, 3.86 mmol) at room temperature. The mixture was stirred at the same temperature under N2for 16 h. Water was added to the mixtureand the mixture was extracted with EtOAc. The water layer was 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 (183 mg) as white solid.

[0296] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.29 (3H, t, J = 7.6 Hz), 2.29- 2.49 (4H, m), 2.71-2.79 (2H, m), 3.29-3.44 (2H, m), 3.52-3.66 (3H, m), 4.21- 4.30 (4H, m), 4.60-4.90 (4H, m), 6.31 (1H, dd, J = 5.9, 2.2 Hz), 6.39 (1H, d, J = 2.2 Hz), 7.96 (1H, d, J = 5.9 Hz).

[0297] m / z 413.2 [M+H]+

[0298] Step 4

[0299] (R)-(4-(Azetidin-1-yl)-2-ethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)pyrrolidin-3-yl)methanone fumarate

[0300] EtOH (5 mL) was added to a mixture of (R)-(4-(azetidin-1-yl)-2-ethyl- 5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(2-chloropyridin-4-yl)- pyrrolidin-3-yl)methanone (161 mg, 389 μmol) and fumaric acid (45.1 mg, 389 μmol) at room temperature. The mixture was stirred at 50 °C for 5 min to give a clear solution. The solution was concentrated in vacuo and the residue was dissolved in EtOH (3 mL). The solution was diluted with MeCN (10 mL) and sonicated. The precipitate appeared. The suspension was stirred at 50 °C for 20 min, cooled to room temperature and leaved at the same temperature over weekend. The precipitate was collected by filtration and washed with small amount of MeCN, dried in vacuo to give a white powder(116 mg, powder A). The filtrate was concentrated in vacuo to give a residue (88 mg). MeCN (2 mL) and EtOAc (2 mL) were added to the residue and the solution was sonicated. The precipitate appeared. iPr2O (3 mL) and the powder A were added to the suspension. The suspension was sonicated, stirred at 50 °C for 20 min, cooled to room temperature and leaved in refrigerator for 20 min. The precipitate was collected by filtration, and the solid was washed with small amount of EtOAc, dried in vacuo to give the titled compound (181 mg) as a white powder.

[0301] 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.14-1.24 (3H, m), 2.08-2.40 (4H, m), 2.58-2.67 (2H, m), 3.33-3.54 (4H, m), 3.56-3.68 (1H, m), 4.10-4.29 (4H, m), 4.34-4.67 (2H, m), 4.68-5.04 (2H, m), 6.44-6.54 (2H, m), 6.63 (2H, s), 7.84-7.94 (1H, m), 13.10 (2H, br s).

[0302] m / z 413.1 [M+H]+

[0303] Example 43

[0304] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)((R)-1-(2,5-dichloropyridin-4-yl)pyrrolidin-3-yl)methanone

[0305] Step 1

[0306] tert-Butyl (R)-3-((R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate

[0307] To a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (1.1 g, 5.1 mmol) in THF (11 mL) and DMF (77 mg, 1.1 mmol) was added oxalyl dichloride (1.3 g, 11 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and dissolved in THF (10 mL). This mixture was added to a stirring mixture 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-methyl- benzoyl)oxy)succinate (1.2 g, 3.0 mmol) and saturated NaHCO3aq.(15 mL) in THF (10 mL), and the mixture was stirred at room temperature for 2 days. The mixture was partitioned between EtOAc and water, and the EtOAc layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) to give the titled compound (1.20 g) as a colorless gum.

[0308] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.39 (3H, d, J = 6.1 Hz), 1.46 (9H, s), 2.06-2.22 (2H, m), 2.37-2.49 (2H, m), 2.51 (3H, s), 3.04-3.17 (1H, m), 3.32-3.43 (1H, m), 3.44-3.67 (3H, m), 4.12-4.17 (2H, m), 4.23-4.34 (2H, m), 4.60 (2H, s), 5.31-5.39 (1H, m).

[0309] m / z 402.2 [M+H]+

[0310] Step 2

[0311] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-pyrrolidin-3-yl)methanone bistrifluoroacetate

[0312] A mixture of tert-butyl (R)-3-((R)-4-(azetidin-1-yl)-2,5-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate (1.2 g, 3.0 mmol) and TFA (10 mL) was stirred at room temperature for 1 h. After removal of the solvent in vacuo, the resulting residue was suspended in toluene and the mixture was concentrated in vacuo at 70 °C to give the crude titled compound (2.20 g) as a colorless gum. This material was used fin the next reaction without further purification.

[0313] m / z 302.1 [M+H]+

[0314] Step 3

[0315] ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)((R)-1-(2,5-dichloropyridin-4-yl)pyrrolidin-3-yl)methanone

[0316] A mixture of ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)((R)-pyrrolidin-3-yl)methanone bistrifluoro- acetate (50 mg, 94 μmol) , 2,5-dichloro-4-fluoropyridine (31 mg, 0.19 mmol)and DIPEA (66 μL, 0.38 mmol) in DMA (5 mL) was stirred at 100 °C overnight. After removal of the solvent in vacuo, the residue was partitioned between EtOAc and water. The EtOAc layer was washed with water 5 times, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in n-hexane) to give the titled compound (19 mg) as a colorless gum.

[0317] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.41 (3H, d, J = 6.1 Hz), 2.23- 2.32 (2H, m), 2.38-2.49 (2H, m), 2.52 (3H, s), 3.14-3.28 (1H, m), 3.67-3.81 (2H, m), 3.83-3.99 (2H, m), 4.06-4.20 (2H, m), 4.24-4.38 (2H, m), 4.64 (2H, d, J = 0.7 Hz), 5.30-5.43 (1H, m), 6.52 (1H, s), 8.00 (1H, s).

[0318] m / z 447.1 [M+H]+

[0319] Example 45

[0320] ((R)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d] pyrimidin-6-yl)((R)-1-(5-chloro-3-fluoropyridin-2-yl)pyrrolidin-3- yl)methanone

[0321] A mixture of ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)((R)-pyrrolidin-3-yl)methanone bistrifluoroacetate (100 mg, 189 μmol), 2-bromo-5-chloro-3-fluoropyridine (71.5 mg, 340 μmol), Cs2CO3(308 mg, 944 μmol), and methanesulfonato(2- dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-methylamino- 1,1'-biphenyl-2-yl)palladium(II) (16.1 mg , 18.9 μmol) in DMF (1 mL) and DME (3 mL) was heated at 120 °C for 2 h under microwave irradiation. The mixture was poured into water at room temperature and 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 30% - 90% EtOAc in n-hexane) to give the titled compound (40 mg) as a colorless gum.

[0322] 1H NMR (400 MHz, CDCl3, 300 K) δ 1.41 (3H, d, J = 6.4 Hz), 2.18- 2.36 (2H, m), 2.38-2.49 (2H, m), 2.52 (3H, s), 3.14-3.26 (1H, m), 3.64-3.76 (1H, m), 3.79-3.95 (3H, m), 4.09-4.16 (2H, m), 4.22-4.34 (2H, m), 4.61-4.69(2H, m), 5.29-5.42 (1H, m), 7.18 (1H, dd, J = 12.3, 2.1 Hz), 7.86-7.89 (1H, m).

[0323] m / z 431.2 [M+H]+

[0324] Example 50

[0325] ((S)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((S)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone ((S,S)-isomer)

[0326] Step 1

[0327] tert-Butyl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0328] tert-butyl (S)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0329] Racemate of tert-butyl 4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro- 6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (240 g, 788 mmol) was separated by chiral separation (Column: DAICEL CHIRALPAK AD (250mm*50 mm, 10 um), Mobile phase: CO2-EtOH (0.1% NH4OH)) to afford tert-butyl (R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate (109 g, tR1) as a brown solid and tert-butyl (S)- 4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (110 g, tR2) as a brown solid. The optical purity was determined as 100%ee for tR1 and 98.7%ee for tR2 respectively by analytical chiral SFC (Column: Chiralpak AD-350×4.6 mm I.D., 3 um, Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% diethylamine))

[0330] Analytical data of tR1:

[0331] 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.34 (3H, m), 1.40-1.50 (9H, m), 2.27-2.40 (5H, m), 4.04-4.21 (4H, m), 4.24-4.39 (2H, m), 4.92-5.10 (1H, m).

[0332] m / z 305.2 [M+H]+.

[0333] Analytical data of tR2:

[0334] 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.34 (3H, m), 1.40-1.50 (9H, m), 2.25-2.40 (5H, m), 4.00-4.42 (6H, m), 4.89-5.09 (1H, m).

[0335] m / z 305.2 [M+H]+.

[0336] Step 2

[0337] (S)-4-(Azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidine dimethanesulfonate

[0338] To a solution of tert-butyl (S)-4-(azetidin-1-yl)-2,5-dimethyl-5,7- dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2.00 g, 6.57 mmol) in CH3CN (20 mL) was added methanesulfonic acid (1.58 g, 16.4 mmol) at room temperature. The mixture was stirred at room temperature for 5 daysand at 60 °C overnight. The reaction mixture was concentrated in vacuo to give crude (S)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidine dimethanesulfonate (3.27 g) as a brown oil.

[0339] 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.48 (3H, d, J = 6.4 Hz), 2.36 (7.5H, s), 2.37-2.45 (2H, m), 2.48 (3H, s), 4.19-5.20 (7H, m), 9.41- 10.07 (2H, m).

[0340] m / z 205.1 [M+H]+.

[0341] Step 3

[0342] tert-Butyl (S)-3-((S)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate

[0343] To a solution of (S)-4-(azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine dimethanesulfonate (995 mg, 89Wt%, 2.23 mmol), (3S)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (578 mg, 2.69 mmol) and DIPEA (2.00 mL, 11.5 mmol) in DMF (10 mL) was added HATU (1,27 g, 3.35 mmol) at room temperature. The mixture was stirred at the same temperature for 3 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 20% - 80% EtOAc in n-hexane) to give tert-butyl (S)-3-((S)-4- (azetidin-1-yl)-2,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6- carbonyl)pyrrolidine-1-carboxylate (608 mg) as a colorless foam.

[0344] 1H NMR (300 MHz, CDCl3, 301 K) δ 1.36-1.51 (12H, m), 2.06-2.32 (2H, m), 2.35-2.57 (5H, m), 3.01-3.24 (1H, m), 3.30-3.45 (1H, m), 3.46-3.81(3H, m), 4.04-4.20 (2H, m), 4.21-4.35 (2H, m), 4.37-4.83 (2H, m), 5.10-5.42 (1H, m).

[0345] m / z 402.2 [M+H]+.

[0346] Step 4

[0347] ((S)-4-(Azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((S)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone

[0348] A mixture of tert-butyl (S)-3-((S)-4-(azetidin-1-yl)-2,5-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)pyrrolidine-1-carboxylate (608 mg, 1.51 mmol) and TFA (8 mL, 0.1 mol) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. To the residue were added toluene and MeCN, and the mixture was concentrated in vacuo. This process was repeated 3 times. To a solution of the residue in DME (16 mL) were added 4-bromo-2-(difluoromethoxy)pyridine (441 mg, 1.97 mmol), Pd2(dba)3(68 mg, 75.7 μmol), Xanthos (88 mg, 151 μmol) and Cs2CO3(2.47 g, 7.57 mmol) at room temperature. The mixture was stirred at 80 °C under Ar for 16 h. The mixture was cooled to room temperature and filtered and washed with EtOAc. The filtrate was concentrated in vacuo, passed through a NH-SiO2pad, and eluted with THF. The eluent was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, eluted with 0% - 10% MeOH in EtOAc) to give ((S)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((S)-1-(2-(difluoromethoxy)pyridin-4-yl)pyrrolidin-3- yl)methanone (536 mg) as a pale yellow amorphous powder.

[0349] 1H NMR (400 MHz, DMSO-d6, 296 K) δ 1.21-1.48 (3H, m), 1.70-2.44 (7H, m), 3.35-3.70 (5H, m), 3.97-4.87 (6H, m), 5.15-5.47 (1H, m), 6.03 (1H, br s), 6.36-6.50 (1H, m), 7.41-7.89 (2H, m).

[0350] m / z 445.2 [M+H]+.

[0351] Example 51, 52: the diastereomers of Example 33 compound Prepared similar to Example 50.

[0352] 51 is ((S)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((R)-1-(2-methyl-6-(trifluoromethyl)pyridin-4- yl)pyrrolidin-3-yl)methanone. m / z 445.2 [M+H]+.1H NMR (400 MHz, DMSO-d6, 296 K) δ 1.25-1.41 (3H, m), 2.04-2.43 (7H, m), 3.27-3.70 (5H, m), 4.04-4.24 (4H, m), 4.28-4.79 (2H, m), 5.19-5.48 (1H, m), 6.00-6.07 (1H, m), 6.39-6.46 (1H, m), 7.64 (1H, t, J = 73.7 Hz), 7.79 (1H, d, J = 5.9 Hz). 52 is ((R)-4-(azetidin-1-yl)-2,5-dimethyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)((S)-1-(2-methyl-6-(trifluoromethyl)pyridin-4- yl)pyrrolidin-3-yl)methanone. m / z 445.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6, 301 K) δ 1.21-1.48 (3H, m), 2.01-2.42 (7H, m), 3.27-3.74 (5H, m), 3.96-4.79 (6H, m), 5.12-5.50 (1H, m), 5.96-6.09 (1H, m), 6.30-6.52 (1H, m), 7.63 (1H, t, J = 73.8 Hz), 7.79 (1H, d, J = 6.0 Hz).

[0353] Table 1. Compound structure, compound name, preparation method and physicochemical data for Examples 1- 49.7000 / 08600ER A 691.v622 4-4 269-1094

[0354] Biological Assay

[0355] In Vitro M4 &M2 Functional Assay

[0356] The functional activity of compounds at the M4 and M2 receptors was determined by measuring changes in the level of intracellular calcium ions caused by signaling cascades mediated by the receptor. Intracellular calcium levels were measured 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.

[0357] 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 °C, 5% CO2.

[0358] Agonist Assays: 10 µL test compound diluted in HBSS, 20mM HEPES, 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.

[0359] Positive allosteric modulator (PAM) assays: 10 µL test compound diluted 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.

[0360] Data analysis: In both Agonist assay and PAM assay, cellular response 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.

[0361] Table 2. Results of Biological Assay.ND – MEANS NOT DETERMINED; NT – MEANS NOT TESTED

[0362] Determination of the in vitro clearance

[0363] Oxidative metabolic clearance with microsomes

[0364] 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).

[0365] The clearance (μL / min / mg protein) was calculated to the following:

[0366] {1000 × rate constant (calculated based on the exponential function of the remaining rate vs time curve on the assumption that it is the first order elimination) / microsomal protein (mg / mL)}

[0367] WO 2018 / 066718 discloses reference compounds T1 as example 29, T2 as example 111 and T3 as example 176.

[0368]

[0369] Activity of the reference compounds towards the M4 receptor, as well as in vitro clearance of the reference compounds and example 33 were also determined. The results are shown in Table 2.

[0370] Table 2

[0371] Example 33 exhibits clearance values reduced significantly compared to clearance values of examples T1, T2 and T3.

[0372] METH-induced hyperlocomotion assays

[0373] Seven-week-old male Wistar rats were purchased from Jackson Laboratory 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 foranimal 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.

[0374] Locomotion activity was measured using a SUPERMEX spontaneous motor 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 33 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.

[0375] Table 3

[0376] As can be seen from Table 3, Example 33 was significantly more effective at reversing METH-induced hyperlocomotion than prior art compound CVL-231 with an MED of 10 mg / kg v 60 mg / kg.

[0377] Cardiovascular Telemetry Study in Monkeys

[0378] The cardiovascular (CV) effects of test compounds can be assessed in a suitable test subject such as male cynomolgus monkeys (n=3 or 4) using a telemetrystudy. 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 each assay 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 33, 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])

[0379] The compounds of the invention are expected to show less severe effects in duration and / or extent in at least one of Systolic BP, Diastolic BP and HR than prior art M4 PAMs.

[0380] The description set forth above is provided to give those of ordinary skill in the 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; 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 having the formulawhereinR4aand 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 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.

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

16. The compound pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-15, wherein A is selected from the group consisting ofeach of which is unsubstituted or substituted.

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

18. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-15 and 17, wherein said heteroatom of A is nitrogen.

19. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-15, wherein A is a 5-membered heteroatomic ring having two heteroatoms.

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

21. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-15 and 17-20, wherein A is an unsubstituted 5-membered heterocyclic ring.

22. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-18, wherein A is a pyrrolidinyl group which is unsubstituted or substituted.

23. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 22, wherein said pyrrolidinyl group is bound to Ar through the nitrogen of the pyrrolidinyl group.

24. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 22, wherein said pyrrolidinyl group is bound to the carbonyl group through the nitrogen of the pyrrolidinyl group.

25. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-24, wherein R3is methyl.

26. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-25, wherein Ar is a 5-10 membered heteroaromatic ring, which is unsubstituted or substituted by one or more substituents and which contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

27. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-26, wherein Ar is substituted by at least one substituent selected from the group consisting of a halogen, a C1-C6alkyl group, optionally in which one or more of the hydrogens may be replaced by a halogen, a C1-C6alkoxy group, optionally in which one or more of the hydrogens may be replaced by a halogen, and a cyano group.

28. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-26, wherein Ar is unsubstituted.

29. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-27, wherein Ar is substituted by one substituent.

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

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

32. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-31, wherein Ar is a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogens.

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 selected from the group consisting ofeach of which is unsubstituted or substituted.

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 a 6-membered heteroaromatic ring having a single heteroatom.

35. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 34, wherein said heteroatom is nitrogen.

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

37. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 36, wherein both of said heteroatoms are nitrogen.

38. The compound of any one of claims 1-37, 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, each of which is unsubstituted or substituted by a substituent.

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

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

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

42. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X1is a heteroatom.

43. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X2is a heteroatom.

44. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X3is a heteroatom.

45. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X4is a heteroatom.

46. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 40, wherein X5is a heteroatom.

47. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 41, wherein each X5is a heteroatom.

48. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 41, wherein the X5adjacent to X4is a heteroatom.

49. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 41, wherein the X5adjacent to the carbon bound to A is a heteroatom.

50. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X1and X2are both heteroatoms.

51. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X1and X3are both heteroatoms.

52. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X1and X4are both heteroatoms.

53. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X2and X3are both heteroatoms.

54. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 39-41, wherein X2and X4are both heteroatoms.

55. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 40, wherein X1and X5are both heteroatoms.

56. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 40, wherein X2and X5are both heteroatoms.

57. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 40, wherein X3and X5are both heteroatoms.

58. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 40, wherein X4and X5are both heteroatoms.

59. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 38-58, wherein one of X1, X2, X3, and X4is a carbon that is substituted by a substituent.

60. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 59, wherein said substituent is bound to X1.

61. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 59, wherein said substituent is bound to X2.

62. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 59, wherein said substituent is bound to X3.

63. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 59, wherein said substituent is bound to X4.

64. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 40 or 42- 45, wherein X5is a carbon that is substituted by a substituent.

65. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 41-45, wherein the X5adjacent to X4is a carbon that is substituted by a substituent.

66. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 41-45, wherein the X5adjacent to the carbon atom bound to A is a carbon that is substituted by a substituent.

67. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 38-58, wherein two of X1, X2, X3, and X4are each a carbon that is substituted by a substituent.

68. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 67, wherein one substituent is bound to X1 and one substituent is bound to X2.

69. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 67, wherein one substituent is bound to X1and one substituent is bound to X3.

70. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 67, wherein one substituent is bound to X1and one substituent is bound to X4.

71. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 67, wherein one substituent is bound to X2and one substituent is bound to X3.

72. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 67, wherein one substituent is bound to X2and one substituent is bound to X4.

73. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 40 or 42- 45, wherein X5and one of X1, X2, X3, and X4are each a carbon 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 41-45,wherein the X5adjacent to X4and one of X1, X2, X3, and X4are each a carbon that is substituted by a substituent.

75. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 41-45, wherein the X5and one of X1, X2, X3, and X4are each a carbon atom substituted by a substituent.

76. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 73-75, wherein X1is substituted by a substituent.

77. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 73-75, wherein X2is substituted by a substituent.

78. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 73-75, wherein X3is substituted by a substituent.

79. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 73-75, wherein X4is substituted by a substituent.

80. The compound pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 41, wherein both X5are 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 1-37, wherein Ar is a 5-membered heteroaromatic or heterocyclic ring selected from the group consisting of:each of which is unsubstituted or substituted by one or more substituents.

82. 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 6-membered heterocyclic or heteroaromatic ring selected from the group consisting of:each of which is unsubstituted or substituted by one or more substituents.

83. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-37, wherein Ar has the structurewhereinm and n are each an integer from 0 to 2, inclusive, wherein at least one of m and n is 0 or 1; 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, oxygen, and sulfur, and a carbon, each of which is unsubstituted or substituted by a substituent.

84. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 83, wherein Ar is selected from the group consisting ofeach of which is unsubstituted or substituted by one or more substituents.

85. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-37, 83, or 84 wherein Ar is a 9-membered bicyclic heteroaromatic ring which is unsubstituted or substituted by one or more substituents.

86. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of any one of claims 1-37 or 83- 85 wherein Ar is a 9-membered bicyclic heteroaromatic ring having at least 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

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

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

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

90. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 38, wherein Ar is a 5- membered heterocyclic ring selected from the group consisting of:

91. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof of claim 38, wherein Ar is a 6- membered heterocyclic ring selected from the group consisting of:

92. 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.

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

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

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

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

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

98. The pharmaceutically acceptable salt of claim 1, having the structureor deuterated analog thereof.

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

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

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 100, having the structureor pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate or deuterated analog thereof.

103. 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 amount of a compound of any one of claims 1-102 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.

104. 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 1-102 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.

Images