Piperazine azaspiro derivatives

Abstract

To provide compounds, pharmaceutical preparations, and methods for treating M4-mediated disorders including Alzheimer's Disease, Parkinson's Disease, schizophrenia, pain, addiction, and a sleep disorder.SOLUTION: The present invention provides compounds of Formula I, or N-oxides thereof, or salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention generally relates to novel piperazine azaspiro derivatives, salts thereof, and pharmaceutical compositions thereof, which are agonists of the muscarinic M4 receptor and are useful for the treatment of M4-mediated diseases and disorders, such as schizophrenia, Alzheimer's disease, Lewy body dementia, Parkinson's disease and related memory and executive function disorders, agitation, and psychosis associated therewith. [Background technology]

[0002] Patients with schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, and various other neurological / neurodegenerative disorders frequently suffer from behavioral and cognitive impairments that cause debilitating disruption to their daily lives. Over the years, many pharmacological treatments have been discovered that provide some improvement in behavioral and cognitive function. However, the improvement is at best moderate, and in most cases, underlying dose-limiting adverse effects associated with these treatments, including extrapyramidal and metabolic side effects, result in partial responses and non-compliance.

[0003] Aiming to discover novel and improved pharmacological treatments, researchers have turned their attention to muscarinic acetylcholine receptors (mAChRs) as a viable mechanism. There are five identified mAChR subtypes (M1-M5), which are part of the G protein-coupled receptor (GPCR) superfamily. These subtypes are widely distributed throughout the peripheral and central nervous systems (CNS), with M1 and M4 subtypes predominantly expressed in the CNS. [Overview of the project] [Problems that the invention aims to solve]

[0004] Researchers have since focused on identifying subtype-selective M4 muscarinic acetylcholine receptor activators. For example, positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor have been studied. In addition to M4 PAMs, research has also focused on identifying M4 receptor agonists. In fact, the M4 agonist HTL0016878, which is being developed for the treatment of the main symptoms of Alzheimer's disease, has entered a Phase I clinical trial. However, novel or improved activators, including muscarinic M4 receptor agonists, are needed to obtain novel and improved therapies for treating M4-mediated diseases and disorders, such as Parkinson's disease, schizophrenia, Alzheimer's disease, and other M4-mediated diseases and disorders described herein. [Means for solving the problem]

[0005] Summary of the Invention The present invention is partly related to compounds of formula I:

[0006] [ka]

[0007] (In the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These are halogen, cyano, hydroxy, -SF5, nitro, -N(R) 6 )(R 7 ), (C1~C6) alkyl, (C2~C6) alkenyl, (C2~C6) alkynyl, (C1~C6) alkylthio, (C1~C6) alkoxy, (C3~C6) cycloalkyl, -O-(4~6 member) heterocycloalkyl, (C6~C 10)Selected from the group consisting of aryl, (5- to 10-membered) heteroaryl, and (4- to 8-membered) heterocycloalkyl, said (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkylthio, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4- to 6-membered) heterocycloalkyl, (C6-C 10 )aryl, (5- to 10-membered) heteroaryl, and (4- to 8-membered) heterocycloalkyl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, -N(R 6 )(R 7 ), (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5- to 6-membered) heteroaryl, and said (C1-C6) alkyl, (C1-C6) alkoxy, and (5- to 6-membered) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy, R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, -SF5, nitro, -N(R 6 )(R 7 ), (C1-C6) alkyl, and (C1-C6) alkoxy, and said (C1-C6) alkyl and (C1-C6) alkoxy are optionally substituted with 1 to 3 halogens, R 6 and R 7 are each independently selected from hydrogen, (C1-C6) alkyl, or C(O)CH3, m is 1 or 2, n is 1 or 2), or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide is provided.

[0008] The compounds of formula I, I A 、I B 、I C and I' are useful for treating M4-mediated (or M4-related) diseases or disorders in a patient, and this method comprises administering to the patient a therapeutically effective amount of formula I, IA , I B , I C The procedure includes administering a compound of I', its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide.

[0009] The present invention also relates to the use of the compounds described herein, or their N-oxides, or pharmaceutically acceptable salts of the compounds or N-oxides, for the treatment of M4-mediated (or M4-related) diseases or disorders, including Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment (e.g., mild cognitive impairment), Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, and other related conditions. These include skinny syndrome, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes mellitus, autism, and atherosclerosis.

[0010] The present invention also relates to the therapeutically effective amount of formulas I, I A , I B , I C The subject matter includes pharmaceutical formulations containing the compound of I', its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, and a pharmaceutically acceptable excipient.

[0011] Please understand that both the general explanation above and the detailed explanation below are illustrative and merely descriptive, and do not limit the claimed invention. [Modes for carrying out the invention]

[0012] Detailed description of the invention The titles within this document are used solely to facilitate the reader's review. These titles should be interpreted as not limiting the scope of the invention or the claims in any way.

[0013] Definitions and Examples The present invention can be more readily understood by referring to the following detailed description of exemplary embodiments of the invention and the examples contained herein.

[0014] It should be understood that the present invention is not limited to any particular synthesis method, which may vary. It should also be understood that the terms used herein are merely for the purpose of describing specific embodiments and are not intended to limit them. In this specification and the subsequent claims, several terms are used to be defined as having the following meanings: As used herein, “a” or “an” may mean one or more. As used in the claims (plural) herein, when used in conjunction with the word “containing,” the word “a” or “an” may mean one or more. As used herein, “another” may mean at least the second or subsequent.

[0015] The term "approximately" refers to a relative term meaning an approximation of the nominal value it refers to, plus or minus 10%, plus or minus 5% in one embodiment, and plus or minus 2% in another embodiment. Unless specifically stated that the value must be within a narrower range, this level of approximation is appropriate for the art of this disclosure.

[0016] As used herein, the term "muscarinic M4 receptor agonist" means that the compounds of the present invention induce the action of the M4 receptor in the absence of a natural ligand (e.g., acetylcholine).

[0017] As used herein, the term “n-membered” (where n is an integer) usually refers to the number of ring-forming atoms in a moiety that has n ring-forming atoms. For example, pyridine is 6-membered. This is an example of a heteroaryl ring, and thiophene is an example of a five-membered heteroaryl ring.

[0018] In various parts of the specification of the present invention, substituents of the compounds of the present invention are disclosed in groups or ranges. The present invention is specifically intended to include all individual subcombinations of members of such groups and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to include C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups. In another example, the term "5- to 10-membered heteroaryl group" is specifically intended to include any 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heteroaryl group.

[0019] The term "(C1-C6)alkyl" as used herein refers to saturated, branched, or linear alkyl groups containing 1 to 6 carbon atoms, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The (C1-C6)alkyl may optionally be substituted, in which case one or more hydrogen atoms may be halogen, cyano, hydroxy, -SF5, nitro, -(C1-C6)alkoxy, and -N(R) 6 )(R 7 )(wherein, R 6 and R 7Each of these is independently replaced by a substituent selected from the group consisting of hydrogen and (C1-C6) alkyl groups. For example, the (C1-C6) alkyl group can be replaced with one or more halogen atoms to form a "halo(C1-C6)alkyl" group. Representative examples of halo(C1-C6)alkyl groups, but not limited to these, include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, and pentafluoroethyl. Other representative examples of substituted (C1-C6) alkyl groups, but not limited to these, include cyanobutyl and ethoxyethyl.

[0020] The term "(C2~C6) alkenyl" refers to an aliphatic hydrocarbon having 2 to 6 carbon atoms and at least one carbon-carbon double bond, and this includes at least one It contains linear or branched groups with carbon-carbon double bonds. Typical examples include these. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl(allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. When the compounds of the present invention contain a (C2-C6) alkenyl group, the compounds may exist in pure E (entgegen) form, pure Z (tuzamen) form, or any mixture thereof. The (C2-C6) alkenyl may optionally be substituted, in which case one or more hydrogen atoms may be halogen, cyano, hydroxy, -SF5, nitro, -(C1-C6) alkoxy, and -N(R) 6 )(R 7 )(wherein, R 6 and R 7 Each of these is independently replaced by a substituent selected from the group consisting of hydrogen and (selected from C1-C6) alkyl groups.

[0021] The term "(C2-C6)alkynyl" refers to aliphatic hydrocarbons having 2 to 6 carbon atoms and at least one carbon-carbon triple bond, including straight and branched chains with at least one carbon-carbon triple bond. Representative examples, but not limited to, include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. (C2-C6)alkynyls may be substituted in some cases, in which case one or more hydrogen atoms are replaced with halogens, cyano, hydroxy, -SF5, nitro, -(C1-C6)alkoxy, and -N(R) 6 )(R 7 ), (where R 6 and R 7 Each of these is independently replaced by a substituent selected from the group consisting of hydrogen and (selected from C1-C6) alkyl groups.

[0022] The term "(C1-C6) alkoxy," as used herein, refers to an (C1-C6) alkyl group (as defined above) bonded to the parent molecule via an oxygen atom. Typical examples of (C1-C6)alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. (C1-C6)alkoxys may be substituted in some cases, in which case one or more hydrogen atoms are replaced with halogen, cyano, hydroxy, -SF5, nitro, -(C1-C6)alkoxy, and -N(R 6 )(R 7 )(wherein, R 6 and R 7 Each of these atoms is independently replaced by a substituent selected from the group consisting of hydrogen and (C1-C6) alkyl groups. For example, a (C1-C6) alkoxy can be substituted with one or more halogen atoms to form a "halo(C1-C6) alkoxy". Typical examples of halo(C1-C6) alkoxys, but not limited to these, include fluoromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

[0023] The term "(C1-C6) alkylthio," as used herein, refers to a (C1-C6) alkyl group (as defined above) bonded to the parent molecule via a sulfur atom. Typical examples of (C1-C6) alkylthios include, but are not limited to, methylthio, ethylthio, and propylthio. (C1-C6) alkylthios may optionally be substituted, in which case one or more hydrogen atoms may be halogen, cyano, hydroxy, -SF5, nitro, -(C1-C6) alkoxy, and -N(R) 6 )(R 7 )(wherein, R 6 and R 7 Each of these is independently replaced by a substituent selected from the group consisting of hydrogen and (selected from C1-C6) alkyl groups.

[0024] As used herein, the term "(C3-C6)cycloalkyl" refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule having 3 to 6 carbon atoms. "Cycloalkyl" may be a monocyclic ring, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. (C3-C6)cycloalkyl may optionally be substituted, in which case one or more hydrogen atoms may be halogen, cyano, hydroxy, -SF5, nitro, -(C1-C6)alkoxy, and -N(R) 6 )(R 7 )(wherein, R 6 and R 7 Each of these is independently replaced by a substituent selected from the group consisting of hydrogen and (selected from C1-C6) alkyl groups.

[0025] As used herein, “heterocycloalkyl” refers to a cycloalkyl (as defined above) in which at least one of the ring carbon atoms is replaced by a heteroatom selected from nitrogen, oxygen, or sulfur. The term “(4-6 member) heterocycloalkyl” means that the heterocycloalkyl substituent contains a total of 4 to 6 ring atoms, of which at least one is a heteroatom. The term “(4-8 member) heterocycloalkyl” means that the heterocycloalkyl substituent contains a total of 4 to 8 ring atoms, of which at least one is a heteroatom. “(6 member) heterocycloalkyl” means that the heterocycloalkyl substituent contains a total of 6 ring atoms, of which at least one is a heteroatom. “(5 member) heterocycloalkyl” means that the heterocycloalkyl substituent contains a total of 5 ring atoms, of which at least one is a heteroatom. The heterocycloalkyl substituent may be bonded via a nitrogen atom with a suitable valency or via any ring carbon atom. The heterocycloalkyl moiety may optionally be substituted with one or more substituents at a nitrogen atom having an appropriate valency, or at any available carbon atom.

[0026] Examples of heterocycloalkyl rings, though not limited to these, include azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydro-triazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, and piperaz. Examples of heterocycloalkyl rings include nyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiadinyl, tetrahydrothiadiazinyl, tetrahydro-oxazolyl, morpholinyl, oxetanyl, tetrahydrodiadinyl, oxazinyl, and oxathiadinyl. Further examples of heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidine-1-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, piperazine-1-yl, piperazine-2-yl, 1 Examples include 3-oxazolidine-3-yl, isothiazolidinyl, 1,3-thiazolidinyl, 1,2-pyrazolidinyl, 1,2-tetrahydrothiadin-2-yl, 1,3-thiadinan-3-yl, 1,2-tetrahydrodiazine-2-yl, 1,3-tetrahydrodiazine-1-yl, 1,4-oxazine-4-yl, 2-oxo-piperidine (e.g., 2-oxo-piperidine-1-yl). Heterocycloalkyls may be substituted in some cases, in which case one or more hydrogen atoms may be halogenated, cyano, hydroxyl, -SF5, nitro, -(C1~C6)alkoxy, and -N(R 6 )(R 7 )(wherein, R 6 and R 7 Each of these is independently replaced by a substituent selected from the group consisting of hydrogen and (selected from C1-C6) alkyl groups.

[0027] (C6~C 10 "Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0028] As used herein, the term “heteroaryl” refers to an aromatic carbocyclic system having one, two, or three rings containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur, and such rings may be fused (condensed as defined above). A “(5-10 member) heteroaryl” ring refers to a heteroaryl ring having 5 to 10 ring atoms, at least one of which is nitrogen, and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, sulfur, and nitrogen. A “(5-6 member) heteroaryl” ring refers to a heteroaryl ring having 5 to 6 ring atoms, at least one of which is nitrogen, and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, sulfur, and nitrogen. Examples of heteroaryls, but not limited to, include pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl.

[0029] It should be understood that heteroaryls may be cycloalkyl groups as defined herein, or optionally condensed with heterocycloalkyl groups. The heteroaryl substituent may be bonded via a nitrogen atom with an appropriate valence or via any carbon atom. The heteroaryl moiety may optionally be substituted with one or more substituents on the nitrogen atom with an appropriate valence or on any available carbon atom. The (5-10 member) heteroaryl may optionally be substituted, in which case one or more hydrogen atoms may be halogen, cyano, hydroxy, -SF5, nitro, -(C1-C6)alkoxy, and -N(R 6 )(R 7 )(wherein, R 6 and R 7Each of these is independently replaced by a substituent selected from the group consisting of hydrogen and (C1-C6) alkyl groups. The substituent can be bonded to the heteroaryl moiety at any available carbon atom, or to the heteroatom if the heteroatom is nitrogen with an appropriate valence.

[0030] When used herein, "halo" or "halogen" refers to chlorine, fluorine, bromine, and "Ta" refers to an iodine atom. "Hydroxy" or "hydroxyl" as used herein means the -OH group.

[0031] Where used herein, "cyano" means the -CN group, which also means:

[0032] [ka]

[0033] This can be illustrated as shown. As used herein, "nitro" refers to the -NO2 group. Where used herein, "optionally substituted" means that the substitution is optional and therefore includes both unsubstituted and substituted atoms and parts. "Substituted" atom or part means that any hydrogen on the specified atom or part can be replaced by a selection from the substituents shown (up to all hydrogen atoms on the specified atom or part being replaced by a selection from the substituents shown), provided that the valence does not exceed the standard valence of the specified atom or part, and the substitution results in a stable compound. For example, if a methyl group (i.e., -CH3) is optionally substituted, up to three hydrogen atoms on the carbon atom can be replaced by substituents.

[0034] "Patient" refers to warm-blooded animals such as pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.

[0035] "Pharmacologically acceptable" implies that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or with the mammal being treated by the formulation.

[0036] Where used herein, the term “therapeutic dose” refers to the amount of a compound (including its N-oxide or a pharmaceutically acceptable salt of the compound or N-oxide) administered that reduces, to some extent, one or more of the symptoms of the disorder being treated. In relation to the treatment of M4-mediated disorders (e.g., Alzheimer's disease or schizophrenia), a therapeutic dose refers to the amount that has some effect of reducing (or, for example, eliminating) one or more symptoms associated with the M4-mediated disorder (e.g., positive, negative, or cognitive symptoms of schizophrenia, or psychotic symptoms of Alzheimer's disease).

[0037] The term “to treat” as used herein, unless otherwise noted, means to reverse, mitigate, or inhibit the progression of one or more symptoms of the disorder or condition to which such term applies, or of one or more symptoms of such disorder or condition. The term “to treat” as used herein, unless otherwise noted, means the act of treating, and “to treat” is as defined herein. The term “to treat” also includes adjuvant and neoadjuvant treatments of the subject.

[0038] "Isomers" refers to "stereoisomers" and "geometric isomers" as defined below. A "stereoisomer" refers to a compound that possesses one or more chiral centers. These can exist in either the R or S configuration, respectively. Stereoisomers include all diastereomers, enantiomers, and epimers, as well as racemates and mixtures thereof.

[0039] "Geometric isomers" refer to compounds that may exist in cis, trans, anti, entgegen (E), and tuzamen (Z) forms, as well as mixtures thereof. Where used herein, unless otherwise specified, the bonding points of substituents may be from any suitable position on the substituent. For example, pyridinyl (or pyridyl) may be 2-pyridinyl (or pyridine-2-yl), 3-pyridinyl (or pyridine-3-yl), or 4-pyridinyl (or pyridine-4-yl).

[0040] If a substituted or optionally substituted moiety is described and it is not indicated which atom the moiety is bonded to the substituent, the substituent may be bonded to any suitable atom in the moiety. For example, in an optionally substituted (5-10 membered) heteroaryl, the substituent of the heteroaryl can be bonded to any carbon atom of the heteroaryl moiety or to any heteroatom of the heteroaryl, provided the valence allows it. A combination of substituents and / or variables is acceptable only if such a combination results in a stable compound.

[0041] In this specification, the terms “substituent,” “radical,” and “group” are used interchangeably. When it is stated that substituents are "independently selected" from the group, each instance of a substituent is selected independently of the others. Therefore, each substituent may be identical to or different from other substituents.

[0042] When used herein, "Formula I", "Formula I'", and "Formula I" are used. A "Formula I" B ", and "Formula I CThe term “compound of the present invention” may hereafter be referred to as “compound(s) of the present invention.” Such terminology is also defined to include all forms of the compound of the present invention, including but not limited to hydrates, solvates, isomers (e.g., rotational stereoisomers), crystalline and amorphous forms, isomorphs, polymorphs, metabolites, and prodrugs. For example, a compound of the present invention, or a pharmaceutically acceptable salt thereof, may exist in both non-solvated and solvated forms with a pharmaceutically acceptable solvent, such as water or ethanol. When the solvent or water is tightly bound, the complex will have a clear stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, such as with channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and dry conditions. In such cases, non-stoichiometry is the standard. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the present invention.

[0043] The compounds of the present invention may exist as clathrates or other complexes (e.g., cocrystals). Complexes in which a drug and a host exist in stoichiometric or non-stoichiometric amounts, such as clathrates and drug-host inclusion complexes, are included within the scope of the present invention. Complexes of the compounds of the present invention containing two or more organic and / or inorganic components are also included, which may be stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or unionized. For an overview of such complexes, see Haleblian, J. Pharm. Sci., Vol. 64 (No. 8), pp. 1269-1288 (August 1975). Cocrystals are defined as crystalline complexes of neutral molecular components, usually bonded together via non-covalent interactions, but may also be complexes with salts of neutral molecules. Cocrystals can be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. O. Almarsson and MJ Zaworotko, C. See hem.Commun., 2004, Vol. 17, pp. 1889–1896. For a general overview of multicomponent complexes, see J.K. Haleblian, J.Pharm.Sci., 1975, Vol. 64, pp. 1269–1288.

[0044] The compounds of the present invention have an asymmetric carbon atom and can therefore exist as geometric isomers that can exist in two or more stereoisomeric forms. The present invention includes all individual stereoisomers and geometric isomers of the compounds of the present invention and mixtures thereof. Individual enantiomers can be obtained by chiral separation or by using the relevant enantiomer in synthesis. The carbon-carbon bond of the compounds of the present invention is solid line

[0045] [ka]

[0046] Solid line wedge shape

[0047] [ka]

[0048] Or a dotted wedge shape

[0049] [ka]

[0050] These can be illustrated herein using the following symbols. The use of solid lines to represent bonds to a chiral carbon atom is intended to indicate that all possible stereoisomers at the carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are present. The use of either solid or dotted wedge shapes to represent bonds to a chiral carbon atom is intended to indicate the presence of the indicated stereoisomers. Where present in racemic compounds, solid and dotted wedge shapes are used to define relative configurations rather than absolute configurations. Racemic compounds possessing such indicated relative configurations may also be denoted with (+ / -) symbols. For example, unless otherwise stated, the compounds of the present invention are intended to exist as stereoisomers including cis and trans isomers, optical isomers, e.g., R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, atrop isomers, and mixtures thereof (e.g., racemic and diastereomer pairs). The compounds of the present invention may exhibit more than one type of isomerism. This also includes acid or base addition salts whose counterions are optically active, such as D-lactic acid or L-lysine, or racemic compounds, such as DL-tartrate or DL-arginine.

[0051] In some embodiments, the compounds of the present invention may exist as atropisomers (e.g., one or more atropenantiomers) and / or be isolated as atropisomers. Those skilled in the art will recognize that atropisomers can exist in compounds having two or more aromatic rings (e.g., two aromatic rings linked by a single bond). See, for example, Freedman, TB et al., Absolute Configuration Determination of Chiral Molecules in the Solution State Using Vibrational Circular Dichroism., Chirality, 2003, vol. 15, 743~ See page 758 and Bringmann, G. et al., Atroposelective Synthesis of Axially Chiral Biaryl Compounds, Angew. Chem., International Edition, 2005, Vol. 44, pp. 5384-5427.

[0052] When any racemic mixture crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemic mixture) mentioned above, which produces one homogeneous form of crystal containing both enantiomers in equimolar amounts. The second type is a racemic mixture or aggregate, which produces two forms of crystals in equimolar amounts, each containing a single enantiomer.

[0053] The compounds of the present invention may also exist as their N-oxides, or as pharmaceutically acceptable salts of the compounds or N-oxides. As is well known to those skilled in the art, amine compounds (i.e., compounds containing one or more nitrogen atoms), such as tertiary amines, can form N-oxides (also known as amine oxides or amine N-oxides). N-oxides are given by formula (R 100 R 200 R 300 )N + -O - It has this parentine amine (R 100 R 200 R 300 )N is, for example, a tertiary amine (for example, R 100 , R 200 , R 300 Each of them is independently alkyl, arylalkyl, aryl, heteroaryl, etc.), heterocyclic or heteroaromatic amines [e.g., (R 100 R 200 R 300 )N can be combined to form 1-alkylpiperidine, 1-alkylpyrrolidine, 1-benzylpyrrolidine, or pyridine. For example, imine nitrogen, especially heterocyclic or heteroaromatic imine nitrogen, or a pyridine-type nitrogen atom [e.g., a nitrogen atom in pyridine, pyridazine, or pyrazine].

[0054] [ka]

[0055] It undergoes N oxidation, and the base

[0056] [ka]

[0057] It is possible to form an N-oxide containing the nitrogen atoms. Thus, a compound according to the present invention containing one or more nitrogen atoms (e.g., an imine nitrogen atom) may be able to form its N-oxide (e.g., a mono-N-oxide, a bis-N-oxide, or a multi-N-oxide, or a mixture thereof, depending on the number of nitrogen atoms suitable for forming a stable N-oxide).

[0058] As used herein, the term “N-oxide” means all possible, and in particular all stable, N-oxide forms of amine compounds described herein (e.g., compounds containing one or more imine nitrogen atoms), e.g., mono-N-oxides (including different isomers if more than one nitrogen atom in the amine compound can form a mono-N-oxide) or multi-N-oxides (e.g., bis-N-oxides), or mixtures thereof in any ratio.

[0059] As described above, the compound of the present invention (or its N-oxide) is an inorganic acid or an organic acid. They may exist in the form of pharmaceutically acceptable salts derived from them. Depending on the particular compound, a salt of a compound may be advantageous in one or more of the physical properties of the salt, such as enhanced pharmaceutical stability at different temperatures and humidity levels, or desirable solubility in water or oil. In some cases, a salt of a compound can also be used as an aid in the isolation, purification, and / or separation of the compound.

[0060] When a salt is intended to be administered to a patient (as opposed to, for example, used in an in vitro setting), it is preferable that the salt be pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining the compound of the present invention with an acid whose anion is generally considered suitable for human consumption, or with a base whose cation is generally considered suitable for human consumption. Because pharmaceutically acceptable salts have higher aqueous solubility than the parent compound, they are particularly useful as products of the method of the present invention.

[0061] Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention include, if possible, inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid, and sulfuric acid, as well as organic acids, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid, and those derived from trifluoroacetic acid. Suitable organic acids generally include, but are not limited to, organic acids of the aliphatic, cyclic aliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxyl, and sulfonic acid classes.

[0062] Appropriate organic acids include, but are not limited to, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, and 2-hydroxybenzoate. Examples include ethanesulfonates, sulfanilates, cyclohexylaminosulfonates, alginates, β-hydroxybutyrates, galactarates, galacturonates, adipines, alginates, butyrates, camphorates, camphorsulfonates, cyclopentanepropionates, dodecyl sulfates, glucoheptonates, glycerophosphates, heptanoates, hexanoates, nicotinates, 2-naphthalene sulfonates, oxalates, pamoates, pectins, 3-phenylpropionates, picrinates, pivalates, thiocyansates, and undecanoates.

[0063] Furthermore, if the compound of the present invention retains an acidic portion, suitable pharmaceutically acceptable salts therefor may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, the base salt is formed from a base to form a non-toxic salt, which includes salts of aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine, and zinc.

[0064] Organic salts include secondary, tertiary, or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, and diethanol. It can be prepared from luanmine, ethylenediamine, meglumine (N-methylglucamine), and procaine. The basic nitrogen-containing group can be quaternized with agents such as lower alkyl (C1-C6) halides (e.g., methyl chloride, ethyl chloride, propyl chloride, and butyl chloride, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, as well as methyl iodide, ethyl iodide, propyl iodide, and butyl iodide), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long-chain halides (e.g., decyl chloride, lauryl chloride, myristyl chloride, and stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide, and stearyl bromide, and decyl iodide, lauryl iodide, myristyl iodide, and stearyl iodide), arylalkyl halides (e.g., benzyl bromide and phenethyl bromide), and others.

[0065] In one embodiment, hemi-salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed. For a general overview of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0066] The compounds of the present invention can exist as a solid continuum ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on the temperature. Typically, such materials do not impart a special X-ray diffraction pattern and exhibit solid properties, but are more formally described as liquids. Heating causes a change from a clearly solid material to a material with liquid properties, which is usually characterized by a second-order transition ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and yields a special X-ray diffraction pattern with defined peaks. Such materials also exhibit liquid properties when sufficiently heated, but the change from solid to liquid is characterized by a phase change, usually a first-order transition ("melting point").

[0067] The compounds of the present invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to appropriate conditions. A mesomorphic state is an intermediate between a true crystalline state and a true liquid state (either molten or in solution). Mesomorphism resulting from a temperature change is described as "thermotropic," and morphism produced by the addition of a second component, such as water or another solvent, is described as "lyotropic." Compounds that have the potential to form a lyotropic mesophase are described as "amphiphilic" and ionic (e.g., -COO - Na + , -COO - K + , or -SO3 - Na + ) or nonionic (e.g., -N - N + It consists of molecules possessing the polar head group (CH3)3). For further information, see Crystals and the Polarizing Microscope, 4th edition, by H.N. Hartshorne and A. Stuart (Edward Arnold, 1970).

[0068] The present invention also relates to prodrugs of the compounds of the present invention. Thus, certain derivatives of the compounds of the present invention, which may themselves have little pharmacological activity or may have no pharmacological activity, can be converted, when administered in the body or on the body, for example by hydrolytic cleavage, into the compounds of formula I having the desired activity. Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Perg amon Press, 1987 (edited by E.B. Roche, American Pharmaceutical Association).

[0069] Prodrugs according to the present invention can be produced, for example, by replacing suitable functional groups present in the compounds of the present invention with certain parts known to those skilled in the art as "pro parts", for example, this is described in Design of Prodrugs by H. Bundgaard (Elsevier, 1985), or Prodrugs: Challenges and Reward, 2007 edition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134-175 (Springer, 2007).

[0070] Furthermore, some compounds of the present invention can themselves act as prodrugs of other compounds of the present invention. The present invention also encompasses compounds of the invention containing protecting groups. Those skilled in the art will also recognize that the compounds of the invention can be prepared using certain protecting groups that are useful for purification or storage and can be removed prior to administration to a patient. Protection and deprotection of functional groups are described in “Protective Groups in Organic Chemistry”, edited by J.W.F. McOmie, Plenum Press (1973) and “Protective Groups in Organic Synthesis”, 3rd Edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

[0071] Metabolites of the compounds of the invention, i.e., compounds formed in vivo upon administration of the drug, are also included within the scope of the present invention. The present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to those recited herein, wherein one or more atoms in these isotopically labeled compounds are replaced with atoms having the same atomic number but a different atomic weight or mass number than the preponderant atomic weight or mass number found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H, 3 H; isotopes of carbon, such as 11 C, 13 C, and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O, 17 O, and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35S is one example. Certain isotope-labeled compounds of the present invention, such as those incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution experiments (e.g., assays). Radioactive isotope tritium, i.e., 3 H, and carbon 14, that is, 14 C is particularly useful for this purpose considering the ease of integration and rapid detection means. Heavier isotopes, such as deuterium, i.e., 2 Substitution with H can result in certain therapeutic benefits arising from greater metabolic stability, such as an increased in vivo half-life or a reduced required dose, and is therefore preferable in some situations. Positron-emitting isotopes, for example, 11 C, 15 F, 18 F, 15 O and 13 Substitution with nitrogen may be useful in positron emission tomography (PET) experiments to test substrate receptor occupancy. The isotope-labeled compounds of the present invention can generally be prepared by prior art known to those skilled in the art, or by using a suitable isotope-labeling reagent instead of a previously used unlabeled reagent, by a process similar to that described in the accompanying schemes and / or examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotope-substituted, e.g., D2O, acetone-d6, or DMSO-d6. The compounds of the present invention, including the compounds exemplified in Examples 1 to 51 described below, are isotope-labeled versions of these compounds, for example, but are not limited to these. This includes deuterated and tritiated isotopes, as well as all other isotopes discussed above.

[0072] In certain embodiments, the present invention relates to novel, selective, radiolabeled M4 agonists useful for imaging and quantifying the distribution of M4 compounds in tissues (e.g., the brain) using positron emission tomography (PET).

[0073] compound The compound of formula I described above contains a piperazine-1-yl-2-azaspirocarboxylate core, and piperazine is R 1 and R 2 The azaspiro moiety is bonded to a 6-membered heteroaryl (pyridine or pyrazine) that is substituted with , and the azaspiro moiety is selected from 2-azaspiro[3.4]octane, 6-azaspiro[3.4]octane, or 2-azaspiro[3.3]heptane.

[0074] In one embodiment, in formula I described above, X 1 is nitrogen, X 2 It is CH. In another embodiment, X 1 It is nitrogen, and X 2 It is nitrogen. In yet another embodiment, X 1 CH is X 2 It is nitrogen.

[0075] X 1 and X 2 Any of the above-described subgenus (embodiments) of the R described above and below in this specification 1 ,R 2 It should be understood that it can be combined with either the subgenus m or n.

[0076] In another embodiment, in formula I described above, R 1The (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are selected from the group consisting of halogens, cyanos, (C1-C6) alkyls, (C1-C6) alkoxys, and (C3-C6) cycloalkyl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, (C1-C6) alkoxys, (C3-C6) cycloalkyl groups, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, and (C1-C6) alkoxys.

[0077] In a particular embodiment, R 1 R is a (C1-C6) alkoxy. 1 If the alkoxy is a (C1-C6) alkoxy, the alkoxy includes, but is not limited to, methoxy, trifluoroethoxy, difluoromethoxy, and trifluoromethoxy.

[0078] In a particular embodiment, R 1 It is a (C3-C6) cycloalkyl group. 1 If the cycloalkyl group is a (C3-C6) cycloalkyl group, the cycloalkyl group is not limited to these groups but includes cyclopropyl.

[0079] In another embodiment, in formula I described above, R 1The (5-10 member) heteroaryl is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, and the (5-10 member) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -(CH2)2-O-CH2CH3, and (5-6 member) heteroaryl, and the (C1-C6) alkyl, (C1-C6) alkoxy, and the (5-6 member) heteroaryl is halogen, cyano, hydroxy, (C1-C6) alkyl, and It may be substituted with 1 to 3 substituents selected from the group consisting of (C1-C6) alkoxys.

[0080] In another embodiment, in formula I described above, R 1 It is a (5-6 member) heteroaryl. R 1 If is a substituted (5-10 member) heteroaryl or substituted (5-6 member) heteroaryl, the substituent(s) are (C1-C6) alkyl or (C1-C6) alkoxy, the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy.

[0081] In another embodiment, in formula I described above, R 1The (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of oxetanyl, morpholino, 2-oxa-6-azaspiro[3.3]hepta-6-yl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperidinyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-C6) heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)alkoxy, and (5-C6) heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy.

[0082] R 1 If is a substituted (4-8 member) heterocycloalkyl, the substituent(s) are (C1-C6) alkyl, (C1-C6) alkoxy, or (5-6 member) heteroaryl, wherein the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy, and the (5-6 member) heteroaryl substituent is pyrazolyl, which is optionally substituted with a methyl substituent.

[0083] R 1 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , R 2 It should be understood that it can be combined with either the subgenus m or n.

[0084] In another embodiment, in formula I described above, R 2 It is hydrogen. In another embodiment, R 2 It is fluoro. R2 Any of the above-described subgenera (embodiments) is X as described above and hereinafter in this specification 1 , X 2 , R 1 , and it should be understood that it can be combined with any of the subgenera for m and n.

[0085] In another embodiment, in Formula I described above, m is 2 and n is 1. In another embodiment, m is 1 and n is 2. In another embodiment, m is 1 and n is 1.

[0086] Any of the above-described subgenera (embodiments) of m and n is X as described above and hereinafter in this specification 1 , X 2 , R 1 , and R 2 , and it should be understood that it can be combined with any of the subgenera for.

[0087] In certain other embodiments, the present invention provides a compound of Formula I A :

[0088]

Chemical Formula

[0089] (wherein, X 1 and X 2 are each independently CH or nitrogen, provided that both X 1 and X 2 cannot both be CH, R 1 is halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, -O-(4-6 member)heterocycloalkyl, (C6-C 10Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10 The )aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy groups, R 2 This is selected from the group consisting of hydrogen, halogens, (C1-C6) alkyls, and (C1-C6) alkoxys, wherein the (C1-C6) alkyls and (C1-C6) alkoxys are optionally substituted with 1 to 3 halogens) or their N-oxides, or pharmaceutically acceptable salts of the compound or N-oxide.

[0090] In one embodiment, the formula I described above A In X 1 It is nitrogen, and X 2 It is CH. In another embodiment, X 1 It is nitrogen, and X 2 It is nitrogen.

[0091] In yet another embodiment, X 1 CH is X 2 It is nitrogen. X 1 and X 2 Any of the above-described subgenus (embodiments) of the R described above and below in this specification 1 ,R 2It should be understood that it can be combined with either the subgenus m or n.

[0092] In another embodiment, formula I described above A In R 1 The (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are selected from the group consisting of halogens, cyanos, (C1-C6) alkyls, (C1-C6) alkoxys, and (C3-C6) cycloalkyl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, (C1-C6) alkoxys, (C3-C6) cycloalkyl groups, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, and (C1-C6) alkoxys.

[0093] In a particular embodiment, R 1 R is a (C1-C6) alkoxy. 1 If the alkoxy is a (C1-C6) alkoxy, the alkoxy includes, but is not limited to, methoxy, trifluoroethoxy, difluoromethoxy, and trifluoromethoxy.

[0094] In a particular embodiment, R 1 It is a (C3-C6) cycloalkyl group. 1 If the cycloalkyl group is a (C3-C6) cycloalkyl group, the cycloalkyl group is not limited to these groups but includes cyclopropyl.

[0095] In another embodiment, formula I described above A In R 1This is a (5-10 member) heteroaryl selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, wherein the (5-10 member) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -(CH2)2-O-CH2CH3, and (5-6 member) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and the (5-6 member) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0096] In another embodiment, formula I described above A In R 1 (5-6 member) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 member) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and the (5-6 member) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0097] R 1 If is a substituted (5-10 member) heteroaryl or substituted (5-6 member) heteroaryl, the substituent(s) are (C1-C6) alkyl or (C1-C6) alkoxy, the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy.

[0098] In another embodiment, formula I described above A In R 1 This group consists of oxetanil, morpholino, 2-oxa-6-azaspiro[3.3]hepta-6-yl, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, and piperidinil. A selected (4-8 member) heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 member) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 member) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy.

[0099] R 1 If is a substituted (4-8 member) heterocycloalkyl, the substituent(s) are (C1-C6) alkyl, (C1-C6) alkoxy, or (5-6 member) heteroaryl, wherein the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy, and the (5-6 member) heteroaryl substituent is pyrazolyl, which is optionally substituted with a methyl substituent.

[0100] R 1 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , and R 2 It should be understood that it can be combined with any of the subgenera.

[0101] In another embodiment, formula I described above A In R2 It is hydrogen. In another embodiment, R 2 It is fluoro. R 2 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , and R 1 It should be understood that it can be combined with any of the subgenera.

[0102] In certain other embodiments, the present invention relates to formula I B Compounds of:

[0103] [ka]

[0104] (In the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These include halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10 Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10The )aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy groups, R 2 This is selected from the group consisting of hydrogen, halogens, (C1-C6) alkyls, and (C1-C6) alkoxys, wherein the (C1-C6) alkyls and (C1-C6) alkoxys are optionally substituted with 1 to 3 halogens) or their N-oxides, or pharmaceutically acceptable salts of the compound or N-oxide.

[0105] In one embodiment, the formula I described above B In X 1 It is nitrogen, and X 2 It is CH. In another embodiment, X 1 It is nitrogen, and X 2 It is nitrogen.

[0106] In yet another embodiment, X 1 CH is X 2 It is nitrogen. X 1 and X 2 Any of the above-described subgenus (embodiments) of the R described above and below in this specification 1 ,R 2 It should be understood that it can be combined with either the subgenus m or n.

[0107] In another embodiment, formula I described above B In R 1The (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are selected from the group consisting of halogens, cyanos, (C1-C6) alkyls, (C1-C6) alkoxys, and (C3-C6) cycloalkyl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, (C1-C6) alkoxys, (C3-C6) cycloalkyl groups, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, and (C1-C6) alkoxys.

[0108] In a particular embodiment, R 1 R is a (C1-C6) alkoxy. 1 If the alkoxy is a (C1-C6) alkoxy, the alkoxy includes, but is not limited to, methoxy, trifluoroethoxy, difluoromethoxy, and trifluoromethoxy.

[0109] In a particular embodiment, R 1 It is a (C3-C6) cycloalkyl group. 1 If the cycloalkyl group is a (C3-C6) cycloalkyl group, the cycloalkyl group is not limited to these groups but includes cyclopropyl.

[0110] In another embodiment, formula I described above B In R 1This is a (5-10 member) heteroaryl selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, wherein the (5-10 member) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 member) heteroaryl, wherein the (C1-C6) alkyl The (C1-C6) alkoxy and the (5-6 membered) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0111] In another embodiment, formula I described above B In R 1 This is a (5-6 member) heteroaryl which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 member) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and the (5-6 member) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0112] R 1 If is a substituted (5-10 member) heteroaryl or substituted (5-6 member) heteroaryl, the substituent(s) are (C1-C6) alkyl or (C1-C6) alkoxy, and the alkyl substituent(s) are not limited to these but include methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy Substituents include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy.

[0113] In another embodiment, formula I described above B In R 1 The (C1-C6) alkyl and the (C1-C6) heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy, and (C1-C6) alkoxy.

[0114] R 1 If is a substituted (4-8 member) heterocycloalkyl, the substituent(s) are (C1-C6) alkyl, (C1-C6) alkoxy, or (5-6 member) heteroaryl, wherein the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy, and the (5-6 member) heteroaryl substituent is pyrazolyl, which is optionally substituted with a methyl substituent.

[0115] R 1 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , and R 2 It should be understood that it can be combined with any of the subgenera.

[0116] In another embodiment, formula I described above B In R2 It is hydrogen. In another embodiment, R 2 It is fluoro. R 2 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , and R 1 It should be understood that it can be combined with any of the subgenera.

[0117] In certain other embodiments, the present invention relates to formula I C Compounds of:

[0118] [ka]

[0119] (In the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These include halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10 Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10The )aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, -(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 membered) heteroaryl groups, and the (C1-C6)alkyl, (C1-C6)alkoxy, and (5-6 membered) heteroaryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy groups, R 2 This is selected from the group consisting of hydrogen, halogens, (C1-C6) alkyls, and (C1-C6) alkoxys, wherein the (C1-C6) alkyls and (C1-C6) alkoxys are optionally substituted with 1 to 3 halogens) or their N-oxides, or pharmaceutically acceptable salts of the compound or N-oxide.

[0120] In one embodiment, the formula I described above C In X 1 It is nitrogen, and X 2 It is CH. In another embodiment, X 1 It is nitrogen, and X 2 It is nitrogen.

[0121] In yet another embodiment, X 1 CH is X 2 It is nitrogen. X 1 and X 2 Any of the above-described subgenus (embodiments) of the R described above and below in this specification 1 and R 2 It should be understood that it can be combined with any of the subgenera.

[0122] In another embodiment, formula I described above C In R 1The (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl group is selected from the group consisting of halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups. The molecules are optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 membered)heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and (5-6 membered)heteroaryl molecules are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy.

[0123] In a particular embodiment, R 1 R is a (C1-C6) alkoxy. 1 If the alkoxy is a (C1-C6) alkoxy, the alkoxy includes, but is not limited to, methoxy, trifluoroethoxy, difluoromethoxy, and trifluoromethoxy.

[0124] In a particular embodiment, R 1 It is a (C3-C6) cycloalkyl group. 1 If the cycloalkyl group is a (C3-C6) cycloalkyl group, the cycloalkyl group is not limited to these groups but includes cyclopropyl.

[0125] In another embodiment, formula I described above C In R 1This is a (5-10 member) heteroaryl selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, wherein the (5-10 member) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -(CH2)2-O-CH2CH3, and (5-6 member) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and the (5-6 member) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0126] In another embodiment, formula I described above C In R 1 This is a (5-6 member) heteroaryl which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 member) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and the (5-6 member) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0127] R 1 If is a substituted (5-10 member) heteroaryl or substituted (5-6 member) heteroaryl, the substituent(s) are (C1-C6) alkyl or (C1-C6) alkoxy, the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy.

[0128] In another embodiment, formula I described above C In R 1 The (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) heteroaryl are (4-8 membered) heterocycloalkyls selected from the group consisting of oxetanyl, morpholino, 2-oxa-6-azaspiro[3.3]hepta-6-yl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperidinyl, wherein the heterocycloalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl are halogen, cyano They are optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy.

[0129] R 1 If is a substituted (4-8 member) heterocycloalkyl, the substituent(s) are (C1-C6) alkyl, (C1-C6) alkoxy, or (5-6 member) heteroaryl, wherein the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy, and the (5-6 member) heteroaryl substituent is pyrazolyl, which is optionally substituted with a methyl substituent.

[0130] R 1 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , and R 2 It should be understood that it can be combined with any of the subgenera.

[0131] In another embodiment, formula I described above C In R2 It is hydrogen. In another embodiment, R 2 It is fluoro. R 2 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , and R 1 It should be understood that it can be combined with any of the subgenera.

[0132] In certain other embodiments, the present invention relates to formula I ’ Compounds of:

[0133] [ka]

[0134] (In the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These include halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10 Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10 )aryl, (5-10 member) heteroaryl, and (4-8 member) heterocycloalkyl groups include halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy groups. The (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of (C3-C6) cycloalkyl and (C1-C6) heteroaryl, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. R 2 The (C1-C6) alkyl and (C1-C6) alkoxy elements are selected from the group consisting of hydrogen, halogens, (C1-C6) alkyl and (C1-C6) alkoxy elements, and the (C1-C6) alkyl and (C1-C6) alkoxy elements are optionally substituted with 1 to 3 halogens. m is either 1 or 2. n is 1 or 2) or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide.

[0135] In one embodiment, in formula I' described above, X 1 It is nitrogen, and X 2 It is CH. In another embodiment, X 1 It is nitrogen, and X 2 It is nitrogen.

[0136] In yet another embodiment, X 1 CH is X 2 It is nitrogen. X 1 and X 2 Any of the above-described subgenus (embodiments) of the R described above and below in this specification 1 ,R 2 It should be understood that it can be combined with either the subgenus m or n.

[0137] In another embodiment, in formula I' described above, R 1The (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are selected from the group consisting of halogens, cyanos, (C1-C6) alkyls, (C1-C6) alkoxys, and (C3-C6) cycloalkyl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, (C1-C6) alkoxys, (C3-C6) cycloalkyl groups, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6) alkyls, and (C1-C6) alkoxys.

[0138] In a particular embodiment, R 1 R is a (C1-C6) alkoxy. 1 If the alkoxy is a (C1-C6) alkoxy, the alkoxy includes, but is not limited to, methoxy, trifluoroethoxy, difluoromethoxy, and trifluoromethoxy.

[0139] In a particular embodiment, R 1 It is a (C3-C6) cycloalkyl group. 1 If the cycloalkyl group is a (C3-C6) cycloalkyl group, the cycloalkyl group is not limited to these groups but includes cyclopropyl.

[0140] In another embodiment, in formula I' described above, R 1The (5-10 member) heteroaryl is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, and the (5-10 member) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, -(CH2)2-O-CH2CH3, and (5-6 member) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 member) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy It has been replaced.

[0141] In another embodiment, in formula I' described above, R 1 This is a (5-6 member) heteroaryl which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 member) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and the (5-6 member) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0142] R 1 If is a substituted (5-10 member) heteroaryl or substituted (5-6 member) heteroaryl, the substituent is (C1-C6) alkyl or (C1-C6) alkoxy, the alkyl substituent includes, but is not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but is not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy.

[0143] In another embodiment, in formula I' described above, R 1 The (C1-C6) alkyl and the (C1-C6) heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkyl, and (C1-C6) alkoxy.

[0144] R 1 If is a substituted (4-8 member) heterocycloalkyl, the substituent(s) are (C1-C6) alkyl, (C1-C6) alkoxy, or (5-6 member) heteroaryl, wherein the alkyl substituent(s) include, but are not limited to, methyl, ethyl, cyanobutyl, and ethoxyethyl, and the alkoxy substituent(s) include, but are not limited to, methoxy, ethoxy, trifluoroethoxy, difluoroethoxy, and fluoromethoxy, and the (5-6 member) heteroaryl substituent is pyrazolyl, which is optionally substituted with a methyl substituent.

[0145] R 1 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , R 2 It should be understood that it can be combined with either the subgenus m or n.

[0146] In another embodiment, in formula I' described above, R 2 It is hydrogen. In another embodiment, R2 It is fluoro. R 2 Any of the above-described subgenus (embodiments) of X described above and below in this specification 1 , X 2 , R 1 It should be understood that it can be combined with either the subgenus m or n.

[0147] In another embodiment, in formula I' described above, m is 2 and n is 1. In another embodiment, m is 1 and n is 2. In another embodiment, m is 1 and n is 1.

[0148] Both of the above-described subgenres (embodiments) of m and n are X as described above and below in this specification. 1 , X 2 , R 1 , and R 2 It should be understood that it can be combined with any of the subgenera.

[0149] In certain other embodiments, the present invention relates to the use of the compounds of the present invention, or an N-oxide or pharmaceutically acceptable salt of any one of the compounds of the present invention, in the treatment of M4-mediated (or M4-related) diseases or disorders.

[0150] In certain other embodiments, the present invention relates to a method for treating an M4-mediated (or M4-related) disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the present invention, or an N-oxide or pharmaceutically acceptable salt of any one of the compounds of the present invention.

[0151] In certain embodiments, the compounds of the present invention are M4 receptor agonists that, in the absence of a natural ligand (e.g., acetylcholine), have binding affinity to the M4 receptor and induce action on the M4 receptor.

[0152] In certain other embodiments, the present invention relates to M4-mediated (or M4-related) diseases or disorders, including Alzheimer's disease, schizophrenia, pain, addiction, sleep disorders, cognitive impairment (e.g., mild cognitive impairment, age-related mild cognitive impairment, and amnesic mild cognitive impairment), Parkinson's disease, Parkinson's disease levodopa-induced dyskinesia (PD-LID), Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, and urinary tract disorders. The above-mentioned uses are for diseases or disorders selected from the group consisting of incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes mellitus, autism, and atherosclerosis.

[0153] In certain embodiments, an M4-mediated (or M4-related) disorder or condition is a disorder or condition selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, pain, addiction, and sleep disorders.

[0154] The present invention also provides compositions (e.g., pharmaceutical compositions) comprising novel compounds of the present invention. Accordingly, in one embodiment, the present invention provides a pharmaceutical composition comprising (a therapeutically effective amount) a novel compound of the present invention and optionally a pharmaceutically acceptable carrier. In one further embodiment, the present invention provides a pharmaceutical composition comprising (a therapeutically effective amount) a compound of the present invention and a pharmaceutically acceptable carrier, and optionally at least one additional pharmaceutically or pharmaceutical agent (e.g., an antipsychotic or anti-schizophrenic agent as described below). In one embodiment, the additional pharmaceutically or pharmaceutical agent is an anti-schizophrenic agent as described below.

[0155] Pharmacology The muscarinic acetylcholine receptor M4 (also known as muscarinic 4 or CHRM4) is a human protein encoded by the CHRM4 gene. The M4 receptor is primarily expressed in the brain. The main brain regions where M4 receptor expression occurs are the striatum, cortex, and hippocampus, with the highest expression occurring in the striatum, where M4 is the major muscarinic subtype (approximately 46%). M4 is expressed sporadically in peripheral tissues (e.g., testes, skin, and colon).

[0156] M4 receptor is G q / i It couples to proteins and inhibits activity in the striatum and midbrain. M4 receptors function as autoreceptors (Zhang et al., 2002; Tzavara et al., 2004), as well as as postsynaptic regulatory receptors in the striatum, neocortex, and hippocampus (Levy et al., 1991; Zhang et al., 1997). M4 receptors are also found presynaptically in glutamatergic synapses from the cortex to the striatum (Pancani, T. et al., "Allosteric activation of M4 improve behavioral and physiological alterations in early symptomatic YAC128 mice," Proceedings of the National Academy of the Sciences of the United States of America, November 10, 2015, Vol. 112 (No. 45): pp. 14078-83), and in hippocampal glutamate neurons (where presynaptic M4 modulates glutamate release). The highest expression of the M4 receptor is found in the striatum, and the M4 receptor also has a modulating effect on dopaminergic neurotransmission and is co-expressed with the D1 dopamine receptor in a subset of striatal medium spiny neurons that contain GABA as the major neurotransmitter (Bernard et al., 1992; DiChiara et al., 1994; Inns et al., 1997).

[0157] It has been hypothesized that selective M4 agonist administration can provide antipsychotic activity for the treatment of schizophrenia (Felder et al., "Elucidating the Role of Muscarinic Receptors in Psychosis," Life Sci., Vol. 68: pp. 2605-2613, 2001). This view has been further supported by experiments demonstrating that M4 receptors modulate the dynamics of dopaminergic and cholinergic neurotransmission, and that hyperdopaminergic states occur with loss of M4 function (Tzavara et al., "M4 Muscarinic Receptors Regulate the Dynamics of Cholinergic and Dopaminergic Neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies," FASEB J., Vol. 18: pp. 1410-1412, 2004).

[0158] The compounds of the present invention may also be useful in treating / alleviating neuropsychiatric symptoms (i.e., behavioral symptoms) associated with Alzheimer's disease and schizophrenia (Foster, Daniel J. et al., "Activation of M1 and M4 muscara"). ("Inic receptors as potential treatments for Alzheimer's disease and schizophrenia," Neuropsychiatric Disease and Treatment, 2014, Vol. 10, pp. 183-191). These behavioral symptoms, though not limited to these, include agitation, anxiety, irritability, combativeness, disorientation, illusions, delusions, emotional blunting, depression, disinhibition, abnormal movements and obsessive-compulsive behaviors, and sleep disturbances (Dillon, Carol et al., "Behavioral symptoms related to cognitive impairment," Neuropsychiatric Disease). (and Treatment 2013, Vol. 9, pp. 1443-1455). By treating / alleviating the behavioral symptoms described above, the compounds of the present invention are also thought to enhance cognition.

[0159] Considering the above, the compounds of the present invention may be useful in the treatment of schizophrenia and Alzheimer's disease. The compounds of the present invention may also be useful in the treatment of Parkinson's disease, Huntington's disease, addiction, depression, and epilepsy.

[0160] The M4 selective activator of the present invention also treats neurological, neurodegenerative, and / or psychiatric disorders. It is believed to have a wide range of other therapeutic uses for the treatment of central nervous system conditions or diseases, including, but not limited to, neurological, neurodegenerative, and / or psychiatric disorders, including: (1) mood [affective] disorders; (2) neurotic, stress-related, and somatoform disorders, including anxiety disorders; (3) disorders, including symptoms of cognitive deficits in mammals, including humans; (4) disorders, including attention deficits, executive function deficits (short-term memory deficits), impulse control dysfunction, extrapyramidal symptoms, and disorders based on abnormalities of the basal ganglia, hippocampus, and prefrontal cortex; (5) behavioral and affective disorders, usually beginning in childhood and adolescence; (6) mental developmental disorders; (7) disorders primarily affecting the central nervous system. (8) Generalized atrophy affecting the body; (9) Extrapyramidal and motor disorders; (10) Behavioral syndromes associated with physiological disorders and physical factors; (11) Personality and behavioral disorders in adults; (12) Schizophrenia and other psychotic disorders; (13) Mental and behavioral disorders due to the use of psychoactive substances; (14) Sexual dysfunction, including hypersexuality; (15) Intellectual disability; (16) Factitious disorders, such as acute hallucinogenic mania; (17) Accidental and paroxysmal disorders, epilepsy; (18) Dementia; and (19) Amyotrophic lateral sclerosis.

[0161] Examples of mood disorders that can be treated in accordance with the present invention include, but are not limited to, bipolar disorder type I, hypomania (manic and mixed forms), bipolar disorder type II; depressive disorders, e.g., single depressive episode or recurrent major depressive disorder, chronic depression, psychotic depression, minor depressive disorder, postpartum depressive disorder, depressive disorder with psychotic symptoms; persistent mood disorders, e.g., cyclothymic mood, dysthymia, normal mood; premenstrual syndrome (PMS) and premenstrual dysphoric disorder.

[0162] Examples of neurotic, stress-related, and somatoform disorders that can be treated in accordance with the present invention include, but are not limited to, anxiety disorders, social anxiety disorder, generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobias, social phobia, chronic anxiety disorder; obsessive-compulsive disorder; severe stress reaction and adjustment disorders, e.g., post-traumatic stress disorder (PTSD), acute stress disorder; and other neurotic disorders, e.g., derealization syndrome.

[0163] As used herein, the terms “cognitive deficit” and “disorder, including symptoms of cognitive deficit” refer to one or more cognitive aspects in a particular individual compared to other individuals in the general population of the same age, such as memory, intelligence, learning and logic abilities, or attention and executive functions (short-term memory), which are below normal or below optimal.

[0164] Examples of “disorders including symptoms of cognitive impairment” that can be treated in accordance with the present invention include, but are not limited to, cognitive deficits, primarily amnesia, psychosis (schizophrenia), Parkinson’s disease, Alzheimer’s disease, multiple sclerosis dementia, senile dementia, Lewis’s dementia, stroke, frontotemporal dementia, progressive supranuclear palsy, Huntington’s disease, HIV disease (HIV-associated dementia), traumatic brain injury, and substance abuse; mild cognitive impairments such as ADHD, Asperger’s syndrome, and age-related memory impairment; and cognitive decline or delirium associated with postoperative or intensive care therapy.

[0165] Examples of disorders that can be treated in accordance with the present invention, which are usually first diagnosed in infancy, childhood, and adolescence, include, but are not limited to, hyperactivity disorders, e.g., disturbance of activity and attention, attention deficit hyperactivity disorder (ADHD), and hyperkinetic disorders; attention deficit disorder (ADD); conduct disorders, but are not limited to, depressive conduct disorder; tic disorders, transient tic disorders, chronic motor or vocal tic disorders, combinations of vocal and multiple motor tic disorders (Gil de la Tourette syndrome), and substance-induced tic disorders; autistic disorders; Batten syndrome, excessive masturbation, nail biting, nose picking, and thumb sucking.

[0166] Examples of mental developmental disorders that can be treated in accordance with the present invention include, but are not limited to, pervasive developmental disorders, which include, but are not limited to, Asperger syndrome and Rett syndrome, autism spectrum disorder, childhood autism and hyperactivity disorder with intellectual disability and stereotyped movements, specific developmental disorders of motor function, and specific developmental disorders of learning ability.

[0167] Examples of systemic atrophy primarily affecting the central nervous system that can be treated according to the present invention include, but are not limited to, multiple sclerosis systemic atrophy primarily affecting the basal ganglia, which includes Huntington's disease and amyotrophic lateral sclerosis.

[0168] Examples of extrapyramidal disorders and motor disorders having basal ganglia abnormalities and / or degeneration that can be treated in accordance with the present invention include, but are not limited to, Huntington's disease; Parkinson's disease; secondary parkinsonism, e.g., post-encephalitis parkinsonism; parkinsonism included in other disorders; Niemann-Pick disease, Lewy body disease; degenerative diseases of the basal ganglia; other extrapyramidal disorders and motor disorders, e.g., tremor, essential tremor and drug-induced tremor, myoclonus, chorea and drug-induced chorea, drug-induced tics and organic tics, drug-induced acute dystonia, drug-induced tardive dyskinesia, including muscle spasms and muscle disorders associated with muscle spasticity or weakness including tremor; mental deficiency (including spasticity, Down syndrome and Fragile X syndrome), L-dopa-induced dyskinesia; restless limb syndrome and Stiffman syndrome.

[0169] Further examples of motor disorders having abnormalities and / or degeneration of the basal ganglia that can be treated in accordance with the present invention include, but are not limited to, dystonia, which includes, but are not limited to, focal dystonia, multifocal or segmental dystonia, torsional dystonia, hemispheric, systemic and tardive dystonia (induced by psychopharmacological agents). Focal dystonia includes cervical dystonia (torticollis), blepharospasm (spasms of the eyelids), limb dystonia (spasms of the extremities such as writer's cramp), or mandibular dystonia and spasmodic dysphonia (spasms of the vocal cords); neuroleptic-induced motor disorders include, but are not limited to, neuroleptic malignant syndrome (NMS), neuroleptic-induced parkinsonism, neuroleptic-induced early-onset or acute dyskinesia, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced late-onset dyskinesia, and neuroleptic-induced tremor.

[0170] Examples of behavioral syndromes associated with physiological disorders and physical factors according to the present invention include, but are not limited to, non-organic sleep disorders, such as, but are not limited to, non-organic hypersomnia, non-organic sleep-wake schedule disorders (circadian rhythm sleep disorders), insomnia, parasomnias, and sleep disturbances; puerperal mental and behavioral disorders, including postnatal and postpartum depression; and eating disorders, such as, but are not limited to, anorexia nervosa, bulimia nervosa, distraction eating disorder, porcini, obesity, obsessive-compulsive eating disorder, and pica.

[0171] Examples of adult personality and behavioral disorders that can be treated in accordance with the present invention include, but are not limited to, personality disorders, such as, but are not limited to, affective-instability, borderline, obsessive-compulsive, compulsive, dependent, and passive-aggressive personality disorders; habitual and impulse disorders (impulse control disorders), such as, for example, intermittent explosive disorder, pathological gambling, pathological arson (pyromania), pathological kleptomania (kleptomania), and trichotillomania; and Munchausen syndrome.

[0172] Examples of schizophrenia and other psychotic disorders that can be treated according to the present invention include, but are not limited to, different types of continuous or incidental schizophrenia (e.g., paranoid, hebephrenic, catatonic, undifferentiated, residual, and schizophrenia-like disorders); and schizotypal disorders (e.g., borderline, latent, prepsychotic, predementia, pseudoneurotic schizophrenia, and schizotypal personality disorder). Disorders include: persistent delusional disorder; acute, transient, and persistent psychotic disorders; induced delusional disorder; different types of schizoaffective disorder (e.g., manic-depressive or mixed); puerperal psychosis and other and unspecified non-organic psychoses, such as social withdrawal in schizophrenia.

[0173] Examples of mental and behavioral disorders caused by the use of psychoactive substances that can be treated in accordance with the present invention include, but are not limited to, mental and behavioral disorders caused by the use of alcohol, opioids, cannabinoids, sedatives or hypnotics, and cocaine; mental and behavioral disorders caused by the use of other stimulants, including caffeine; mental and behavioral disorders caused by drug dependence and abuse (e.g., narcotic addiction, alcoholism, amphetamine and methamphetamine addiction, opioid addiction, cocaine addiction, nicotine addiction, and drug withdrawal syndrome, as well as relapse prevention), hallucinogens, tobacco (nicotine), and volatile solvents; and mental and behavioral disorders caused by the use of multiple drugs and other psychoactive substances, including, for example, the following subtypes of symptoms: adverse use, dependence syndrome, withdrawal state, and withdrawal state with delirium.

[0174] Examples of dementias that can be treated according to the present invention include, but are not limited to, vascular dementia, Creutzfeldt-Jakob disease, HIV, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, and Alzheimer's disease.

[0175] In certain embodiments, the present invention relates to the use of the compound of the present invention for the treatment of schizophrenia, by administering a therapeutically effective amount of the compound to a patient requiring treatment for schizophrenia.

[0176] In certain other embodiments, the present invention further relates to the use of the compounds of the present invention for the treatment of cognitive impairment associated with schizophrenia, by administering a therapeutically effective amount of the compounds of the present invention to patients who require treatment for cognitive impairment associated with schizophrenia.

[0177] The aforementioned compounds of the present invention, their N-oxides, and pharmaceutically acceptable salts may be useful for one or more of the following conditions of schizophrenia or psychosis: schizophrenia (paranoid, dissociative, catatonic, or undifferentiated), schizophrenia-like disorder, schizoaffective disorder, delusional disorder, short-term psychotic disorder, shared psychotic disorder, psychotic disorder due to systemic conditions, and substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine) psychotic disorders, psychosis associated with affective disorders, short-term reaction psychosis, schizoaffective psychosis, "integration "Schizophrenia spectrum" disorders, e.g., schizophrenia or schizotypal personality disorder, or disorders associated with psychosis (e.g., major depressive disorder, bipolar disorder, Alzheimer's disease, and post-traumatic stress syndrome), including both the positive and negative symptoms of schizophrenia and other psychoses; cognitive impairments, e.g., dementia (associated with Alzheimer's disease, ischemia, multiple sclerosis, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, birth hypoxia, other systemic medical conditions or substance abuse); delirium, amnesia, or age-related cognitive decline.

[0178] In addition to the central nervous system disorders described above, the compounds of the present invention can be used to treat other M4-mediated (or M4-related) disorders, including, but not limited to, addiction (e.g., substance addiction, e.g., opioid, cocaine, or alcohol addiction), pain (e.g., acute pain, inflammatory pain, and neuropathic pain), and sleep disorders (e.g., those related to REM sleep regulation, e.g., those related to the onset of REM sleep). Additional M4-mediated (or M4-related) disorders or conditions that can be treated with the compounds of the present invention include dry mouth, cognitive impairment (e.g., mild cognitive impairment), dyskinesia, pulmonary hypertension, and chronic urinary tract obstruction. These include obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia (e.g., degenerative dementia), hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes mellitus, autism, and atherosclerosis. See, for example, US8,664,234.

[0179] The following are some of the potential sleep disorders for which the aforementioned compounds of the present invention, their N-oxides, and pharmaceutically acceptable salts may be useful: enhancing sleep quality; improving sleep quality; increasing sleep maintenance; increasing the value calculated by dividing the time the subject slept by the time the subject tried to sleep; reducing sleep latency or fall asleep (time required to fall asleep); reducing difficulty falling asleep; increasing sleep duration; reducing the number of awakenings during sleep; reducing nighttime awakenings; reducing the time spent from initial sleep onset to wakefulness; increasing total sleep volume; reducing sleep fragmentation; altering the timing, frequency, or duration of REM sleep; altering the timing, frequency, or duration of slow-wave (i.e., stage 3 or 4) sleep; increasing the volume and percentage of stage 2 sleep; To promote wave sleep; to enhance EEG delta activity during sleep; to increase daytime attention; to reduce daytime sleepiness; to treat or reduce excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy; sleep interruption; sleep apnea; wakefulness; nocturnal myoclonus; REM sleep interruption; jet lag; sleep disorders in shift workers; sleep disorders; night terrors; insomnia associated with depression, affective / mood disorders, as well as sleep walking and enuresis, and age-related sleep disorders; Alzheimer's sunset phenomenon; conditions associated with circadian rhythms, as well as mental and physical disorders associated with transtemporal travel and shift work schedules; conditions caused by drugs that cause reduced REM sleep as a side effect; syndromes that manifest as unrecoverable sleep and sleep apnea associated with myalgia or sleep-disordered breathing; and conditions resulting from poor sleep quality.

[0180] The aforementioned compounds of the present invention, their N-oxides, and pharmaceutically acceptable salts may be useful for pain disorders such as neuropathic pain (e.g., postherpetic neuralgia, nerve injury, "dynias," e.g., vulvovaginal pain, phantom limb pain, nerve root avulsion injury, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndrome (potentially caused by substantially any lesion at any level of the nervous system); and postoperative pain syndrome (e.g., postmastectomy syndrome, thoracotomy). Postoperative syndrome, stump pain; bone and joint pain (osteoarthritis), pain due to repetitive movements, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia); pre- and postoperative pain (general surgery, gynecological), chronic pain, dysmenorrhea, and pain associated with angina, as well as inflammatory pain of various origins (e.g., osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis, and gout), headache, migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain resulting from central sensitization.

[0181] The aforementioned compounds of the present invention, their N-oxides, and pharmaceutically acceptable salts can be used to reduce tolerance and / or dependence on opioid treatment for pain, as well as to treat, for example, alcohol, opioid, and cocaine withdrawal syndromes.

[0182] formulation The compounds of the present invention can be administered orally. Oral administration may include swallowing the compound so that it enters the gastrointestinal tract, or it may also involve oral buccal or sublingual administration so that the compound enters the bloodstream directly from the mouth.

[0183] In another embodiment, the compounds of the present invention may also be administered directly into the bloodstream, muscles, or internal organs. Appropriate means of parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, lateral ventricle, urethral, ​​intrasternal, intracerebral, intramuscular, and subcutaneous methods. Appropriate devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0184] In another embodiment, the compounds of the present invention may also be formulated so that topical administration to the skin or mucous membrane (i.e., transdermally) results in the absorption of the compound into the body. In another embodiment, the compounds of the present invention may also be formulated so that intranasal administration or inhalation results in the absorption of the compound into the body. In another embodiment, the compounds of the present invention may be formulated so that rectal or vaginal administration results in the absorption of the compound into the body.

[0185] The dosage regimen for the compound and / or compositions containing the compound is based on various factors including the patient's type, age, weight, sex, and medical condition; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosage regimen can vary widely. Dosage levels of approximately 0.01 mg to approximately 100 mg per kilogram of body weight per day are useful for treating the conditions described above. In one embodiment, the total daily dose of the compound of the present invention (administered as a single dose or in divided doses) is typically about 0.01 to approximately 100 mg / kg. In another embodiment, the total daily dose of the compound of the present invention is about 0.1 to approximately 50 mg / kg, and in yet another embodiment, it is about 0.5 to approximately 30 mg / kg (i.e., the mg value of the compound of the present invention per kg of body weight). In one embodiment, the dosage is 0.01 to 10 mg / kg / day. In another embodiment, the dosage is 0.1 to 1.0 mg / kg / day. A unit dosage form composition may contain an amount or a fraction thereof that totals a daily dose. In most cases, the compound will be administered multiple times a day (usually four times or less). Typically, multiple daily doses can be used to increase the total daily dose if desired.

[0186] For oral administration, the composition may be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, and 500 milligrams of the active ingredient for symptomatic dose adjustment to patients. The pharmaceutical product typically contains about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, about 1 mg to about 100 mg of the active ingredient. For intravenous administration, the dose during constant-rate infusion may range from about 0.1 to about 10 mg / kg / min.

[0187] Suitable subjects according to the present invention include mammals. Examples of mammals according to the present invention, but not limited to these, include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, lagomorphs, primates, and other intrauterine mammals. In one embodiment, humans are suitable subjects. Human subjects may be of any sex and at any developmental stage.

[0188] In another embodiment, the present invention includes the use of one or more compounds of the present invention for the preparation of a medicament for treating the conditions enumerated herein. For the treatment of the conditions described above, the compounds of the present invention can be administered as compounds themselves. Alternatively, pharmaceutically acceptable salts are suitable for medical applications because they have higher water solubility compared to the parent compounds.

[0189] In another embodiment, the present invention comprises a pharmaceutical composition. Such a pharmaceutical composition comprises a compound of the present invention presented together with a pharmaceutically acceptable carrier. The carrier may be solid, liquid, or both, and may be formulated together with the compound as a single-dose composition, for example, a tablet, which may contain 0.05% to 95% of the active compound by body weight. The compound of the present invention may couple with a suitable polymer as a targetable drug carrier. It can be made to do so. Other pharmacologically active substances may also be present.

[0190] The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. The active compounds and compositions may be administered, for example, orally, rectally, parenterally, or topically (e.g., intranasally or ocularly).

[0191] The oral administration in solid dosage form may be presented as separate units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, the oral administration may be in the form of a powder or granules. In yet another embodiment, the oral administration form is sublingual, such as a lozenge. In such solid dosage forms, the compounds of the present invention are usually used in combination with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms may also contain a buffer or may be prepared using an enteric coating.

[0192] In another embodiment, oral administration may be in liquid form. Examples of liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent commonly used in the art (e.g., water). Such compositions may also contain adjuvants, such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), and / or fragrances.

[0193] In another embodiment, the present invention includes parenteral administration forms. Examples of "parenteral administration" include subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and intravenous infusion. Preparations for injection (i.e., aqueous or oily suspensions for sterile injection) can be formulated according to known techniques using appropriate dispersants, wetting agents, and / or suspending agents, and include depot formulations.

[0194] In another embodiment, the present invention includes topical administration forms. “Topical administration” includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the compounds of the present invention are administered via a transdermal device, administration is achieved using either a reservoir and porous membrane type, or a patch having various solid matrices. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Transdermal absorption enhancers may also be incorporated. See, for example, Finnin and Morgan, J. Pharm. Sci., Vol. 88 (No. 10), pp. 955-958 (1999).

[0195] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compound of the present invention is dissolved or suspended in a suitable carrier. Typical formulations suitable for administration to the eye or ear may be in the form of a finely powdered suspension or solution droplets in isotonic, pH-adjusted sterile saline. Other formulations suitable for administration to the eye and ear include ointments, biodegradable (e.g., absorbent gel sponge, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and microparticles, or vesicle systems, such as niosomes or riboplasmic receptacles. Posomes are one example. Polymers, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers, such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, such as gellan gum, can be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0196] For intranasal or inhalation administration, the active compounds of the present invention are conveniently delivered in the form of a solution or suspension by the patient squeezing or pumping a pump spray container, or as an aerosol spray from a pressurized container or nebulizer using a suitable spraying agent. Formulations suitable for intranasal administration are typically administered from a dry powder inhaler in the form of a dry powder (any of the following: alone; as a mixture, e.g., as a dry mixture with lactose; or as component particles mixed with phospholipids such as phosphatidylcholine, e.g.), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without a suitable spraying agent such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, powders may contain bioadhesive agents, e.g., chitosan or cyclodextrin.

[0197] In another embodiment, the present invention includes a rectal administration form. Such a rectal administration form may be, for example, a suppository. Cocoa butter is a conventional suppository base, but various alternative forms can be used as needed.

[0198] Other carrier materials and administration modes known in the field of pharmacy may also be used. The pharmaceutical compositions of the present invention may be prepared by any of the well-known techniques of pharmacy, for example, effective formulation and administration procedures. The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. The formulation of drugs is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

[0199] The compounds of the present invention can be used alone or in combination with other therapeutic agents to treat a variety of conditions or pathologies. The compounds(s) of the present invention and other therapeutic agents(s) may be administered simultaneously (in the same dosage form or in different dosage forms) or sequentially. Exemplary therapeutic agents may be, for example, metabotropic glutamate receptor agonists.

[0200] Administering two or more compounds "in combination" means that these two compounds are administered within a time period close enough that the presence of one alters the biological effect of the other. Two or more compounds may be administered simultaneously, in parallel, or sequentially. Furthermore, simultaneous administration may be achieved by mixing the compounds before administration, or by administering the compounds at different anatomical sites or via different routes of administration, even at the same time point.

[0201] The phrases "simultaneous administration," "co-administration," "simultaneous administration," and "administered at the same time" all mean that the compounds are administered in combination. The present invention relates to the M4 activator compound of the present invention and one or more additional pharmaceutically active compounds This includes the use in combination with other drugs. When a combination of activators is administered, they may be administered sequentially or simultaneously in separate dosage forms, or they may be combined within a single dosage form. Accordingly, the present invention also includes a pharmaceutical composition comprising a certain amount of (a) a first drug comprising the compound of the present invention or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active drug; and (c) a pharmaceutically acceptable carrier, vehicle, or diluent.

[0202] Various pharmaceutically active agents may be selected for use in combination with the compounds of the present invention, depending on the disease, disorder, or condition being treated. Examples of pharmaceutically active agents that can be used in combination with the compositions of the present invention include, without limitation: (i) Acetylcholinesterase inhibitors, e.g., donepezil hydrochloride (ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium (MYTELASE), demar potassium, Debio 9902 (also known as ZT-1; Debiopharm), rivastigmine (EXELON), radostigyl, NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX), tolcerin, vernacrine maleate, memokin, huperzine A (HUP-A; NeuroHitech), fencerin, edrophonium (ENLON, TENSILON), and INM-176; (ii) Amyloid-beta (or its fragments), such as the pan-HLA DR-binding epitope (PADRE), ACC-001 (Elan / Wyeth), ACI-01, ACI-24, AN-1792, Affitope AD-01, CAD106, and Aβ conjugated with V-950. 1~15 ; (iii) Antibodies against amyloid-beta (or its fragments), e.g., ponezumab, solanezumab, bapineozumab (also known as AAB-001), AAB-002 (Wyeth / Elan), ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanized m266Lilly), R1450 (Roche), ACU-5A5, huC091, and international patent publication WO Disclosed in patents 04 / 032868, WO05 / 025616, WO06 / 036291, WO06 / 069081, WO06 / 118959, U.S. Patent Publications US2003 / 0073655, US2004 / 0192898, US2005 / 0048049, US2005 / 0019328, European Patent Publications EP0994728 and 1257584, and U.S. Patent No. 5,750,349, etc. (iv) Amyloid-reducing agents or amyloid inhibitors (including those that reduce amyloid production, accumulation, and fibrosis), e.g., Dimebon, dabnetide, eprodize, leuprolide, SK-PC-B70M, celecoxib, lovastatin, anapsos, oxiracetam, pramicetam, varenicline, nicergoline, colostrinin, bisnorcimusserine (also known as BNC), NIC5-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its R-enantiomer, tarenflurvir (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofen licinate, meclofenamic acid, sodium meclofenamate (MECLOMEN), indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenac potassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID), naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (Archer Pharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin-degrading enzyme (also known as insulinin), Ginkgo biloba extract EGb-761 (ROKA) N, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodiseate (FIBRILLEX, KIACTA), compound W[3,5-bis(4-nitrophenoxy)benzoic acid], NGX-96992, neprilysin (also known as neutral endopeptidase (NEP)), silinositol (also known as silitol), atorvastatin (LIPITOR), simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamorene mesylate, BACE inhibitors, for example ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gamma-secretase modulators, e.g., ELND-007; and RAGE (receptor to advanced glycation end products) inhibitors, e.g., TTP488 (Transtech) and TTP4000 (Transtech), as disclosed in U.S. Patent No. 7,285,293, including PTI-777; (v) Alpha-adrenergic receptor agonists, e.g., guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metalaminol (ARAMINE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as neosynephrine), methoxamine, silazolin, guanfacine (INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, and almodafinil (NUVIGIL); (vi) Beta-adrenergic receptor blockers (beta-blockers), e.g., carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL), sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC), acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate (LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN), butoxamine, and SR 59230A (Sanofi); (vii) Anticholinergic drugs, e.g., amitriptyline (ELAVIL, ENDEP), buttriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), methylscopolamine bromide (PARMINE), dicycloberine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL) XL (OXYTROL), pentienate bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL); (viii) Anticonvulsants, e.g., carbamazepine (TEGRETOL, CARBATROL), oxycarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin (CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin (NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid (DEPAKENE), sodium valproate (DEPACON), 1-benzyl-5-bromouracil, progavid, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, talanpaner, and primidone (MYSOLINE); (ix) Antipsychotics, e.g., lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), Aripiprazole (ABILIFY), Chlorpromazine (THORAZINE), Haloperidol (HALDOL), Iloperidone (FANAPTA), Flupentixol Decanoate (DEPIXOL, FLUANXOL), Reserpine (SERPLAN), Pimozide (ORAP), Fluphenazine Decanoate, Fluphenazine Hydrochloride, Prochlorperazine (COMPRO), Asenapine (SAPHRIS), Loxapine (LOXITANE), Morindone (MOBAN), Perphenazine, Thioridazine, Thiotix Sen (thiothixine), Trifluoperazine (STELAZINE), Ramelteon, Clozapine (CLOZARIL), Norclozapine (ACP-104), Risperidone (RISPERDAL), Paliperidone (INVEGA), Merperone, Olanzapine (ZYPREXA), Quetiapine (SEROQUEL), Tarnetant, Amisulpride, Ziprasidone (GEODON), Blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals); (x) Calcium channel blockers, e.g., lomerizine, diconotide, nilvadipine (ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN), felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compounds, nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS), lercanidipine (ZANIDIP), rifaridine, diltiazem (CARDIZEM), verapamil (CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enekazin; (xi) Catechol O-methyltransferase (COMT) inhibitors, e.g., nitecapone, tolcapone (TASMAR), entacapone (COMTAN), and tropolone; (xii) Central nervous system stimulants, e.g. atomoxetine, reboxetine, yohimbine, caffeine, fenmetrazine, fendimetrazine, pemoline, fencamfamine (glucoenergan, reactivan), phenethrine (captagon), piperadol (meretran), deanol (also known as dimethylaminoethanol), methylphenidate (daytrana), methylphenidate hydrochloride (ritalin), dexmethylphen Nidate (FOCALIN), amphetamine (alone or in combination with other CNS stimulants, e.g., ADDERALL (amphetamine aspartate, amphetamine sulfate, dextroamphetamine glucose, and dextroamphetamine sulfate)), dextroamphetamine sulfate (DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamphetamine (VYVANSE), and benzfetamine (DIDREX); (xiii) Corticosteroids, such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PREDFORTE), sodium prednisolone phosphate (ORAPRED ODT), methylprednisolone (MEDROL); methylprednisolone acetate (DEPO-MEDROL), and sodium methylprednisolone succinate (A-METHAPRED, SOLU-MEDROL); (xiv) Dopamine receptor agonists, e.g., apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydroexidine, dihydroergocriptine, phenoldopam (CORLOPAM), rislide (DOPERGIN), terguride pergolide (spergolide) (PERMAX), pyribezil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quimpyrole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKline), caliprazine, pardoprnox, and salizotane; (xv) Dopamine receptor antagonists, e.g., chlorpromazine, fluphenazine, haloperidol, roxapine, risperidone, thioridazine, thiothixen, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN), domperidone (MOTILIUM), L-741742, L-745870, lacloprid, SB-277011A, SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN); (xvi) Dopamine reuptake inhibitors, such as bupropion, safinamide, nomifensin maleate (MERITAL), banoxerin (also known as GBR-12909) and its decanoate ester, DBL-583, and amineptin; (xvii) Gamma-aminobutyric acid (GABA) receptor agonists, such as baclofen (LIORESAL, KEMSTRO), cyclofen, pentobarbital (NEMBUTAL), progavid (GABRENE), and clomethiazole; (xviii) Histamine 3(H3) antagonists, e.g., siproxifan, ticprolisant, S-38093, yldabisant, pitrisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidine-1-ylmethyl)phen [Nyl]-cyclobutanecarboxamide (PF-3654746 and U.S. Patent Publications US2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955, US2007-1079175, and US2008-0176925; International Patent Publications WO2006 / 136924, WO2007 / 063385, WO2007 / 0690 (xix) Immunomodulatory substances, e.g., glatiramer acetate (also known as copolymer 1; COPAXONE), MBP-8298 (synthetic myelin basic protein) (Sodium peptide), dimethyl fumarate, fingolimod (also known as FTY720), lokinimex (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI); (xx) Immunosuppressants, e.g., methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), sodium mycophenolate (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4-(benzyloxy)-5-[(5-undecyl-2H-pyrrole-2-ylidene)methyl]-1H,1'H-2,2'-bipyrrole (also known as PNU-156804); (xxi) Includes interferon, interferon beta-1a (AVONEX, REBIF) and interferon beta-1b (BETASERON, BETAFERON); (xxii) Levodopa (or its methyl or ethyl ester), either alone or in combination with a dopa decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), α-methyldopa, monofluoromethyldopa, difluoromethyldopa, brocresin, or m-hydroxybenzylhydrazine); (xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, for example Memantine (NAMENDA, AXURA, EBIXA), Amantadine (SYMMETREL), Acamprosate (CAMPRAL), Besonprodil, Ketamine (KETALAR), Dersemin, Dexanabinol, Dexephaloxane, Dextromethorphan, Dextrorphan, Traxoprodil, CP-283097, Himantan, Indantadol (idantadol), Ipenoxazone, L-701252 (Merck), Lanicemine, Re Volufanol (DROMORAN), LY-233536 and LY-235959 (both Lilly), Methadone (DOLOPHINE), Neramexane, Perzinhotel, Phencyclidine, Thianeptine (STABLON), Dizosilpine (also known as MK-801), EAB-318 (Wyeth), Ibogaine, Boacangine, Tiletamine, Riluzole (RILUTEK), Aptiganel (CERES0TAT), Gabestinel, and Remasemide; (xxiv) Monoamine oxidase (MAO) inhibitors, e.g., selegiline (EMSAM), selegiline hydrochloride (l-deprenyl, ELDEPRYL, ZELAPAR), dimethyl selegiline (dimethylselegilene), brophalomine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isocarboxazide (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), iproniazid (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, troxatone (humoryl, perenum), bifemeran, desoxypeganin, harmine (also known as telepathin or banasterine), harmanine, linezolid (zyvox, zyvoxid), and pargiline (eudatin, supirdyl); (xxv) Muscarinic receptor (especially M1 subtype) agonists, e.g., cevimeline, levetiracetam, betanethyl chloride (DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), flutrethonium iodide (FURAMON, FURANOL), flutrethonium benzenesulfonate, flutrethonium p-toluenesulfonate, McN-A-343, oxotremoline, subcomeline, AC-90222 (Acadia Pharmaceuticals), and carbachol (CARBASTAT, MIOSTAT, CARBOPTIC); (xxvi) Neuroprotective agents, e.g., bosutinib, chondriase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprime, riluzole, N-hydroxy-1,2,4,9-tetrahydro-3H-carbazole-3-imine, desmoteplase, anative, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; both Allon) Therapeutics), neurostrol, perampenel, ispronicline, bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyl taltarate (also known as dactyloline B or DHB), formobactin, xaliproden (XAPRILA), lactacystine, dimevorin hydrochloride (DIMEBON), disfenton (CEROVIVE), arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known as cytidine 5'-diphosphocholine), edaravone (RADICUT), AEOL-10113 and AEOL-10150 (both Aeolus Pharmaceuticals), AGY-94806 (also known as SA-450 and Msc-1), granulocyte colony-stimulating factor (also known as AX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), Anclod (VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220 (17-β-hydroxyepiandrosterone; Newron Pharmaceutica) ls), HF-0420 (also known as oligotropin), pyridoxal 5'-phosphate (also known as MC-1), microplasmin, S-18986, piclozotan, NP031112, tacrolimus, L-ceryl-L-methionyl-L-alanil-L-lysyl-L-glutamyl-glycyl-L-valine, AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes of Health), stilbazrenylnitrone, SUN-N8075 (Daiichi Suntory Biomedical Research), and Zonan panel; (xxvii) Nicotinic receptor agonists, e.g., epivatidine, bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche / Memory Pharmaceuticals), R4996 (also known as MEM63908; Roche / Memory Pharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403; (xxviii) Norepinephrine (norepinephrine) reuptake inhibitors, e.g., atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viroxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), and radaxafine; (xxix) Phosphodiesterase (PDE) inhibitors, including but not limited to the following: (a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in U.S. Patent No. 6,235,742) (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY60-7550 and those described in U.S. Patent No. 6,174,884) (c) PDE3 inhibitors (e.g., anagrelide, cilostazol, milrinone, olprinone, palogrelyl, and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilast, roflumilast, rolipram, Ro20-1724, ibudilast (KETAS), picramiralast (also known as RP73401), CDP840, siromilast (ARIFLO), roflumilast, tofimilast, ogremilast (GRC) (e) PDE5 inhibitors (e.g., sildenafil (VIAGRA, REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIVANZA), udenafil, avanafil, dji (f) PDE7 inhibitors; (g) PDE8 inhibitors; (f) Pyridamole (PERSANTINE), E-4010, E-4021, E-8010, Zaprinast, iodenafil, mirodenafil, DA-8159, and those disclosed in international patent applications WO2002 / 020521, WO2005 / 049616, WO2006 / 120552, WO2006 / 126081, WO2006 / 126082, WO2006 / 126083, and WO2007 / 122466; (g) PDE8 inhibitors;(h) PDE9 inhibitors (e.g., those disclosed in BAY73-6691 (Bayer AG) and U.S. Patent Publications US2003 / 0195205, US2004 / 0220186, US2006 / 0111372, US2006 / 0106035, and USSN12 / 118,062 (filed May 9, 2008)), (i) PDE10 inhibitors, e.g., 2-({4-[1-methyl-4-(pyridine-4-yl)-1H-pyrazole-3-yl]phenoxy}methyl)quinoline-3(4H)-one and SCH-1518291; Rabini(j)PDE11 inhibitor; (xxx) Quinolines, for example, quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate, and gluconate), chloroquine, sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE); (xxxi)β-secretase inhibitors, e.g., ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721, E-2609, HPP-854, (+)-Phenserine tartrate (POSIPHEN), LSN-2434074 (also known as LY-2434074), KMI-574, SCH-745966, Ac-rER(N 2 -Acetyl-D-arginyl-L-arginine), roxistatin (also known as E64d), and CA074Me; (xxxii)γ-secretase inhibitors and modulators, e.g., BMS-708163 (Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELAN-G, ELAN-Z, 4-chloro-N-[(2S)-3-ethyl-1-hydroxypentan-2-yl]benzenesulfonamide; (xxxiii) Serotonin (5-hydroxytryptamine) 1A (5-HT 1A) Receptor antagonists, e.g., spiperone, levopindolol, BMY7378, NAD-299, S-(-)-UH-301, NAN190, recozotan; (xxxiv) Serotonin (5-hydroxytryptamine) 2C (5-HT 2c ) Receptor agonists, such as babicaserin and diclonapine; (xxxv) Serotonin (5-hydroxytryptamine) 4 (5-HT4) receptor agonists, e.g., PRX-03140 (Epix); (xxxvi) Serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor antagonists, e.g., A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), methiotepine (also known as metitepine), ritanserin, ALX-1161, ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046, SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A / S), and PRX-07034 (Epix); (xxxvii) Serotonin (5-HT) reuptake inhibitors, e.g., alaprocrate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LU VOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), dimmerizine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), prasofensin, bilazodone, caliprazine, neuralstem, and tesofensin; (xxxviii) Nutritional factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, meteorin, and glial neurotrophic factor (GDNF), as well as propentophilin, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-08 Drugs that stimulate the production of trophic factors such as 2(NEOTROFIN); (xxxix) Glycine transporter 1 inhibitors, e.g., paliflutin, ORG-25935, JNJ-17305600, and ORG-26041; (xl) AMPA-type glutamate receptor modulators, e.g., perampanel, mivanpatol, celampanel, GSK-729327, N-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydrofuran-3-yl}propan-2-sulfonamide, etc. (xli) Janus kinase inhibitors (JAKs), for example, but not limited to, tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, restoltinib, pacritinib, and TG101348. (xlii) Interleukin-1 receptor-related kinase 4 inhibitors (IRAK4), for example, but not limited to PF-06650833.

[0203] The present invention further includes a kit suitable for use in carrying out the treatment method described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention, and a container for that dosage, in an amount sufficient to carry out the method of the present invention.

[0204] In another embodiment, the kit of the present invention comprises one or more compounds of the present invention. An example of such a kit is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists of a sheet of relatively rigid material covered with a transparent plastic foil. A groove is formed in the plastic foil during the packaging process. The groove has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the groove, and the sheet of relatively rigid material is sealed against the plastic foil on the side of the foil opposite to the direction in which the groove was formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. In some embodiments, the strength of the sheet is such that an opening is formed at the location of the groove in the sheet by applying pressure to the groove by hand, allowing the tablet or capsule to be removed from the blister pack. The tablet or capsule can then be removed through the opening.

[0205] For example, it may be desirable to provide a memory aid on the kit in the form of a number next to each tablet or capsule, where the number corresponds to the day of the regimen in which the specified tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Monday, Tuesday of the first week... Monday, Tuesday of the second week..." Other variations of the memory aid are readily apparent. "Daily dose" can be one tablet or capsule or several pills or capsules to be taken on a given day. Also, the daily dose of compound I may consist of one tablet or capsule, while the daily dose of compound II may consist of several tablets or capsules, and vice versa. The memory aid should reflect such regimens.

[0206] In another specific embodiment of the present invention, a dispenser is provided which is designed to dispense daily doses one by one in the order of these intended uses. For example, the dispenser is equipped with a memory aid, which further facilitates compatibility with the regimen. An example of such a memory aid is a mechanical counter that indicates the number of times a daily dose has been dispensed. Another example of such a memory aid is a battery-powered microchip memory connected to a liquid crystal display, or an audible cue signal that, for example, reads out the date the last daily dose was taken and / or alerts a person to when the next dose should be taken.

[0207] As described above, the compounds of the present invention are one or more additional compounds as described herein. It can be used in combination with anti-schizophrenic drugs. When combination therapy is used, one or more additional anti-schizophrenic drugs are administered sequentially or concurrently with the compound of the present invention. In one embodiment, the additional anti-schizophrenic drug is administered to the mammal (e.g., human) before administration of the compound of the present invention. In another embodiment, the additional anti-schizophrenic drug is administered to the mammal after administration of the compound of the present invention. In yet another embodiment, the additional anti-schizophrenic drug is administered to the mammal (e.g., human) concurrently with administration of the compound of the present invention (or its N-oxide or a pharmaceutically acceptable salt thereof).

[0208] The present invention also provides a pharmaceutical composition for the treatment of schizophrenia in mammals, including humans, comprising a certain amount of the compound of the present invention as defined above (including its N-oxide or a salt of the compound or N-oxide) (including the compound or a pharmaceutically acceptable salt thereof, including its hydrate, solvate, and polymorph), in combination with one or more (e.g., one to three) anti-schizophrenic agents, such as ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, or iloperidone, wherein the amounts of the activator and combination are therapeutically effective in treating schizophrenia when taken together.

[0209] The present invention also provides a pharmaceutical composition for treating M4-mediated (or M4-related) diseases or disorders in mammals, including humans, comprising a certain amount of the compound of the present invention as defined above (including its N-oxide or a salt thereof) (including hydrates, solvates, and polymorphs of the compound N-oxide or the pharmaceutically acceptable salt thereof) in combination with one or more (e.g., 1 to 3) other agents for treating M4-mediated (or M4-related) diseases or disorders, wherein the amount of the activator and combination, when taken together, is therapeutically effective in treating M4-mediated (or M4-related) diseases or disorders.

[0210] It should be understood that the compounds of the present invention shown above (Formula I, Formula Ia, and Formula Ib) are not limited to the specific stereoisomers shown (e.g., enantiomers or atropisomers), but include all stereoisomers and mixtures thereof.

[0211] General Scheme Equations I, I A , I B , I C Compounds of , and I' may be prepared by the methods described below, along with synthetic methods known in the art of organic chemistry, or modifications and transformations familiar to those skilled in the art. The starting materials used herein are commercially available or may be prepared by certain methods known in the art [e.g., methods disclosed in standard reference books, e.g., Compendium of Organic synthetic methods, Volumes I-XIII (published by Wiley-Interscience)]. Preferred methods, but not limited to, include those described below.

[0212] During any of the following synthetic sequences, it may be necessary and / or desirable to protect any sensitive or reactive groups of the relevant molecules. This can be achieved by conventional protecting groups, for example, by means of those described herein by reference: TWGreene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; TWGreene and PGMWuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991; and TWGreene and PGMWuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999.

[0213] Equations I, I A , I B , I CCompounds of , and I' or pharmaceutically acceptable salts thereof can be prepared according to the reaction schemes discussed below herein. Unless otherwise noted, substituents in the schemes are defined as above. For example, formula I A Then m is 2 and n is 1. Equation I B Then m is 1 and n is 2. Equation I C Then both m and n are 1. Isolation and purification of the product are achieved by standard procedures known to a chemist of ordinary skill.

[0214] Those skilled in the art will understand that the various symbols, superscripts, and subscripts used in the schemes, methods, and examples are used for visual convenience and / or to reflect the order in which they are introduced in the schemes, and are not necessarily intended to correspond to the symbols, superscripts, or subscripts in the appended claims. Furthermore, those skilled in the art will recognize that in many cases these compounds are mixtures and enantiomers, and that these mixtures and enantiomers produce a single enantiomer by separating them at various stages of the synthetic scheme using prior art, e.g., crystallization, normal-phase chromatography, reverse-phase chromatography, and chiral chromatography, but not limited to these. The schemes are representative of methods useful for synthesizing the compounds of the present invention. The schemes do not limit the scope of the present invention in any way.

[0215] [ka]

[0216] Scheme 1 describes one synthetic sequence for the preparation of the compound of formula I. Referring to Scheme 1, compound II (wherein X of formula II) 1 , X 2 , and R 2 The substituents should be represented by the same part as desired in the final product or its protected variant, R 1A palladium(0) (where 'aryl' refers to an aryl or 5- or 6-membered heteroaryl) can be coupled with a heteroaryl bromide to produce compound III via a palladium-catalyzed Suzuki coupling reaction using a standard selection of palladium source, ligand, and base in a standard solvent, for example, but not limited to acetonitrile, toluene, or ethanol. Examples of Pd / ligand / base combinations, but not limited to, include tetrakis(triphenylphosphine)palladium(0) plus sodium carbonate. Examples include tris(dibenzylideneacetone)dipalladium(0)plus dicyclohexylphosphino-2',4',6'-triisopropylbiphenylplus potassium carbonate. Protecting group P 1 The removal of protecting group P results in compound IV. 1 In this case, P refers to a group well known to those skilled in the art for amine protection. For example, P 1 This may be tert-butoxycarbonyl (BOC), which can be cleaved via acidic conditions in a suitable solvent, including treatment with a solution of HCl in 1,4-dioxane, but is not limited to these. 1 The protecting group may be one of many other protecting groups suitable for amines, including a carboxybenzyl (Cbz) or benzoyl (Bz) group, and can be cleaved under standard conditions known to those skilled in the art. Compounds IV and V (wherein m and n are independently represented by integers selected from 1 or 2) can be coupled using a standard reductive amination procedure, for example, using a combination of sodium borohydride and titanium(IV) ethoxide in a suitable solvent, to produce the racemic compound of formula I. For example, chiral separation via chiral chromatography, e.g., HPLC or supercritical fluid chromatography, can produce the compound of formula I'.

[0217] [ka]

[0218] Scheme 2 describes alternative synthetic routes for the preparation of compounds of formulas I and I'. Referring to Scheme 2a, compound IV (wherein X of formula IV) 1 , X 2 , R 1 Oh biR 2 The substituents should be represented in the same part as desired in the final product or its protected variant) as an enantiomer of the pure compound VI sulfonate (wherein R 3 (wherein X is an aryl or alkyl substituent, e.g., methyl or 4-methylphenyl, and m and n are independently integers selected from 1 or 2), which can be replaced in the presence of a base such as potassium carbonate in a suitable solvent, including but not limited to acetonitrile. Referring to Scheme 2b, compound IV (wherein X is a substituent in the formula) can be replaced in the presence of a base such as potassium carbonate in a suitable solvent, e.g., acetonitrile. 1 , X 2 , R 1 and R 2 (wherein R should be represented by the same part as desired in the final product or its protected variant) is an alkyl sulfonate of chiral compound VII (wherein R 3 Compound VIII can be produced by similarly substituting (where is an aryl or alkyl substituent, and m and n are independently integers selected from 1 or 2). The BOC group, which can be cleaved via acidic conditions in a suitable solvent, including trifluoroacetic acid in dichloromethane, can be removed, followed by treatment with ethyl chloroformate in dichloromethane or another suitable solvent, to produce the compound of formula I'. Alternatively, compound IV (wherein X of formula IV, X of formula IV) can be produced as shown in scheme 2c. 1 , X 2 , R 1 and R 2The substituents (which should be represented by the same parts as desired in the final product or its protected variants) can be coupled with compound IX (wherein m and n are independently integers selected from 1 or 2) using a standard reductive amination procedure, for example, but not limited to, a combination of sodium borohydride and titanium(IV) ethoxide in a suitable solvent, to produce compounds of general formula X. The BOC group, which can be cleaved via acidic conditions in a suitable solvent containing trifluoroacetic acid in dichloromethane (but not limited to), can be removed, followed by treatment with ethyl chloroformate in dichloromethane or another suitable solvent, to produce racemic compounds of general formula I. The compounds of formula I' can be isolated, for example, after chiral separation by chiral supercritical fluid chromatography or HPLC.

[0219] [ka]

[0220] Scheme 3 describes the preparation of the compound of formula Ia. Compound II (wherein X of formula II) 1 , X 2 , and R 2 Compound XII can be formed via Ullman coupling by coupling compound XI (wherein R4 is a small alkyl or alkoxy) (the substituent should be represented by the same part as desired in the final product or its protected variant) with a copper catalyst such as copper(I) iodide, a ligand such as (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine, and a base such as potassium phosphate in a suitable solvent such as NMP. Yes, it is possible. Protection base P 1 The removal of results in compound XIII. In this case, P 1 This refers to a base well known to those skilled in the art for amine protection. For example, P 1This is tert-butoxycarbonyl (BOC), which can be cleaved by treatment with a solution of 1,4-dioxane in HCl, but not limited to, via acidic conditions in a suitable solvent. The synthesis of the compound of formula Ia is as follows: chiral sulfonate compound VI (wherein R 3 This can be carried out by the reaction of compound XIII with an aryl or alkyl substituent (where m and n are integers independently selected from 1 or 2) in a suitable solvent, including but not limited to acetonitrile, in the presence of a base such as potassium carbonate.

[0221] [ka]

[0222] Scheme 4 refers to the preparation of the compound of formula Ib. Compound XIV (wherein R is used in the formula) is used to produce compound XV. 2The cross-coupling reaction between tert-butylpiperazine-1-carboxylate (the substituent should be represented by the same part as desired in the final product or its protected variant) can be carried out using a palladium source such as tris(dibenzylideneacetone)dipalladium(0), a ligand such as RuPhos([2',6'-bis(propane-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane), and a suitable base such as sodium tert-butoxide in 1,4-dioxane or another suitable solvent. Removal of the BOC group using acidic conditions such as HCl in 1,4-dioxane, without limit, results in the formation of compound XVI. Compounds XVI and V (wherein m and n are independently represented by integers selected from 1 or 2) can be coupled using a standard reductive amination procedure, for example, using a combination of sodium borohydride and titanium(IV) ethoxide in a suitable solvent, without limit, to produce compound XVII. Using a suitable base such as sodium hydride in a suitable solvent such as DMF, the fluorine of compound XVII is removed by an alcohol (wherein R is used in the formula). 5 (As described above) Nucleophilic substitution is performed to produce the compound of formula Ib.

[0223] [ka]

[0224] Scheme 5 describes the synthesis of the compound of formula I'. Compound XVIII (wherein X 1 , X 2 , and R 2The substituents (which should be represented by the same part as desired in the final product or its protected variant) can be coupled with an aryl or heteroarylboronic acid via a Suzuki coupling reaction to produce the compounds of formula XIX, using a standard selection of palladium sources, ligands, and bases in a standard solvent, e.g., acetonitrile, toluene, or ethanol, but not limited to these. Examples of Pd / ligand / base combinations include, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and sodium carbonate. Protecting group P 1 The removal of P results in compound XX. 1 is tert-butoxycarbonyl (BOC), which can be cleaved via acidic conditions in a suitable solvent, including treatment with HCl in a solution in 1,4-dioxane, but is not limited to these. The synthesis of the compound of formula I' is carried out by cleaving the sulfonate of compound VI (wherein R is found in formula I') in a suitable solvent, including acetonitrile, but is not limited to these, in the presence of a suitable base such as potassium carbonate. 3 This can be achieved by substitution with compound XX (where m and n are aryl or alkyl substituents, and m and n are independently integers selected from 1 or 2).

[0225] [ka]

[0226] Scheme 6 describes the preparation of general formulas VI and VII. Referring to Scheme 6a, the BOC protecting group of compound IX (wherein m and n are independently integers selected from 1 or 2) can be removed using an acidic medium such as methanol with HCl, for example, but not limited to these. The crude material can be combined with a base such as ethyl chloroformate and triethylamine in a solvent such as dichloromethane to form ethyl carbamate of formula V. Reduction to pure alcohol XXI as the enantiomer of the ketone can be achieved using an enzymatic reagent such as Codex® keto reductase KRED-P3-G09 and NADP+ (nicotinamide adenine dinucleotide phosphate) in a suitable buffer. Alternatively, racemic reduction can also be carried out using a reducing agent such as sodium borohydride, for example, and chiral separation can be performed in a later step. Compound VI can be obtained by combining XXI with an activated alkyl or aryl sulfonyl chloride or an anhydride in a suitable solvent in the presence of a base such as triethylamine. Referring to Scheme 6b, the ketone reduction of compound IX to pure alcohol XXII as an enantiomer can be achieved using Codex® keto reductase KRED-P3-G09 and an enzyme reagent such as NADP+ (nicotinamide adenine dinucleotide phosphate) in a suitable buffer. Alkyl or aryl sulfonyl chloride or anhydride can be added together with a suitable base such as triethylamine and 4-(dimethylamino)pyridine (DMAP) in a suitable solvent such as dichloromethane. This results in the formation of the compound of formula VII. The removal of the BOC group can be carried out under suitable acidic conditions, such as trifluoroacetic acid in dichloromethane, for example, and then the resulting crude material can be treated with ethyl chloroformate under basic conditions, such as triethylamine in dichloromethane, which can result in the formation of the compound of formula VI.

[0227] As used herein, the term “react” (or “reacted” or “reacted”) refers to a chemical transformation that occurs when specified chemical reactants are brought together to produce a compound different from any of the compounds initially introduced into the system. The reaction may be carried out in the presence or absence of a solvent.

[0228] Compounds of formula I may exist as stereoisomers, e.g., atropisomers, racemates, enantiomers, or diastereomers. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor, or separation of racemates using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may react with a suitable optically active compound, e.g., an alcohol, or, if the compound contains an acidic or basic moiety, with an acid or base, e.g., tartaric acid or 1-phenylethylamine. The resulting diastereomer mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. Chiral compounds of formula I (and their chiral precursors) can be obtained in enantiomer-enriched form by chromatography, usually HPLC, but not limited to, using a mixed solvent system such as aqueous plus acetonitrile (one or both of which may contain additives such as trifluoroacetic acid, formic acid, or concentrated ammonium hydroxide), or by supercritical fluid chromatography performed on an asymmetric resin using a mobile phase consisting of a hydrocarbon such as heptane or hexane containing 0% to 50% 2-propanol, usually 2% to 20%, and 0% to 5% alkylamines, and usually 0.1% diethylamine, combined with carbon dioxide and an organic solvent such as methanol or acetonitrile (which may optionally contain additives such as diethylamine or ammonium hydroxide). Concentration of the eluate yields an enriched mixture. Stereoisomers can be separated by prior art known to those skilled in the art. See, for example, Stereochemistry of Organic Compounds by ELEliel and SHWilen (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety. Appropriate stereoselective techniques are well known to those skilled in the art.

[0229] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way. Those skilled in the art will readily recognize various less important parameters that can be changed or modified to produce essentially the same results. Additional compounds within the scope of the invention can be prepared by using the methods illustrated in these examples alone or in combination with techniques generally known in the art. In the following examples and preparations, "DMSO" means dimethyl sulfoxide, "N" means normal, where concentration is mentioned, "M" means mole, "mL" means milliliter, "mmol" means millimoles, "μmol" means micromoles, "eq." means equivalent, "℃" means Celsius, "MHz" means megahertz, and "HPLC" means high-performance liquid chromatography. [Examples]

[0230] Experimental Procedure The following exemplifies the synthesis of various compounds of the present invention. Additional compounds within the scope of the present invention may be prepared using the methods exemplified in these examples, either alone or in combination with techniques generally known in the art.

[0231] Experiments were generally carried out under an inert atmosphere (nitrogen or argon), especially when oxygen-sensitive or water-sensitive reagents or intermediates were used. Commercial solvents and reagents were generally used without further purification. Anhydrous solvents, where appropriate, were generally AcroSeal® products from Acros Organics, Aldrich® Sure / Seal® products from Sigma-Aldrich, or DriSolv® products from EMD Chemicals. Otherwise, commercial solvents were passed through a column packed with 4Å molecular sieves until the following quality control standards for water were achieved: a) <100 ppm for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For highly sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves and distilled immediately before use. Products were generally dried under vacuum or subjected to biological testing before being used in further reactions. Mass spectrometry data are reported by either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI), or gas chromatography-mass spectrometry (GCMS). Chemical shifts relative to nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) with reference to residual peaks from the deuterated solvent used. In some examples, chiral separation was performed to separate enantiomers of certain compounds of the present invention (in some examples, the separated enantiomers were designated ENT-1 and ENT-2 according to their elution order). In some examples, the optical rotation of the enantiomers was measured using a polarimeter. According to the observed rotational data (or specific rotation data), enantiomers with clockwise rotation were designated (+)-enantiomers, and enantiomers with counterclockwise rotation were designated (-)-enantiomers. Racemic compounds are indicated by the presence of adjacent (+ / -) components in the structure; in these cases, the indicated stereochemistry represents the relative (rather than absolute) stereochemistry of the substituents of the compound.

[0232] The reaction procedure, which involves a detectable intermediate, is generally followed by LC-MS, allowing the process to proceed to complete conversion before the subsequent addition of reagents. Reaction conditions (reaction time and temperature) may differ from the synthetic reference procedure in other examples or methods. Generally, the reaction is followed by thin-layer chromatography or mass spectrometry, subject to work-up if appropriate. Purification may vary experimentally: generally, the solvent and solvent ratio used for the eluate / gradient are appropriate. f The materials are selected to obtain a certain retention time or duration. All starting materials in these preparations and examples can be commercially available or prepared by methods known in the art or as described herein.

[0233] The compounds and intermediates described below were named using the nomenclature provided in ACD / ChemSketch 2012, file version C10H41, Build 69045 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The nomenclature provided in ACD / ChemSketch 2012 is well known to those skilled in the art and is generally considered to conform to the IUPAC (International Union for Pure and Applied Chemistry) recommendations for organic chemical nomenclature and CAS index rules.

[0234] Preparation P1 Ethyl 6-oxo-2-azaspiro[3,4]octane-2-carboxylate (P1)

[0235] [ka]

[0236] Acetyl chloride (88 mL, 1.24 mol) was added to methanol (500 mL) at 0°C, and the resulting solution was stirred in a sealed container for 1 hour. To this hydrogen chloride solution in methanol, tert-butyl 6-oxo-2-azaspiro[3,4]octane-2-carboxylate (20.0 g, 88.8 mmol) and magnesium sulfate (20 g) were added. The reaction mixture was stirred at 55°C for 2 hours, then cooled to room temperature and concentrated under vacuum. The residue (18.4 g) was mixed with dichloromethane (700 mL) and cooled to 0°C under vigorous stirring. After the dropwise addition of ethyl chloroformate (30 mL, 310 mmol), the reaction mixture was treated dropwise with triethylamine (60 mL, 430 mmol) and stirred at 0°C for 1.5 hours. Then it was warmed to room temperature and stirred overnight. Hydrochloric acid (1M; 200 mL, 200 mmol) was added, and stirring was continued at room temperature for 10 minutes. The organic layer was washed with saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained as an amber-colored oily substance by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane). Yield: 13.2 g, 66.9 mmol, 75%. 1 H NMR (400 MHz, CDCl3) δ 4.13 (q, J=7.2 Hz, 2H), 3.92 (AB quartet, J AB =8.6 Hz, Δ νAB =9.1 Hz, 4H), 2.46 (s, 2H), 2.33-2.27 (m, 2H), 2.23-2.17 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). Preparation P2 tert-butyl(6S)-6-[(methylsulfonyl)oxy]-2-azaspiro[3,4]octane-2-carboxylate(P2)

[0237] [ka]

[0238] Step 1. tert-butyl(6S)-6-hydroxy-2-azapiro[3.4] Synthesis of octane-2-carboxylate (C1). This experiment was performed in two batches. A mixture of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (40.0 g, 178 mmol) in 2-propanol (64 mL, 840 mmol) was heated at 50°C until a solution was formed. Buffer solution [potassium phosphate aqueous solution, pH 7.5 (containing 0.1 M, 2 mM magnesium chloride)] (280 mL) was added to a Mettler EasyMax reactor at 30°C and while stirring at 600 rpm. Codex® keto reductase KRED-P3-G09 (800 mg) and NADP were added. + (Nicotinamide adenine dinucleotide phosphate) (80 mg) was added, and the resulting mixture was stirred for 10 minutes. The hot substrate solution was slowly added, while maintaining the reaction temperature below 33°C. The substrate flask was rinsed with additional 2-propanol (10 mL and 6 mL). The stirring speed of the reactants was increased to 600 rpm, and a nitrogen sparge needle was applied at a flow rate of 100 cc / min. Aliquots were taken periodically. Approximately 80 μL of the reaction mixture was mixed with deuterated chloroform (920 μL), the sample was vortexed, and the mixture was centrifuged. 1 The organic layer was analyzed via 1H NMR. After 23 hours, additional Codex® keto reductase KRED-P3-G09 (200 mg) and NADP were added. +(20 mg) was added as a solution in pH 7.5 buffer (4 mL), followed by 2-propanol (20 mL). After an additional 22 hours, the reaction mixture was diluted with ethyl acetate (400 mL) and stirred for 50 minutes. At this point, diatomaceous earth (25 g) was added, and the mixture was stirred for an additional 10 minutes. This was then filtered through diatomaceous earth (25 g), and the filter pad was rinsed with ethyl acetate (200 mL). Using this 200 mL filtrate, the aqueous layer was extracted from the first filtration, the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum to produce a brown oily substance (39.6 g). The two batches were then combined in dichloromethane (600 mL), treated with silica gel (150 g), and concentrated under vacuum for chromatography. Silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane; the product began to elute at approximately 50% ethyl acetate) produced the product as a solid. Combined yield: 63.4g, 279mmol, 78%. 1 H NMR (400 MHz, CDCl3) δ4.39-4.33 (m, 1H), 3.87 (AB quartet, J AB =8.4 Hz, Δ νAB =41.1 Hz, 2H), 3.80-3.74 (m, 2H), 2.12-2.01 (m, 2H), 1.97-1.77 (m, 3H), 1.69-1.59 (m, 1H), 1.44 (s, 9H). Analysis revealed that ee (enanthi) An excess of >99% was obtained [supercritical fluid chromatography]. Column: Chiral Technologies Chiralpak AD-3, 100 × 3.0 mm, 3 μm; Mobile phase A: Carbon dioxide; Mobile phase B: [Methanol containing 0.2% (7M ammonia in methanol)]; Gradient: 5%B for 1.0 min, then 5%~15%B over 7.0 min; Flow rate: 2.0 mL / min; Back pressure: 1800 psi].

[0239] For the absolute stereochemistry of C1, please refer to the following [Stereochemical correlation between tert-butyl(6S)-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (C1) and ethyl(6S)-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (C2)].

[0240] Step 2. Synthesis of tert-butyl(6S)-6-[(methylsulfonyl)oxy]-2-azaspiro[3.4]octane-2-carboxylate (P2). Triethylamine (13.5 mL, 96.9 mmol) and 4-(dimethylamino)pyridine (295 mg, 2.41 mmol) were added to a solution of C1 (11.0 g, 48.4 mmol) in dichloromethane (400 mL). Then, methanesulfonyl chloride (8.40 mL, 108 mmol) was added {caution: exothermic reaction}, and the reaction mixture was stirred overnight. After removing the solvent under vacuum, the residue was mixed with dichloromethane and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane) to obtain the product as an oily substance. Yield: 14.6 g, 47.8 mmol, 99%. LCMS m / z 328.2[M+Na + ] 1 1H NMR (400 MHz, CDCl3) δ 5.19-5.14 (m, 1H), 3.93 (d, half of AB quadruplet, J=8.2 Hz, 1H), 3.85-3.78 (m, 3H), 3.00 (s, 3H), 2.26 (br d, half of AB quadruplet, J=14.4 Hz, 1H), 2.16 (dd, ABX pattern) The components are as follows: J=14.6, 6.0 Hz, 1H), 2.13-1.99 (m, 3H), 1.92-1.83 (m, 1H), 1.44 (s, 9H). Preparation P3 Ethyl(6S)-6-[(methylsulfonyl)oxy]-2-azaspiro[3,4]octane-2-carboxylate(P3)

[0241] [ka]

[0242] A mixture of P2 (14.6 g, 47.8 mmol) in dichloromethane (250 mL) and trifluoroacetic acid (55 mL, 710 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was diluted with dichloromethane (250 mL) and sequentially treated with ethyl chloroformate (9.10 mL, 95.2 mmol) and triethylamine (26.7 mL, 192 mmol). After stirring this reaction mixture at room temperature for 2 hours, it was concentrated under reduced pressure and purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane). The product was obtained as a yellow oily substance, which is 1 ¹H NMR analysis revealed it was not completely pure. Yield: 13.1 g, 47.2 mmol, 99%. LCMS m / z 278.2[M+H] + . 1 1H NMR (400 MHz, CDCl3), peak of the product mi: δ5.20-5.15 (m, 1H), 4.12 (q, J=7.1 Hz, 2H), 4.00 (d, half of the AB quadruplet, J=8.6 Hz, 1H), 3.91-3.85 (m, 3H), 3.00 (s, 3H), 2.29 (br d, half of the AB quadruplet, J=14.8 Hz, 1H), 2.20-2.02 (m, 4H), 1.93-1.85 (m, 1H), 1.25 (t, J=7.0 Hz, 3H). Preparation P4 Ethyl(6S)-6-{[(4-methylphenyl)sulfonyl]oxy}-2-azaspiro[3,4]octane-2-carboxylate(P4)

[0243] [ka]

[0244] Step 1. Synthesis of ethyl(6S)-6-hydroxy-2-azaspiro[3,4]octane-2-carboxylate (C2). The Mettler EasyMax reactor contains Codex® ketoreductase KRED-P3-G09 (60 mg) and NADP. + 8.0 mL of buffer containing (nicotinamide adenine dinucleotide phosphate) (6 mg) [potassium phosphate aqueous solution, pH 7.0 (containing 0.1 M, 2 mM magnesium chloride)] was added. The glassware was rinsed with an additional buffer (2.5 mL) and added to the reaction mixture. Next, a solution of P1 (1.5 g, 7.6 mmol) in 2-propanol (1.5 mL) was added together with 2-propanol rinse solution (1.5 mL). The reaction mixture was stirred at 300 rpm and 30°C with a nitrogen stream of 10 SCCM (cubic centimeters per minute). Aliquots were taken periodically, and approximately 50 μL of the reaction mixture was mixed with deuterated chloroform (0.75 mL), the sample was vortexed, and the mixture was centrifuged. 1The organic layer was analyzed via 1H NMR. When the reaction reached approximately 80% conversion, the nitrogen flow rate was increased to 25 SCCM and the reaction was allowed to proceed overnight. Ethyl acetate (15 mL) was added, and the resulting mixture was vigorously stirred for 10 minutes. At this point, it was treated with diatomaceous earth (1.5 g) and filtered through a moist pad of diatomaceous earth (1.5 g). After washing the filter pad with ethyl acetate (5 mL), the aqueous layer of the combined filtrate was mixed with ethyl acetate (15 mL), vigorously stirred for 5 minutes, and injected through the filter pad. The filter pad was washed again with ethyl acetate (5 mL), and the aqueous layer was extracted from these filtrates in the same manner. The combined organic layer from these operations was dried over sodium sulfate, filtered, and concentrated under vacuum. By silica gel chromatography (gradient: 20% to 80% ethyl acetate in heptane), the product was obtained as a pale yellow oily substance. Analysis yielded an enantiomeric excess (ee) > 99% {supercritical fluid chromatography}. Column: Chiral Technologies Chiralpak AD, 250 × 4.6 mm, 5 μm; Mobile phase: 85: 15 carbon dioxide / [methanol containing 0.2% (7 M ammonia in methanol)]; Flow rate: 3.0 mL / min; Back pressure: 120 bar. Yield: 1.20 g, 6.02 mmol, 79%. 1 H NMR (400 MHz, CDCl3) δ4.41-4.33 (m, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.93 (AB quartet, J AB =8.4 Hz, Δ νAB (=42.3 Hz, 2H), 3.86-3.80 (m, 2H), 2.13-2.02 (m, 2H), 1.98-1.78 (m, 3H), 1.70-1.6 (m, 1H, estimated; partially obscured by water peaks), 1.42 (d, J=3.1 Hz, 1H), 1.24 (t, J=7.0 Hz, 3H). The absolute configurations shown were specified based on the conversion of C2 to P4, and then to P6 (see alternative synthesis in Example 6 below).

[0245] Step 2. Synthesis of ethyl(6S)-6-{[(4-methylphenyl)sulfonyl]oxy}-2-azaspiro[3,4]octane-2-carboxylate (P4). 4-methylbenzenesulfonic anhydride (6.29 g, 19.3 mmol) was added to a mixture of C2 (synthesized via in vivo reduction of P1; see previous step; 3.20 g, 16.1 mmol) in pyridine (80 mL) at 0°C. After the addition of 4-(dimethylamino)pyridine (196 mg, 1.60 mmol), the reaction mixture was stirred overnight until the ice bath melted. LC-MS analysis at this point yielded the product: LC-MS m / z 354.3 [M+H] + The presence of [substance name] was demonstrated. The reaction mixture was concentrated under vacuum and then diluted with an aqueous sodium bisulfate solution (10%; 100 mL). The aqueous layer was then sequentially extracted with diethyl ether (150 mL) and dichloromethane (150 mL). The combined organic layers were concentrated under reduced pressure and purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane) to obtain the product as an oily substance. Yield: 4.54 g, 12.8 mmol, 80%. 1 H NMR (400 MHz, CDCl3) δ7.78 (d, J=8.2 Hz, 2H), 7.35 (d, J=7.8 Hz, 2H), 5.01-4.92 (br m, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.87 (AB quartet, J AB =8.6 Hz, Δ νAB (=32.4 Hz, 2H), 3.82-3.76 (m, 2H), 2.46 (s, 3H), 2.12 (br d, half of the AB quadruplet, J=14.8 Hz, 1H), 2.09-1.96 (m, 2H), 1.94-1.86 (m, 2H), 1.85-1.76 (m, 1H), 1.24 (t, J=7.2 Hz, 3H). The shown absolute configuration of this material was established by using it as follows in the alternative synthesis of Example 6. The sample of 6 is described below. It was shown to be the same material used for the X-ray crystal structure determination.

[0246] Stereochemical relationship between tert-butyl(6S)-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (C1) and ethyl(6S)-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (C2)

[0247] [ka]

[0248] Synthesis of ethyl 6-hydroxy-2-azaspiro[3,4]octane-2-carboxylate (C3). Sodium borohydride (95 mg, 2.5 mmol) was added all at once to a solution of P1 (280 mg, 1.42 mmol) in methanol (10 mL) {caution: exothermic reaction}. The reaction mixture was stirred for 2 hours, then diluted with hydrochloric acid (1 M; 5 mL) and stirred at room temperature for 5 minutes. Water (5 mL) was then added, and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the product as an oily substance. Yield: 233 mg, 1.17 mmol, 82%. 1 H NMR (400 MHz, CDCl3) δ4.41-4.34 (m, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.93 (AB quartet, J AB =8.4 Hz, Δ νAB =41.9 Hz, 2H), 3.86-3.80 (m, 2H), 2.14-2.02 (m, 2H), 1.98-1.78 (m, 3H), 1.70-1.6 (m, 1H, estimated; partially unclear due to water peak), 1.45-1.32 (br s, 1H), 1.24 (t, J=7.2 Hz, 3H). Step 1. Synthesis of (6S)-2-azaspiro[3.4]octan-6-ol, hydrochloride (C4).

[0249] A solution of hydrogen chloride in 1,4-dioxane (4M; 8 mL, 32 mmol) was added to a mixture of C1 (512 mg, 2.25 mmol) in ethyl acetate (12 mL), and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum to produce the product, which was used in the following reaction without purification.

[0250] Step 2. Synthesis of ethyl(6S)-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (C1 to C2). Ethyl chloroformate (0.258 mL, 2.70 mmol) was added dropwise to a mixture of C4 (from a previous step, ≤2.25 mmol) and triethylamine (0.943 mL, 6.76 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 1 hour, then diluted with hydrochloric acid (1 M; 10 mL) and stirred at room temperature for 5 minutes. The aqueous layer was extracted with dichloromethane (15 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The product was obtained as an oily substance by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane). 1 By 1H NMR analysis It turned out that this material was not completely pure. Yield: 100 mg, 0.502 mmol, 22% over two steps. 1 1H NMR (400 MHz, CDCl3), product peaks only: δ 4.34-4.26 (br m, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.89 (AB quartet, J AB =8.6 Hz, Δ νAB =44.8 Hz, 2H), 3.81-3.75 (m, 2H), 2.09-1.96 (m, 2H), 1.93-1.82 (m, 2H), 1.82-1.73 (m, 1H), 1.66-1.56 (m, 1H), 1.20 (t, J=7.2 Hz, 3H). The absolute stereochemistry of C1 and C2 from KRED-P3-G09 reduction (preparation P4) is shown to be the same in the following manner: Compound C1 was converted from C1 to sample C2 (steps 1 and 2 above). The racemic mixture of C2 (C3) was tested via supercritical fluid chromatography [column: Chiral Technologies Chiralpak AD-H, 250 × 4.6 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol containing 0.2% (7 M ammonia in methanol); gradient: 5% B for 1.0 minute, then 5% to 40% B for 8.0 minutes; flow rate: 3.0 mL / min; back pressure: 1800 psi]. The two enantiomers eluted with retention times of 4.57 minutes and 4.94 minutes. The C2 sample obtained from the reduction of P1 using KRED-P3-G09 (preparation P4) yielded a retention time of 4.9 minutes under the same chromatographic conditions as when the C2 sample was obtained from C1.

[0251] Examples 1, 2, and 3 Ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate(1), Ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-1(2), and Ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-2(3)

[0252] [ka]

[0253] Step 1. Synthesis of tert-butyl 4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-carboxylate (C5). A solution of tetrakis(triphenylphosphine)palladium(0) (89 mg, 77 μmol) in toluene (5 mL) and ethanol (2 mL) was added to a mixture of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]piperazine-1-carboxylate (300 mg, 0.771 mmol), 2-bromo-5-methoxypyrazine (146 mg, 0.772 mmol), and aqueous sodium carbonate solution (2 M, 10 mL). The reaction mixture was stirred at 100 °C under microwave irradiation for 3 hours, and then concentrated under vacuum. [Experiments based on this method often used standard heating above 60 °C.] The product was obtained as a yellow solid by purification of the residue using silica gel chromatography (gradient: 0% to 40% ethyl acetate in petroleum ether). Yield: 260 mg, 0.700 mmol, 91%. LCMS m / z372.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ8.80-8.72 (br s, 1H), 8.33 (d, J=1.5 Hz, 1H), 8.33-8.28 (m, 1H), 7.86 (br d, J=6.8 Hz, 1H), 7.08-7.01 (m, 1H), 4.03 (s, 3H), 3.50-3.41 (br m, 4H), 3.21-3.05 (br m, 4H), 1.46 (s, 9H). Step 2. Synthesis of 2-methoxy-5-[2-(piperazin-1-yl)pyridine-3-yl]pyrazine, tetrahydrochloride salt (C6). 1,4-dioxane of hydrogen chloride ( A 4M (3 mL, 12 mmol) solution was added to a C5 (260 mg, 0.700 mmol) solution in acetonitrile (6 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, producing a yellow oily product, which was used directly in the next step. 1 According to 1H NMR analysis, this material was not perfectly pure. Yield: 290 mg, 0.695 mmol, 99%. LCMS m / z 272.2[M+H] + . 1H NMR (400 MHz, DMSO-d6), product peaks only: δ 9.57-9.42 (br m, 2H), 8.77 (d, J=1.2 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.30 (dd, J=5.1, 1.7 Hz, 1H), 7.98 (dd, J=7.3, 1.5 Hz, 1H), 7.22 (dd, J=7.5, 5.3 Hz, 1H), 3.98 (s, 3H), 3.36-3.28 (br m, 4H), 3.12-3.04 (br m, 4H). Step 3. Synthesis of ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate (1).

[0254] A mixture of C6 (220 mg, 0.527 mmol) and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (40 mL) was stirred at room temperature for 30 minutes. At this point, P1 (156 mg, 0.791 mmol) was added, followed by titanium(IV) ethoxide (1.5 mL, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 hours, then sodium borohydride cyanohydride (490 mg, 7.80 mmol) was added, followed by methanol (6 mL), and stirring was continued at room temperature for another 4 hours. Water (4 mL) was then added, and the resulting mixture was concentrated under vacuum. Purification was performed using silica gel chromatography (gradient: 0%~10% methanol in dichloromethane), followed by reverse-phase chromatography (column: Agela Technologies C18; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 45%~60% B). The product was isolated as a pale yellow solid. Yield: 170 mg, 0.376 mmol, 71%. LCMS m / z 453.3 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ8.76 (br s, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.28 (dd, J=4.9, 1.7 Hz, 1H), 7.81 (dd, J=7.5, 1.8 Hz, 1H), 6.99 (dd, J=7.5, 5.0 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 4.04 (s, 3H), 3.86 (AB quadruple, low-field double line spreading, J AB =8.3 Hz, Δ νAB =22.5 Hz, 2H), 3.81-3.74 (m, 2H), 3.29-3.10 (br m, 4H), 2.67-2.40 (br m, 5H), 2.11 (dd, J=12, 7 Hz, 1H), 2.02-1.45 (m, 5H, estimated; partially unclear due to water peak), 1.24 (t, J=7.1 Hz, 3H). Step 4. Isolation of ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-1(2) and ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-2(3).

[0255] The enantiomers of compound 1 (150 mg, 0.331 mmol) were separated via reverse-phase HPLC [column: Chiral Technologies ChiralCel OD, 10 μm; mobile phase: 4:1 hexane / ethanol]. The isolated enantiomers were then individually subjected to reverse-phase chromatography (column: Agela Technologies C18; mobile phase A: water containing 0.1% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 0%~60%B) to produce yellow solid products. The first eluted enantiomer was designated as 2, and the second eluted enantiomer was designated as 3.

[0256] 2. Yield: 40 mg, 88 μmol, 27%. LCMS m / z 453.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ8.76 (br s, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.28 (dd, J=4.8, 1.8 Hz, 1H), 7.81 (dd, J=7.5, 1.8 Hz, 1H), 6.99 (dd, J=7.3, 4.9 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 4.03 (s, 3H), 3.86 (AB quadruple, low field double line spreads out) ru, J AB =8.3 Hz, Δ νAB =22.5 Hz, 2H), 3.80-3.74 (m, 2H), 3.30-3.10 (br m, 4H), 2.69-2.41 (br m, 5H), 2.11 (dd, J=12.5, 6.8 Hz, 1H), 2.00-1.48 (m, 5H, estimated; Mizupi (Partially unclear due to the work), 1.24 (t, J=7.1 Hz, 3H). Retention time: 3.52 min (Analytical conditions. Column: Chiral Technologies ChiralCel OD-H, 150 × 4.6 mm, 5 μm; Mobile phase: 80:20:0.1 hexane / ethanol / diethylamine; Flow rate: 1.0 mL / min).

[0257] 3-Yield: 43mg, 95μmol, 29%. LCMS m / z453.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ8.75 (br s, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.28 (dd, J=4.9, 2.0 Hz, 1H), 7.81 (dd, J=7.5, 1.8 Hz, 1H), 6.99 (dd, J=7.3, 4.9 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 4.04 (s, 3H), 3.93-3.86 (br m, 1H), 3.84 (d, half of the AB quadruplet, J=8.3 Hz, 1H), 3.80-3.75 (m, 2H), 3.33-3.06 (br m, 4H), 2.71-2.35 (br m, 5H), 2.18-2.06 (m, 1H), 2.04-1.45 (m, 5H, estimated; partially unclear due to water peak), 1.24 (t, J=7.1 Hz, 3H). Retention time: 4.53 mins (same analytical conditions as used for sample 2). ).

[0258] Example 4 Ethyl(6R)-6-{4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate(4)

[0259] [ka]

[0260] Step 1. Synthesis of tert-butyl 4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-carboxylate (C7). Ethanol (30 mL) and sodium carbonate (8.85 g, 83.5 mmol) in water The solution in (33 mL) was added to a mixture of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]piperazine-1-carboxylate (13.0 g, 33.4 mmol) and 4-bromo-1,3-thiazole (6.57 g, 40.1 mmol) in toluene (180 mL). Tetrakis(triphenylphosphine)palladium(0) (2.69 g, 2.33 mmol) was then added, and the reaction mixture was stirred at 90°C for 12 hours. After removing the solvent under vacuum, the residue was purified using silica gel chromatography (gradient: 0%~60%, ethyl acetate in petroleum ether) to obtain the product as a pale yellow solid. Yield: 7.00 g, 20.2 mmol, 60%. LCMS m / z 347.1[M+H] + .

[0261] Step 2.1 - Synthesis of [3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine (C8). A solution of hydrogen chloride in 1,4-dioxane (4M; 50 mL, 200 mmol) was added at 0°C to a solution of C7 (11.0 g, 31.8 mmol) in acetonitrile (100 mL). The reaction mixture was stirred at room temperature for 16 hours and filtered at this point. The collected solid was washed with ethyl acetate and then suspended in a mixture of dichloromethane (150 mL) and methanol (25 mL). Potassium carbonate (20 g, 145 mmol) was added, and the mixture was stirred at room temperature for 16 hours and then filtered. The filter cake was washed with a mixture of dichloromethane and methanol (10:1, 60 mL), and the combined filtrate was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the product as a yellow oily substance. 1 According to 1H NMR analysis, this material was not completely pure. Yield: 7.5g, 30 mmol, 94%. LCMS m / z 247.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6), raw Peaks of the product only: δ9.19 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.22 (dd, J=4.8, 1.8 Hz, 1H), 8.10 (dd, J=7.5, 1.8 Hz, 1H), 7.04 (dd, J=7.5, 4.8 Hz, 1H), 2.97-2.91 (m, 4H), 2.80-2.73 (m, 4H). Step 3. Synthesis of tert-butyl(6R)-6-{4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate (C9).

[0262] This experiment was performed using two identical batches. A mixture of C8 (1.10 g, 4.47 mmol), P2 (1.91 g, 6.25 mmol), and potassium carbonate (1.54 g, 11.1 mmol) in acetonitrile (20 mL) was placed in a sealed container and heated at 95°C for 16 hours. At this point, it was concentrated under vacuum. Silica gel chromatography (gradient: 0%-10% methanol in dichloromethane) yielded the product as a pale yellow oily substance. Total yield: 1.70 g, 3.73 mmol, 42%. LCMS m / z 456.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.20 (d, J=1.5 Hz, 1H), 8.23 ​​(dd, J=4.6, 1.5 Hz, 1H), 8.20 (br s, 1H), 8.10 (br d, J=7.6 Hz, 1H), 7.06 (dd, J=7.3, 4.6 Hz, 1H), 3.76-3.58 (br m, 4H), 3.07-2.96 (br m, 4H), 2.64-2.39 (m, 5H, estimated; significantly obscured by solvent peaks), 2.07-1.96 (m, 1H), 1.87-1.69 (m, 3H), 1.69-1.57 (m, 1H), 1.50-1.4 (m, 1H), 1.36 (s, 9H). Step 4. Synthesis of (6R)-6-{4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane(C10).

[0263] Trifluoroacetic acid (15 mL) was added to a solution of C9 (6.00 g, 13.2 mmol) in dichloromethane (120 mL), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then concentrated under vacuum, and the residue was dissolved in a mixture of dichloromethane and methanol (9:1, 150 mL). Sodium carbonate (15 g) was added, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain the product as a yellow oily substance. Yield: 4.50 g, 12.7 mmol, 96%. LCMS m / z 356.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ9.15-9.13 (m, 1H), 8.31-8.27 (m, 1H), 8.16-8.1 3 (m, 1H), 8.07 (br d, J=7.6 Hz, 1H), 7.18-7.12 (m, 1H), 3.69 (br d, AB quadruple line Half, J=12 Hz, 1H), 3.65–3.49 (m, 5H), [3.40–3.24 (m) and 3.16–3.07 (m), total 7H, estimated; partially unclear due to solvent peaks], 2.41–2.28 (m, 2H), 2.02–1.81 (m, 3H), 1.72–1.63 (br m, 1H). Step 5. Synthesis of ethyl(6R)-6-{4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate (4). Ethyl chloroformate (3.66 g, 33.7 mmol) was added to a mixture of C10 (4.00 g, 11.2 mmol) and N,N-diisopropylethylamine (8.73 g, 67.5 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with dichloromethane (2 × 50 mL). The combined organic layer was concentrated and purified by silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) to produce a pale yellow gum-like substance (2.1 g). The material was re-purified using silica gel chromatography (gradient: 0% to 20% methanol in dichloromethane) to obtain the product as a yellowish-brown foamy substance. Yield: 1.77 g, 4.14 mmol, 37%. LCMS m / z 428.4[M+H] + . 1 H NMR (400 MHz, CDCl3) δ8.88 (d, J=2.0 Hz, 1H), 8.26 (dd, J=4.7, 2.0 Hz, 1H), 8.11 (dd, J=7.4, 2.0 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 6.98 (dd, J=7.6, 4.9 Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.86 (AB quartet, J AB =8.4 Hz, Δ νAB =20.8 Hz, 2H), 3.79 (AB quartet, J AB =8.4 Hz, Δ νAB =6.0 Hz, 2H), 3.21-3.15 (m, 4H), 2.62-2.48 (br m, 5H), 2.12 (dd, J=12.7, 6.8 Hz, 1H), 1.98-1.78 (m, 3H), 1.72 (dd, J=12.7, 9.6 Hz, 1H), 1.61-1.50 (m, 1H), 1.24 (t, J=7.2 Hz, 3H). Example 5 Ethyl(6R)-6-{4-[3-(1,3,4-thiadiazole-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate(5)

[0264] [ka]

[0265] Step 1. tert-butyl4-[3-(1,3,4-thiadiazole-2-yl) Synthesis of pyridine-2-yl]piperazine-1-carboxylate (C11). This experiment was performed in eight identical batches.

[0266] To a mixture of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]piperazine-1-carboxylate (400 mg, 1.03 mmol) in acetonitrile (20 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos; 147 mg, 0.308 mmol) was added, followed by 2-bromo-1,3,4-thiadiazole (203 mg, 1.23 mmol), sodium carbonate (163 mg, 1.54 mmol), water (4 mL), and tris(dibenzylideneacetone)dipalladium (0) (94.0 mg, 0.103 mmol). The reaction mixture was stirred in a sealed container at 100°C for 7 hours. At this point, it was concentrated under vacuum and purified by silica gel chromatography (gradient: 0% to 80% ethyl acetate in petroleum ether) to obtain a pale yellow oily substance (550 mg). The products from all eight reactions were combined and subjected to silica gel chromatography (gradient: 0% to 70% ethyl acetate in petroleum ether) to produce a pale yellow solid. Combined yield: 1.20 g, 3.45 mmol, 42%. LCMS m / z 348.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ9.20 (s, 1H), 8.50 (dd, J=7.7, 1.8 Hz, 1H), 8.47 (dd, J=4.8, 1.8 Hz, 1H), 7.19 (dd, J=7.7, 4.8 Hz, 1H), 3.61 (dd, J=5, 5 Hz, 4H), 3.10 (dd, J=5, 5 Hz, 4H), 1.48 (s, 9H). Step 2.1 - Synthesis of [3-(1,3,4-thiadiazole-2-yl)pyridine-2-yl]piperazine (C12). A solution of hydrogen chloride in 1,4-dioxane (4M; 15 mL, 60 mmol) was added to a mixture of C11 (1.10 g, 3.17 mmol) in acetonitrile (30 mL), and the reaction mixture was stirred at room temperature for 3 hours. After removing the solvent under vacuum, the residue was pulverized with ethyl acetate to obtain a white solid (1.0 g). This material was dissolved in a mixture of dichloromethane and methanol (10:1, 150 mL) and treated with potassium carbonate (5.0 g, 36.2 mmol). The mixture was stirred at room temperature for 16 hours, and then filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to produce the product as a pale yellow solid. Yield: 700 mg, 2.83 mmol, 89%. LCMS m / z 248.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ9.20 (s, 1H), 8.52-8.45 (m, 2H), 7.17 (dd, J=7.6, 4.9 Hz, 1H), 3.14-3.04 (m, 8H). Step 3. Synthesis of ethyl(6R)-6-{4-[3-(1,3,4-thiadiazole-2-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3,4]octane-2-carboxylate(5).

[0267] A mixture of C12 (700 mg, 2.83 mmol), P3 (1.23 g, 4.43 mmol), and potassium carbonate (511 mg, 3.70 mmol) in acetonitrile (20 mL) was placed in a sealed container and stirred at 100°C for 16 hours. The reaction mixture was then concentrated under vacuum and purified using silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) to obtain the product as a white solid. Yield: 400 mg, 0.933 mmol, 33%. LCMS m / z 429.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ9.20 (s, 1H), 8.47-8.41 (m, 2H), 7.14 (dd, J=7.6, 4.9 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.88 (AB quartet, J AB =8.3 Hz, Δ νAB =21.7 Hz, 2H), 3.83-3.76 (m, 2H), 3.25-3.12 (br m, 4H), 2.73-2.55 (br m, 5H), 2.13 (dd, J=12.6, 7.0 Hz, 1H), 2.02-1.51 (m, 5H, estimated; partially unclear due to water peak), 1.24 (t, J=7.1 Hz, 3H). Examples 6 and 7 Ethyl(6R)-6-[4-(3-methoxypyridine-2-yl)piperazine-1-yl]-2-azaspiro[3.4]octane-2-carboxylate(6) and Ethyl(6S)-6-[4-(3-methoxypyridine-2-yl)piperazine-1-yl]-2-azaspiro[3.4]octane-2-carboxylate(7)

[0268] [ka]

[0269] Step 1. Synthesis of tert-butyl 6-[4-(3-methoxypyridine-2-yl)piperazine-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C13). A suspension of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (2.00 g, 8.88 mmol), 1-(3-methoxypyridine-2-yl)piperazine, trihydrochloride (2.71 g, 8.96 mmol), triethylamine (7.38 mL, 52.9 mmol), sodium borohydride cyanohydride (3.35 g, 53.3 mmol), and magnesium sulfate (3.21 g, 26.7 mmol) in ethanol (50 mL) was stirred at 45 °C for 16 hours. The reaction mixture was then concentrated and dried under vacuum. The product was obtained as a pale yellow oily substance by silica gel chromatography (eluent: 1:10 methanol / dichloromethane), and this was used in the next step without purification. LCMS m / z 403.1[M+H] + .

[0270] Step 2.6 - Synthesis of [4-(3-methoxypyridine-2-yl)piperazin-1-yl]-2-azaspiro[3.4]octane, trifluoroacetate (C14). Trifluoroacetic acid (20 mL) was added dropwise to a solution of C13 (from a previous step; ≤8.88 mmol) in dichloromethane (80 mL). The reaction mixture was stirred at 10°C for 2 hours. At this point, it was concentrated and dried under reduced pressure to obtain the product as a pale yellow oily substance, which was used directly in the following steps. LCMS m / z 302.9[M+H] + .

[0271] Step 3. Synthesis of ethyl 6-[4-(3-methoxypyridine-2-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C15). Ethyl chloroformate (2.89 g, 26.6 mmol) was added to a solution of C14 (from the previous step, ≤8.88 mmol) and triethylamine (12.3 mL, 88.2 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 10°C for 16 hours, and at this point it was concentrated and dried under vacuum. Silica gel chromatography (gradient: The product was purified via dichloromethane (0%-9% methanol), followed by reverse-phase HPLC (column: Phenomenex Gemini C18, 10 μm; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase B: acetonitrile; gradient: 25%-44% B). The resulting material was then subjected to silica gel chromatography (ethyl acetate eluate, followed by a gradient of dichloromethane (0%-9% methanol)) to obtain the product as a white solid. Yield: 1.68 g, 4.49 mmol, 51% over 3 steps. LCMS m / z 375.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ7.80 (dd, J=5.0, 1.5 Hz, 1H), 7.29 (dd, J=8.0, 1.0 Hz, 1H), 6.98 (dd, J=8.0, 5.0 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.99-3.78 (m, 4H), 3.87 (s, 3H), 3.68-3.44 (br m, 4H), 3.41-3.3 (m, 1H, estimated; partially unclear due to solvent peaks), 3.28-3.11 (br m, 4H), 2.40 (dd, J=13.0, 8.0 Hz, 1H), 2.22-2.11 (m, 1H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 2H), 1.83-1.70 (m, 1H), 1.23 (t, J=7.0 Hz, 3H). Step 4. Isolation of ethyl(6R)-6-[4-(3-methoxypyridine-2-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (6) and ethyl(6S)-6-[4-(3-methoxypyridine-2-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (7).

[0272] The separation of C15 (1.67 g, 4.46 mmol) into its constituent enantiomers was performed via supercritical fluid chromatography {column: Phenomenex Lux Amylose-1, 5 μm; mobile phase: 4:1 carbon dioxide / [ethanol containing 0.2% (7 M ammonia in ethanol)]; back pressure: 120 bar}. The first eluted enantiomer was designated as 6, and the second eluted enantiomer as 7. The absolute configurations shown were determined based on X-ray structural analysis performed on the hydrochloride salt of 6 (see below).

[0273] 6. Yield: 394 mg, 1.05 mmol, 24%. Retention time: 5.80 min {Analytical conditions: Column: Phenomenex Lux Amylose-1, 250 × 4.6 mm, 5 μm; Mobile phase A: Carbon dioxide; Mobile phase B: [Ethanol containing 0.2% (7 M ammonia in ethanol)]; Gradient: 5% for 1 minute, then 5% to 60% B over 8.0 minutes; Flow rate: 3.0 mL / min; Back pressure: 120 bar}.

[0274] 7. Yield: 453 mg, 1.21 mmol, 27%. LCMS m / z 375.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ7.87 (br d, J=4.7 Hz, 1H), 7.03 (br d, J=7.8 Hz, 1H), 6.83 (dd, J=8.0, 4.9 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.90 (d, AB quadruple Half of the line, J=8.6 Hz, 1H), 3.86-3.82 (m, 1H), 3.84 (s, 3H), 3.79 (AB quadruple line, J AB =8.4 Hz, Δ νAB =8.4 Hz, 2H), 3.47-3.39 (br m, 4H), 2.71-2.57 (br m, 5H), 2.14 (dd, J=12.9, 7.0 Hz, 1H), 1.99-1.81 (m, 3H), 1.77 (dd, J=12.5, 9.8 Hz, 1H), 1.67-1.55 (m, 1H), 1.24 (t, J=7.0 Hz, 3H).Retention time: 6.68 minutes (analytical conditions used for 6). (Same as the one used).

[0275] Conversion of 6 to its hydrochloride salt (6·HCl) for single-crystal X-ray structure determination A solution of hydrogen chloride in 1,4-dioxane (4M; 6.3 μL, 25 μmol) was added to a 1.77 g (1 dram) vial containing 6 (9.5 mg, 25 μmol) of ethanol (254 μL). The vial was manually shaken for 30 seconds, and then left to stand with the lid open for 18 hours. At that point, the ethanol had evaporated, leaving behind small needle-shaped crystals of 6·HCl, one of which was analyzed by single-crystal X-ray structure determination, as outlined below.

[0276] Single-crystal X-ray structure determination of 6-HCl Single-crystal X-ray analysis Data acquisition was performed using a Bruker APEX diffractometer at -150°C. It consisted of Omega and Facecan.

[0277] The structure was elucidated directly using the SHELX software suite in the orthorhombic class space group P212121. Subsequently, the structure was refined using the full matrix least squares method. All non-hydrogen atoms were discovered and refined using anisotropy displacement parameters.

[0278] Hydrogen atoms positioned as proton acceptors on nitrogen atoms were discovered using a Fourier difference map and refined using a limited distance. The hydrogen atoms were then placed at their calculated positions and superimposed onto these support atoms. The final refinement included isotropic displacement parameters for all hydrogen atoms.

[0279] A squeeze algorithm via Platon was applied to eliminate the observed residual electron density of the presumably disordered ethyl acetate solvent located at the center of symmetry. The agreement factor was improved by 1.7%.

[0280] An analysis of the absolute structure using a possible method (Hooft, 2008) was performed using PLATON (Spek). The results indicate that the absolute structure is correctly specified. The method calculates that the probability of the structure being correct is 1.000. The Hooft parameter is reported to be 0.035 with an ESD of 0.011.

[0281] The asymmetric unit consists of two molecules of protonated 6 (2 + ), 2 chloride ions (2 - It contained ), and one water molecule (half-occupying). The final R-index was 5.3%. The final differential Fourier analysis revealed no defects or incorrect electron density.

[0282] Relevant crystals, data collections, and refinement information are summarized in Table A. Atomic coordinates, bond lengths, bond angles, and substitution parameters are listed in Tables B through D. Software and References SHELXTL, Version 5.1, Bruker AXS, 1997. PLATON, ALSpek, J.Appl.Cryst.2003, vol. 36, pp. 7-13. MERCURY, CFMacrae, PREdington, P.McCabe, E.Pidcock, GPShields, R.Taylor, M.Towler, J.van de Streek, J.Appl.Cryst. 2006, Volume 39, Pages 453~457. OLEX2, OVDolomanov, LJBourhis, RJGildea, JAKHoward, H.Puschmann, J.Appl.Cryst., 2009, Volume 42, Pages 339~341. RWWHooft, LHStraver ALSpek, J.Appl.Cryst., 2008, volume 41, pages 96~103. HDFlack, ActaCryst., 1983. Volume A39, pages 867~881.

[0283] Table 1

[0284] Table 2-1

[0285] Table 2-2

[0286] Table 2-3

[0287] Table 2-4

[0288] Table 2-5

[0289] [Table 2-6]

[0290] [Table 2-7]

[0291] [Table 3-1]

[0292] [Table 3-2]

[0293] [Table 3-3]

[0294] Alternative synthesis in Example 6 Ethyl(6R)-6-[4-(3-methoxypyridine-2-yl)piperazine-1-yl]-2-azaspiro[3,4]octane-2-carboxylate(6)

[0295] [ka]

[0296] 1-(3-methoxypyridine-2-yl)piperazine hydrochloride (130 mg, 0.566 mmol), P4 (240 mg, 0.679 mmol), potassium carbonate (313 mg, 2.26 mmol), and acetonitrile (2.3 mL) were placed in a sealed container and heated overnight at 90°C. After the reaction mixture cooled to room temperature, it was adsorbed onto silica gel and purified via silica gel chromatography (gradient: 0% to 20% methanol in dichloromethane) to obtain the product as a light brown oily substance. Yield: 80 mg, 0.21 mmol, 37%. LCMS m / z 375.1[M+H] + . 11H NMR (400 MHz, CDCl3) δ7.88 (dd, J=4.9, 1.4 Hz, 1H), 7.03 (dd, J=7.8, 1.2 Hz, 1H), 6.84 (dd, J=8.0, 4.9 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.91 (d, half of AB quartet, J=8.2 Hz, 1H), 3.87-3.83 (m, 1H), 3.85 (s, 3H), 3.80 (AB quartet, J AB =8.2 Hz, Δ νAB =8.4 Hz, 2H), 3.48-3.39 (br m, 4H), 2.69-2.56 (br m, 5H), 2.15 (dd, J=12.9, 7.0 Hz, 1H), 2.00-1.80 (m, 3H), 1.76 (dd, J=12.7, 9.6 Hz, 1H), 1.65-1.53 ​​(m, 1H, Estimated; partially unclear due to water peak), 1.24 (t, J=7.0 Hz, 3H). The absolute configuration of this synthesized material (6-alternative synthesis) was established as follows by comparison with the material used to prepare the X-ray crystal structure sample described above (6-X-ray preparation). Racemic C15 was tested using supercritical fluid chromatography {column: Phenomenex Lux Amylose-1, 250 × 4.6 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol containing 0.2% (7 M ammonia in methanol); gradient: 5% B for 1.0 minute, then 5% to 60% B for 8.0 minutes; flow rate: 3.0 mL / min; back pressure: 120 bar}. Two peaks were observed for the two enantiomers: one at 5.82 min and the other at 6.54 min. Under the same conditions, 6 -A retention time of 5.83 minutes was obtained by alternative synthesis. A retention time of 5.83 minutes was obtained by 6-X-ray preparation. This confirms that the two samples possess the same absolute configuration.

[0297] Example 8 Ethyl(6R)-6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate(8)

[0298] [ka]

[0299] Step 1. Synthesis of tert-butyl 4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-carboxylate (C16). 6.00 g, 15.4 mmol of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]piperazine-1-carboxylate, 2-bromopyrazine (2.7 g, 17 mmol), tetrakis(triphenylphosphine)palladium (0) (1.78 g, 1.54 mmol), and potassium carbonate (6.39 g, 46.2 mmol) were stirred at 100°C for 16 hours in a mixture of toluene (80 mL), ethanol (30 mL), and water (3 mL). Next, the reaction mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (gradient: 0% to 50% ethyl acetate in petroleum ether) to produce a yellow, gum-like product. Yield: 5.00 g, 14.6 mmol, 95%. LC-MS m / z 342.2 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ9.22 (br s, 1H), 8.68 (dd, J=2.4, 1.5 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.35 (dd, J=4.9, 1.7 Hz, 1H), 7.90 (dd, J=7.6, 1.7 Hz, 1H), 7.06 (dd, J=7.6, 4.9 Hz, 1H), 3.46-3.39 (m, 4H), 3.16-3.07 (br m, 4H), 1.45 (s, 9H). Step 2.2 - Synthesis of [2-(piperazin-1-yl)pyridine-3-yl]pyrazine (C17). The mixture of C16 (5.30 g, 15.5 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4 M; 15.5 mL, 62 mmol) in dichloromethane (60 mL) and methanol (20 mL) was stirred at room temperature for 2 hours, followed by heating at 40 °C for 1 hour. After removing the solvent under vacuum, the residue was dissolved in methanol (100 mL), treated with potassium carbonate (12.0 g, 86.8 mmol), and stirred at room temperature for 1 hour. The mixture was then subjected to reduced pressure. The solution was concentrated under the following conditions, and the residue was purified using silica gel chromatography (gradient: 0%-10% methanol in dichloromethane) to obtain the product. Yield: 2.90 g, 12.0 mmol, 77%. LCMS m / z 242.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.18 (d, J=1.7 Hz, 1H), 8.74 (dd, J=2.6, 1.6 Hz, 1H), 8.57 (d, J=2.7 Hz, 1H), 8.30 (dd, J=4.9, 2.0 Hz, 1H), 7.85 (dd, J=7.6, 2.0 Hz, 1H), 7.07 (dd, J=7.5, 4.8 Hz, 1H), 2.95-2.90 (m, 4H), 2.67-2.62 (m, 4H). Step 3. Synthesis of ethyl(6R)-6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate(8).

[0300] A mixture of C17 (2.50 g, 10.4 mmol), P4 (5.13 g, 14.5 mmol), and potassium carbonate (4.3 g, 31.1 mmol) in acetonitrile (25 mL) was placed in a sealed container and stirred at 100°C for 48 hours. After removing the solvent under vacuum, the residue was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over sodium sulfate, filtered, concentrated under vacuum, and purified via silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) to produce a yellow, gum-like substance. Yield: 2.90 g, 6.86 mmol, 66%. LCMS m / z 423.2[M+H] + . 1 ¹H NMR (400 MHz, CDCl3) δ9.23 (br s, 1H), 8.66 (dd, J=2.4, 1.5 Hz, 1H), 8.48 (d, J=2.7 Hz, 1H), 8.33 (dd, J=4.8, 1.8 Hz, 1H), 7.88 (dd, J=7.5, 1.8 Hz, 1H), 7.03 (dd, J=7.3, 4.9 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.85 (AB quadruplet, low field double line broadened, J AB =8.3 Hz, Δ νAB =22.7 Hz, 2H), 3.79-3.74 (m, 2H), 3.32-3.09 (br m, 4H), 2.69-2.38 (br m, 5H), 2.10 (dd, J=12.5, 6.8 Hz, 1H), 2.01-1.46 (m, 5H, estimated; partially unclear due to water peak), 1.24 (t, J=7.1 Hz, 3H). Example 9 Ethyl(6R)-6-{4-[3-(4-methyl-1H-pyrazole-1-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate(9)

[0301] [ka]

[0302] Step 1. Synthesis of tert-butyl 4-[3-(4-methyl-1H-pyrazole-1-yl)pyridine-2-yl]piperazine-1-carboxylate (C18). A mixture of tert-butyl 4-(3-bromopyridine-2-yl)piperazine-1-carboxylate (400 mg, 1.17 mmol), 4-methyl-1H-pyrazole (144 mg, 1.75 mmol), copper(I) iodide (22 mg, 0.12 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.24 mmol), and potassium phosphate (746 mg, 3.51 mmol) in 1-methylpyrrolidine-2-one (4 mL) was placed in a sealed container and stirred at 140°C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was subjected to silica gel chromatography (gradient: 0% to 100% ethyl acetate in petroleum ether) to produce a pale yellow solid (160 mg), which was used directly in the following steps. 1 According to 1H NMR analysis, this material was not perfectly pure. LCMS m / z 344.2[M+H] + . 1 1H NMR (400 MHz, CDCl3), product peak only: δ8.24 (dd, J=4.9, 1.7 Hz, 1H), 7.78-7.76 (m, 1H), 7.71 (dd, J=7.8, 1.7 Hz, 1H), 7.54 (br s, 1H), 6.97 (dd, J=7.7, 4.8 Hz, 1H), 3.46-3.38 (m, 4H), 2.97-2.89 (m, 4H), 2.16 (s, 3H), 1.46 (s, 9H). Step 2.1 - Synthesis of [3-(4-methyl-1H-pyrazole-1-yl)pyridine-2-yl]piperazine (C19). The mixture of C18 (from the previous step; 160 mg, ≤0.466 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4 M; 0.5 mL, 2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 3 hours, and at this point it was concentrated under vacuum. The residue was dissolved in methanol (20 mL), treated with potassium carbonate (200 mg, 1.45 mmol), stirred at room temperature for 20 minutes, and concentrated under reduced pressure. The product was purified by silica gel chromatography (gradient: 0% to 70% methanol in dichloromethane) to obtain the product as a pale yellow solid. Yield: 60 mg, 0.25 mmol, 21% over two steps. LCMS m / z 244.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ8.24 (dd, J=4.8, 1.6 Hz, 1H), 7.70 (dd, J=7.6, 1.7 Hz, 1H), 7.66 (br s, 1H), 7.54 (br s, 1H), 7.01 (dd, J=7.6, 4.9 Hz, 1H), 3.27-3.20 (m, 4H), 3.16-3.08 (m, 4H), 2.17 (s, 3H). Step 3. Synthesis of ethyl(6R)-6-{4-[3-(4-methyl-1H-pyrazole-1-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate(9).

[0303] A mixture of C19 (60 mg, 0.25 mmol), P4 (131 mg, 0.371 mmol), and potassium carbonate (102 mg, 0.738 mmol) in acetonitrile (3 mL) was placed in a sealed container and stirred at 100°C for 48 hours. After removing the solvent under vacuum, the residue was purified by silica gel chromatography (gradient: 0% to 20% methanol in dichloromethane), followed by reversed-phase HPLC (column: Waters XBridge C18, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 40% to 50% B). The product was isolated as a pale yellow solid. Yield: 25 mg, 59 μmol, 24%. LCMS m / z 425.3 [M+H] + . 1 ¹H NMR (400 MHz, CDCl3) δ 8.23 ​​(dd, J=4.8, 1.8 Hz, 1H), 7.73 (br s, 1H), 7.68 (dd, J=7.8, 1.7 Hz, 1H), 7.52 (br s, 1H), 6.93 (dd, J=7.7, 4.8 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.86 (AB quadruplet, low field double line broadened, J AB =8.3 Hz, Δ νAB =21.4 Hz, 2H), 3.78 (AB quartet, J AB =8.3 Hz, Δ νAB =6.0 Hz, 2H), 3.09-2.94 (br m, 4H), 2.62-2.39 (br m, 5H), 2.17 (s, 3H), 2.11 (dd, J=12.7, 6.8 Hz, 1H), 1.99-1.48 (m, 5H, estimated; partially unclear due to water peak), 1.24 (t, J=7.1 Hz, 3H). Example 10 Ethyl 6-{4-[2-(2,2,2-trifluoroethoxy)pyridine-3-yl]piperazin-1-yl}-2-azaspiro[3,4]octane-2-carboxylate(10)

[0304] [ka]

[0305] Step 1. Synthesis of tert-butyl 4-(2-fluoropyridine-3-yl)piperazine-1-carboxylate (C2O). A mixture of 3-bromo-2-fluoropyridine (10.0 g, 56.8 mmol), tert-butylpiperazine-1-carboxylate (12.7 g, 68.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.60 g, 2.84 mmol), [2',6'-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane (RuPhos; 2.67 g, 5.72 mmol), and tert-sodium butoxide (11.0 g, 114 mmol) in 1,4-dioxane (150 mL) was stirred at 110 °C for 16 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (300 mL), sequentially washed with water (2 x 150 mL) and saturated sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (gradient: 50%-100% ethyl acetate in petroleum ether) yielded the product as a brown, gum-like substance. Yield: 5.20 g, 18.5 mmol, 33%. LCMS m / z 282.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ7.79 (ddd, J=4.9, 1.7, 1.5 Hz, 1H), 7.30-7.23 (m, 1H), 7.12 (ddd, J=7.8, 4.8, 1.4 Hz, 1H), 3.61 (br dd, J=5.1, 5.1 Hz, 4H), 3.06 (br dd, J=5.1, 4.9 Hz, 4H), 1.50 (s, 9H). Step 2.1-(2-fluoropyridine-3-yl)piperazine hydrochloride (C21) Synthesis of C2O (5.20 g, 18.5 mmol) in dichloromethane (20 mL) was mixed with a solution of 1,4-dioxane hydrogen chloride (4.0 M; 18.5 mL, 74.0 mmol). The reaction mixture was stirred at room temperature for 4 hours, at which point it was concentrated under vacuum to obtain the crude product as a light brown solid, which was used in the next step without purification. 1 According to 1H NMR analysis, this material was not perfectly pure. LCMS m / z 182.2[M+H] + . 1 ¹H NMR (400 MHz, DMSO-d6), product peak only: δ9.7-9.4 (br m, 2H), 7.80 (br d, J=4.9 Hz, 1H), 7.58 (ddd, J=10.9, 7.9, 1.5 Hz, 1H), 7.29 (ddd, J=7.7, 4.9, 1.2 Hz, 1H), 3.33-3.15 (m, 8H). Step 3. Synthesis of ethyl 6-[4-(2-fluoropyridine-3-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C22). The mixture of C21 (from the previous step; ≤18.5 mmol), P1 (4.00 g, 18.4 mmol), titanium(IV) ethoxide (16.8 g, 73.6 mmol), and triethylamine (9.3 g, 92 mmol) in dichloromethane (80 mL) and methanol (80 mL) was stirred overnight at room temperature. Then sodium triacetoxyborohydride (19.5 g, 92.0 mmol) was added, and the reaction mixture was stirred at room temperature for another 3 hours. The reaction was quenched with water (10 mL), which produced a white precipitate. The mixture was then dried over sodium sulfate and filtered. The filter pad was washed with ethyl acetate (100 mL), and the combined filtrate was concentrated under vacuum. The product was obtained as a white, gum-like substance by silica gel chromatography (gradient: 50% to 100% ethyl acetate in petroleum ether). Yield: 2.4 g, 6.6 mmol, 36% over two steps. LCMS m / z 363.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ7.81 (ddd, J=4.9, 1.7, 1.5 Hz, 1H), 7.29 (ddd, J=10.3, 7.8, 1.7 Hz, 1H), 7.13 (ddd, J=7.8, 4.8, 1.3 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.90 (AB quartet, J AB =8.6 Hz, Δ νAB =30.4 Hz, 2H), 3.80 (AB quartet, J AB =8.3 Hz, Δ νAB =7.6 Hz, 2H), 3.31 (br dd, J=4.9, 4.6 Hz, 4H), 3.11-2.98 (br m, 5H), 2.24 (dd, half of ABX pattern, J=13.1, 7.7 Hz, 1H), 2.18-2.09 (m, 1H), 2.08-1.82 (m, 4H), 1.24 (t, J=7.1 Hz, 3H). Step 4. Synthesis of ethyl 6-{4-[2-(2,2,2-trifluoroethoxy)pyridine-3-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate (10). Sodium hydride (60% dispersion in mineral oil; 32 mg, 0.80 mmol) in tetrahydrofuran (1 mL) was added to a solution of 2,2,2-trifluoroethanol (75 mg, 0.75 mmol) in N,N-dimethylformamide (1 mL) at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. A solution of C22 (90 mg, 0.25 mmol) in tetrahydrofuran (1 mL) was added, and the reaction mixture was stirred at 50°C for 16 hours. At this point, it was diluted with ethyl acetate (30 mL), washed sequentially with water (2 × 10 mL) and saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The product was obtained as a pale yellow, gum-like substance by reversed-phase HPLC (column: Phenomenex Gemini C18, 5 μm; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase B: acetonitrile; gradient: 0%~100% B). Yield: 29.5 mg, 66.7 μmol, 27%. LCMS m / z 443.2 [M+H] + .1 H NMR (400 MHz, CDCl3) δ7.76 (dd, J=4.9, 1.5 Hz, 1H), 7.14 (dd, J=7.7, 1.6 Hz, 1H), 6.94 (dd, J=7.6, 4.9 Hz, 1H), 4.81 (q, J HF =8.6 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.89 (AB quadruple, low-field double line is spreading, J AB =8.4 Hz, Δ νAB =23.3 Hz, 2H), 3.81 (AB quartet, J AB =8.2 Hz, Δ νAB =9.6 Hz, 2H), 3.25-3.07 (br m, 4H), 2.79-2.57 (br m, 5H), 2.18 (br dd, J=12, 7 Hz, 1H), 2.04-1.52 (m, 5H, estimated; (Partially unclear due to the 'k'), 1.25 (t, J=7.1 Hz, 3H). Example 11 Ethyl(6R)-6-{4-[3-(1,3-thiazole-5-yl)pyrazine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate(11)

[0306] [ka]

[0307] Step 1. Synthesis of tert-butyl 4-[3-(1,3-thiazole-5-yl)pyrazine-2-yl]piperazine-1-carboxylate (C23). To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (848 mg, 4.02 mmol) and tert-butyl 4-(3-chloropyrazine-2-yl)piperazine-1-carboxylate (1.00 g, 3.35 mmol) in toluene (35 mL), water (5 mL) and sodium carbonate (1.06 g, 10.0 mmol) were added, followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (245 mg, 0.335 mmol). The reaction vessel was then sealed and heated at 100 °C for 16 hours. After removing the solvent under vacuum, the residue was purified by silica gel chromatography (gradient: 0% to 90% ethyl acetate in petroleum ether) to obtain the product as a yellow oily substance. Yield: 500 mg, 1.44 mmol, 43%. LCMS m / z 348.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ9.0-8.8 (br s, 1H), 8.8-8.6 (br s, 1H), 8.23 ​​(d, J=2.4 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 3.68-3.57 (br m, 4H), 3.24-3.14 (br m, 4H), 1.48 (s, 9H). Step 2. Synthesis of 2-(piperazin-1-yl)-3-(1,3-thiazole-5-yl)pyrazine hydrochloride (C24).

[0308] A solution of hydrogen chloride in 1,4-dioxane (4M; 3 mL, 12 mmol) was added to a solution of C23 (500 mg, 1.44 mmol) in acetonitrile (9 mL), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then concentrated under vacuum, and the residue was ground with ethyl acetate to obtain the product as a yellow solid. Yield: 330 mg, 1.16 mmol, 81%. LCMS m / z 248.1[M+H] + . 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ8.36 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 3.40-3.33 (br m, 4H), 3.32-3.23 (br m, 4H). Step 3. Synthesis of ethyl(6R)-6-{4-[3-(1,3-thiazole-5-yl)pyrazine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate (11). C24 (free base; 120 mg, 0.485 mmol), P3 (242 mg, 0.873 mmol), and potassium carbonate (67 mg, 0.4 The mixture in 8 mmol) acetonitrile (4 mL) was stirred in a sealed container at 95°C for 16 hours. After concentration under vacuum, the residue was purified using silica gel chromatography (gradient: 0%-10% methanol in dichloromethane), followed by reverse-phase HPLC (column: Phenomenex Gemini C18, 5 μm; mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; gradient: 12%-20% B). The product was isolated as a pale yellow gum-like substance. Yield: 30 mg, 70 μmol, 14%. LCMS m / z 429.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ8.88 (s, 1H), 8.68 (s, 1H), 8.22 (d, J=2.4 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.89 (AB quartet, J AB =8.4 Hz, Δ νAB =27.7 Hz, 2H), 3.83-3.77 (m, 2H), 3.44-3.29 (br m, 4H), 2.90-2.77 (br m, 5H), 2.18 (dd, J=13.0, 7.3 Hz, 1H), 2.05-1.70 (m, 5H), 1.24 (t, J=7.1 Hz, 3H). Examples 12-53 were synthesized using the methods described above for Examples 1-11, and similar starting materials as shown in the table. Please refer to Table 1 for the specific methods used and the characterization data for these examples.

[0309] [Table 4-1]

[0310] [Table 4-2]

[0311] [Table 4-3]

[0312] [Table 4-4]

[0313] [Table 4-5]

[0314] [Table 4-6]

[0315] [Table 4-7]

[0316] [Table 4-8]

[0317] [Table 4-9]

[0318] Table 4-10

[0319] Table 4-11

[0320] Table 4-12

[0321] Table 4-13

[0322] Table 4-14

[0323] Table 4-15

[0324] Table 4-16

[0325] Table 4-17

[0326] Table 4-18

[0327] Table 4-19

[0328] 1. tert-butyl 2-oxo-6-azaspiro[3,4]octane-6-carboxylate, 1,4-diode The protecting group was removed by treatment with xane-hydrogen chloride. The subsequent reaction with ethyl chloroformate yielded the necessary ethyl 2-oxo-6-azaspiro[3,4]octane-6-carboxylate. A T was generated. 1 H NMR (400 MHz, CDCl3) δ4.15 (q, J=7.2 Hz, 2H), 3.63-3.43 (br m, 4H), 3.05 (br AB quartet, J AB =17 Hz, Δ νAB =38 Hz, 4H), 2.08 (dd, J=6.8, 6.8 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). 2. In this case, Suzuki coupling was performed using [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd-118) and cesium carbonate or potassium carbonate. 3. In this case, reductive amination is performed using sodium cyanoborohydride and N,N-diisopropyl The tests were performed using ethylamine and magnesium sulfate. 4. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1 × 50 mm, 5 μm; Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 1% to 5% B over 0.6 minutes; 5% to 100% B over 3.4 minutes; Flow rate: 0.8 mL / min. 5. In this case, instead of P1, use tert-butyl6-oxo-2-azapiro[3.4]octane-2-carb Xylates were used. The resulting tert-butyl6-{4-[3-(pyrimidine-5-yl)pyridine-2- Example 14 was prepared by deprotecting [yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate with trifluoroacetic acid and then reacting it with 1-chloroethyl ethyl carbonate. 6. In this case, the Suzuki coupling was performed using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium carbonate. 7. The required 1-[2-(difluoromethoxy)pyridine-3-yl]piperazine is 3-bromo-2-flu For the conversion of olopyridine to C21, the method described in Example 10 was used to convert 3-bromo-2-(di It was synthesized from fluoromethoxypyridine. 8. Reverse-phase HPLC (Column: Chiral Technologies Chiralpak IG; Mobile phase: 7:3 hexane / ethanol) The racemic product was separated into its enantiomers via (L) and the first eluted enantiomer was designated as Example 19. Then, both enantiomers were individually subjected to reverse-phase chromatography (Column: Agela Technologies C18; Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B: A The samples were subjected to cetonitrile (gradient: 0%~100% B). Analytical HPLC (column: Chiral Technologies Chiralpak IG, 4.6 × 150 mm, 5 μm; mobile phase: 7:3 hexane / ethanol; flow rate: 1.0 mL / min) was used. Above, Example 19 showed a holding time of 5.25 minutes. The enantiomer of Example 19, ethyl 6-{4-[ 2-(difluoromethoxy)pyridine-3-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-2, had a retention time of 6.08 minutes under the same conditions. Enantiomer of Example 19, LCMS m / z 411.2[M+H] + The following biological data was shown: M4 EC 50 , 201nM (3 judgments); M4 E max 74% (based on 3 assessments). 9. The required 1-[2-(trifluoromethoxy)pyridine-3-yl]piperazine is 3-bromo-2-yl For the conversion of luoropyridine to C21, the method described in Example 10 was used to convert 3-br It was synthesized from rom-2-(trifluoromethoxy)pyridine. 10. The racemic product was separated into its enantiomers via reverse-phase HPLC (column: Chiral Technologies Chiralcel OD, 10 μm; mobile phase: 90:10 hexane / ethanol). 1. Elution of enantiomer The enantiomer was designated as Example 20. Then, both enantiomers were individually subjected to reverse-phase chromatography (column: Agela Technologies C18; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase A: water). The sample was subjected to dynamic phase B (acetonitrile; gradient: 0% to 100% B). On analytical HPLC (column: Chiral Technologies Chiralcel OD-H, 4.6 × 150 mm, 5 μm; mobile phase: 90:10 hexane / ethanol; flow rate: 1.0 mL / min), Example 20 showed a retention time of 4.31 minutes. The enantiomer of Example 20, eth Lu6-{4-[2-(trifluoromethoxy)pyridine-3-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-2 had a retention time of 4.93 minutes under the same conditions. Example 20 enantiomer, LCMS m / z 429.2[M+H] + The following biological data was shown: M4 EC 50 , 3600nM (2 judgments); M4 E max 95.3% (based on two assessments). 11. In this case, the starting material 1-(3-methylpyridine-2-yl)piperazine was commercially available. . 12. The racemic product is separated into its enantiomers via reverse-phase HPLC (column: Chiral Technologies ChiralcelOZ-H, 5 μm; mobile phase: 80:20:0.1 hexane / ethanol / diethylamine). They were separated. The first eluted enantiomer was designated as Example 21. Then both enantiomers Each sample was subjected to reverse-phase HPLC (column: C18; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase B: acetonitrile; gradient: 70%~75% B). Analytical HPLC (column: Chiral Technologies Chiralcel OZ-H, 4.6×150 mm, 5 μm; mobile phase: 80:20:0.1 hexane / ethanol / diethylammonium) was performed individually. (Flow rate: 1.0 mL / min) Example 21 showed a retention time of 5.29 minutes. The enantiomer of Example 21 Ethyl 6-[4-(3-methylpyridine-2-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate, ENT-2, had a retention time of 6.04 minutes under the same conditions. Enantiomer of Example 21, LCMS m / z 359.3 [M+H] + The following biological data was presented: M4 EC 50 >241nM (4 judgments); M4 E max 76.2% (based on 3 assessments). 13. Tert-butyl 4-(3-bromopyridine-2-yl)piperazine-1-carboxylate in the presence of dichlorobis(tricyclohexylphosphine)palladium(II) and tripotassium phosphate. The required tert-butyl 4-(3-cyclopropylpyridine-2-yl)piperazine-1-carboxylate was produced by the Suzuki reaction of tert and cyclopropylboronic acid. 14. Reverse-phase HPLC (Column: Chiral Technologies Chiralpak AD-H, 5 μm; Mobile phase: 100:0.1 ethanol) The racemic product was separated into its enantiomer via (1) (nol / diethylamine). The eluted enantiomer was designated as Example 22. Both enantiomers were then subjected individually to reverse-phase chromatography (column: Agela Technologies C18; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase B: methanol; gradient: 5%~80% B). On analytical HPLC (column: Chiral Technologies Chiralpak AD-H, 4.6 × 250 mm, 5 μm; mobile phase: 100: 0.1 ethanol / diethylamine; flow rate: 1.0 mL / min), Example 22 showed a retention time of 12.00 minutes. The enantiomer of Example 22, ethyl 6-[4-(3-cyclopropylpyridine-2-yl)piperazine-1-yl]-2-azaspi [3.4]Octane-2-carboxylate, ENT-2, had a retention time of 14.94 minutes under the same conditions. Enantiomer of Example 22, LCMS m / z 385.2[M+H] + The following biological data was shown: M4 EC 50 , 11.6nM (6 judgments); M4 E max 103% (6 judgments). 15. In this case, reductive amination was carried out using sodium triacetoxyborohydride. 16. Supercritical fluid chromatography [Column: Chiral Technologies Chiralpak IG, 5 μm; Mobile phase 7: 3 carbon dioxide (containing 0.2% 1-aminopropan-2-ol in 2-propanol) The racemic product was then separated into its enantiomer. The second eluted enantiomer was designated as Example 23. On analytical HPLC [column: Phenomenex Lux Cellulose-4, 4.6 × 250 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: ethanol containing 0.2% (7 M ammonia in methanol); gradient: 5% B, 1.00 min, then 5% to 60% B over 8.00 min; flow rate: 3.0 mL / min; back pressure: 120 bar], Example 23 showed a retention time of 7.31 min. The enantiomer of Example 23, ethyl 2-[4-(5-cyano-2,3'-bipyridine-2'-yl)piperazine-1-yl]-6-azaspiro[3.4]octane-6-carboxylate, ENT-1, had a retention time of 7.01 min under the same conditions. Enantiomer of Example 23, LCMS m / z 447.3 [M+H] + The following biological data was presented: M4 EC 50 >10,000nM (one judgment); M4 E max , undetermined. 17. In this case, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate was used instead of P1. The resulting tert-butyl 6-[4-(5-cyano-2,3'-bipyridine-2'-yl)piperazine-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate was converted to trifluorocarbonate. The compound was deprotected with acid and then reacted with ethyl chloroformate to produce Example 24. 18. tert-butylpiperazine-1-carboxylate 2,3-dibromo-5-fluoropyridine Reaction with potassium carbonate yielded tert-butyl 4-(3-bromo-5-fluoropyridine-2-yl)piperazine-1-carboxylate. This material was then processed using tetrakis(triphenylphosphorus). 4-(tributylstannanyl)-1,3- in the presence of palladium(0) and cesium fluoride By subjecting it to still coupling with thiazole, the required tert-butyl 4-[5-fluoro-3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-carboxylate A T was generated. 19. The racemic product was separated into its enantiomers via reverse-phase HPLC (column: Chiral Technologies Chiralpak AD-H, 5 μm; mobile phase: 1:1 hexane / ethanol). The first eluted enantiomer was designated as Example 26. On analytical HPLC (column: Chiral Technologies Chiralpak AD-H, 4.6 x 250 mm, 5 μm; mobile phase: 1:1 hexane / ethanol; flow rate: 1.0 mL / min), Example 26 showed a retention time of 7.81 minutes. Example 26, ethyl 6-{4-[5-fluoro-3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate The enantiomer of ENT-2 had a retention time of 16.42 minutes under the same conditions. Enantiomer of Example 26, LCMS m / z 446.2 [M+H] + The following biological data was shown: M4 EC 50 , 152nM (4 judgments); M4 E max 67.1% (based on 4 assessments). 20. The required tetrasubstituted tert-butylpiperazine-1-carboxylate is synthesized via the reaction of tert-butylpiperazine-1-carboxylate with a suitable chlorosubstituted heteroaromatic reactant. Ta. 21. Separation of racemic products into their enantiomers via reverse-phase HPLC (column: Chiral Technologies Chiralcel OJ, 10 μm; mobile phase: 90:10:0.1 hexane / ethanol / diethylamine). The second eluted enantiomer was designated as Example 27. Then, both enantiomers were used. Each sample was subjected to reverse-phase chromatography (column: Agela Technologies C18; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase B: methanol; gradient: 0%~100% B). Analytical HPLC (column: Chiral Technologies Chiralcel OJ-H, 4.6 × 150 mm, 5 μm; mobile phase: 90:10:0.1 hexane / ethanol / diethylamine; flow rate: 1.0 mL / min) showed that Example 27 had a retention time of 5.19 minutes. Enantiomer of Example 27, ethyl 6-[4-(3-methoxypyrazine-2-yl)piperazine-1-yl [L]-2-azaspiro[3.4]octane-2-carboxylate, ENT-1 had a retention time of 4.42 minutes under the same conditions. Enantiomer of Example 27, LCMS m / z 376.2[M+H] + The following biological data was shown: M4 EC 50 >10,000nM (one judgment); M4 E max , undetermined. 22. Appropriate tert-butyl 4-(3-bromopyridine-2-yl)piperazine-1-carboxylate With amines, Tert-butoxide sodium, tris(dibenzylideneacetone)dipalladium(0), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene(xanthophos) The reaction yielded a coupled product, which was deprotected using trifluoroacetic acid. The resulting secondary amine was subjected to reductive amination with P1, sodium triacetoxyborohydride, and N,N-diisopropylethylamine to produce the example. . 23. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid (v / v) in water; mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile; gradient: 5.0% to 95% B, linear over 4.0 minutes; flow rate: 2 mL / min. 24. 6,6-dimethoxy-2-azaspiro[3.3]heptane-2-carboxylate was reacted with acetyl chloride in methanol to produce 6,6-dimethoxy-2-azaspiro[3.3]heptane. The required ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate was obtained by treatment with ethyl chloroformate and triethylamine, followed by ketal deprotection with hydrochloric acid. Luboxylate was obtained. 1 H NMR (400 MHz, CDCl3) δ4.19 (s, 4H), 4.14 (q, J=7.0 Hz, 2H), 3.31 (s, 4H), 1.26 (t, J=7.0 Hz, 3H). 25. Reverse-phase HPLC (Column: Chiral Technologies Chiralpak IG, 5 μm; Mobile phase: 50 / 50 / 0.1 hexagonal) Racemic Example 33 was divided into its enantiomer via (San / ethanol / diethylamine). They were separated. The first eluted enantiomer was designated as Example 34. Then, both enantiomers were separated. Each sample was subjected to silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane). Analytical HPLC (column: Chiral Technologies Chiralpak IG, 4.6 × 150 mm, 5 μm; transfer) was performed. In dynamic phase (1:1 hexane / ethanol; flow rate: 1.0 mL / min), Example 34 showed a retention time of 9.66 minutes. The enantiomer of Example 34, ethyl 6-{4-[3-(1,2,5-thiadiazole-3-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-2 is The holding time was 15.53 minutes under the same conditions. Enantiomer of Example 34, LCMS m / z 429.2 [M+H] + The following biological data was shown: M4 EC 50 , 347nM (3 judgments); M4 E max 72.3% (3 judgments) ). 26. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1 × 50 mm, 5 μm; Mobile phase A: Water Phase B: 0.0375% trifluoroacetic acid in acetonitrile; Mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: over 4.0 minutes; Flow rate 10%~100% B: 0.8 mL / min. 27. Reverse-phase HPLC (Column: Chiral Technologies Chiralcel OD, 10 μm; Mobile phase: 3:2 hexane / The racemic product was separated into its enantiomers via ethanol. The second eluted enantiomer was designated Example 41. Both enantiomers were then subjected individually to reverse-phase chromatography (column: Agela Technologies C18; mobile phase A: 0.1% ammonium hydroxide in water; mobile phase B: acetonitrile; gradient: 10%~60% B). Analytical HPLC (column: Chiral Technologies Chiralcel OD-H, 4.6 × 150 mm, 5 μm; mobile phase: 7:3 hexane / ethanol; flow rate: 1.0 mL / min) In Example 41, the retention time was 6.02 minutes. The enantiomer of Example 41 was ethyl 6-{4-[3-(5-cyanopyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]o Cutane-2-carboxylate, ENT-1, had a retention time of 4.96 minutes under the same conditions. Enantiomer of Example 41, LCMS m / z 448.3 [M+H] + The following biological data was shown: M4 EC 50 , 268nM (3 judgments); M4 E max 52.7% (based on 3 assessments). 28. Morpho tert-butyl 4-(3-chloropyrazine-2-yl)piperazine-1-carboxylate The reaction with phosphorus and potassium carbonate yields the necessary tert-butyl 4-[3-(morpholine-4-yl) Pyrazine-2-yl]piperazine-1-carboxylate was obtained. 29. tert-butyl 4-(3-chloropyrazine-2-yl)piperazine-1-carboxylate 4-meth The reaction with xypiperidine and potassium carbonate yields the required tert-butyl 4-[3-(4-methyl We obtained cypiperidine-1-yl)pyrazine-2-yl]piperazine-1-carboxylate. 30. rac-BINAP-Pd-G3 (Aldrich, catalog number 804967), 1,1'-binaphthalene-2,2'-diyl Using bis(diphenylphosphine) and tert-butoxide sodium, tert-butyl 4-(3-bromopyridine-2-yl)piperazine-1-carboxylate and 2-oxa-6-azaspirate Coupling with [3.3]heptane was performed. The product was deprotected with trifluoroacetic acid. The required 6-[2-(piperazine-1-yl)pyridine-3-yl]-2-oxa-6-azaspiro[3.3]hepta I generated n. 31. In this case, the Suzuki coupling is [1,1'-bis(diphenylphosphino)ferrocene] The procedure was performed using dichloropalladium(II) and sodium bicarbonate. 32. In this case, hydroxypyrazine was introduced as a (4-methoxybenzyl)oxy derivative. 5-bromopyrazine-2-ol was converted with 1-(chloromethyl)-4-methoxybenzene and silver carbonate. By reacting, 2-bromo-5-[(4-methoxybenzyl)oxy]pyrazine is obtained, and this is coupled. It was used in the reaction. Using trifluoroacetic acid-mediated deprotection, tert-butoxycarbon The 4-methoxybenzyl group was removed. This also removed the 4-methoxybenzyl moiety. 33. The desired 1-substituted 4-iodo-1H-pyrazole was obtained by the reaction of 4-iodo-1H-pyrazole with a suitable haloalkyl reactant in the presence of cesium carbonate and potassium iodide. 34. The Suzuki reaction was carried out using [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd-118) and tripotassium phosphate. 35. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid (v / v) in water; mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile; gradient: 5.0% to 80% B, linear over 3.75 minutes, then 80% to 95% B over 0.25 minutes, then 95% B for 1.0 minute; flow rate: 2 mL / min. 36. tert-butyl4-[3-(ethoxycarbonyl)pyridine-2-yl]piperazine-1-carboxy The rate is reacted with hydrazine, followed by acetylation with acetyl chloride and N,N-diisopropylethylamine to obtain tert-butyl 4-{3-[(2-acetylhydrazinyl) [carbonyl]pyridine-2-yl]piperazine-1-carboxylate was obtained. By treating this material with p-toluenesulfonyl chloride and triethylamine, the desired tert-butyl 4-[3-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-2-yl]piperazine-1-carboxylate was obtained. Xylates were produced. 37. The required 1-[2-(methoxy)pyridine-3-yl]piperazine is converted to 3-bromo-2-fluoropyridine using the method described in Example 10. It was synthesized from xypyridine. 38. The racemic product is separated into its enantiomers via reverse-phase HPLC (column: Chiral Technologies Chiralcel OD, 10 μm) using a hydrocarbon / ethanol solvent mixture as the mobile phase. They were separated. If further purification is required, the enantiomers are subjected to reverse-phase chromatography individually.

[0329] The M4 agonist binding affinity to the compounds of the present invention was determined using the following biological assays: Biological assays Muscarinic hM4 agonist GloSensor cAMP assay method The compound was prepared prior to the assay. The test compound was solubilized in 100% dimethyl sulfoxide (DMSO, SIGMA D8418) to a concentration of 30 mM. Using a semi-logarithmic dilution ratio, a 10-point intermediate dilution series was prepared in 100% DMSO, with a maximum concentration of 4 mM. The serially diluted compound was placed in a 384-well plate (matrix catalog number 4325) at a concentration of 200 nL / well. The final compound concentration range in the assay was 10 μM to 0.3 nM, and the final DMSO concentration was 0.25%.

[0330] Using parental HEK cells expressing the GloSensor structure (Promega Sor-L9 HEK293 human / M4 / GloSensor cell clone number 40), a stable human M4 mAChR cell line was generated. Cells were grown in 90% Dulbecco's Modified Eagle Medium (DMEM, Gibco 11960), 10% fetal bovine serum (FBS, Hyclone CH.30160-03), 1% penicillin / streptomycin (Gibco 15070-063), 500 μg / mL genethecin (Gibco 10131-027), 200 μg / mL hygromycin B (Invitrogen 10687-010), and 1% Glutamax (Thermo Fisher 35050061).

[0331] One day before the assay, the cells were lifted using dissociation buffer (Gibco 13151-014) and centrifuged at 250x gravity at room temperature for 5 minutes. The supernatant was removed, and the cells were extracted. The pellet was placed in the growth medium at a concentration of 6.25 × 10⁻⁶. 6The cells were resuspended in cells / mL. Then, 40 μL (25,000 cells) per well was added to a white poly-d-lysine coated plate (Becton Dickinson 356661) and incubated overnight (20-24 hours) in a humidified incubator at 37°C with 5% carbon dioxide (CO2).

[0332] The following day, the culture medium was removed from the cell plate and replaced with 40 μL of equilibrated medium containing 88% CO2-independent medium (Invitrogen 18045088), 10% FBS, and 2% GloSensor cAMP reagent (Promega E1291), which had been warmed to 37°C. The plate was then covered and incubated at room temperature for 2 hours, with light blocked out.

[0333] To previously prepared serially diluted compound plates, 200 nL of 4 mM ACh (SIGMA A2661, final 10 μM) or 200 nL of 100% DMSO (final 0.25%) was added to the positive and negative control wells, respectively. Then, 10% FBS and EC were added. 80 The compound plate was diluted by adding 16 μL of CO2-independent medium containing isoproterenol (SIGMA16504) at a specified concentration. Before testing the compound, a concentration-response curve was run against isoproterenol to obtain the EC2 response. 80 The concentration was determined. At the end of the 2-hour equilibration period, 10 μL was transferred from the compound plate to the cell plate. The cell plate was incubated at room temperature for an additional 7 minutes, and then the luminescence was read using a Multi-label EnVision plate reader (Perkin Elmer).

[0334] Raw data, expressed as relative optic units, were analyzed using Activity Base (IDBS). Percentage effects at each compound concentration were calculated based on the amount of cAMP generated by the positive and negative control wells contained on each assay plate, and compared to these amounts. The positive control wells were EC 100The wells contained ACh at a specific concentration, while the negative control wells contained only DMSO. A four-parameter logistic dose-response equation was used to fit the concentration and action value %, and the 50% action (EC) was determined. 50 The required concentration and the maximum asymptote of the concentration response curve were determined, and the efficacy was defined.

[0335] [Table 5-1]

[0336] [Table 5-2]

[0337] [Table 5-3]

[0338] [Table 5-4]

[0339] [Table 5-5]

[0340] [Table 5-6]

[0341] [Table 5-7]

[0342] Throughout this application, various publications are referenced. For all purposes, the disclosures of these publications are incorporated herein by reference to this application.

[0343] It will be apparent to those skilled in the art that various modifications and variations can be made without departing from the scope or spirit of the present invention. Other embodiments of the present invention will be apparent to those skilled in the art, considering the specification disclosed herein and the practice of the present invention. The specification and examples are intended to be illustrative only, and the true scope and spirit of the present invention are intended to be shown in the following claims. Claims at the time of filing [Section 1] Compounds of formula I: [ka] or its N-oxide, or a compound or a pharmaceutically acceptable salt of the N-oxide (in the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These are halogen, cyano, hydroxy, -SF5, nitro, -N(R) 6 )(R 7 ), (C1~C6) alkyl, (C2~C6) alkenyl, (C2~C6) alkynyl, (C1~C6) alkylthio, (C1~C6) alkoxy, (C3~C6) cycloalkyl, -O-(4~6 member) heterocycloalkyl, (C6~C 10 Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkylthio, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10 )aryl, (5-10 member) heteroaryl and (4-8 member) heterocycloalkyl groups include halogens, cyano, hydroxy, and -N(R 6 )(R 7The (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl compounds may be substituted with 1 to 3 substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl compounds, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl compounds may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy compounds. R 2 These are hydrogen, halogen, cyano, hydroxy, -SF5, nitro, -N(R) 6 )(R 7 A (C1-C6) alkyl and (C1-C6) alkoxy group is selected, and the (C1-C6) alkyl and (C1-C6) alkoxy groups may be substituted with 1 to 3 halogens. R 6 and R 7 Each of these is independently selected from hydrogen, (C1-C6) alkyl, or C(O)-CH3. m is either 1 or 2. n is either 1 or 2. [Section 2] X 1 is nitrogen, X 2 The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the compound is CH. [Section 3] X 1 is nitrogen, X 2 The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the nitrogen atom is nitrogen. [Section 4] X 1 CH is, X 2 The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the nitrogen atom is nitrogen. [Section 5] R 1A compound according to any one of claims 1 to 4, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein is selected from the group consisting of halogens, cyanos, (C1-C6)alkyls, (C1-C6)alkoxys, and (C3-C6)cycloalkyls, and the (C1-C6)alkyl, (C1-C6)alkoxys, and (C3-C6)cycloalkyls may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6)alkyls, (C1-C6)alkoxys, (C3-C6)cycloalkyls, and (5-6 membered) heteroaryls, and the (C1-C6)alkyl, (C1-C6)alkoxys, and (5-6 membered) heteroaryls may each be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyanos, hydroxys, (C1-C6)alkyls, and (C1-C6)alkoxys, respectively. [Section 6] R 1 However, the (5-10 member) heteroaryl is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, wherein the (5-10 member) heteroaryl is halogen, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -(CH2)2-O-CH2CH3, and (5-6 member) hetero The compound according to any one of claims 1 to 4, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl may be substituted with one to three substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. [Section 7] R 1The compound according to any one of claims 1 to 4, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the heterocycloalkyl is a (4-8 member) heterocycloalkyl selected from the group consisting of oxetanyl, morpholino, 2-oxa-6-azaspiro[3.3]hepta-6-yl, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, and piperidinil, and the heterocycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 member) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy. [Section 8] R 2 A compound according to any one of claims 1 to 7, wherein the compound is hydrogen, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide. [Section 9] A compound according to any one of claims 1 to 8, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein m is 2 and n is 1. [Section 10] A compound according to any one of claims 1 to 9, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein m is 1 and n is 2. [Section 11] A compound according to any one of claims 1 to 10, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein m is 1 and n is 1. [Section 12] Equation I A Compounds of: [ka] or its N-oxide, or a compound or a pharmaceutically acceptable salt of the N-oxide (in the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These include halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10 Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10 The aryl, (5-10 membered) heteroaryl, and (4-8 membered) heterocycloalkyl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy groups. R 2 (The (C1-C6) alkyl and (C1-C6) alkoxy elements are selected from the group consisting of hydrogen, halogens, (C1-C6) alkyl and (C1-C6) alkoxy elements, and the (C1-C6) alkyl and (C1-C6) alkoxy elements may be substituted with 1 to 3 halogens.) [Section 13] X 1 is nitrogen, X 2 The compound according to claim 12, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein is CH. [Section 14] X 1 is nitrogen, X 2The compound according to claim 12, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the nitrogen atom is nitrogen. [Section 15] X 1 CH is, X 2 The compound according to claim 12, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the nitrogen atom is nitrogen. [Section 16] R 1 The compound according to any one of claims 12 to 15, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl are selected from the group consisting of halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl may each be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. [Section 17] R 1The compound according to any one of claims 12 to 15, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (5-10 member) heteroaryl is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, and the (5-10 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 member) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy. [Section 18] R 1 The compound according to any one of claims 12 to 15, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the heterocycloalkyl is a (4-8 membered) heterocycloalkyl selected from the group consisting of oxetanyl, morpholino, 2-oxa-6-azaspiro[3.3]hepta-6-yl, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, and piperidinil, and the heterocycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 membered) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 membered) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy. [Section 19] Equation I B Compounds of: [ka] or its N-oxide, or a compound or a pharmaceutically acceptable salt of the N-oxide (in the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These include halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10 Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10 The aryl, (5-10 membered) heteroaryl, and (4-8 membered) heterocycloalkyl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy groups. R 2 (The (C1-C6) alkyl and (C1-C6) alkoxy elements are selected from the group consisting of hydrogen, halogens, (C1-C6) alkyl and (C1-C6) alkoxy elements, and the (C1-C6) alkyl and (C1-C6) alkoxy elements may be substituted with 1 to 3 halogens.) [Section 20] X 1 is nitrogen, X 2 The compound according to claim 19, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein is CH. [Section 21] R 1The compound according to any one of claims 19 to 20, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl are selected from the group consisting of halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl may each be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. [Section 22] R 1 The compound according to any one of claims 19 to 20, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (5-10 member) heteroaryl is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, and the (5-10 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 member) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy. [Section 23] R 1The heterocycloalkyl group is a (4-8 member) heterocycloalkyl group selected from the group consisting of oxetanyl, morpholino, 2-oxa-6-azaspiro[3.3]hepta-6-yl, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, and piperidinil, wherein the heterocycloalkyl group is halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, -(CH2)2-O-CH2CH3, and (5-6 member) heteroalkyl groups. The compound according to any one of claims 19 to 20, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl may be substituted with one to three substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. [Section 24] Equation I C Compounds of: [ka] or its N-oxide, or a compound or a pharmaceutically acceptable salt of the N-oxide (in the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These include halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10 )aryl, (5-10 member) heteroaryl and (4-8 member) heterocycloalkyl Selected from the group, the (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10The aryl, (5-10 member) heteroaryl, and (4-8 member) heterocycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, -(C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 member) heteroaryl, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. R 2 (The (C1-C6) alkyl and (C1-C6) alkoxy elements are selected from the group consisting of hydrogen, halogens, (C1-C6) alkyl and (C1-C6) alkoxy elements, and the (C1-C6) alkyl and (C1-C6) alkoxy elements may be substituted with 1 to 3 halogens.) [Section 25] X 1 is nitrogen, X 2 The compound according to claim 24, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein is CH. [Section 26] R 1 The compound according to any one of claims 24 to 25, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl are selected from the group consisting of halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl may each be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. [Section 27] R1 The compound according to any one of claims 24 to 25, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (5-10 member) heteroaryl is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, and the (5-10 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 member) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy. [Section 28] R 1 The compound according to any one of claims 24 to 25, or its N-oxide, or A pharmaceutically acceptable salt of a compound or N-oxide. [Section 29] Compound of formula I': [ka] or its N-oxide, or a compound or a pharmaceutically acceptable salt of the N-oxide (in the formula, X 1 and X 2 Each is independently CH or nitrogen, however X 1 and X 2 It is not possible for both to be CH. R 1 These include halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 member) heterocycloalkyl, (C6-C 10 Selected from the group consisting of aryl, (5-10 membered) heteroaryl and (4-8 membered) heterocycloalkyl, and the aforementioned (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, -O-(4-6 membered) heterocycloalkyl, (C6-C 10 The aryl, (5-10 membered) heteroaryl, and (4-8 membered) heterocycloalkyl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl groups, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy groups. R 2 The (C1-C6) alkyl and (C1-C6) alkoxy elements are selected from the group consisting of hydrogen, halogens, (C1-C6) alkyl and (C1-C6) alkoxy elements, and the (C1-C6) alkyl and (C1-C6) alkoxy elements may be substituted with 1 to 3 halogens. m is either 1 or 2. n is either 1 or 2. [Section 30] X 1 is nitrogen, X 2The compound according to claim 29, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein is CH. [Section 31] X 1 is nitrogen, X 2 The compound according to claim 29, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the nitrogen atom is nitrogen. [Section 32] X 1 CH is, X 2 The compound according to claim 29, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the nitrogen atom is nitrogen. [Section 33] R 1 The compound according to any one of claims 29 to 32, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl are selected from the group consisting of halogens, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) cycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, and (5-6 membered) heteroaryl, and the (C1-C6) alkyl, (C1-C6) alkoxy, and (5-6 membered) heteroaryl may each be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxy, (C1-C6) alkyl, and (C1-C6) alkoxy. [Section 34] R 1The compound according to any one of claims 29 to 32, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the (5-10 member) heteroaryl is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridadinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, and the (5-10 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 member) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 member) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy. [Section 35] R 1 The compound according to any one of claims 29 to 32, or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein the heterocycloalkyl is a (4-8 membered) heterocycloalkyl selected from the group consisting of oxetanyl, morpholino, 2-oxa-6-azaspiro[3.3]hepta-6-yl, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, and piperidinil, and the heterocycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, and (5-6 membered) heteroaryl, and the (C1-C6)alkyl, (C1-C6)alkoxy, and the (5-6 membered) heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C1-C6)alkyl, and (C1-C6)alkoxy. [Section 36] Ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-1; Ethyl 6-{4-[3-(5-methoxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-2; Ethyl(6R)-6-{4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(1,3,4-thiadiazole-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl(6R)-6-[4-(3-methoxypyridine-2-yl)piperazine-1-yl]-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6S)-6-[4-(3-methoxypyridine-2-yl)piperazine-1-yl]-2-azaspiro[3,4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(4-methyl-1H-pyrazole-1-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-{4-[2-(2,2,2-trifluoroethoxy)pyridine-3-yl]piperazin-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(1,3-thiazole-5-yl)pyrazine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 2-[4-(3-methoxypyridine-2-yl)piperazine-1-yl]-6-azaspiro[3,4]octane-6-carboxylate; Ethyl 2-{4-[3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl]piperazine-1-yl}-6-azaspiro[3,4]octane-6-carboxylate; Ethyl 6-{4-[3-(pyrimidine-5-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-(3-methylpyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 2-{4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-yl}-6-azaspiro[3,4]octane-6-carboxylate; Ethyl 6-{4-[3-(pyridazin-4-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-(1,3-oxazol-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[2-(difluoromethoxy)pyridine-3-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-1; Ethyl 6-{4-[2-(trifluoromethoxy)pyridine-3-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-1; Ethyl 6-[4-(3-methylpyridine-2-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate, ENT-1; Ethyl 6-[4-(3-cyclopropylpyridine-2-yl)piperazine-1-yl]-2-azaspiro[3.4]octane-2-carboxylate, ENT-1; Ethyl 2-[4-(5-cyano-2,3'-bipyridine-2'-yl)piperazine-1-yl]-6-azaspiro[3.4]octane-6-carboxylate, ENT-2; Ethyl 6-[4-(5-cyano-2,3'-bipyridine-2'-yl)piperazine-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate; Ethyl 6-{4-[2-(oxetane-3-yloxy)pyridine-3-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-{4-[5-fluoro-3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-1; Ethyl 6-[4-(3-methoxypyrazine-2-yl)piperazine-1-yl]-2-azaspiro[3.4]octane-2-carboxylate, ENT-2; Ethyl 6-(4-{3-[4-(1-methyl-1H-pyrazole-5-yl)piperidine-1-yl]pyridine-2-yl}piperazine-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-{4-[3-(3,3-difluoropyrroridine-1-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-(3-cyanoazetidine-1-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-(4-methyl-1,2-thiazole-5-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.3]heptan-2-carboxylate; Ethyl 6-{4-[3-(3-methyl-1,2-thiazole-5-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.3]heptan-2-carboxylate; Ethyl 6-{4-[3-(1,2,5-thiadiazole-3-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-(1,2,5-thiadiazole-3-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-1; Ethyl 6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate; Ethyl 6-{4-[3-(2,4-dimethyl-1,3-thiazole-5-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[5'-(difluoromethoxy)-3,3'-bipyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-[4-(6'-methoxy-3,3'-bipyridine-2-yl)piperazine-1-yl]-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-(imidazo[1,2-a]pyridine-6-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-([1,2,4]triazolo[4,3-a]pyridine-6-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-{4-[3-(5-cyanopyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, ENT-2; Ethyl(6R)-6-{4-[3-(morpholine-4-yl)pyrazine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(4-methoxypiperidine-1-yl)pyrazine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(2-oxa-6-azaspiro[3.3]hepta-6-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-{4-[3-(pyridazin-3-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(pyrimidine-4-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(2-methylpyrimidine-5-yl)pyridine-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-{4-[3-(5-hydroxypyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-(4-{3-[1-(4-cyanobutyl)-1H-pyrazole-4-yl]pyridine-2-yl}piperazine-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-(4-{3-[1-(2-ethoxyethyl)-1H-pyrazole-4-yl]pyridine-2-yl}piperazine-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-{4-[3-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3,4]octane-2-carboxylate; Ethyl 6-(4-(3-(4-acetamidophenyl)pyridine-2-yl)piperazine-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-(4-(3-(4-cyanophenyl)pyridine-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-(4-(2-methoxypyridine-3-yl)piperazine-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl(6R)-6-(4-(2-methoxypyridine-3-yl)piperazine-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; and Ethyl(6S)-6-(4-(2-methoxypyridine-3-yl)piperazine-1-yl)-2-azaspiro[3,4]octane-2-carboxylate A compound or its N-oxide, or a pharmaceutically acceptable salt of the compound or its N-oxide, selected from the above. [Section 37] Ethyl(6R)-6-{4-[3-(1,3-thiazole-4-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide. [Section 38] Ethyl(6R)-6-{4-[3-(1,3,4-thiadiazole-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide. [Section 39] Ethyl(6R)-6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide. [Section 40] Ethyl 6-(4-(2-methoxypyridine-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate or its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide. [Section 41] A therapeutically effective amount of formula I, I according to any one of claims 1 to 40 A , I B , I C A pharmaceutical preparation comprising a compound of I', its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide, and a pharmaceutically acceptable excipient. [Section 42] A method for treating an M4-mediated (or M4-related) disease or disorder in a patient, comprising: a therapeutically effective amount of formula I, I according to any one of claims 1 to 41, in the patient. A , I B , I C A method comprising the step of administering a compound of I', its N-oxide, or a pharmaceutically acceptable salt of the compound or N-oxide. [Section 43] The method according to claim 42, wherein the M4-mediated (or M4-related) disease or disorder is a disease or disorder selected from the group consisting of Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment (e.g., mild cognitive impairment), Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes mellitus, autism, and atherosclerosis. [Section 44] The method according to claim 43, wherein the M4-mediated (or M4-related) disorder or disorder is a disorder or disorder selected from the group consisting of Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, and sleep disorders.

Claims

1. Ethyl (6R)-6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate, or a pharmaceutically acceptable salt thereof.

2. Ethyl(6R)-6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate.

3. A pharmaceutically acceptable salt of ethyl(6R)-6-{4-[3-(pyrazine-2-yl)pyridine-2-yl]piperazine-1-yl}-2-azaspiro[3.4]octane-2-carboxylate.

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