M4 activators / modulators and their uses

Abstract

The present disclosure provides a compound of formula I:(1), or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or N-oxide, wherein A, Y, m, n, p, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 , R 7 and Z are as described herein; processes for their preparation; intermediates used in their preparation; and compositions containing such compounds, N-oxides or salts, and their uses for treating M4-mediated (or M4-associated) disorders, including, for example, Alzheimer's disease, Parkinson's disease, schizophrenia (e.g., the cognitive and negative symptoms thereof), pain, addiction, and sleep disorders.

Description

[Technical Field]

[0001] The present disclosure relates generally to novel pyridine azaspiro compounds that are agonists / activators / modulators of the muscarinic M4 receptor and are useful in the treatment of M4-mediated diseases and disorders, including but not limited to, schizophrenia, Alzheimer's disease, dementia-related psychosis, dementia with Lewy bodies, Parkinson's disease and related memory and executive dysfunction disorders, bipolar disorder, agitation, and psychoses associated therewith. [Background technology]

[0002] Patients with schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, and various other neurological / neurodegenerative diseases frequently suffer from behavioral and cognitive deficits that disrupt their daily lives in debilitating ways. Over the years, many pharmacological treatments have been discovered that provide some improvement in behavioral and cognitive function. However, the improvements are modest, and often the underlying dose-limiting adverse effects associated with these treatments, including extrapyramidal and metabolic side effects, lead to partial response and noncompliance.

[0003] Muscarinic acetylcholine receptors (mAChRs) are a viable mechanism for treating these diseases. Five mAChR subtypes (M1-M5) have been identified and are part of the G protein-coupled receptor (GPCR) superfamily. These subtypes are widely distributed throughout the periphery and central nervous system (CNS), with the M1 and M4 subtypes being expressed primarily in the CNS. HTL0016878, an M4 agonist being developed for the treatment of core symptoms of Alzheimer's disease, has entered phase 2 clinical studies. Summary of the Invention [Problem to be solved by the invention]

[0004] Thus, there is a need for agonists of the muscarinic M4 receptor to treat M4-mediated diseases and disorders such as Parkinson's disease, schizophrenia, Alzheimer's disease and others described herein. [Means for solving the problem]

[0005] Provided herein are compounds having the structure of Formula (I), or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide thereof:

[0006] [ka] In the formula, A is a 6- to 8-membered heterocycle containing 1 or 2 ring nitrogen atoms and 1 to 3 C 1~3 optionally substituted with an alkyl group; Y is a bond, S, CH, CHF, CF, or C(OH)H; m is 1 or 2; n is 1 or 2; p is 1 or 2; R 1 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8 membered heterocycle, -[O] 0~1 -5-10 membered heteroaryl, -NH-C 3~6 Cycloalkyl, -NH-C 6~10 Aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C 1~6 Alkyl)-C 3~6 Cycloalkyl, -N(C 1~6 Alkyl)-C 6~10 Aryl, -N(C 1~6 alkyl)-4 to 8-membered heterocycle, -N(C 1~6alkyl)-5 to 10-membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - When R is a 5- to 10-membered heteroaryl, 1 is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ═O, SO, and C alkyl; R 2 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Heteroalkyl, C 3~6 cycloalkyl or a 4-8 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 3 are halogens, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8 membered heterocycle, -[O] 0~1 -5-10 membered heteroaryl, -NH-C 3~6 Cycloalkyl, -NH-C 6~10Aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C 1~6 Alkyl)-C 3~6 Cycloalkyl, -N(C 1~6 Alkyl)-C 6~10 Aryl, -N(C 1~6 alkyl)-4 to 8-membered heterocycle or -N(C 1~6 alkyl)-5 to 10-membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 3 But -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8 membered heterocycle, -[O] 0~1 -5-10 membered heteroaryl, -NH-C 3~6 Cycloalkyl, -NH-C 6~10 Aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C 1~6 Alkyl)-C 3~6 Cycloalkyl, -N(C 1~6 Alkyl)-C 6~10 Aryl, -N(C 1~6 alkyl)-4 to 8-membered heterocycle or -N(C 1~6 When R is a 5- to 10-membered heteroaryl, it is selected from the group consisting of 1, 2, or 3 R 3a optionally substituted with a substituent; each R 3a are halogens, CN, OH, =O, SO2, C 1~6 Alkyl, C 2~10 Alkene, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylene-OC 1~6 Alkyl, C 0-6 Alkylene-NH2, C 0-6 Alkylene-NH(C 1~6 alkyl), C 0-6 Alkylene-N(C 1~6Alkyl)2, -SC 1~6 Alkyl, C 0-6 Alkylene-SO2C 1-6 Alkyl, C 0-6 Alkylene-C(O)NH2, C 0-6 Alkylene-C(O)NH(C 1~6 alkyl), C 0-6 Alkylene-C(O)N(C 1~6 Alkyl)2, C 0-6 Alkylene-NHC(O)C 1~6 Alkyl, C 0-6 alkylene-COOH and C containing 1, 2 or 3 heteroatoms selected from N, O and S 0-6 alkylene-3 to 6-membered heterocycles; R 4 is H, halogen, CN or OH; R 5 is -CO2-Z or a bioisostere thereof; each R 6 and R 7 are independently H, C 1~6 Alkyl, C(O)-C 1~6 Alkyl, spiro or bicyclic C 8~14 cycloalkyl, an 8-14 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 6 or R 7 If is other than H, it is a halogen, CN, OH, =O, SO2, C 0-6 Alkylene-NH2, C 0-6 Alkylene-NH(C 1~6 alkyl), C 0-6 Alkylene-N(C 1~6 Alkyl)2, C 0-6 Alkylene-SO2C 1-6 Alkyl, C 1~6 Alkyl and C 1~6 alkoxy, or R 6 and R 7 together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N, O and S; Z is C 1~7 Alkyl, C 1~7Haloalkyl, C 3~6 Cycloalkyl or C 2~6 alkynyl and Z is C 1~6 Alkoxy or C 3~6 optionally substituted with cycloalkyl; 1 , R 2 and R 4 are each H, Y is CH2, m, n and p are each 1, and A is

[0007] [ka] and R 3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy, or

[0008] [ka] If R 5 is not CO2CH2CH3.

[0009] A pharmaceutical composition comprising the compound as disclosed herein.Further provided herein is a method for treating an M4-mediated (or M4-related) disease or disorder related to abnormal M4 receptor activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein.

[0010] Further aspects and advantages will be apparent to those skilled in the art from a review of the following detailed description in conjunction with the drawings. While the compounds and methods disclosed herein are capable of being exemplified in various forms, and the following description includes specific examples, it will be understood that the disclosure is illustrative and is not intended to limit the invention to the specific examples described herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] Formula (I):

[0012] [ka] Provided herein is a compound having the structure: or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or its N-oxide. Also provided herein are compounds that act on the M4 receptor. The compounds described herein can be used to treat M4-mediated or M4-related diseases.

[0013] chemical definition As used herein, the term "alkyl" refers to straight-chain and branched saturated hydrocarbon groups containing 1 to 30 carbon atoms, e.g., 1 to 20 carbon atoms or 1 to 10 carbon atoms. n The term "alkyl" means that the alkyl group has "n" carbon atoms. For example, C6 alkyl refers to an alkyl group having 6 carbon atoms. 1~7 Alkyl refers to alkyl groups having any number of carbon atoms, including all ranges (i.e., 1 to 7 carbon atoms), and all subgroups (e.g., 2 to 6, 2 to 5, 3 to 6, 2, 3, 4, 5, 6, and 7 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), and t-butyl (1,1-dimethylethyl). Unless otherwise indicated, alkyl groups can be unsubstituted or substituted alkyl groups.

[0014] As used herein, the term "alkylene" refers to a divalent saturated aliphatic group. n The term "alkylene" means that the alkylene group has "n" carbon atoms, for example, C alkylene is CH. 1~6 Alkylene refers to alkylene groups having a number of carbon atoms, including all ranges and all subgroups as previously described for "alkyl" groups.

[0015] As used herein, the terms "alkene" or "alkenyl" are defined identically to "alkyl," except that they contain at least one carbon-carbon double bond and have 2 to 30 carbon atoms, e.g., 2 to 20 carbon atoms or 2 to 10 carbon atoms. n The term "alkenyl" means that the alkenyl group has "n" carbon atoms. For example, C4 alkenyl refers to an alkenyl group having 4 carbon atoms. 2~7 Alkenyl refers to alkenyl groups having any number of carbon atoms, including all ranges (i.e., 2 to 7 carbon atoms), and all subgroups (e.g., 2 to 6, 2 to 5, 3 to 6, 2, 3, 4, 5, 6, and 7 carbon atoms). Specific contemplated alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, and butenyl. Unless otherwise indicated, alkenyl groups can be unsubstituted or substituted. Unless otherwise indicated, alkenyl groups can be cis-alkenyl or trans-alkenyl.

[0016] As used herein, the term "alkyne" or "alkynyl" is defined identically to "alkyl," except that it contains at least one carbon-carbon triple bond and has 2 to 30 carbon atoms, e.g., 2 to 20 carbon atoms or 2 to 10 carbon atoms. n The term "alkynyl" means that the alkynyl group has "n" carbon atoms. For example, C4 alkynyl refers to an alkynyl group having 4 carbon atoms. C 2~7 Alkynyl refers to alkynyl groups having any number of carbon atoms, including all ranges (i.e., 2-7 carbon atoms), and all subgroups (e.g., 2-6, 2-5, 3-6, 2, 3, 4, 5, 6, and 7 carbon atoms). Specifically contemplated alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, and butynyl. Unless otherwise indicated, alkynyl groups can be unsubstituted or substituted.

[0017] As used herein, the term "cycloalkyl" specifically refers to a non-aromatic ring in which each atom of the ring is carbon, i.e., a carbocyclic ring, which may be monocyclic, bicyclic, bridged, fused, or spirocyclic. n The term "cycloalkyl" means that the cycloalkyl group has "n" ring carbon atoms. For example, C5 cycloalkyl refers to a cycloalkyl group having 5 ring carbon atoms in the ring. C 3~8 Cycloalkyl refers to cycloalkyl groups having any number of ring carbon atoms, including all ranges (i.e., 3-8 carbon atoms), and all subgroups (e.g., 4-8, 3-7, 4-7, 3-6, 4-6, 3-5, 4-5, 3, 4, 5, 6, 7, and 8 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Non-limiting examples of bridged cycloalkyl groups include:

[0018] [ka] Non-limiting examples of spirocycloalkyl groups include:

[0019] [ka] Unless otherwise specified, a cycloalkyl group may be an unsubstituted cycloalkyl group or a substituted cycloalkyl group.

[0020] As used herein, the term "heterocycle" is defined similarly to cycloalkyl, except that the ring contains 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Additionally, heterocycles of the present disclosure can be monocyclic, bicyclic, bridged, fused, or spirocyclic. For example, a heterocycle can be a monocyclic, bicyclic, bridged, fused, or spirocyclic 4-8 membered ring having 1, 2, or 3 heteroatoms selected from N, O, and S. As another example, a heterocycle can be an 8-10 membered bicyclic, bridged, fused, or spirocyclic group having 1, 2, or 3 ring heteroatoms selected from N, O, and S in the bicyclic ring. Non-limiting examples of heterocyclic groups include azepane, aziridine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, dihydrofuran, dihydropyran, morpholine, oxazepane, thiazole, pyrrole, pyridinone, and pyridine.

[0021] [ka] Examples include:

[0022] The cycloalkyl and heterocyclic groups may be saturated or partially unsaturated ring systems (e.g., having double or triple bonds), but the groups are not aromatic. Cycloalkyl and heterocyclic groups include, for example, alkyl, alkoxy, alkylene, OH, C 0~6 Alkylene-C(O)NH2, NH2, =O, SO2, aryl, haloalkyl, haloalkoxy, C 0~6 Alkylene-C(O)-alkyl, C 0~6 Alkylene-SO2 alkyl, halogen, OH, NHC 1~3 Alkylene-aryl, OC 1~3 Alkylene-aryl, C 1~3 alkylene-aryl and C having 1 to 3 heteroatoms selected from N, O and S 0~6 Alkylene-C 3~6Heterocycles may be optionally substituted with 1 to 3 groups independently selected from the group consisting of: Specific substitutions for these groups are described elsewhere in this disclosure.

[0023] As used herein, the term "aryl" refers to an aromatic ring in which each atom of the ring is carbon, and may be a monocyclic or polycyclic (e.g., fused bicyclic and fused tricyclic) carbocyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, indenyl, anthracenyl, fluorenyl, and tetralinyl. Unless otherwise specified, an aryl group may be an unsubstituted aryl group or a substituted aryl group.

[0024] As used herein, the term "heteroaryl" refers to an aromatic heterocycle, which may be a monocyclic or polycyclic (e.g., fused bicyclic and fused tricyclic) aromatic ring system, in which one to four (e.g., one to three) ring atoms are selected from oxygen, nitrogen, and sulfur, and the remaining ring atoms are carbon, and the ring system is joined to the rest of the molecule by any of the ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thienyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, triazinyl, triazolyl, purinyl, pyrazinyl, purinyl, indolinyl, phthaldinyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyridopyridinyl, indolyl, 3H-indolyl, pteridinyl, and quinoxalinyl.

[0025] [ka] TIFF2025532632000009.tif99162. Unless otherwise specified, a heteroaryl group may be an unsubstituted heteroaryl group or a substituted heteroaryl group.

[0026] As used herein, the term "hydroxy" or "hydroxyl" refers to an "-OH" group. Thus, a "hydroxyalkyl" refers to an alkyl group substituted with one or more -OH groups.

[0027] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced with one or more halogens.

[0028] As used herein, the term "alkoxy" or "alkoxyl" refers to an "-O-alkyl" group.

[0029] As used herein, the term "halogen" is defined as fluoro, chloro, bromo, and iodo. Accordingly, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. In some cases, the haloalkyl group is a perhaloalkyl, i.e., all hydrogen atoms of the alkyl group are replaced with halogens. Some non-limiting examples of haloalkyl groups include CF, CHF, CHF, CCl, CI, and CHCF. Similarly, "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, such as OCF.

[0030] As used herein, the term "heteroalkyl" refers to an alkyl chain interrupted by one or more heteroatoms selected from N, O, and S and having 2 to 30 carbon atoms, e.g., 2 to 20 carbon atoms or 2 to 10 carbon atoms. n The term heteroalkyl refers to an alkyl group having "n" carbon atoms. For example, C6 heteroalkyl refers to an alkyl group having 6 carbon atoms, where the carbon chain is interrupted by one or more heteroatoms. 2~6Heteroalkyl refers to alkyl groups having any number of carbon atoms, including all ranges (i.e., 2-6 carbon atoms) and all subgroups (e.g., 2-5, 3-6, 3-5, 4-6, 2, 3, 4, 5, and 6 carbon atoms).

[0031] As used herein, the term "bioisostere" refers to a molecule resulting from the replacement of an atom or group of atoms with an alternative, broadly similar atom or group of atoms. For example, an ester group can be replaced by one of the following bioisosteres of esters, including, but not limited to, acylsulfonamide (CONR-S0R), hydroxamic acid (CONROH), hydroxamate (CONR0R), tetrazole, hydroxyisoxazole, isoxazol-3-one, and sulfonamide (S0NR), where each R can independently represent hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0032] A "substituted" functional group (e.g., substituted alkyl, cycloalkyl, aryl, or heteroaryl) is a functional group having at least one hydrogen group replaced with a non-hydrogen group (i.e., substituent). Examples of non-hydrogen groups (or substituents) include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, ether, aryl, O-alkylenearyl, N-alkylenearyl, alkylenearyl, heteroaryl, heterocycle, hydroxy, hydroxyalkyl, haloalkoxy, amido, =0, SO2, alkoxy, ester, thioester, acyl, carboxyl, cyano, nitro, amino, sulfhydryl, and halogen. When a substituted alkyl group contains more than one non-hydrogen group, the substituents may be attached to the same carbon or to two or more different carbon atoms.

[0033] Compounds of the Disclosure Formula (I):

[0034] [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or N-oxide thereof, wherein: A is a 6- to 8-membered heterocycle containing one or two ring nitrogen atoms and is not substituted with halogen, OH, or C 1~3 optionally substituted with 1 to 3 substituents independently selected from alkyl; Y is a bond, S, O, CH2, CHF, CF2, or C(OH)H; m is 1 or 2; n is 1 or 2; p is 1 or 2; R 1 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8 membered heterocycle, -[O] 0~1 -5-10 membered heteroaryl, -NH-C 3~6 Cycloalkyl, -NH-C 6~10 Aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C 1~6 Alkyl)-C 3~6 Cycloalkyl, -N(C 1~6 Alkyl)-C 6~10 Aryl, -N(C 1~6 alkyl)-4 to 8-membered heterocycle or -N(C 1~6 alkyl)-5 to 10-membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 1 But C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - When R is a 5- to 10-membered heteroaryl, 1 is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ═O, SO and C alkyl; R 2 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Heteroalkyl, C 3~6 cycloalkyl or a 4-8 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 3 are halogens, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S; C 3~6 Cycloalkyl, C 6~10 The aryl, 4- to 8-membered heterocycle, or 5- to 10-membered heteroaryl may have 0, 1, 2, or 3 R 3ais substituted with a substituent; Each R 3a are halogens, CN, OH, =O, =N(C 1~3 alkyl), C 1~6 Alkyl, C 2~10 Alkene, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylene-OC 1~6 Alkyl, C 0~6 Alkylene-NH2, C 0~6 Alkylene-NH(C 1~6 alkyl), C 0~6 Alkylene-N(C 1~6 Alkyl)2, -SC 1~6 Alkyl, C 0~6 Alkylene-SO2C 1~6 Alkyl, C 0~6 Alkylene-C(O)NH2, C 0~6 Alkylene-C(O)NH(C 1~6 alkyl), C 0~6 Alkylene-C(O)N(C 1~6 Alkyl)2, C 0~6 Alkylene-NHC(O)C 1~6 Alkyl, C 0~6 Alkylene-COOH, C 0~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkylene-OC 1~6 Alkylene Si(C 1~3 alkyl)3 and C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 alkylene-3 to 6 membered heterocycle; R 4 is H, halogen, CN or OH; R 5 is -CO2-Z or a biological equivalent thereof; Each R 6 and R 7 are independently H, C 1~6 Alkyl, C(O)-C 1~6 Alkyl, spiro or bicyclic C8~14 cycloalkyl, an 8-14 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 6 or R 7 If is other than H, it is a halogen, CN, =O, SO2, OH, C 0~6 Alkylene-NH2, C 0~6 Alkylene-NH(C 1~6 alkyl), C 0~6 Alkylene-N(C 1~6 Alkyl)2, C 0~6 Alkylene-SO2C 1~6 Alkyl, C 1~6 Alkyl and C 1~6 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy; R 6 and R 7 together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N, O and S; Z is C 1~7 Alkyl, C 1~7 Haloalkyl, C 3~6 Cycloalkyl or C 2~6 Alkyne and Z is C 1~6 Alkoxy or C 3~6 optionally substituted with cycloalkyl; However, R 1 , R 2 and R 4 are each H, Y is CH2, m, n and p are each 1, and A is

[0035] [ka] and R 3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy or

[0036] [ka] If R 5is not CO2CH2CH3.

[0037] In the compounds of formula (I), A may be a 6-8 membered heterocycle containing 1 or 2 ring nitrogen atoms and 1 to 3 C 1~3 In various cases, A is optionally substituted with an alkyl group.

[0038] [ka] and X is N, CH, CF or C(OH). In various cases, A is

[0039] [ka] In compounds of formula (I), X can be N or CH. In various cases, X is N. In various cases, X is CH.

[0040] In some instances, the compound has the formula (Ia):

[0041] [ka] It has the following structure.

[0042] In some instances, the compound has the formula (Ib):

[0043] [ka] It has the following structure.

[0044] In various cases, Y can be a bond, S, CH, CHF, CF, or C(OH)H. In various cases, Y is CH, CHF, CF, or C(OH)H. In some cases, Y is CH.

[0045] In various cases, m can be 1 or 2. In various cases, m is 1.

[0046] In various cases, n can be 1 or 2. In various cases, n is 1.

[0047] In various cases, p can be 1 or 2. In various cases, p is 1.

[0048] In some instances, the compound has the formula (Ic):

[0049] [ka] It has the following structure.

[0050] In some instances, the compound has the formula (Id):

[0051] [ka] It has the following structure.

[0052] In various cases, R 5 is -CO2-Z or a biological equivalent thereof. 5 teeth,

[0053] [ka] In various cases, R 5 CO2-C 1~7 Alkyl,

[0054] [ka] In some cases, R 5 CO2-C 1~7 In some cases, R 5 is CO2CH2CH3.

[0055] In some instances, the compound has the formula (Ie):

[0056] [ka] It has the following structure.

[0057] In various cases, R 4 can be H, halogen, CN, or OH. In various cases, R 4 is H or halogen. In some cases, R 4 is H.

[0058] In various cases, R 1 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - When R is a 5- to 10-membered heteroaryl, 1may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ═O, SO, and C alkyl. 1 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl or C 1~6 In some cases, R 1 is H or a halogen.

[0059] In various cases, R 2 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Heteroalkyl, C 3~6 It can be a cycloalkyl or a 4-8 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S. In various cases, R 2 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 In some cases, R 2 H, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl or C 1~6 In some cases, R 2 is H or halogen. In some cases, R 2 is H. In some cases, R 2 and R 4 Each of is H.

[0060] In various cases, each R 6 and R 7 are independently H, C1~6 Alkyl, C(O)-C 1~6 Alkyl, spiro or bicyclic C 8~14 cycloalkyl, an 8-14 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 6 or R 7 If is other than H, it is a halogen, CN, OH, =O, SO2, C 0~6 Alkylene-NH2, C 0~6 Alkylene-NH(C 1~6 alkyl), C 0~6 Alkylene-N(C 1~6 Alkyl)2, C 0~6 Alkylene-SO2C 1~6 Alkyl, C 1~6 Alkyl and C 1~6 alkoxy, or R 6 and R 7 together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N, O, and S. In various instances, each R 6 and R 7 are independently H, C 1~6 Alkyl or C(O)-C 1~6 In some cases, each R 6 and R 7 are independently H or C 1~6 In various cases, at least one R 6 and R 7 together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N and O.

[0061] In various cases, R 3 are halogens, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 3 Ga-[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - When it is a 5- to 10-membered heteroaryl, it is one, two, or three R 3a In various cases, R 3 is -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, and 1, 2 or 3 R 3a Optionally substituted with R 1 , R 2 , R 3 and R 4 At least one of R is halogen. 1 , R 2 , R 3 and R 4 At least one of R is F. In various cases, 3 teeth,

[0062] [ka] TIFF2025532632000023.tif217163, and one, two or three R 3a In some cases, R3 teeth,

[0063] [ka] and one, two or three R 3a In some cases, R 3 is C 3~6 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocycle, and one, two, or three R 3a In some cases, R 3 is a 5- to 6-membered heterocycle containing one ring heteroatom selected from S and O, or a 5- to 6-membered heteroaryl containing two or three ring heteroatoms independently selected from N and S, and is selected from halogen, CN, OH, and C 1~6 one or two R independently selected from alkyl 3a It is optionally substituted with a substituent.

[0064] In the compounds of formula (I), R 3 is one, two or three R 3a In many cases, R 3 is unsubstituted. In many cases, R 3 is one or two R 3a In some cases, R 3 is one R 3a In the compounds of formula (I), each R 3a are independently halogens, CN, OH, =O, SO2, C 1~6 Alkyl, C 2~10 Alkene, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylene-OC 1~6 Alkyl, C 0~6 Alkylene-NH2, C 0~6 Alkylene-NH(C 1~6 alkyl), C 0~6Alkylene-N(C 1~6 Alkyl)2, -SC 1~6 Alkyl, C 0~6 Alkylene-SO2C 1~6 Alkyl, C 0~6 Alkylene-C(O)NH2, C 0~6 Alkylene-C(O)NH(C 1~6 alkyl), C 0~6 Alkylene-C(O)N(C 1~6 Alkyl)2, C 0~6 Alkylene-NHC(O)C 1~6 Alkyl, C 0~6 alkylene-COOH and C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 In various cases, at least one R 3a are halogens, CN, OH, =O, SO2, C 1~6 Alkyl, C 2~10 Alkene, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylene-OC 1~6 Alkyl, C 0~6 Alkylene-N(C 1~6 Alkyl)2, -SC 1~6 Alkyl, C 0~6 Alkylene-NHC(O)C 1~6 alkyl or C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 Alkylene-3 to 6-membered heterocycle. Often, at least one R 3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2 OCH3, CH2OCH2CH3, F, CN, =O, SO2, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, SCH3, N(CH3)2, NHCOCH3, CD3,

[0065] [ka] In some cases, at least one R 3a is CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH or OCHF2.

[0066] In some cases, the compound has the formula (If):

[0067] [ka] wherein R 1 is a halogen; R 3 is -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 3 is 0, 1, 2 or 3 R 3a Substituted with a substituent; R 5 is -CO2-Z or a biological equivalent thereof, and Z is C 1~7 Alkyl, C 1~7 Haloalkyl, C 3~6 Cycloalkyl or C 2~6 Alkyne, C 1~6 Alkoxy or C 3~6 In some cases, R is optionally substituted with cycloalkyl. 1 is Cl or F. In some cases, R 3 is a 5- to 6-membered heterocycle containing one ring heteroatom selected from S and O, or a 5- to 6-membered heteroaryl containing two or three ring heteroatoms independently selected from N and S, and is selected from halogen, CN, OH, and C 1~6 0, 1 or 2 R independently selected from alkyl 3a In various cases, R5 is CO2C 1~7 It is alkyl.

[0068] Examples of compounds according to formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If) of the present disclosure are shown in Table A.

[0069] [Table 1] TIFF2025532632000028.tif242163TIFF2025532632000029.tif236161TIFF2025532632000030.tif240162TIFF202 5532632000031.tif249161TIFF2025532632000032.tif241161TIFF2025532632000033.tif250161TIFF2025532632 000034.tif246161TIFF2025532632000035.tif228161TIFF2025532632000036.tif245162TIFF2025532632000037. tif220161TIFF2025532632000038.tif249161TIFF2025532632000039.tif226162TIFF2025532632000040.tif22916 1TIFF2025532632000041.tif239161TIFF2025532632000042.tif238161TIFF2025532632000043.tif230161TIFF20 25532632000044.tif239160TIFF2025532632000045.tif249161TIFF2025532632000046.tif244161TIFF2025532632 000047.tif240161TIFF2025532632000048.tif220161TIFF2025532632000049.tif243161TIFF2025532632000050. tif241162TIFF2025532632000051.tif231161TIFF2025532632000052.tif247161TIFF2025532632000053.tif54161

[0070] The present disclosure also includes all pharmaceutically acceptable isotopically labeled compounds identical to those listed herein, where one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to: 2 H,3 Isotopes of hydrogen such as H; 11 C. 13 C and 14 isotopes of carbon such as C; 36 isotopes of chlorine such as Cl; 18 isotopes of fluorine, such as F; 123 I and 125 Isotopes of iodine, such as I: 13 N and 15 isotopes of nitrogen such as N; 15 O. 17 O and 18 isotopes of oxygen such as O; 32 Isotopes of phosphorus, such as P; and 35 Included are sulfur isotopes such as S. Isotopically labeled compounds can contain two or more combinations of the same or different isotopes mentioned above. Certain isotopically labeled compounds of the present disclosure, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium, i.e., 3 H or "T" and carbon 14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. Heavier isotopes, such as deuterium, i.e. 2 Substitution with H, or "D" can offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Positron-emitting isotopes, such as 11 C. 18 F, 15 O and 13Substitution with N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying schemes and / or examples and preparations, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent. Pharmaceutically acceptable solvates according to the present disclosure include those in which the solvent of crystallization may be isotopically substituted, for example, DO, acetone-d6, or DMSO-d6.

[0071] The dashed lines and thick wedge bonds (i.e.,

[0072] [ka] Chemical structures having one or more stereocenters depicted with a ) are meant to depict the absolute stereochemistry of the stereocenter(s) present in the chemical structure. Bonds symbolized by simple lines do not indicate stereo preference. Broken or thick straight bonds (i.e.,

[0073] [ka] ) are meant to indicate the relative stereochemistry of the stereocenter(s) present in the chemical structure. Unless otherwise indicated to the contrary, chemical structures containing one or more stereocenters illustrated herein without indicating absolute or relative stereochemistry encompass all possible stereoisomeric forms (e.g., diastereomers, enantiomers) of the compound and mixtures thereof. Structures with a single bold or dashed wedge line and at least one additional simple line encompass a single enantiomeric series of all possible diastereomers. Similarly, chemical structures with alkenyl groups are meant to encompass both cis and trans orientations, or, if substituted, E and Z isomers of the chemical structure.

[0074] Pharmaceutically Acceptable Salts and Cocrystals As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals, without undue adverse side effects, such as toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio.

[0075] Pharmaceutically acceptable salts are well known in the art.For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.The pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.These salts can be prepared in situ during the final isolation and purification of the compound.

[0076] As used herein, "Formula (I)," "Formula (Ia)," "Formula (Ib)," "Formula (Ic)," "Formula (Id)," and "Formula (Ie)" are further defined to include all forms of the compounds of the present disclosure, including, but not limited to, hydrates, solvates, isomers (including, for example, rotational isomers), crystalline and non-crystalline forms, isomorphs, polymorphs, metabolites, and prodrugs thereof. For example, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can exist in unsolvated forms and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. When the solvent or water is tightly bound, the complex has a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content depends on humidity and drying conditions. In such cases, non-stoichiometry is the norm. In general, solvated forms are considered equivalent to unsolvated forms for purposes of this disclosure.

[0077] The compounds of the present disclosure can exist as inclusion complexes or other complexes (e.g., cocrystals). Complexes such as inclusion complexes, drug-host inclusion complexes, and the like, in which the drug and host are present in stoichiometric or non-stoichiometric amounts, are included within the scope of the present disclosure. Also included are complexes of the compounds of the present disclosure containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see Haleblian, J. Pharm. Sci., 64(8), 1269-1288 (August 1975). Cocrystals are typically defined as crystalline complexes of neutral molecular constituents bound together through non-covalent interactions, but may also be complexes of neutral molecules with salts. Co-crystals can be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together; see O. Almarsson and MJ Zaworotko, Chem. Commun. 2004, 17, 1889-1896. For a general review of multi-component complexes, see JK Haleblian, J. Pharm. Sci. 1975, 64, 1269-1288.

[0078] In some cases, compounds of the present disclosure can exist in and / or be isolated as atropisomers (e.g., one or more atropenantiomers). Those skilled in the art will recognize that atropisomerism can exist in compounds having two or more aromatic rings (e.g., two aromatic rings connected via a single bond). See, for example, Freedman, T.B. et al., Absolute Configuration Determination of Chiral Molecules in the Solution State Using Vibrational Circular Dichroism. Chirality 2003, 15, 743-758; and Bringmann, G. et al., Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44, 5384-5427.

[0079] When any racemate crystallizes, two different types of crystals are possible: the first type is the racemate (true racemate) referred to above, where one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts; the second type is a racemic mixture or conglomerate, where two forms of crystal are produced in equimolar amounts, each containing a single enantiomer.

[0080] The compounds of the present disclosure may also be present as their N-oxides or as pharmaceutically acceptable salts of the compounds or N-oxides.

[0081] As is known to those skilled in the art, amine compounds (i.e., those containing one or more nitrogen atoms), such as tertiary amines, can form N-oxides (also known as amine oxides or amine N-oxides). Generally, N-oxides are represented by the formula R3N +The parent amine R3N has the formula -O~, where the parent amine R3N can be, for example, a tertiary amine (e.g., each R is independently alkyl, arylalkyl, aryl, heteroaryl, etc.), a heterocyclic or heteroaromatic amine (e.g., R3N together form a 1-alkylpiperidine, 1-alkylpyrrolidine, 1-benzylpyrrolidine, or pyridine). For example, an imine nitrogen, particularly a heterocyclic or heteroaromatic imine nitrogen, or a pyridinic nitrogen (=N-) atom, such as the nitrogen atom in pyridine, pyridazine, or pyrazine, can be N-oxidized to ≡N + N-oxides containing the -O- group can be formed. Thus, compounds according to the present disclosure that contain one or more nitrogen atoms (e.g., imine nitrogen atoms) may be capable of forming their N-oxides (e.g., mono-N-oxides, bis-N-oxides, or multi-N-oxides, or mixtures thereof, depending on the number of nitrogen atoms suitable for forming stable N-oxides).

[0082] As used herein, the term "N-oxide(s)" refers to all possible and in particular all stable N-oxide forms of the amine compounds described herein (e.g., compounds containing one or more imine nitrogen atoms), such as mono-N-oxides (including different isomers when more than one nitrogen atom of an amine compound is capable of forming a mono-N-oxide) or multi-N-oxides (e.g., bis-N-oxides), or mixtures thereof in any ratio.

[0083] As noted above, the compounds of the present disclosure (or their N-oxides) can exist in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Depending on the particular compound, a salt of a compound can be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability at different temperatures and humidities, 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 resolution of the compound.

[0084] When a salt is intended to be administered to a patient (e.g., as opposed to being used in an in vitro context), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of the present disclosure with an acid whose anion is generally considered suitable for human consumption, or a base whose cation is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present disclosure due to their increased aqueous solubility relative to the parent compound.

[0085] Suitable pharmaceutically acceptable acid addition salts of the compounds of the present disclosure, where possible, include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, meta-phosphoric acid, nitric acid, carbonic acid, sulfonic acid, and sulfuric acid, and organic acids such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothioic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid, and trifluoroacetic acid. Suitable organic acids generally include, but are not limited to, the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids.

[0086] Specific examples of suitable organic acid salts include 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 the like. phosphate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylamino-sulfonate, algenate, β-hydroxybutyrate, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalene-sulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate and undecanoate salts.

[0087] Furthermore, when a compound of the present disclosure contains an acidic moiety, suitable pharmaceutically acceptable salts thereof can include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts. In another embodiment, base salts are formed from bases that form non-toxic salts, including aluminum salts, arginine salts, benzathine salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, meglumine salts, olamine salts, tromethamine salts, and zinc salts.

[0088] Organic salts can be made from secondary, tertiary, or quaternary amine salts such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C-Cs) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aryl alkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0089] In some cases, hemisalts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts, or sesquifumarates.

[0090] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the present disclosure are known to those skilled in the art.

[0091] The compounds of the present disclosure can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on the temperature, can exhibit the physical properties of a solid or a liquid. Typically, such materials do not exhibit a distinctive X-ray diffraction pattern and, while exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change from an apparent solid to a material with liquid properties occurs, which is characterized by a change of state, typically second-order order ("glass transition"). The term "crystalline" refers to a solid phase in which a material has a regularly ordered internal structure at the molecular level and exhibits a distinctive X-ray diffraction pattern with distinct peaks. When heated sufficiently, such materials also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first-order order ("melting point").

[0092] The compounds of the present disclosure can also exist in a mesophase (mesophase or liquid crystal) when subjected to appropriate conditions. A mesophase is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphs that arise as a result of a change in temperature are described as "thermotropic," and those that result from the addition of a second component, e.g., water or another solvent, are described as "lyotropic." Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic," and may be ionic (-COO'Na * , -COOK * or -SO3s'Na * etc.) or non-ionic (-N"N * It consists of molecules possessing a polar head group (such as (CHs)3). For more information, see Crystals and the Polarizing Microscope, 4th Edition, by N.H. Hartshorne and A. Stuart (Edward Arnold, 1970).

[0093] The present disclosure also relates to prodrugs of the compounds of the present disclosure. Thus, certain derivatives of the compounds of the present disclosure, which themselves have little or no pharmacological activity, can be converted, for example, by hydrolytic cleavage, into compounds of Formula I with the desired activity when administered into or on the body. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in Prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).

[0094] Prodrugs according to the present disclosure can be generated by replacing appropriate functional groups present in the compounds of the present disclosure with certain moieties known to those skilled in the art as "pro moieties," for example, as described in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985) or in "Prodrugs: Challenges and Reward," edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, and Jefferson Tilley, 2007 edition, pp. 134-175 (Springer, 2007).

[0095] Furthermore, certain compounds of the present disclosure can themselves act as prodrugs of other compounds of the present disclosure. This disclosure also encompasses compounds of the present disclosure that contain protecting groups. Those skilled in the art will also understand that compounds of the present disclosure can be prepared with certain protecting groups that are useful for purification or storage and can be removed before 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.W. Buts, Wiley-Interscience (1999).

[0096] Metabolites of the compounds of the present disclosure, that is, compounds formed in vivo upon administration of the drug, are also included within the scope of the present disclosure.

[0097] Other acids and bases may be used in the preparation of salts which, while not themselves pharmaceutically acceptable, are useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0098] It should be understood that the compounds disclosed herein can exist as mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of compounds in free form and pharmaceutically acceptable salts are also contemplated.

[0099] Pharmaceutical preparations Also provided herein are pharmaceutical formulations comprising an effective amount of a compound of the present disclosure and one or more pharmaceutically acceptable excipients. As used herein, the term "formulation" is used interchangeably with "composition."

[0100] "Effective amount" includes "therapeutically effective amount" and "prophylactically effective amount." The term "therapeutically effective amount" refers to an amount effective to treat and / or ameliorate a disease or condition in a subject. The term "prophylactically effective amount" refers to an amount effective to prevent and / or substantially reduce the likelihood of a disease or condition in a subject. As used herein, the terms "patient" and "subject" can be used interchangeably and refer to animals such as dogs, cats, cows, horses, and sheep (i.e., non-human animals), as well as humans. A particular patient or subject is a mammal (e.g., a human). The terms "patient" and "subject" include males and females.

[0101] As used herein, the term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), that is appropriately selected with regard to the intended mode of administration and consistent with conventional pharmaceutical practice.

[0102] The compound of the present disclosure can be administered alone or as part of pharmaceutically acceptable compositions or preparations.In addition, the compound can be administered all at once, for example by bolus injection, or can be administered multiple times, for example by a series of tablets, or can be delivered substantially uniformly over a period of time, for example by using transdermal delivery.It will also be appreciated that the dose of the compound can vary over time.

[0103] The compounds disclosed herein and other pharmaceutically active compounds can be administered to a subject or patient by any suitable route, if desired, for example, orally, topically, rectally, parenterally (e.g., subcutaneous injection, intravenous, intramuscular, intrasternal, and intrathecal injection or infusion techniques), or buccal, inhaled, or nasal spray. Administration can provide a systemic effect (e.g., enterally or parenterally). All methods that can be used by those skilled in the art to administer pharmaceutically active agents are contemplated. In some cases, the disclosed formulations can be administered orally or topically.

[0104] Suitable oral compositions or formulations according to the present disclosure include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, syrups, or elixirs. Compositions or formulations suitable for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0105] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents.

[0106] Solid dosage forms for oral administration include capsules, tablets, pills, powders, or granules. In these solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dibasic calcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, and the like. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0107] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0108] The active compound may be in microencapsulated form with one or more excipients as noted above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In these solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0109] The pharmaceutical compositions and formulations described herein can also be administered topically or transdermally, especially when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract.Suitable topical formulations are easily prepared for each of these areas or organs.Topical application for the lower intestinal tract can be effected, for example, in a rectal suppository formulation or in a suitable enema formulation.Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, suppositories, or patches.

[0110] For topical application, the pharmaceutical composition can be formulated into a suitable ointment, cream, lotion or gel containing the active ingredient suspended or dissolved in one or more carriers, and any necessary preservatives or buffers as may be required.Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0111] Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0112] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0113] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0114] To prolong the effect of the compounds described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Depot injectable formulations are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the properties of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0115] Compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0116] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0117] The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0118] The compounds for use in the methods of the present disclosure can be formulated in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for a subject to be treated, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0119] For oral administration, the compositions can 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 active ingredient for symptomatic adjustment of patient dosage. Medicaments typically contain from about 0.01 mg to about 500 mg of active ingredient, or, in another embodiment, from about 1 mg to about 100 mg. Intravenously, doses can range from about 0.1 mg to about 10 mg / kg / minute during a constant rate infusion.

[0120] Treatment methods The compounds disclosed herein (e.g., compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), and Formula (Id)), and pharmaceutically acceptable salts thereof, can act on the M4 receptor. The muscarinic acetylcholine receptor M4 (also known as muscarinic 4 or CHRM4) is a protein in humans encoded by the CHRM4 gene. The M4 receptor is primarily expressed in the brain. Key brain regions where M4 receptor expression occurs are the striatum, cortex, and hippocampus, with the highest expression occurring in the striatum (approximately 46%), where M4 is the predominant muscarinic subtype. M4 is sporadically expressed in the periphery (e.g., testis, skin, and colon).

[0121] M4 receptors are G q / iMuscarinic acetylcholine receptors are coupled to proteins and function as inhibitory autoreceptors in the striatum and midbrain (Zhang et al., "Multiple Muscarinic Acetylcholine Receptor Subtypes Modulate Striatal Dopamine Release, as Studied with M1-M5 Muscarinic Receptor Knock-Out Mice," Journal of Neuroscience, August 1, 2002, 22(15):6347-6352; Tzavara et al., "M4 Muscarinic Receptors Regulate the Dynamics of Cholesteric and Dopaminergic Neurotransmission: Relevance to the Pathophysiology and Treatment of Related Central Nervous System Pathologies," The FASEB Journal, 2004;18:1410-1412), and as postsynaptic modulatory receptors in the striatum, neocortex, and hippocampus (Levey et al., "Identification and Localization of Muscarinic Acetylcholine Receptor Proteins in the Brain with Subtype-Specific Antibodies," Journal of Neuroscience. October 1, 1991, 11(10)3218-3226; Gil et al.; "Muscarinic receptor subtypes in human iris-ciliary body measured by immunoprecipitation." Investigative Ophthalmology & Visual Science 38.7(1997):1434-1442) function.M4 receptors are also found on glutamatergic synapses from the cortex to the striatum (Pancani, T. et al., "Allosteric activation of M4 improves behavioral and physiological alterations in early symptomatic YAC128 mice," Proceedings of the National Academy of the Sciences of the United States of America, 2015 Nov. 10;112(45):14078-83), and presynaptically on glutamatergic neurons in the hippocampus, where presynaptic M4 modulates glutamate release. The highest expression of M4 receptors is found in the striatum, where they are coexpressed with D1 dopamine receptors in a subset of striatal medium spiny neurons that, in addition, have a modulatory effect on dopaminergic neurotransmission and contain GABA as the primary neurotransmitter (Bernard et al., "Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes," Journal of Neuroscience, September 1, 1992, 12(9), 3591-3600; Di Chiara et al., "Modulatory functions of neurotransmitters in the striatum: ACh / dopamine / NMDA interactions," Trends in Neurosciences, Vol. 17, No. 6, 1994, pp. 228-233; Ince et al., "Differential expression of D1 and D2 dopamine and m4 muscarinic acetylcholine receptor proteins in identified striatonigral neurons"). Synapse, (1997)27:357~366).

[0122] It has been hypothesized that administration of selective M4 agonists provides antipsychotic activity for the treatment of schizophrenia (Felder et al., "Elucidating the Role of Muscarinic Receptors in Psychosis," Life Sci. 68:2605-2613, 2001). This belief was further supported by studies demonstrating that M4 receptors modulate the dynamics of dopaminergic and cholinergic neurotransmission and that states of dopaminergic hyperactivity occur with loss of M4 function (Tzavara et al., 2004).

[0123] The compounds of the present disclosure may also be useful in treating / alleviating neuropsychiatric symptoms (i.e., behavioral symptoms) associated with Alzheimer's disease and schizophrenia (Foster et al., "Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia," Neuropsychiatric Disease and Treatment; 2014. Vol. 10, pp. 183-191). These behavioral symptoms include, but are not limited to, agitation, vocal outbursts, obsessive-compulsive behavior, anxiety, irritability, combativeness, disorientation, hallucinations, delusions, hallucinations, suspiciousness, blunted affect, depression, disinhibition, abnormal motor and compulsive behavior, and sleep disturbances (Dillon, Carol et al., "Behavioral symptoms related to cognitive impairment," Neuropsychiatric Disease and Treatment; 2013:9 1443-1455). By treating / alleviating the behavioral symptoms described above, the compounds of the present disclosure are also believed to enhance cognition.

[0124] In view of the above, the compounds of the present disclosure may be useful for treating schizophrenia and Alzheimer's disease. The compounds of the present disclosure may also be useful for treating Parkinson's disease, Huntington's disease, addiction, substance abuse disorders, depression, and epilepsy. The compounds of the present disclosure may also be useful for treating Alzheimer's disease psychosis.

[0125] It is believed that the M4 selective activators of the present disclosure may also have a wide range of other therapeutic applications for the treatment of conditions or diseases of the central nervous system, including neurological, neurodegenerative, and / or psychiatric disorders, including, but not limited to, (1) mood [affective] disorders; (2) neurotic, stress-related, and somatoform disorders, including anxiety disorders; (3) disorders involving symptoms of cognitive deficits in mammals, including humans; (4) disorders including attention deficits, executive function deficits (working memory deficits), impulse control dysfunction, extrapyramidal symptoms, and disorders based on dysfunction of the basal ganglia, hippocampus, and prefrontal cortex; (5) behavioral and emotional disorders whose onset typically occurs in childhood and adolescence; (6) disorders of psychological development; and (7) disorders of the central nervous system. (8) generalized atrophy primarily affecting the neuropsychiatric system; (9) extrapyramidal and movement disorders; (10) behavioral syndromes associated with physiological disturbances and physical factors; (11) adult personality and behavioral disorders; (12) schizophrenia and other psychotic disorders; (13) mental and behavioral disorders due to psychoactive substance use; (14) sexual dysfunction, including excessive sexual drive; (15) mental retardation; (16) factitious disorder, e.g., acute hallucinatory mania; (17) episodic and seizure disorders, epilepsy; (18) narcolepsy; (19) dementia; and (20) amyotrophic lateral sclerosis.

[0126] Examples of mood (affective) disorders that can be treated in accordance with the present disclosure include, but are not limited to, bipolar disorder I, hypomania (manic and mixed forms), bipolar disorder II; depressive disorders, such as a single depressive episode or recurrent major depressive disorder, chronic depression, psychotic depression, minor depressive disorder, postpartum-onset depressive disorder, depressive disorder with psychotic symptoms; persistent mood (affective) disorders, such as cyclothymia, dysthymia, euthymia; premenstrual syndrome (PMS) and premenstrual dysphoric disorder.

[0127] Examples of neurotic, stress-related, and somatoform disorders that can be treated in accordance with the present disclosure include, but are not limited to, anxiety disorders, social anxiety disorder, generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobias, social phobias, chronic anxiety disorders; obsessive-compulsive disorders; reactions to severe stress and adjustment disorders, such as post-traumatic stress disorder (PTSD), acute stress disorder, and other neurotic disorders, such as depersonalization-derealization syndrome.

[0128] The phrases "cognitive deficit" and "disorders comprising symptoms of cognitive deficit" as used herein refer to subnormal or suboptimal functioning in one or more aspects of cognition, such as memory, intelligence, learning and reasoning abilities, or attention and executive function (working memory), in a particular individual compared to other individuals within the same general age group.

[0129] Examples of "disorders comprising symptoms of cognitive deficits" that can be treated in accordance with the present disclosure include, but are not limited to, cognitive deficits primarily, but not exclusively, associated with amnesia, psychosis (schizophrenia), Parkinson's disease, Alzheimer's disease, multi-infarct dementia, senile dementia, Lewis body dementia, stroke, frontotemporal dementia, progressive supranuclear palsy, Huntington's disease, HIV disease (HIV-associated dementia), brain trauma, and substance abuse; mild cognitive impairment ADHD, Asperger's syndrome, and age-related memory deficits; cognitive decline or delirium associated with post-operative or intensive care treatment.

[0130] Examples of disorders, typically first diagnosed in infancy, childhood, and adolescence, that can be treated in accordance with the present disclosure include, but are not limited to, hyperactivity disorder, including activity and attention disturbance, attention deficit / hyperactivity disorder (ADHD), hyperactivity-conduct disorder; attention deficit disorder (ADD); conduct disorder, including but not limited to depressive-conduct disorder; tic disorders, including transient tic disorder, chronic motor or vocal tic disorder, combined vocal and complex motor tic disorder (Gilles de la Tourette syndrome), substance-induced tic disorder; autistic disorder; Batten disease, excessive masturbation, nail biting, nose picking, and thumb sucking.

[0131] Examples of disorders of psychological development that can be treated in accordance with the present disclosure include, but are not limited to, pervasive developmental disorders, including, but not limited to, Asperger's syndrome and Rett's syndrome, autistic disorder, childhood autism and hyperactivity disorder associated with mental retardation and stereotypic movements, specific developmental disorder of motor function, and specific developmental disorder of academic skills.

[0132] Examples of systemic atrophy primarily affecting the central nervous system that can be treated in accordance with the present disclosure include, but are not limited to, multiple sclerosis systemic atrophy primarily affecting the basal ganglia, including Huntington's disease and amyotrophic lateral sclerosis.

[0133] Examples of extrapyramidal and movement disorders with basal ganglia dysfunction and / or degeneration that can be treated in accordance with the present disclosure include, but are not limited to, Huntington's disease; Parkinson's disease; secondary parkinsonism, e.g., postencephalitic parkinsonism; parkinsonism among other disorders; Niemann-Pick disease, Lewy body disease; degenerative diseases of the basal ganglia; other extrapyramidal and movement disorders, e.g., tremor, essential tremor and drug-induced tremor, myoclonus, chorea and drug-induced chorea, drug-induced tics and tics of organic origin, drug-induced acute dystonia, drug-induced tardive dyskinesia, muscle spasms, and disorders associated with muscle spasticity or weakness, e.g., tremor; mental retardation (including spasticity, Down syndrome, and Fragile X syndrome), L-dopa-induced dyskinesia; restless legs syndrome and stiff man syndrome.

[0134] Further examples of movement disorders with basal ganglia dysfunction and / or degeneration that can be treated in accordance with the present disclosure include, but are not limited to, dystonias, including, but not limited to, focal dystonia, multiple focal or segmental dystonia, torsion dystonia, hemispheric, generalized, and tardive dystonia (induced by psychopharmacological drugs). Focal dystonias include cervical dystonia (torticollis), blepharospasm (spasms of the eyelids), limb dystonia (spasms of the limbs, such as writer's cramp), or mandibular dystonia and spasmodic dysphonia (spasms of the vocal cords); neuroleptic-induced movement disorders, such as, but 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 tardive dyskinesia, and neuroleptic-induced tremor.

[0135] Examples of behavioral syndromes associated with physiological disturbances and physical factors according to the present disclosure include, but are not limited to, non-organic sleep disorders, such as, but not limited to, non-organic hypersomnia, non-organic disorders of sleep-wake schedules (circadian rhythm sleep disorders), insomnia, parasomnia, and sleep deprivation; mental and behavioral disorders associated with the postpartum period, such as, but not limited to, postnatal and postnatal depression; eating disorders, such as, but not limited to, anorexia nervosa, bulimia nervosa, binge eating disorder, binge eating disorder, obesity, compulsive eating disorder, and pagophagia.

[0136] Examples of adult personality and behavioral disorders that can be treated in accordance with the present disclosure include, but are not limited to, personality disorders, such as, but not limited to, emotionally unstable, borderline, obsessive-compulsive, anakastic, addictive, and passive-aggressive personality disorders; habit and impulse disorders (impulse control disorders), such as intermittent explosive disorder, pathological gambling, pathological fire-setting (pyromania), pathological kleptomania (kleptomania), trichotillomania; and Munchausen syndrome.

[0137] Examples of schizophrenia and other psychotic disorders that can be treated in accordance with the present disclosure include, but are not limited to, different types of continuous or episodic schizophrenia (e.g., paranoid, depraved, catatonic, undifferentiated, residual and schizophreniform disorders); schizotypal disorders (e.g., borderline, latent, prepsychotic, prodromal, pseudoneurotic, pseudopsychotic schizophrenia and schizotypal personality disorders); persistent delusional disorder; acute, transient and persistent psychotic disorders; induced delusional disorder; different types of schizoaffective disorder (e.g., manic-depressive or mixed); postpartum psychosis and other and unspecified non-organic psychoses, such as social withdrawal in schizophrenia.

[0138] Examples of mental and behavioral disorders due to psychoactive substance use that can be treated in accordance with the present disclosure include, but are not limited to, mental and behavioral disorders due to alcohol, opioid, cannabinoid, sedative or hypnotic drug, cocaine use; mental and behavioral disorders due to other stimulant use, including caffeine; drug dependence and abuse (e.g., narcotic dependence, alcohol dependence, amphetamine and methamphetamine dependence, opioid dependence, cocaine addiction, nicotine dependence and drug withdrawal syndrome, and relapse prevention), hallucinogen, tobacco (nicotine), volatile solvent use, and mental and behavioral disorders due to multiple drug use and other psychoactive substance use, including the following symptom subtypes: harmful use, dependence syndrome, withdrawal, and withdrawal with delirium.

[0139] Examples of dementia that can be treated in accordance with the present disclosure 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.

[0140] Schizophrenia or psychosis for which the aforementioned compounds of the present disclosure, their N-oxides, and pharmaceutically acceptable salts may be useful includes one or more of the following conditions: schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other stimulants, and cocaine) psychosis / psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia." "psychiatric spectrum" disorders, such as schizophrenia or schizotypal personality disorder, or illnesses associated with psychosis, including both the positive and negative symptoms of schizophrenia and other psychoses (e.g., major depression, manic-depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome); cognitive disorders, including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other common medical conditions or substance abuse); delirium, amnesic disorders, or age-related cognitive decline.

[0141] In addition to the central nervous system disorders described above, the compounds of the present disclosure can be used to treat other M4-mediated (or M4-associated) disorders, including, but not limited to, addiction (e.g., substance addiction, such as addiction to opioids, cocaine, or alcohol), pain (e.g., acute pain, inflammatory pain, and neuropathic pain), and sleep disorders (e.g., those associated with REM sleep regulation, e.g., those associated with REM sleep onset). Additional M4-mediated (or M4-associated) disorders or conditions that can be treated by the compounds of the present disclosure include dry mouth, cognitive impairment (e.g., mild cognitive deficit), dyskinesia, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia (e.g., degenerative dementia), hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, and atherosclerosis. See, e.g., U.S. Pat. No. 8,664,234.

[0142] Potential sleep disorders for which the aforementioned compounds of the present disclosure, their N-oxides, and pharmaceutically acceptable salts may be useful include: enhancing sleep quality; improving sleep quality; increasing sleep maintenance; increasing the value calculated from the time a subject is asleep divided by the time a subject is attempting to sleep; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing the difficulty of falling asleep; increasing sleep duration; decreasing the number of waking states during sleep; decreasing nighttime awakenings; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing sleep fragmentation; altering the timing, frequency, or duration of REM sleep periods; altering the timing, frequency, or duration of slow wave (i.e., stage 3 or 4) sleep periods; the amount and duration of stage 2 sleep. increasing the fraction of REM sleep; promoting slow-wave sleep; enhancing EEG delta activity during sleep; increasing daytime alertness; reducing daytime somnolence; treating or reducing excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy; sleep disruption; sleep apnea; awakenings; nocturnal myoclonus; REM sleep disruption; jet lag; shift worker sleep disturbance; sleep paralysis; night terrors; insomnia associated with depression, emotional / mood disorders, as well as sleepwalking and enuresis, and sleep disorders associated with aging; Alzheimer's nightfall symptoms; conditions associated with circadian rhythmicity, as well as mental and physical disorders associated with cross-time travel and rotating shift work schedules; conditions caused by drugs that have reduced REM sleep as a side effect; syndromes manifested by sleep apnea associated with non-restorative sleep and muscle pain or disturbed breathing during sleep; and conditions resulting from reduced sleep quality.

[0143] Pain disorders in which the aforementioned compounds of the present disclosure, their N-oxides, and pharmaceutically acceptable salts may be useful include neuropathic pain (e.g., post-herpetic neuralgia, nerve injury, "pain" such as vulvodynia, phantom limb pain, ulcerative colitis, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); post-operative pain syndromes (e.g., post-mastectomy syndrome, post-thoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia); perioperative pain (general surgery, gynecology), chronic pain, dysmenorrhea, and pain associated with angina pectoris, and 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 caused by central sensitization.

[0144] The aforementioned compounds of the present disclosure, their N-oxides, and pharmaceutically acceptable salts can be used to reduce tolerance to and / or dependence on opioid treatment of pain, and for the treatment of, for example, alcohol, opioid, and cocaine withdrawal syndromes.

[0145] In various cases, the M4-mediated (or M4-associated) disease or disorder can be selected from the group consisting of Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive impairment (e.g., mild cognitive deficit), Parkinson's disease, Parkinson's disease levodopa-induced dyskinesia, Huntington's disease, dyskinesia, tardive dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down's syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, and atherosclerosis. In some cases, the M4-mediated (or M4-associated) disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease levodopa-induced dyskinesia, and sleep disorders.

[0146] Synthesis of Compounds of the Present Disclosure The compounds of the present disclosure can be synthesized by any method known in the art. For example, the compounds of the present disclosure (compounds of formula (I)) can be synthesized according to Schemes 1, 2, 3, 4, 5, and 6.

[0147] [ka]

[0148] Scheme 1 illustrates one synthetic sequence for the preparation of compounds of Formulas I and I'. According to Scheme 1, compound II can be coupled to heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl, and heteroalkyl boronic acids, boronic esters, or potassium trifluoroborate via Suzuki-Miyaura coupling reactions. The reaction types include, but are not limited to, Suzuki-Miyaura couplings, Stille, Negishi, Hiyama, and decarboxylative couplings; Sonogashira couplings using alkynes / silylalkynes; and nucleophilic aromatic substitution (S) of amines and alcohols. N Ar), where R 1 , R 2 , R 3 , R 4 and A substituents should be represented by the same moieties as desired in the final product or a protected variation thereof, and G 1 Coupling reaction using S N Ar reaction to produce compound III, while G 1 is a boronic acid / ester / trifluoroborate, stannane, magnesium, zinc, carboxylic acid, carboxylate, or alcohol / amine; or terminal alkyne / silylalkyne, using standard selection of metal source, ligand, and base in standard solvents / cosolvents, including but not limited to, DMF, acetonitrile, 1,4-dioxane, THF, pyridine, toluene, ethanol, n-butanol, and t-butanol. Examples of Pd / ligand / base combinations in coupling reactions include, but are not limited to, tetrakis(triphenylphosphine)palladium(0) plus sodium carbonate and tris(dibenzylideneacetone)palladium(0) plus dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl plus potassium carbonate. S N In the Ar reaction, examples of bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, K2CO3, Cs2CO3, K3PO4, K3PO4.H2O, tBuOK, and NaH. 1Removal of the protecting group P in this case results in compound IV. 1 refers to groups well known to those skilled in the art for amine protection. For example, P 1 may be tert-butoxycarbonyl (Boc), which can be cleaved via acidic conditions in a suitable solvent, including but not limited to, treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM). 1 may be one of many other protecting groups suitable for amines, including carboxybenzyl (Cbz) or benzoyl (Bz) groups, and can be cleaved under standard conditions known to those skilled in the art. Compound IV can be coupled with compound V (where m, n, and p are independently represented by integers selected from 1 or 2) using standard reductive amination procedures, such as, but not limited to, a combination of sodium cyanoborohydride and titanium(IV) ethoxide or sodium triacetoxyborohydride in a suitable solvent, to produce racemic compound VI. The protecting group Boc can be cleaved via acidic conditions in a suitable solvent, including, but not limited to, treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM), followed by the addition of R. 5 to introduce a carbamate or carbamate bioisostere to produce compounds of formula I as a racemic mixture, where R 5should be represented by the same moiety as desired in the final product or its protected variant in dichloromethane or other suitable solvent. Chiral separation of a racemic mixture, e.g., chiral chromatographic methods such as chiral HPLC or chiral supercritical fluid chromatography (SFC), can produce enantiomerically enriched or enantiomerically pure (e.g., at least 98% %ee) compounds of Formula I'. Enantiomerically enriched compounds are those having an enantiomeric excess (%ee) of at least 80% (i.e., a 9 to 1 enantiomeric ratio of one enantiomer to the other). The %ee of an enantiomerically enriched compound can be at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Measurement of %ee can be performed using known laboratory techniques.

[0149] [ka]

[0150] Scheme 2 depicts an alternative synthetic route for the preparation of compounds of formula I and I'. With reference to Scheme 2a, compound IV (R of formula IV) 1 , R 2 , R 3 , R 4 and A substituents should be represented by the same moieties as desired in the final product or a protected variation thereof.) can be displaced by the sulfonate of enantiomerically pure compound VII in the presence of a base such as potassium carbonate or potassium phosphate tribasic in a suitable solvent, including but not limited to DMSO, DMF, MeCN, or THF, where R of formula VII 5 should be represented by the same moiety as desired in the final product or a protected variation thereof, and R 6is an aryl, alkyl, or fluoroalkyl substituent, e.g., 4-methylphenyl, methyl, nonafluorobutyl; m, n, and p are independently represented by integers selected from 1 or 2, and Y should be represented by the same moiety as desired in the final product. With reference to Scheme 2b, compound IV (where R 1 , R 2 , R 3 , R 4 and A should be represented by the same moiety as desired in the final product or a protected variation thereof.) similarly displaces the arylalkyl / fluoroalkyl sulfonate on chiral compound VIII to produce compound IX, where R 6 is an aryl, alkyl, or fluoroalkyl substituent, e.g., 4-methylphenyl, methyl, nonafluorobutyl; m, n, and p are independently represented by integers selected from 1 or 2, and Y should be represented by the same moiety as desired in the final product. Removal of the BOC group can be achieved via acidic conditions in a suitable solvent, including but not limited to, trifluoroacetic acid in dichloromethane (DCM), followed by the addition of R 5 to introduce a carbamate or carbamate bioisostere to produce a compound of formula I' as a single enantiomer, where R 5 should be represented by the same moiety as desired in the final product or a protected variation thereof. Alternatively, as shown in Scheme 2c, compound IV (where R of formula IV) can be prepared by 1 , R 2 , R 3 , R 4 and A substituents should be represented by the same moieties as desired in the final product or a protected variant thereof.) can be converted to compound X (R of formula X) using standard reductive amination procedures, such as, but not limited to, a combination of sodium cyanoborohydride and titanium(IV) ethoxide or sodium triacetoxyborohydride in a suitable solvent. 5should be represented by the same moiety as desired in the final product or a protected variant thereof, m, n, and p are independently represented by integers selected from 1 or 2, and Y should be represented by the same moiety as desired in the final product. Compounds of general formula I can be produced as racemic mixtures by coupling to a compound of formula I as a racemic mixture. Chiral separation of the racemate of formula I can be achieved by chiral SFC to provide compounds of formula I' as single enantiomers. In Scheme 2d, compound XI (where R 1 , R 2 , R 3 and R 4 should be represented by the same moiety as desired in the final product or a protected variation thereof, and G 2 is a sulfonate or halogen.) can be used in standard coupling procedures, such as, but not limited to, Suzuki-Miyaura coupling or Buchwald-Hartwig coupling reactions, as well as S-coupling of amines. N The Ar reaction was used to obtain enantiomerically pure compound XII (wherein A and R of formula XII 5 should be represented by the same moiety as desired in the final product or a protected variant thereof, m, n, and p are independently represented by integers selected from 1 or 2, and Y should be represented by the same moiety as desired in the final product. ) can be coupled to generate compounds of Formula I'. Additionally, with reference to Scheme 2e, enantiomerically pure compound XIII can be coupled to heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl, and heteroalkyl boronic acids, boronic esters, or potassium trifluoroborate via Suzuki-Miyaura coupling reactions. The scope of reaction types includes, but is not limited to, Suzuki-Miyaura, Stille, Negishi, Hiyama, and decarboxylative couplings; Sonogashira couplings using alkynes / silylalkynes; and nucleophilic aromatic substitution of amines and alcohols (S N Ar), generating formula I' as a single enantiomer, where R1 , R 2 , R 3 , R 4 , R 5 and A substituents should be represented by the same moieties as desired in the final product or protected variations thereof, m, n, and p are independently represented by integers selected from 1 or 2, and Y should be represented by the same moieties as desired in the final product.

[0151] [ka]

[0152] Scheme 3 illustrates one synthetic sequence for the preparation of compounds of Formula Ia. According to Scheme 3, compound XIV can be coupled to heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl, and heteroalkyl boronic acids, boronic esters, or potassium trifluoroborate via Suzuki-Miyaura coupling reactions. The reaction types include, but are not limited to, Suzuki-Miyaura couplings, Stille, Negishi, Hiyama, and decarboxylative couplings; Sonogashira couplings using alkynes / silylalkynes; and nucleophilic aromatic substitution (S) of amines and alcohols. N Coupling reactions or S-coupling reactions using standard selection of metal sources, ligands and bases in standard solvents such as, but not limited to, DMF, acetonitrile, 1,4-dioxane, THF, pyridine, toluene, ethanol, n-butanol, t-butanol. N via Ar reaction to produce compound XV, where R 1 , R 2 , R 3 and R 4The substituents, as well as Y, should be represented by the same moieties as desired in the final product or its protected variant. Examples of Pd / ligand / base combinations in coupling reactions include, but are not limited to, tetrakis(triphenylphosphine)palladium(0) plus potassium carbonate and tris(dibenzylideneacetone)palladium(0) plus dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl plus potassium carbonate. S N In the Ar reaction, examples of bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, K2CO3, Cs2CO3, K3PO4, t-BuOK, and NaH. 1 Removal of the protecting group P in this case gives compound XVI. 1 refers to groups well known to those skilled in the art for amine protection. For example, P 1 may be tert-butoxycarbonyl (Boc), which can be cleaved via acidic conditions in a suitable solvent, including, but not limited to, treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM). 1 may be one of many other suitable protecting groups for amines, including a carboxybenzyl (Cbz) group or a benzoyl (Bz) group, which can be cleaved under standard conditions known to those skilled in the art. Compound XVI can be prepared by standard reductive amination procedures, such as, but not limited to, a combination of sodium cyanoborohydride and titanium(IV) ethoxide or sodium triacetoxyborohydride in a suitable solvent, followed by deprotection of the Boc protecting group and the formation of R 5 can be used to introduce a carbamate or carbamate bioisostere by treatment with 5 should be represented by the same moiety as desired in the final product or a protected variation thereof.

[0153] [ka]

[0154] Scheme 4 illustrates one synthetic sequence for the preparation of compounds of Formula Ib. With reference to Scheme 4, compound XVIII can be coupled to heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl, and heteroalkyl boronic acids, boronic esters, or potassium trifluoroborate via Suzuki-Miyaura coupling reactions. The reaction types include, but are not limited to, Suzuki-Miyaura couplings, Stille, Negishi, Hiyama, and decarboxylative couplings; Sonogashira couplings using alkynes / silylalkynes; and nucleophilic aromatic substitution of amines and alcohols (S). N Coupling reactions or S-coupling reactions using standard selection of metal sources, ligands and bases in standard solvents such as, but not limited to, DMF, acetonitrile, 1,4-dioxane, THF, pyridine, toluene, ethanol, n-butanol, t-butanol. N via Ar reaction to produce compound XIX, where R 1 , R 2 , R 3 and R 4 The substituents should be represented by the same moieties as desired in the final product or its protected variant. Examples of Pd / ligand / base combinations in coupling reactions include, but are not limited to, tetrakis(triphenylphosphine)palladium(0) plus sodium carbonate and tris(dibenzylideneacetone)palladium(0) plus dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl plus potassium carbonate. S N In the Ar reaction, examples of bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, K2CO3, Cs2CO3, K3PO4, tBuOK, and NaH. 1Removal of the protecting group P in this case leads to compound XX. 1 refers to groups well known to those skilled in the art for amine protection. For example, P 1 may be tert-butoxycarbonyl (Boc), which can be cleaved via acidic conditions in a suitable solvent, including, but not limited to, treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM). 1 may be one of many other suitable protecting groups for amines, including a carboxybenzyl (Cbz) or benzoyl (Bz) group, which can be cleaved under standard conditions known to those skilled in the art. Compound XX can be prepared in dichloromethane or other suitable solvent by standard reductive amination procedures, such as, but not limited to, a combination of sodium cyanoborohydride and titanium(IV) ethoxide or sodium triacetoxyborohydride in a suitable solvent, followed by deprotection of the BOC group and removal of R. 5 can be used to introduce a carbamate or carbamate bioisostere by treatment with 5 should be represented by the same moiety as desired in the final product or a protected variation thereof.

[0155] [ka]

[0156] Scheme 5 shows an alternative synthetic route for the preparation of compounds of formula Ic. With reference to Scheme 5a, compound XXVII can be prepared via two synthetic methods, and the enantiomeric compound XXIII (wherein R 6is to be represented by an aryl, alkyl or fluoroalkyl substituent, such as 4-methylphenyl, methyl or nonafluorobutyl. ) can be coupled with XXIV in the presence of a base such as potassium carbonate or tribasic potassium phosphate in a suitable solvent, including but not limited to MeCN, DMSO, DMF or THF. In addition, the alternative route can be achieved by coupling compounds XXV and XXVI. The protecting group P 1 Removal of the protecting group P in this case leads to compound XXVIII. 1 refers to groups well known to those skilled in the art for amine protection. For example, P 1 P may be a carboxybenzyl (Cbz) that can be cleaved via H gas conditions in an appropriate solvent, including, but not limited to, treatment with a solution of wet 10% Pd / C in methanol (MeOH). 1 can be one of many other protecting groups suitable for amines, including a benzyl (Bn) or benzoyl (Bz) group, which can be cleaved under standard conditions known to those skilled in the art. Compound XXVIII can be prepared by standard C-N coupling procedures, such as, but not limited to, Buchwald-Hartwig coupling and S-coupling of the amine. N The Ar reaction can be used, where appropriate, to prepare compounds XI (where R 1 , R 2 , R 3 and R 4 should be represented by the same moiety as desired in the final product or a protected variation thereof, and G 1 is a sulfonate or halogen. The tert-butoxycarbonyl (Boc) of compound XXIX can then be cleaved via acidic conditions in a suitable solvent, including but not limited to, treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM), to provide enantiomeric compound XXX, which can then be coupled to R in dichloromethane or other suitable solvent. 5to introduce a carbamate or carbamate bioisostere to produce compounds of formula Ic, where R 5 should be represented by the same moiety as desired in the final product or a protected variant thereof. Alternatively, as shown in Scheme 5b, compound XXXI (where R 1 , R 2 , R 3 and R 4 should be represented by the same moiety as desired in the final product or a protected variation thereof. N Coupling to XXVI via bicyclization can give compound XIX. 1 Removal of the protecting group P in this case leads to compound XX. 1 refers to groups well known to those skilled in the art for amine protection. For example, P 1 may be tert-butoxycarbonyl (Boc), which can be cleaved via acidic conditions in a suitable solvent, including, but not limited to, treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM). 1 may be one of many other protecting groups suitable for amines, including a carboxybenzyl (Cbz) group or a benzoyl (Bz) group, which can be cleaved under standard conditions known to those skilled in the art. Compound XX can be cleaved to give enantiomerically pure compound XXIII (where R 6is an aryl, alkyl, or fluoroalkyl substituent, e.g., 4-methylphenyl, methyl, nonafluorobutyl; e.g., 4-methylphenyl or methyl.) can be displaced from the sulfonate to generate compound XXIX. The tert-butoxycarbonyl (Boc) of compound XXIX can then be cleaved via acidic conditions in a suitable solvent, including but not limited to, treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM), to provide enantiomeric compound XXX, which can then be further reacted with R in dichloromethane or another suitable solvent. 5 A carbamate or carbamate bioisostere can be introduced by treatment with 5 should be represented by the same moiety as desired in the final product or a protected variation thereof.

[0157] [ka]

[0158] Scheme 6 refers to a synthetic sequence for the preparation of compounds of formula Id. With reference to Scheme 6, compound XXX (wherein R 1 , R 2 , R 3 and R 4The substituents should be represented by the same moiety as desired in the final product or a protected variant thereof. ) can then be followed by treatment with CO gas, DBU, and a base such as Z-sulfate-Z, or halide / sulfonate-Z in DMF or other suitable solvent to produce a compound of formula Id, where Z should be represented by the same moiety as desired in the final product or a protected variant thereof. An alternative synthetic route for the preparation of formula Id is to react compound XXX using triphosgene and ZOH in a suitable solvent such as DCM and a base such as pyridine to synthesize a carbamate of formula Id, where Z should be represented by the same moiety as desired in the final product or a protected variant thereof.

[0159] Embodiments of the present disclosure 1. Formula (I):

[0160] [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or its N-oxide, wherein: A is a 6- to 8-membered heterocycle containing one or two ring nitrogen atoms and is not substituted with halogen, OH, or C 1~3 optionally substituted with 1 to 3 substituents independently selected from alkyl; Y is a bond, O, S, CH2, CHF, CF2, or C(OH)H; m is 1 or 2; n is 1 or 2; p is 1 or 2; R 1 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8 membered heterocycle, -[O] 0~1 -5-10 membered heteroaryl, -NH-C 3~6 Cycloalkyl, -NH-C 6~10 Aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C 1~6 Alkyl)-C 3~6 Cycloalkyl, -N(C 1~6 Alkyl)-C 6~10 Aryl, -N(C 1~6 alkyl)-4 to 8-membered heterocycle or -N(C 1~6 alkyl)-5 to 10-membered heteroaryl, R 1 is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ═O, SO and C alkyl; R 2 is H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Heteroalkyl, C 3~6 cycloalkyl or a 4-8 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R3 are halogens, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 2~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8 membered heterocycle, or -[O] 0~1 -5-10 membered heteroaryl, -NH-C 3~6 Cycloalkyl, -NH-C 6~10 Aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C 1~6 Alkyl)-C 3~6 Cycloalkyl, -N(C 1~6 Alkyl)-C 6~10 Aryl, -N(C 1~6 alkyl)-4 to 8-membered heterocycle or -N(C 1~6 alkyl)-5 to 10-membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; 3~6 Cycloalkyl, C 6~10 The aryl, 4- to 8-membered heterocycle, or 5- to 10-membered heteroaryl may have 0, 1, 2, or 3 R 3a is substituted with a substituent; Each R 3a are halogens, CN, OH, =O, =N(C 1~3 alkyl), SO2, C 1~6 Alkyl, C 2~10 Alkene, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylene-OC 1~6 Alkyl, C 0~6 Alkylene-NH2, C 0~6 Alkylene-NH(C 1~6 alkyl), C0~6 Alkylene-N(C 1~6 Alkyl)2, -SC 1~6 Alkyl, C 0~6 Alkylene-SO2C 1~6 Alkyl, C 0~6 Alkylene-C(O)NH2, C 0~6 Alkylene-C(O)NH(C 1~6 alkyl), C 0~6 Alkylene-C(O)N(C 1~6 Alkyl)2, C 0~6 Alkylene-NHC(O)C 1~6 Alkyl, C 0~6 Alkylene-COOH, C 0~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkylene-OC 1~6 Alkylene Si(C 1~3 alkyl)3 and C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 alkylene-3 to 6 membered heterocycle; R 4 is H, halogen, CN or OH; R 5 is -CO2-Z or a biological equivalent thereof; Each R 6 and R 7 are independently H, C 1~6 Alkyl, C(O)-C 1~6 Alkyl, spiro or bicyclic C 8~14 cycloalkyl, an 8-14 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 6 or R 7 If is other than H, it is a halogen, CN, OH, =O, SO2, C 0~6 Alkylene-NH2, C 0~6 Alkylene-NH(C 1~6 alkyl), C 0~6 Alkylene-N(C 1~6 Alkyl)2, C 0~6 Alkylene-SO2C 1~6 Alkyl, C 1~6 Alkyl and C 1~6optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy; R 6 and R 7 together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N, O and S; Z is C 1~7 Alkyl, C 1~7 Haloalkyl, C 3~6 Cycloalkyl or C 2~6 Alkyne and Z is C 1~6 Alkoxy or C 3~6 optionally substituted with cycloalkyl; However, R 1 , R 2 and R 4 are each H, Y is CH2, m, n and p are each 1, and A is

[0161] [ka] and R 3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy, or

[0162] [ka] If R 5 is provided that it is not CO2CH2CH3.

[0163] 2.A is

[0164] [ka] and X is N, CF, C(OH) or CH.

[0165] 3. Structure of Formula (Ia):

[0166] [ka] or a pharmaceutically acceptable salt thereof.

[0167] 4.Formula (Ib):

[0168] [ka] The compound or salt of embodiment 3, having the structure:

[0169] 5. The compound or salt of any one of embodiments 1-3, wherein Y is CH2, CHF, CF2, or C(OH)H.

[0170] 6. The compound or salt of embodiment 5, wherein Y is CH2.

[0171] 7. The compound or salt of any one of embodiments 1-3, 5 and 6, wherein m is 1.

[0172] 8. The compound or salt of any one of embodiments 1-3 and 5-7, wherein n is 1.

[0173] 9. The compound or salt of any one of embodiments 1-3 and 8, wherein p is 1.

[0174] 10.Formula (Ic):

[0175] [ka] 5. The compound or salt of embodiment 4, having the structure:

[0176] 11. Formula (Id):

[0177] [ka] 5. The compound or salt of embodiment 4, having the structure:

[0178] 12.R 5is the CO2Z bioequivalent,

[0179] [ka] 12. The compound or salt of any one of embodiments 1 to 11, selected from the group consisting of:

[0180] 13. Formula (Ie):

[0181] [ka] 2. The compound or salt of embodiment 1, having the structure:

[0182] 14.R 5 But CO2C 1~7 Alkyl,

[0183] [ka] 14. The compound or salt of any one of embodiments 1 to 11 and 13, selected from the group consisting of:

[0184] 15.R 5 The compound or salt of embodiment 14, wherein is CO2CH2CH3.

[0185] 16.R 4 16. The compound or salt of any one of embodiments 1 to 15, wherein is H or halogen.

[0186] 17.R 1 H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl or C 1~6 The compound or salt of any one of embodiments 1 to 16, wherein the alkoxy group is alkoxy.

[0187] 18.R 1 18. The compound or salt of embodiment 17, wherein is H or halogen.

[0188] 19.R 2 H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 The compound or salt of any one of embodiments 1 to 18, wherein the compound or salt is haloalkoxy.

[0189] 20.R 2 But H, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl or C 1~6 20. The compound or salt of embodiment 19, wherein the compound or salt is haloalkoxy.

[0190] 21.R 2 21. The compound or salt of embodiment 20, wherein is H or halogen.

[0191] 22.Each R 6 and R 7 However, independently, H, C 1~6 Alkyl or C(O)-C 1~6 22. The compound or salt of any one of embodiments 1 to 21, wherein is alkyl.

[0192] 23.Each R 6 and R 7 are independently H or C 1~6 23. The compound or salt of embodiment 22, wherein R is alkyl.

[0193] 24. At least one R 6 and R 7 together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N and O.

[0194] 25.R 1 , R 2 and R 425. The compound or salt of any one of embodiments 1 to 24, wherein at least one of is halogen.

[0195] 26.R 1 , R 2 and R 4 26. The compound or salt of embodiment 25, wherein at least one of is F or Cl.

[0196] 27.R 3 But -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, and 1, 2 or 3 R 3a 27. The compound or salt of any one of embodiments 1-26, optionally substituted with:

[0197] 28.R 3 But C 3~6 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocycle, and one, two, or three R 3a 28. The compound or salt of any one of embodiments 1 to 27, optionally substituted with:

[0198] 29.R 3 but,

[0199] [ka] TIFF2025532632000074.tif165165, 1, 2 or 3 R 3a 29. The compound or salt of any one of embodiments 25 to 28, optionally substituted with:

[0200] 30.R 3 but,

[0201] [ka] and one, two or three R 3a 30. The compound or salt of embodiment 29, optionally substituted with:

[0202] 31.R 3 The compound or salt of any one of embodiments 1 to 30, wherein is unsubstituted.

[0203] 32.R 3 But one or two R 3a 31. The compound or salt of any one of embodiments 1 to 30, substituted with:

[0204] 33.R 3 But one R 3a 33. The compound or salt of any one of embodiments 1 to 30 and 32, substituted with:

[0205] 34. At least one R 3a But halogens, CN, OH, =O, SO2, C 1~6 Alkyl, C 2~10 Alkene, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylene-OC 1~6 Alkyl, C 0~6 Alkylene-N(C 1~6 Alkyl)2, -SC 1~6 Alkyl, C 0~6 Alkylene-NHC(O)C 1~6 alkyl or C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 The compound or salt of any one of embodiments 1 to 30, 32, and 33, wherein alkylene-3 to 6 membered heterocycle.

[0206] 35. At least one R 3ais CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CHF2, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2OCH3, CH2 OCH2CH3, F, CN, =O, SO2, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, CH2OCH3, CH2OCF3, SCH3, NH2, N(CH3)2, NHCOCH3, CD3,

[0207] [ka] 35. The compound or salt of embodiment 34, wherein

[0208] 36. At least one R 3a 36. The compound or salt of embodiment 35, wherein is CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH, or OCHF2.

[0209] 37. Expression (If):

[0210] [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 1 is a halogen; R 3 is -[O] 0~1 -C 3~6 Cycloalkyl, -[O] 0~1 -C 6~10 Aryl, -[O] 0~1 -4 to 8-membered heterocycle or -[O] 0~1 - 5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R 3 is 0, 1, 2 or 3 R 3a is substituted with a substituent; R 5 is CO2Z or its biological equivalent; Z is C 1~7 Alkyl, C 1~7 Haloalkyl, C 3~6 Cycloalkyl or C 2~6 Alkyne, C 1~6 Alkoxy or C 3~6 cycloalkyl).

[0211] 38.R 1 The compound or salt of embodiment 37, wherein is Cl or F.

[0212] 39.R 3 is a 5- to 6-membered heterocycle containing one ring heteroatom selected from S and O, or a 5- to 6-membered heteroaryl containing two or three ring heteroatoms independently selected from N and S, and R 3 But halogens, CN, OH and C 1~6 0, 1 or 2 R independently selected from alkyl 3a The compound or salt of embodiment 37 or 28, which is substituted with a substituent.

[0213] 40.R 5 CO2C 1~7 40. The compound or salt of embodiment 37, 38 or 39, wherein is alkyl.

[0214] 41.R 5 The compound or salt of embodiment 40, wherein is CO2Et.

[0215] 42. A compound as listed in Table A or a pharmaceutically acceptable salt thereof.

[0216] 43. A pharmaceutical formulation comprising a therapeutically effective amount of a compound or salt of any one of embodiments 1-42, and a pharmaceutically acceptable excipient.

[0217] 44. A method for treating an M4-mediated (or M4-associated) disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound or salt of any one of embodiments 1-42.

[0218] 45. The M4-mediated (or M4-related) disease or disorder is Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive impairment (e.g., mild cognitive deficit), 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's syndrome), cerebral amyloid angiopathy, Alzheimer's disease psychosis, dementia-related psychosis, 45. The method of embodiment 44, wherein the cause is selected from the group consisting of bipolar I disorder, bipolar II disorder, bipolar depression, missed and / or manic episodes associated with bipolar disorder, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob Disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, and atherosclerosis.

[0219] 46. ​​The method of embodiment 45, wherein the M4-mediated (or M4-associated) disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, and sleep disorders. [Example]

[0220] The following examples are offered for illustrative purposes and are not intended to limit the scope of the present disclosure.

[0221] As used throughout these examples, common organic abbreviations are defined as follows:

[0222] [Table 2]

[0223] An inert atmosphere (nitrogen or argon) was generally required, especially when oxygen- or moisture-sensitive reagents, such as dry Pd / C, intermediates, and / or inert conditions were used. Commercially available solvents and reagents were generally used without further purification. Where appropriate, anhydrous solvents were generally used from WuXi-EHS, where the following QC specifications for water were achieved: a) <50 ppm for N'N-dimethylformamide; b) <100 ppm for dichloromethane, toluene, and tetrahydrofuran; c) <200 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. Products were generally dried under vacuum before further reactions or biological testing. Mass spectroscopy data are reported from either liquid chromatography-mass spectroscopy (LCMS) and high-performance liquid chromatography (HPLC). 1 H NMR spectra were recorded on a Bruker instrument at 400 MHz. Chemical shifts (δ) for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm) referenced to residual peaks from the deuterated solvent used. Additionally, chiral separations were performed to separate enantiomers of certain compounds of the present disclosure by supercritical fluid chromatography (SFC). In some instances, the separated enantiomers are designated as Peak 1 and Peak 2 according to their order of elution. Based on their potency, chirality can be carried out as either the (R)- or (S)-isomer. Reactions that proceed through detectable intermediates were generally followed by LCMS and allowed to proceed to complete conversion before the addition of subsequent reagents.

[0224] For syntheses that refer to procedures in other examples or methods, reaction conditions (reaction times and temperatures) can be varied. Microwave-mediated reactions were carried out in a Biotage Initiator microwave reactor for some compounds. Reactions were generally monitored by thin-layer chromatography or mass spectrometry and subjected to workup where appropriate. Purification can vary between experiments: generally, solvents and solvent ratios used for eluents / gradients were selected to provide appropriate Rf or retention times. All starting materials in these preparations and examples are either commercially available or can be prepared by methods known in the art or as described herein.

[0225] LCMC Method 1: Instrument: SHIMADZU LC20-MS2010; Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B) using an elution gradient of 5% to 95% (solvent B) over 0.7 min and held at 95% for 0.4 min at a flow rate of 1.5 mL / min; Column: MERCK, RP-18e 25-2 mm; Wavelength: UV 220 nm–254 nm; Column temperature: 50°C; MS ionization: ESI.

[0226] LCMC Method 2: Instrument: SHIMADZU LC20-MS2020; Mobile phase: 0.8 mL / 4 L NH₃·H₂O in water (solvent A) and acetonitrile (solvent B), using an elution gradient of 10% to 80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes at a flow rate of 0.8 mL / min; Column: Titank C18, 5 μm, 2.1 × 50 mm; Wavelength: UV 220 nm–254 nm; Column temperature: 50°C; MS ionization: ESI.

[0227] LCMC Method 3: Instrument: SHIMADZU LCMS-2020; Mobile Phase: Gradient from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 min, flow rate set at 2.0 mL / min; then hold at 95% ACN for 0.18 min, flow rate set at 2.0 mL / min; return to 5% ACN in water, hold for 0.02 min, flow rate set at 2.0 mL / min; Column: Kinetex® EVO C18 2.1 x 30 mm, 5 µm. Column Temperature: 50 °C.

[0228] HPLC Method 1: Instrument: SHIMADZU LC20-MS2020; Mobile phase: 0.2 mL / 1 L NH₃·H₂O in water (solvent A) and acetonitrile (solvent B), elution gradient 10% to 80% (solvent B) over 6 minutes, held at 80% for 2 minutes at a flow rate of 0.8 mL / min; Column: Titank C18, 5 μm, 2.1 × 50 mm; Wavelength: UV 220 nm, 215 nm & 254 nm; Column temperature: 50°C.

[0229] HPLC Method 2: Instrument: Shimadzu LC-20AD; Mobile Phase: Gradient from 10% ACN (0.018% TFA) in water (0.037% TFA) to 80% CAN in water over 3.00 min, flow rate set at 1.5 mL / min; then hold at 80% CAN for 0.70 min, flow rate set at 1.5 mL / min; return to 10% CAN in water, hold for 0.30 min, flow rate set at 2.0 mL / min; Column: Kinetex C18 LC column, 4.6 x 50 mm, 5 µm. Wavelength: UV 220 nm & 254 nm. Column Temperature: 50°C.

[0230] SFC Method 1: Instrument: CAS-SH-ANA-SFC-G (Agilent 1260 with DAD detector); Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 um; Mobile phase: A: CO2, B: Methanol (0.05% DEA) Isostatic: 40% B; Flow rate: 2.5 mL / min; Column temperature: 40 °C; Back pressure: 100 bar.

[0231] SFC Method 2: Instrument: CAS-SH-ANA-SFC-L (Waters UPCC with PDA Detector); Column: Chiralcel OD-3 150 x 4.6 mm ID, 3 um; Mobile phase: A:CO2 B:methanol (0.05% DEA) Gradient: 5% to 40% B in 4 min and 40% to 5% B in 0.2 min, then hold at 5% B for 1.8 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C; Back pressure: 1500 psi.

[0232] Example #1: Synthesis of ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate P1)

[0233] [ka]

[0234] Step 1. Synthesis of tert-butyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C1). To a mixture of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (commercially available, 100 g, 444 mmol), benzylpiperazine-1-carboxylate (commercially available, 117 g, 532 mmol), and 4 Å molecular sieves (67.5 g) in DCE (2.30 L) was added CH3COOH (13.2 g, 221 mmol) at 25 °C. The mixture was stirred at 25 °C for 60 min, then NaBH(OAc)3 (235 g, 1.10 mol) was added in portions and stirred at 25 °C for 15 h. The mixture was poured into saturated aqueous NaHCO3 (1.70 L), stirred for 10 minutes, and separated. The aqueous phase was extracted with DCM (3 x 800 mL). The combined organic phases were washed with brine (1.20 L), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo at 50 °C. The crude product was triturated with petroleum ether (1.80 L) at 25 °C for 60 minutes. The suspension was filtered, and the filter cake was dried in vacuo at 50 °C to give Intermediate C1.

[0235] Step 2. Synthesis of benzyl 4-(2-azaspiro[3.4]octan-6-yl)piperazine-1-carboxylate (C2). To a solution of tert-butyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (170 g, 381 mmol) in DCM (800 mL) was added TFA (286 g, 2.51 mol). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure at 50° C. to give intermediate C2 (TFA salt), which was used directly in the next step without further purification. LCMS [M+H] + 330.

[0236] Step 3. Synthesis of ethyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C3). To a mixture of benzyl 4-(2-azaspiro[3.4]octan-6-yl)piperazine-1-carboxylate (220 g, 496 mmol, TFA salt) in DCM (1.50 L) and HO (750 mL) was added NaHCO (541 g, 6.45 mol) at 25 °C. The reaction mixture was stirred at 25 °C for 10 minutes, and ethyl carbonochloridate (178 g, 1.64 mol) was added dropwise at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into water (500 mL), stirred for 30 minutes at 25 °C, and separated. The aqueous phase was extracted with DCM (2 × 600 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give intermediate C3.

[0237] Step 4. Ethyl (6R)-6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate and ethyl (6S)-6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C4A and C4B) A racemic mixture of ethyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (430 g, 1.07 mol) was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm) * 50 mm, 10 μm); Mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 20%, min) to give intermediates C4A and C4B. LCMS [M+H] + 402.

[0238] Step 5. Synthesis of ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (P1) To a solution of ethyl (6R)-6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (120 g, 299 mmol) in MeOH (1200 mL) was added wet 10% Pd / C (15.0 g) at 20 °C. The suspension was degassed under vacuum and purged with H gas several times. The mixture was stirred under H gas (15 psi) at 25 °C for 16 h. The reaction mixture was filtered and washed with MeOH (2 × 1,000 mL). The filter was concentrated to give intermediate P1.

[0239] Example #2: Synthesis of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (Intermediate P2)

[0240] [ka]

[0241] Step 1. Synthesis of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P2) and ethyl (6R)-6-[4-(6-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C5A). A mixture of 2-bromo-3,5-difluoropyridine (5.00 g, 25.7 mmol) and K2CO3 (7.13 g, 51.5 mmol) in DMF (100 mL) was added to ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (7.24 g, 27.0 mmol). The mixture was then heated to 110°C and stirred at 110°C for 22 hours under a N2 atmosphere. The mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-3% MeOH / DCM) to give a mixture of P2 and C5A.

[0242] Step 2. Synthesis of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P2) The mixture of P2 and C5A was further separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 35%-35%, B3.5; 60 min) to give intermediate P2. 1 H NMR (CDCl3 400 MHz) δ H = 7.97 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.98-3.84 (m, 2H), 3.82-3.77 (m, 2H), 3.16 (brs, 4H), 2.72 (brs, 5H), 2.20-2.15 (m, 1H), 2.05-1.75 (m, 5H), 1.24 (t, J = 6.8 Hz, 3H). 19F NMR (CDCl3 400 MHz) δ F = -128.178.

[0243] Example #3: Synthesis of ethyl (6R)-6-[4-[2-(5-methoxy-3-pyridyl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A1)

[0244] [ka]

[0245] Step 1. Synthesis of ethyl (6R)-6-[4-(2-chloro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C6). A mixture of 2-chloro-3-iodo-pyridine (373 mg, 1.56 mmol), Intermediate P1 (500 mg, 1.87 mmol), Pd(dba) (143 mg, 156 mmol), Xantphos (180 mg, 312 mmol), and t-BuONa (225 mg, 2.34 mmol) in 1,4-dioxane (10.0 mL) was degassed under vacuum and purged with N gas several times. The reaction mixture was heated to 110 °C and stirred at 110 °C for 16 h under N atmosphere. The mixture was cooled to 20 °C, and dichloromethane (50 mL) was added to the mixture, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: 0–10% methanol in dichloromethane) to give Intermediate C6. LCMS m / z [M+H] 379.

[0246] Step 2. Synthesis of ethyl (6R)-6-[4-[2-(5-methoxy-3-pyridyl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A1). A mixture of intermediate C6 (50.0 mg, 132 μmol), (5-methoxy-3-pyridyl)boronic acid (40.4 mg, 264 μmol), NaCO (42.0 mg, 396 μmol), and PdCl(dtpbf) (8.60 mg, 13.2 μmol) in 1,4-dioxane (4.00 mL) and HO (1.00 mL) was degassed under vacuum and purged with N several times. The reaction mixture was heated to 85 °C and stirred at 85 °C for 16 hours under a N atmosphere. The mixture was filtered and concentrated in vacuo to give the crude product. The crude product was purified by pre-HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 26% to 50%, 8 min) to give A1. 1 H NMR (CDCl3 400MHz) δ H = 8.90 (s, 1H), 8.41 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 7.50-7.34 (m, 1H), 7.26-7.22 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.98-3.82 (m, 5H), 3.80-3.74 (m, 2H), 3.28-2.86 (m, 4H), 2.83-2.25 (m, 5H), 2.21-1.80 (m, 5H),1.57-1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 452.

[0247] Example #4: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(6-fluoro-3-pyridyl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A2)

[0248] [ka]

[0249] Step 1: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(6-fluoro-3-pyridyl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A2). A mixture of intermediate P2 (40.0 mg, 90.6 μmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30.3 mg, 136 μmol), Pd(dppf)Cl (6.63 mg, 9.06 μmol), and NaCO (28.8 mg, 272 μmol) in 1,4-dioxane (2.00 mL) and HO (0.500 mL) was degassed and purged with N gas three times, and then the mixture was stirred at 90 °C under a N atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Welch Ultimate C18 150 × 25 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 7% to 37%, 10 min) to give A2. 1 H NMR (CDCl3 400MHz) δ H = 8.86 (d, J = 2.4 Hz, 1H), 8.32 (dt, J = 2.4 Hz, 8.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.17 - 7.10 (m, 1H), 7.01 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.92 - 3.74 (m, 4H), 3.04 - 2.78 (m, 4H), 2.76 - 2.34 (m, 5H), 2.17 - 1.66 (m, 6H), 1.23 (t, J = 7.2Hz, 3H). 19 F NMR (CDCl3 400MHz) δ F = -68.347, -126.520.LCMS m / z [M+H] + 458.

[0250] Example #5: Synthesis of ethyl (6R)-6-[4-(2-pyrrolidin-1-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A3)

[0251] [ka]

[0252] Step 1: Synthesis of ethyl (6R)-6-[4-(2-pyrrolidin-1-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (A3). A mixture of intermediate C6 (29.0 mg, 76.5 μmol) and pyrrolidine (10.9 mg, 153 μmol, 12.8 μL) in DIPEA (0.500 mL) was heated to 100°C and stirred for 16 hours. The mixture was then stirred at 120°C-130°C for an additional 32 hours. The mixture was then cooled to 20°C and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-ACN]; B%: 40% to 70%, 8 min) to give A3. 1 H NMR (CDCl3 400MHz) δ H = 7.93-7.88 (m, 1H), 719-7.14 (m, 1H), 6.64 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.94-3.83 (m, 2H), 3.82-3.76 (m, 2H), 3.56-3.50 (m, 4H), 3.11-2.79 (m, 4H), 2.78-2.36 (m, 5H), 2.21-2.10 (m, 1H), 2.02-1.64 (m, 9H), 1.24 (t, J = 7.2 Hz, 3H).LCMS m / z [M+H] + 414.

[0253] Example #6: Synthesis of ethyl 6-(4-(2-(azetidin-1-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (A4)

[0254] [ka]

[0255] Step 1. Synthesis of tert-butyl 4-(2-fluoro-3-pyridyl)piperazine-1-carboxylate (C7). To a mixture of 3-bromo-2-fluoropyridine (2.00 g, 11.4 mmol), tert-butyl piperazine-1-carboxylate (2.54 g, 13.6 mmol), tert-butyl piperazine-1-carboxylate (2.54 g, 13.6 mmol), and tBuONa (1.64 g, 17.1 mmol) in toluene (30.0 mL) was added Pd2(dba)3 (520 mg, 568 mmol) and Xantphos (658 mg, 1.14 mmol). The mixture was degassed under vacuum and purged with N2 gas several times. The reaction mixture was then heated to 100 °C and stirred at 100 °C for 16 h under a N2 atmosphere. The mixture was cooled to 25° C., and then H2O (50 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (4×50 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give intermediate C7, LCMS m / z 282 [M+H]. + . 1 H NMR (CDCl3 400MHz) δ H LCMS m / z [M+H] + 282.

[0256] Step 2. Synthesis of 1-(2-fluoro-3-pyridyl)piperazine (C8). To a mixture of intermediate C7 (2.19 g, 7.78 mmol) in EA (25.0 mL) was added a solution of HCl in EA (4 M, 15.0 mL). The mixture was stirred at 25° C. for 3 hours. The mixture was concentrated in vacuo to give crude C8 HCl salt, which was used in the next step without further purification.

[0257] Step 3. Synthesis of ethyl 6-[4-(2-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C9). A mixture of intermediate C8 (1.69 g, 7.76 mmol, HCl salt) and EtN (3.93 g, 38.8 mmol) in DCE (20.0 mL) was stirred at 25 °C for 10 minutes. Then, ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (3.06 g, 15.5 mmol) and AcOH (233 mg, 3.88 mmol) were added to the mixture. The mixture was stirred at 25 °C for 20 minutes. Then, NaBH(OAc) (4.94 g, 23.3 mmol) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 16 hours. Saturated aqueous NaHCO3 (80 mL) was added to the mixture, and then the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: 0-5% methanol in dichloromethane) to give intermediate C9. LCMS m / z [M+H] + 363.

[0258] Step 4: Synthesis of ethyl 6-[4-[2-(azetidin-1-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate (A4). A mixture of intermediate C9 (100 mg, 276 μmol), CsCO (360 mg, 1.10 mmol), and azetidine (77.4 mg, 828 μmol, HCl salt) in DMA (5.00 mL) was heated to 130-140 °C and stirred for 26 h at 130-140 °C. The mixture was cooled to 25 °C. Then, HO (20 mL) was added to the mixture. The aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phase was washed with HO (3 × 50 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH 3 H 2 O)-ACN]; B%: 33% to 59%, 8 min) to give A4. 1 H NMR (CDCl3 400MHz) δ H= 7.88 (dd, J = 1.6 Hz, 5.2 Hz, 1H), 7.09 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 6.62 (dd, J = 5.2 Hz, 7.6 Hz, 1H), 4.14-4.02 (m, 6H), 3.90-3.81 (m, 2H), 3.80-3.72 (m, 2H), 3.09-2.78 (m, 4H), 2.75-2.37 (m, 5H), 2.27-2.18 (m, 2H), 2.16-2.08 (m, 1H), 1.94-1.78 (m, 3H), 1.76-1.68 (m, 1H), 1.62-1.49 (m, 1H), 1.22 (t, J = 6.8 Hz, 3H). LCMS m / z [M+H] + 400.

[0259] Example #7: Synthesis of (R)-ethyl 6-(4-(2-cyclobutoxypyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (A5)

[0260] [ka]

[0261] Step 1. Synthesis of 2-(cyclobutoxy)-3-iodo-pyridine (C10). A mixture of 2-fluoro-3-iodo-pyridine (100 mg, 448 μmol), cyclobutanol (32.3 mg, 448 μmol), and CsCO (292 mg, 897 μmol) in DMSO (1.00 mL) was heated to 90°C and stirred at approximately 90°C to 100°C for 17 hours. The reaction mixture was cooled to 20°C. H2O (10 mL) was then added to the mixture. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: petroleum ether) to give intermediate C10. LCMS m / z [M+H] + 276.

[0262] Step 2. Synthesis of ethyl (6R)-6-[4-[2-(cyclobutoxy)-3-pyridyl]piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (A5). To a mixture of Intermediate P1 (38.5 mg, 144 μmol), Intermediate C10 (33.0 mg, 120 μmol), and t-BuONa (23.1 mg, 240 μmol) in 1,4-dioxane (0.500 mL), XPhos (11.4 mg, 24.0 μmol) and Pd(OAc) (5.39 mg, 24.0 μmol) were added. The mixture was then degassed under vacuum and purged with N several times. The mixture was heated to 90 °C and stirred for 16 h. The mixture was cooled to 20 °C, filtered, concentrated in vacuo, and purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 40%-70%, 8 min) to give A5. 1 H NMR (CDCl3 400MHz) δ H = 7.75 (d, J = 4.0 Hz, 1H), 7.07 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.80 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 5.29-5.19 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95-3.84 (m, 2H), 3.83-3.77 (m, 2H), 3.33-3.01 (m, 4H), 2.95-2.55 (m, 5H), 2.54-2.43 (m, 2H), 2.25-2.05 (m, 3H), 2.03-1.77 (m, 5H), 1.75-1.65 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 415.

[0263] Example #8: Synthesis of (R)-ethyl 6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (A6)

[0264] [ka]

[0265] Step 1. Synthesis of 2-(3,5-difluoropyridin-2-yl)pyrazine (C11). A mixture of 2-bromo-3,5-difluoropyridine (50.0 mg, 258 μmol), tributyl(pyrazin-2-yl)stannane (142 mg, 387 μmol), CuI (4.91 mg, 25.8 μmol), and Pd(PPh3)4 (29.8 mg, 25.8 μmol) in toluene (2.00 mL) was degassed and purged with N2 several times at 20 °C. The mixture was then heated to 110 °C and stirred at 110 °C for 12 h. The mixture was cooled to 20 °C and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (eluent: 0–3% methanol in dichloromethane) to give intermediate C11. 1 H NMR (CDCl3 400MHz) δ H = 9.24 (s, 1H), 8.74 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.45-7.35 (m, 1H). LCMS m / z [M+H] + 194.

[0266] Step 2: Synthesis of (R)-ethyl 6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (A6). A mixture of Intermediate P1 (69.2 mg, 259 μmol), Intermediate C11 (50.0 mg, 259 μmol), and DIPEA (0.500 mL, 2.87 mmol) in pyridine (0.500 mL) was stirred at 130 °C for 24 hours. The mixture was concentrated in vacuo and purified by flash silica gel chromatography and prep-HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 40% to 70%, 7 min) to give A6. 1 H NMR (CDCl3 400MHz) δ Hδ = 9.23 (s, 1H), 8.73 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 7.16 (br d, J = 10.0 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.88 - 3.74 (m, 4H), 2.91 (br s, 4H), 2.63 - 2.38 (m, 5H), 2.12 - 2.03 (m, 1H), 1.95 - 1.75 (m, 3H), 1.70 - 1.60 (m, 1H), 1.52 - 1.42 (br s, 1H), 1.23 (t, J = 7.2 Hz, 3H). 19 19F NMR (CDCl3, 400 MHz) δ F δ = -124.49. LCMS m / z [M + H] + 441.

[0267] Example #9: Synthesis of ethyl (6R)-6-[4-(5-fluoro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A7)

[0268]

Chem.

[0269] Step 1: Synthesis of ethyl (6R)-6-[4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C12). A mixture of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 227 μmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (71.4 mg, 340 μmol), Pd(dppf)Cl (16.6 mg, 22.7 μmol), and NaCO (72.0 mg, 680 μmol) in 1,4-dioxane (2.00 mL) and HO (0.250 mL) was degassed and purged with N several times at 20° C. The mixture was then heated to 90° C. and stirred at 90° C. for 12 hours. The mixture was cooled to 20 °C, concentrated in vacuo, and purified by flash silica gel chromatography (eluent: 0–5% MeOH / DCM) to give the crude product. The crude product was purified by prep-HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 40%–70%, 7 min) to give C12 (19.8 mg, 42.3 μmol, 18.7% yield, 94.9% purity). 1 H NMR (CDCl3 400MHz) δ H= 8.08 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 6.36 (br s, 1H), 4.33 (d, J = 2.8 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.95-3.72 (m, 6H), 3.03 (br s, 4H), 2.70-2.49 (m, 7H), 2.14 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.02-1.79 (m, 3H), 1.77-1.71 (m, 1H), 1.62-1.49 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 445.

[0270] Step 2: Synthesis of ethyl (6R)-6-[4-(5-fluoro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A7). To a solution of ethyl (6R)-6-[4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (50.0 mg, 112 μmol) in EtOH (5.00 mL), wet Pd / C (50.0 mg, 10.0% purity) was added under N at 20 °C, and the mixture was degassed and purged with H three times. The mixture was then stirred at 40 °C for 16 hours under an H (15 psi) atmosphere. The mixture was filtered, and the filtrate was concentrated under vacuum and purified by prep-HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 40%-70%, 7 min) to give compound 7 (27.0 mg, 58.1 μmol, 51.7% yield, 96.1% purity). 1 H NMR (CDCl3 400MHz) δ H= 8.20 (broad singlet, 1H), 7.11 (broad doublet, J = 9.6 Hz, 1H), 4.10 (quartet, J = 7.2 Hz, 4H), 3.96 - 3.77 (multiplet, 4H), 3.53 (broad triplet, J = 11.6 Hz, 2H), 3.32 (broad triplet, J = 12.4 Hz, 1H), 2.90 (broad singlet, 4H), 2.66 (broad singlet, 5H), 2.18 - 1.69 (multiplet, 6H), 1.58 (singlet, 4H), 1.24 (triplet, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 447.

[0271] Example #10: Synthesis of ethyl (6R)-6-[4-(5-fluoro-2-thiazol-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A8)

[0272]

Chem.

[0273] To a mixture of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 227 μmol), tributyl(thiazol-4-yl)stannane (127 mg, 340 μmol) in toluene (1.00 mL) was added CuI (4.32 mg, 22.7 μmol) and Pd(PPh3)4 (26.2 mg, 22.7 μmol). The mixture was degassed under vacuum and purged with N2 gas several times. The reaction mixture was stirred at 110 °C for 12 hours under N2 gas atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–5% MeOH / DCM) and further purified by prep-HPLC (column: Welch Xtimate C18, 150 × 30 mm × 5 μm; mobile phase: [water(FA)-ACN]; gradient: 0%–40% B over 9 min) to afford ethyl (6R)-6-[4-(5-fluoro-2-thiazol-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (52.0 mg, 117 μmol, 51.5% yield, 100% purity) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H = 8.92 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.19-7.09 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95-3.73 (m, 4H), 3.04 (br s, 4H), 2.90-2.70 (m, 5H), 2.23-2.11 (m, 1H), 2.03-1.90 (m, 3H), 1.88-1.78 (m, 1H), 1.77-1.68 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 446.

[0274] Example #11: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(tetrahydropyran-4-ylamino)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A9)

[0275] [ka]

[0276] A mixture of tetrahydropyran-4-amine (68.8 mg, 680 μmol), ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (150 mg, 340 μmol), Pd(dba) (31.1 mg, 34.0 μmol), t-BuONa (98.0 mg, 1.02 mmol), 2-[bis(3,5-trifluoromethylphenylphosphino)-3,6-dimethoxy]-2,6-dimethylamino-1,1-biphenyl) (L7, 25.7 mg, 34.0 μmol) in 1,4-dioxane (2.00 mL) was degassed under vacuum and purged with N gas three times, and then the mixture was stirred at 100 °C under N gas atmosphere for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (eluent: 0–3% MeOH / DCM) and further purified by prep-HPLC (column: Boston Prime C18, 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 52%–82%, 7 min) to give ethyl (6R)-6-[4-[5-fluoro-2-(tetrahydropyran-4-ylamino)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (28.7 mg, 61.7 μmol, 14.0% yield, 99.3% purity) as an off-white solid. 11H NMR (CDCl3, 400 MHz): δH = 7.73 (s, 1H), 6.94 (dd, J = 2.4 Hz, 9.2 Hz, 1H), 4.83 (d, J = 7.2 Hz, 1H), 4.18 - 4.03 (m, 3H), 4.01 - 3.77 (m, 6H), 3.58 (t, J = 10.8 Hz, 2H), 2.89 (br s, 4H), 2.70 - 2.55 (m, 5H), 2.20 - 2.10 (m, 1H), 2.05 (d, J = 11.2 Hz, 2H), 1.98 - 1.80 (m, 3H), 1.78 - 1.66 (m, 1H), 1.56 - 1.46 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 462.

[0277] Example #12: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(4-methylpyrazol-1-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A10)

[0278] [Chemical formula]

[0279] To a mixture of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (30.0 mg, 68.0 μmol), 4-methyl-1H-pyrazole (8.37 mg, 102 μmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (9.67 mg, 68.0 μmol) in DMF (1.00 mL), CuI (13.0 mg, 68.0 μmol) and K3PO4 (43.3 mg, 204 μmol) were added in one portion. The mixture was degassed under vacuum and purged with N2 gas several times. The reaction mixture was stirred at 130 °C for 12 hours under N2 gas atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18, 80 × 40 mm × 3 um; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; gradient: 39% to 69% B over 8 min) to give ethyl (6R)-6-[4-[5-fluoro-2-(4-methylpyrazol-1-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (9.40 mg, 21.2 μmol, 31.3% yield, 100% purity) as an off-white solid. 1 H NMR (CD3OD 400 MHz) δ H = 8.09-7.83 (m, 2H), 7.60 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.93-3.70 (m, 4H), 2.75 (d, J = 4.4 Hz, 4H), 2.69-2.45 (m, 5H), 2.20(s, 3H)), 2.18-2.11 (m, 1H), 1.99-1.81 (m, 3H), 1.70 (dd, J= 9.6 Hz, 12.8 Hz, 1H), 1.57-1.46 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H).LCMS m / z [M+H] + 443.

[0280] Example #13: Synthesis of ethyl (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A11) and ethyl (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A12)

[0281] [ka]

[0282] Step 1: Synthesis of 5-fluoro-2-(pyrazin-2-yl)pyridin-3-amine (C13) A mixture of 2-bromo-5-fluoro-pyridin-3-amine (1.00 g, 5.24 mmol), tributyl(pyrazin-2-yl)stannane (1.93 g, 5.24 mmol), CuI (99.7 mg, 524 µmol), and Pd(PPh3)4 (605 mg, 524 µmol) in toluene (20.0 mL) was degassed under reduced pressure and purged with N2 gas three times. The mixture was then stirred at 100 °C for 12 h under a N2 gas atmosphere. The mixture was filtered and concentrated under reduced pressure to remove toluene. The residue was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-17% ethyl acetate / petroleum ether) to afford 5-fluoro-2-pyrazin-2-yl-pyridin-3-amine (700 mg, 3.52 mmol, 67.1% yield, 95.5% purity) as an off-white solid. LCMS m / z [M+H] + 191.

[0283] Step 2: Synthesis of 2-(3-bromo-5-fluoropyridin-2-yl)pyrazine (C14) A solution of 5-fluoro-2-pyrazin-2-yl-pyridin-3-amine (700 mg, 3.68 mmol) in water (4.00 mL) was added in one portion to a solution of HBr in HO (4.00 mL, 48% purity) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, a solution of NaNO (279 mg, 4.05 mmol) in water (2.00 mL) was added in one portion at 0 °C, and the mixture was stirred at 0 °C for another 0.5 h. The mixture was added to a solution of CuBr (581 mg, 4.05 mmol) in water (2.00 mL) at 60 °C. The mixture was stirred at 60 °C for 2 h. The mixture was poured into saturated aqueous NaHCO (100 mL) and stirred for 5 min. The mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-11% ethyl acetate / petroleum ether) to afford 2-(3-bromo-5-fluoro-2-pyridyl)pyrazine (580 mg, 2.09 mmol, 56.8% yield, 91.5% purity) as an off-white solid. LCMS m / z [M+H] + 254, 256.

[0284] Step 3: Synthesis of tert-butyl 5-fluoro-2-(pyrazin-2-yl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (C15) A mixture of 2-(3-bromo-5-fluoro-2-pyridyl)pyrazine (580 mg, 2.28 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (706 mg, 2.28 mmol), Pd(PPh3)4 (264 mg, 228 mmol), and Na2CO3 (726 mg, 6.85 mmol) in water (1.00 mL) and 1,4-dioxane (8.00 mL) was degassed under reduced pressure and purged with N2 gas three times. The mixture was then stirred at 100 °C for 12 h under a N2 gas atmosphere. The mixture was filtered, and the organic phase was concentrated under reduced pressure to give a residue. The residue was diluted with water (80 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–14% ethyl acetate / petroleum ether) to afford tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (840 mg, 1.87 mmol, 81.9% yield, 79.3% purity) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H = 9.10 (s, 1H), 8.67-8.42 (m, 3H), 7.37 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 5.60 (s, 1H), 3.97 (s, 2H), 3.51 (t, J = 5.2 Hz, 2H), 2.15 (s, 2H), 1.48 (s, 9H). LCMS m / z [M+H] + 357.

[0285] Step 4: Synthesis of 5-fluoro-2-(pyrazin-2-yl)-1',2',3',6'-tetrahydro-3,4'-bipyridine (C16) To a solution of tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 2.24 mmol) in DCM (12.0 mL) was added HCl / 1,4-dioxane (4 M, 4.00 mL). The mixture was stirred at room temperature for 12 hours. The mixture was adjusted to pH = 8 with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (3 x 40 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-[5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-2-pyridyl]-pyrazine (510 mg, crude) as a yellow oil. The crude product was used in the next step without further purification. LCMS m / z [M+H] + 257.

[0286] Step 5: Synthesis of ethyl 6-(5-fluoro-2-(pyrazin-2-yl)-5',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)-2-azaspiro[3.4]octane-2-carboxylate (C17) A mixture of 2-[5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-2-pyridyl]pyrazine (510 mg, 1.99 mmol) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (432 mg, 2.19 mmol) in DCE (16.0 mL) was stirred at room temperature for 1 hour. NaBH(OAc) (1.27 g, 5.97 mmol) and AcOH (12.0 mg, 199 mmol) were then added. The mixture was stirred at room temperature for 2 hours. The mixture was poured into saturated aqueous NaHCO (80 mL) and stirred for 5 minutes. The mixture was extracted with DCM (3 × 60 mL). The combined organic phase was washed with brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–4% MeOH / DCM) to give ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (600 mg, 1.35 mmol, 67.6% yield, 98.1% purity) as a yellow oil. The yellow oil (100 mg) was purified by prep-HPLC (column: Boston Prime C18, 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 45%–75%, 7 min) to give ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (41.1 mg, 93.9 μmol, 41.1% yield, 100% purity) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H= 9.03 (s, 1H), 8.81-8.30 (m, 3H), 7.47-7.33 (m, 1H), 5.58 (s, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.96-3.83 (m, 2H), 3.84-3.74 (s, LCMS m / z [M+H] + 438.

[0287] Step 6: Synthesis of ethyl (R)-6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (A11) and ethyl (S)-6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (A12) A mixture of ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 457 μmol) and Pd / C (50.0 mg, 10% purity) in EtOH (6.00 mL) was degassed under reduced pressure and purged with H gas three times, and then the mixture was stirred under H gas atmosphere (40 psi) at 40 ° C. for 48 hours. The mixture was filtered, and the organic phase was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-5% MeOH / DCM) and further separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH₃HO MeOH]; B%: 50%-50%) to give peak 1 ethyl (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (14.7 mg, 33.2 μmol, 14.6% yield, 99.4% purity) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H = 9.07 (s, 1H), 8.70-8.52 (m, 2H), 8.43 (d, J = 2.4 Hz, 1H), 7.68-7.38 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.98-3.80 (m, 2H), 3.77 LCMS m / z [M+H] + 440. Peak 2 Ethyl (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (15.7 mg, 33.6 umol, 14.8% yield, 93.9% purity) was obtained as a yellow oil. 1 H NMR (CDCl3 400 MHz) δH = 9.08 (s, 1H), 8.68-8.54 (m, 2H), 8.44 (d, J = 2.8 Hz, 1H), 7.71-7.39 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 4.02-3.81 (m, 2H), 3.77 LCMS m / z [M+H] + 440.

[0288] Example #14: Synthesis of ethyl (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A13) and ethyl (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A14)

[0289] [ka]

[0290] Step 1: Synthesis of tert-butyl 4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (C18) To a solution of tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (400 mg, 1.12 mmol) in i-PrOH (20.0 mL) and DCM (4.00 mL) was added phenylsilane (486 mg, 4.49 mmol) and tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese (204 mg, 337 μmol). The reaction mixture was stirred at room temperature under an O atmosphere (15 psi) for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–30% ethyl acetate / petroleum ether) to afford tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-piperidine-1-carboxylate (60.0 mg, 160 μmol, 14.3% yield) as a yellow oil.1 H NMR (CD3OD 400 MHz) δ H = 9.05-8.85 (m, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.63-8.60 (m, 1H), 8.52 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 3.89 (d, J = 12.8 Hz, 2H), 3.24-3.07 (m, 2H), 1.97-1.74 (m, 4H), 1.44 (s, 9H). LCMS m / z [M+H-56] + 319.

[0291] Step 2: Synthesis of 4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperidin-4-ol (C19) To a solution of tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-piperidine-1-carboxylate (60.0 mg, 160 μmol) in DCM (8.00 mL) was added HCl / 1,4-dioxane (4 M, 4.00 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)piperidin-4-ol (50.0 mg, crude, HCl salt) as a yellow solid. The crude product was used in the next step without further purification. LCMS m / z [M+H] + 275.

[0292] Step 3: Synthesis of ethyl 6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)-4-hydroxypiperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C20) A mixture of 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)piperidin-4-ol (50.0 mg, 161 μmol, HCl salt) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (31.7 mg, 161 μmol) and EtN (48.8 mg, 483 μmol) in DCE (10.0 mL) was stirred at room temperature for 1 h. Then, AcOH (9.66 mg, 16.1 μmol) and NaBH(OAc) (102 mg, 483 μmol) were added in one portion. The reaction mixture was stirred at room temperature for 11 h. The mixture was poured into saturated aqueous NaHCO (30 mL) and extracted with DCM (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–6% MeOH / DCM) to give ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (36.0 mg, 79.0 μmol, 49.1% yield) as a yellow oil. 1 H NMR (CD3OD 400 MHz) δ H = 9.10-8.90 (m, 1H), 8.81-8.51 (m, 3H), 7.91 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 4.11-4.03 (m, 2H), 3.94-3.75 (m, 4H), 3.07-2.85 (m, LCMS m / z [M+H] + 456.

[0293] Step 4: Synthesis of ethyl (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A13) and ethyl (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A14) The yellow oil was purified by SFC (column: DAICEL CHIRALPAK IC, (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3HO)]; B%: 55%, isocratic elution mode) to give peak 1 of ethyl (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (6.50 mg, 13.7 μmol, 95.9% purity) as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 9.37 (s, 1H), 8.70 (d, J = 2.8 Hz, 1H), 8.56-8.45 (m, 2H), 7.65 (dd, J = 2.4 Hz, 10.2 Hz, 1H), 7.44 (br s, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.91-3.72 (m, 4H), 2.89-2.38 (m, 5H), 2.17-2.05 (m, 1H), 1.98-1.74 (m, 7H), 1.73-1.66 (m, 1H), 1.57-1.46 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + Peak 2 of 456. ethyl (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-4-hydroxy-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (6.60 mg, 13.2 μmol, 91.4% purity) was obtained as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H= 9.37 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.55-8.46 (m, 2H), 7.65 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 7.44 (br s, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.91-3.72 (m, 4H), 2.89-2.34 (m, 5H), 2.17-2.06 (m, 1H), 1.97-1.79 (m, 6H), 1.76-1.63 (m, 2H), 1.57-1.41 (m, 1H), 1.23 (t, J = 6.8 Hz, 3H). LCMS m / z [M+H] + 456.

[0294] Example #15: Synthesis of ethyl (6R)-6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A15) and ethyl (6S)-6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A16)

[0295] [ka]

[0296] Step 1: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-pyridyl)piperazine-1-carboxylate (C21) A mixture of tert-butyl piperazine-1-carboxylate (4.43 g, 23.8 mmol), 2-bromo-5-chloro-3-fluoro-pyridine (5.00 g, 23.8 mmol), and K2CO3 (6.57 g, 47.5 mmol) in DMSO (50.0 mL) was stirred at 110 °C for 36 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–3% ethyl acetate / petroleum ether) to give tert-butyl 4-(5-chloro-3-fluoro-2-pyridyl)piperazine-1-carboxylate (3.89 g, 10.2 mmol, 42.9% yield, 82.7% purity) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δH = 8.04 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 3.74-3.50 (m, 4H), 3.11-2.90 (m, 4H), 1.48 (s, 9H). LCMS m / z [M+H] + 376, 378.

[0297] Step 2: Synthesis of tert-butyl 4-[5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (C22) A solution of tert-butyl 4-(2-bromo-5-chloro-3-pyridyl)piperazine-1-carboxylate (1.00 g, 2.65 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (558 mg, 2.65 mmol), Pd(dppf)Cl (194 mg, 265 μmol), and NaCO (563 mg, 5.31 mmol) in 1,4-dioxane (10.0 mL) and water (2.50 mL) was degassed and purged with N gas three times. The reaction mixture was stirred at 90 °C for 12 hours under N gas atmosphere. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-30% ethyl acetate / petroleum ether) to afford tert-butyl 4-[5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (775 mg, 1.82 mmol, 68.7% yield, 89.4% purity) as a colorless oil. LCMS m / z [M+H] + 380.

[0298] Step 3: Synthesis of tert-butyl 4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazine-1-carboxylate (C23) To a solution of tert-butyl 4-[5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (775 mg, 2.04 mmol) in EtOAc (8.00 mL) was added PtO (100 mg, 440 μmol). The reaction mixture was degassed under vacuum, purged with H gas several times, and stirred at room temperature under an H gas atmosphere (15 psi) for 12 hours. The mixture was filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–30% ethyl acetate / petroleum ether) to give tert-butyl 4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazine-1-carboxylate (357 mg, 874 μmol, 42.8% yield, 93.5% purity) as a colorless oil. 1 H NMR (CDCl3 400 MHz) δ H = 8.31 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 4.17-4.06 (m, 4H), 3.60 (br s, 4H), 3.39-3.33(m, 1H), 2.82 (t, J = 4.4 Hz, 4H), 2.13-2.06 (m, 2H), 1.59 (d, J = 12.8 Hz, 2H), 1.49 (s, 9H). LCMS m / z [M+H] + 383.

[0299] Step 4: Synthesis of 1-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazine (C24) Tert-butyl 4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazine-1-carboxylate (357 mg, 935 μmol) in DCM (3.00 mL) was added to HCl / EtOAc (4 M, 3.00 mL), and the mixture was then stirred for 12 h at 20° C. The mixture was concentrated under reduced pressure to give 1-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazine (298 mg, 935 μmol, 100% yield, HCl salt) as a yellow oil, which was used in the theoretical amount in the next step without purification.

[0300] Step 5: Synthesis of ethyl 6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C25) A mixture of 1-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazine (298 mg, 935 μmol, HCl salt), ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (184 mg, 935 μmol), and TEA (473 mg, 4.67 mmol) in DCE (3.00 mL) was stirred at room temperature for 1 h. Then, AcOH (56.1 mg, 935 μmol) and NaBH(OAc) (594 mg, 2.80 mmol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–3% methanol / dichloromethane) to afford ethyl 6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (176 mg, 349 μmol, 37.3% yield, 91.8% purity) as an off-white solid. LCMS m / z [M+H] + 463.

[0301] Step 6: Synthesis of ethyl (6R)-6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A15) and ethyl (6S)-6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A16) Ethyl 6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (176 mg, 380 μmol) was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO₂-MeOH (0.1% NH₃HO)]; B%: 60%, isocratic elution mode) to give peak 1 ethyl (6R)-6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (25.7 mg, 54.3 μmol, 14.3% yield, 97.8% purity) as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 8.29 (s, 1H), 7.34 (s, 1H), 4.10 (q, J = 7.2 Hz, 4H), 3.99-3.76 (m, 4H), 3.52 (t, J = 11.6 Hz, 2H), 3.39-3.24 (m, 1H), 3.22-2.24 (m, 9H), 2.23-2.10 (m, 1H), 2.11-1.98 (m, 3H), 1.97-1.62 (m, 4H), 1.61-1.59 (m, 1H), 1.52-1.50 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).LCMS m / z [M+H] +463. Peak 2 Ethyl (6S)-6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (27.3 mg, 56.8 μmol, 14.9% yield, 96.3% purity) was obtained as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 8.29 (s, 1H), 7.34 (s, 1H), 4.10 (q, J = 7.2 Hz, 4H), 3.99-3.75 (m, 4H), 3.52 (t, J = 11.6 Hz, 2H), 3.37-3.25 (m, 1H), 3.21-2.41 (m, 9H), 2.20-2.10 (m, 1H), 2.12-1.98 (m, 3H), 1.98-1.62 (m, 4H), 1.62-1.59 (m, 1H), 1.52-1.50 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).LCMS m / z [M+H] + 463.

[0302] Example #16: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A17) and ethyl (6S)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A18)

[0303] [ka]

[0304] Step 1. Synthesis of tert-butyl 4-(2-bromo-5-fluoropyridin-3-yl)piperazine-1-carboxylate (C26) To a solution of 2-bromo-3,5-difluoro-pyridine (10.0 g, 51.6 mmol) in DMSO (100 mL), tert-butyl piperazine-1-carboxylate (11.5 g, 61.9 mmol) and K2CO3 (14.3 g, 103 mmol) were added in one portion. The mixture was stirred at 110 °C for 12 h. The reaction mixture was cooled to room temperature. H2O (300 mL) was added to the mixture. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with 3% aqueous LiCl (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–18% ethyl acetate / petroleum ether) to afford tert-butyl 4-(2-bromo-5-fluoro-3-pyridyl)piperazine-1-carboxylate (8.00 g, 22.2 mmol, 43.1% yield) as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 7.97 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 3.67-3.57 (m, 4H), 3.09-2.91 (m, 4H), 1.46 (s, 9H). LCMS m / z [M+H] + 360, 362.

[0305] Step 2: Synthesis of tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (C27) A mixture of tert-butyl 4-(2-bromo-5-fluoro-3-pyridyl)piperazine-1-carboxylate (1.00 g, 2.78 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (700 mg, 3.33 mmol), KCO (767 mg, 5.55 mmol), and Pd(dppf)Cl (203 mg, 278 μmol) in 1,4-dioxane (10.0 mL) and water (1.00 mL) was degassed under vacuum and purged with N gas several times. The reaction mixture was stirred at 100 °C for 12 hours under N gas atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–14% ethyl acetate / petroleum ether) to afford tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridyl]piperazine-1-carboxylate (930 mg, 2.56 mmol, 92.2% yield) as an off-white solid. 1 H NMR (CD3OD 400 MHz) δ H = 8.05 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 6.35-6.25 (m, 1H), 4.32 (q, J = 2.4 Hz, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.66-3.46 (m, 4H), 3.07-2.91 (m, 4H), 2.67-2.55 (m, 2H), 1.47 (s, 9H). LCMS m / z [M+H] + 364.

[0306] Step 3: Synthesis of tert-butyl 4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazine-1-carboxylate (C28) To a mixture of tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridyl]piperazine-1-carboxylate (1.20 g, 3.30 mmol) and tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]-manganese (39.9 mg, 66.0 μmol) in DCM (1.00 mL) and i-PrOH (8.00 mL), phenylsilane (715 mg, 6.60 mmol) was added at 0° C. The mixture was stirred at room temperature under an O gas atmosphere (15 psi) for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-26% ethyl acetate / petroleum ether) to afford tert-butyl 4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (430 mg, 1.13 mmol, 61.4% yield) as an off-white solid. LCMS m / z [M+H] + 382.

[0307] Step 4: Synthesis of 4-(5-fluoro-3-(piperazin-1-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (C29) To a solution of tert-butyl 4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (150 mg, 393 μmol) in DCM (6.00 mL) was added HCl / 1,4-dioxane (4 M, 1.96 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoro-3-piperazin-1-yl-2-pyridyl)tetrahydropyran-4-ol (130 mg, crude, HCl salt) as an off-white solid. The crude product was used in the next step without further purification. LCMS m / z [M+H] + 282.

[0308] Step 5: Synthesis of ethyl 6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C30) A mixture of 4-(5-fluoro-3-piperazin-1-yl-2-pyridyl)tetrahydropyran-4-ol (130 mg, 409 μmol, HCl salt), ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (80.7 mg, 409 μmol), and EtN (124 mg, 1.23 mmol) in DCE (10.0 mL) was stirred at room temperature for 1 h. Then, AcOH (2.46 mg, 40.91 μmol) and NaBH(OAc) (260 mg, 1.23 mmol) were added in one portion. The reaction mixture was stirred at room temperature for 11 h. The mixture was poured into saturated aqueous NaHCO (30 mL) and extracted with DCM (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-7% MeOH / DCM) to afford ethyl 6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (140 mg, 303 μmol, 74.0% yield) as a colorless oil. LCMS m / z [M+H] + 463.

[0309] Step 6: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A17) and ethyl (6S)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A18) A sample of ethyl 6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (140 mg, 303 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD, 250 mm × 30 mm, 10 μm; mobile phase: [CO₂-MeOH (0.1% NH₃HO)]; B%: 25%, isocratic elution mode) to give peak 1 ethyl (6R)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (24.1 mg, 51.3 μmol, 98.5% purity) as an off-white solid. 1 H NMR (CD3OD 400 MHz) δ H = 8.37 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 2.4 Hz, 10.0 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 4.00-3.89 (m, 3H), 3.88-3.77 (m, 5H), 3.24-2.59 (m, 8H), 2.57-2.39 (m, 3H), 2.25-2.16 (m, 1H), 2.04-1.86 (m, 3H), 1.80-1.71 (m, 1H), 1.64-1.52 (m, 3H), 1.23 (t, J = 6.8 Hz, 3H).LCMS m / z [M+H] + 463, found 463. Peak 2. Ethyl (6S)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (25.0 mg, 54.1 μmol, 17.9% yield) was obtained as an off-white solid. 1 H NMR (CD3OD 400 MHz) δ H= 8.37 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.8 Hz, 9.6 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 4.01-3.78 (m, 8H), 3.20-2.85 (m, 6H), 2.83-2.64 (m, 2H), 2.61-2.37 (m, 3H), 2.22 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.09-1.84 (m, 3H), 1.77 (dd, J=9.2 Hz, 12.8 Hz, 1H), 1.69-1.48 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 463.

[0310] Example #17: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A19) and ethyl (6S)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A20)

[0311] [ka]

[0312] Step 1: Synthesis of tert-butyl 4-(5-fluoro-2-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazine-1-carboxylate (C31) To a solution of tert-butyl 4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (200 mg, 524 μmol) in DCM (8.00 mL) was added DAST (338 mg, 2.10 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into saturated aqueous NaHCO (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–14% ethyl acetate / petroleum ether) to afford tert-butyl 4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (170 mg, 443 μmol, 84.6% yield) as a colorless oil. 1 H NMR (CD3OD 400 MHz) δ H = 8.27 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 2.4 Hz, 10.0 Hz, 1H), 3.96-3.81 (m, 4H), 3.56 (br s, 4H), 2.90 (t, J = 4.8 Hz, 4H), 2.51-2.25 (m, 4H), 1.48 (s, 9H). LCMS m / z [M+H] + 384.

[0313] Step 2: Synthesis of 1-(5-fluoro-2-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazine (C32) To a solution of tert-butyl 4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (170 mg, 443 μmol) in DCM (8.00 mL) was added HCl / 1,4-dioxane (4 M, 3.00 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]-piperazine (140 mg, crude, HCl salt) as an off-white solid. The crude product was used in the next step without further purification. 1 H NMR (CD3OD 400 MHz) δ H = 8.41 (d, J = 2.4 Hz, 1H), 7.89 (br d, J = 9.6 Hz, 1H), 3.99-3.79 (m, 4H), 3.44-3.34 (m, 4H), 3.26-3.15 (m, 4H), 2.57-2.18 (m, 4H).LCMS m / z [M+H] + 284.

[0314] Step 3: Synthesis of ethyl 6-(4-(5-fluoro-2-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C33) A mixture of 1-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazine (140 mg, 438 μmol, HCl salt) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (86.4 mg, 438 μmol) and EtN (133 mg, 1.31 mmol) in DCE (10.0 mL) was stirred at room temperature for 1 h. Then, AcOH (2.63 mg, 43.8 μmol) and NaBH(OAc) (278 mg, 1.31 mmol) were added in one portion. The mixture was stirred at room temperature for 11 h. The mixture was poured into saturated aqueous NaHCO (30 mL) and extracted with DCM (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–3% MeOH / DCM) to give ethyl 6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (130 mg, 280 μmol, 63.9% yield) as a colorless oil. 1 H NMR (CDCl3 400 MHz) δ H = 8.30-8.15 (m, 1H), 7.38 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.01-3.70 (m, 8H), 2.95 (br s, 4H), 2.78-2.22 (m, LCMS m / z [M+H] + 465.

[0315] Step 4: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (19) and ethyl (6S)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (20) A sample of ethyl 6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (130 mg, 280 μmol) was subjected to SFC (column: DAICEL CHIRALPAK Separation on IG, 250 mm x 30 mm, 10 μm; mobile phase: [CO2-MeOH (0.1% NH3HO)]; B%: 60%, isocratic elution mode) afforded peak 1 ethyl (6R)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (26.0 mg, 51.1 μmol, 29.7% yield, 91.2% purity) as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 8.29-8.18 (m, 1H), 7.38 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.99-3.72 (m, 8H), 3.06-2.87 (m, 4H), 2.85-2.45 (m, 5H), 2.45-2.24 (m, 4H), 2.14 (dd, J = 6.8 Hz, 12.4 Hz, 1H), 2.03-1.79 (m, 3H), 1.78-1.66 (m, 1H), 1.59-1.51 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).LCMS m / z [M+H] +465. Peak 2 Ethyl (6S)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (27.1 mg, 51.8 μmol, 30.1% yield, 88.7% purity) was obtained as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 8.29-8.18 (m, 1H), 7.38 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.98-3.73 (m, 8H), 3.03-2.84 (m, 4H), 2.82-2.45 (m, 5H), 2.45-2.22 (m, 4H), 2.14 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.03-1.79 (m, 3H), 1.77-1.67 (m, 1H), 1.57-1.47 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).LCMS m / z [M+H] + 465.

[0316] Example #18: Synthesis of ethyl (6S)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A21) and ethyl (6R)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A22)

[0317] [ka]

[0318] Step 1: Synthesis of methyl 3-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-5-fluoro-pyridine-2-carboxylate (C34) To a solution of methyl 3-bromo-5-fluoro-pyridine-2-carboxylate (3.50 g, 15.0 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.09 g, 16.4 mmol) in HO (4.00 mL) and 1,4-dioxane (32.0 mL), NaCO (3.17 g, 29.9 mmol) and Pd(dppf)Cl (1.09 g, 1.50 mmol) were added in one portion. The mixture was degassed under vacuum and purged with N gas three times. The mixture was stirred at 80 °C for 16 hours. The mixture was poured into water (30 mL) and stirred for 5 minutes. The mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-16% ethyl acetate / petroleum ether) to give methyl 3-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-5-fluoro-pyridine-2-carboxylate (6.50 g, 19.3 mmol, 96.4% yield) as a colorless oil. LCMS m / z [M+H] + 337.

[0319] Step 2: Synthesis of methyl 3-(1-tert-butoxycarbonyl-4-piperidyl)-5-fluoro-pyridine-2-carboxylate (C35) To a solution of methyl 3-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-5-fluoro-pyridine-2-carboxylate (3.00 g, 8.92 mmol) in MeOH (30.0 mL) was added dry Pd / C (300 mg, 10% w / w) under an Ar atmosphere. The suspension was degassed and purged with H gas three times. The mixture was stirred at 45 °C for 72 hours under an H gas atmosphere (45 psi). The mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-25% ethyl acetate / petroleum ether) to afford methyl 3-(1-tert-butoxycarbonyl-4-piperidyl)-5-fluoro-pyridine-2-carboxylate (2.00 g, 5.91 mmol, 66.3% yield) as a colorless oil. LCMS m / z [M+H] + 339.

[0320] Step 3: Synthesis of tert-butyl 4-[5-fluoro-2-(hydrazinecarbonyl)-3-pyridyl]piperidine-1-carboxylate (C36) To a solution of methyl 3-(1-tert-butoxycarbonyl-4-piperidyl)-5-fluoro-pyridine-2-carboxylate (2.00 g, 5.91 mmol) in EtOH (20.0 mL) was added NH2NH2 . HO (6.00 g, 102 mmol, 85% purity) was added in one portion. The mixture was then stirred at 60 °C for 6 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-3% methanol / dichloromethane) to give tert-butyl 4-[5-fluoro-2-(hydrazinecarbonyl)-3-pyridyl]piperidine-1-carboxylate (1.44 g, 4.26 mmol, 72.0% yield) as a colorless oil. LCMS m / z [M-Boc] + 239.

[0321] Step 4: Synthesis of tert-butyl 4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazine-1-carboxylate (C37) To a solution of tert-butyl 4-[5-fluoro-2-(hydrazinecarbonyl)-3-pyridyl]piperidine-1-carboxylate (1.44 g, 4.26 mmol) in toluene (15.0 mL) was added HCOH (2.09 g, 42.6 mmol). The solution was degassed under vacuum and purged with N gas three times, and then the mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 8 with saturated aqueous NaHCO solution. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a colorless oil. The oil was purified by flash silica gel chromatography (eluent: 0-78% methanol / dichloromethane) to give tert-butyl 4-[5-fluoro-2-(formamidocarbamoyl)-3-pyridyl]piperidine-1-carboxylate (980 mg, 2.67 mmol, 62.8% yield) as a colorless oil. LCMS m / z [M-Boc] + 267.

[0322] Step 5: Synthesis of tert-butyl 4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]piperidine-1-carboxylate (C38) To a solution of tert-butyl 4-[5-fluoro-2-(formamidocarbamoyl)-3-pyridyl]piperidine-1-carboxylate (200 mg, 546 μmol) in toluene (2.00 mL) and pyridine (0.500 mL) was added Lawesson's reagent (265 mg, 655 μmol) in one portion. The reaction mixture was stirred at 90° C. for 12 hours. The mixture was poured into water (5 mL) and stirred for 5 minutes. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–19% ethyl acetate / petroleum ether) to afford tert-butyl 4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]piperidine-1-carboxylate (140 mg, 384 μmol, 70.4% yield) as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 9.16 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.48-4.38 (m, 1H), 4.37-4.10 (m, 2H), 3.09-2.84 (m, 2H), 1.95 (d, J = 12.8 Hz, 2H), 1.65-1.55 (m, 2H), 1.49 (s, 9H). LCMS m / z [M-Boc] + 265.

[0323] Step 6: Synthesis of 2-[5-fluoro-3-(4-piperidyl)-2-pyridyl]-1,3,4-thiadiazole (C39) To a solution of tert-butyl 4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]piperidine-1-carboxylate (140 mg, 384 μmol) in DCM (1.50 mL), HCl / 1,4-dioxane (4 M, 1.50 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give 2-[5-fluoro-3-(4-piperidyl)-2-pyridyl]-1,3,4-thiadiazole (115 mg, crude, HCl salt) as an off-white solid, which was used in the next step without purification. LCMS m / z [M+H] + 265.

[0324] Step 7: Synthesis of ethyl (6S)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A21) and ethyl (6R)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A22) To a mixture of 2-[5-fluoro-3-(4-piperidyl)-2-pyridyl]-1,3,4-thiadiazole (115 mg, 382 μmol, HCl salt) in DCE (1.50 mL) was added TEA (193 mg, 1.91 mmol) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (75.4 mg, 382 μmol) in one portion. The mixture was then stirred at room temperature for 2 hours. NaBH(OAc) (243 mg, 1.15 mmol) and AcOH (2.30 mg, 38.2 μmol) were added in one portion to the mixture. The mixture was stirred at room temperature for 32 hours. The mixture was poured into saturated aqueous NaHCO (5 mL) and extracted with DCM (3 × 10 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–5% methanol / dichloromethane) and further separated by SFC (column: DAICEL CHIRALCEL OD-H, 250 mm × 30 mm, 5 μm; mobile phase: [CO2-i-PrOH (0.1% NH3HO)]; B%: 45%, isocratic elution mode) to give peak 1 ethyl (6S)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (21.7 mg, 48.7 μmol, 24.1% yield) as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H= 9.15 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.25 (t, J = 11.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.92-3.76 (m, 4H), 3.11 (t, J = 10.4 Hz, 2H), 2.73-2.58 (m, 1H), 2.26-2.12 (m, 3H), 2.02-1.90 (m, 4H), 1.88-1.71 (m, 4H), 1.62-1.53 ​​(m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 446. Peak 2 Ethyl (6R)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (18.5 mg, 41.5 μmol, 20.6% yield) was obtained as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 9.15 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 2.4 Hz, 10.0 Hz, 1H), 4.25 (t, J = 11.2 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.92-3.75 (m, 4H), 3.11 (t, J = 10.4 Hz, 2H), 2.73-2.59 (m, 1H), 2.28-2.11 (m, 3H), 2.01-1.89 (m, 4H), 1.88-1.71 (m, 4H), 1.62-1.52 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 446. Chirality was later determined based on potency.

[0325] Example #19: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A23) and ethyl (6S)-6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A24)

[0326] [ka]

[0327] Step 1: Synthesis of 3-bromo-5-fluoro-2-(4-methyltriazol-1-yl)pyridine (C41) A mixture of 1,1-dimethoxypropan-2-one (618 mg, 5.24 mmol) and 4-methylbenzenesulfonohydrazide (975 mg, 5.24 mmol) in DMSO (10.0 mL) was stirred at room temperature for 1 hour. Then, 3-bromo-5-fluoro-pyridin-2-amine (1.00 g, 5.24 mmol) was added to the mixture. The reaction mixture was stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature. Water (20 mL) was added, and the mixture was stirred for 15 minutes. The mixture was extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-40% ethyl acetate / petroleum ether) to give 3-bromo-5-fluoro-2-(4-methyltriazol-1-yl)pyridine (428 mg, 1.49 mmol, 28.4% yield, 89.4% purity) as a yellow oil. LCMS m / z [M+H] + 257, 259.

[0328] Step 2: Synthesis of tert-butyl 4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (C42) A mixture of 3-bromo-5-fluoro-2-(4-methyltriazol-1-yl)pyridine (428 mg, 1.66 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (515 mg, 1.66 mmol), Pd(dppf)Cl (122 mg, 167 μmol), and NaCO (353 mg, 3.33 mmol) in 1,4-dioxane (5.00 mL) and HO (1.00 mL) was degassed under vacuum and purged with N gas three times. The reaction mixture was then stirred at 90 °C for 12 hours under N gas atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–40% ethyl acetate / petroleum ether) to give tert-butyl 4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (490 mg, 1.31 mmol, 78.5% yield, 95.9% purity) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H = 8.31 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 7.48 (dd, J = 2.8 Hz, 8.0 Hz, 1H), 5.73 (s, 1H), 4.02 (br s, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.43 (s, 3H), 1.94 (br s, 3H), 1.47 (s, 9H). LCMS m / z [M+H] + 360.

[0329] Step 3: Synthesis of tert-butyl 4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]piperidine-1-carboxylate (C43) To a solution of tert-butyl 4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (490 mg, 1.36 mmol) in MeOH (5.00 mL) was added dry Pd / C (300 mg, 10% w / w). The mixture was degassed and purged with H gas three times. The reaction was stirred at 30 °C under an H gas atmosphere (15 psi) for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]piperidine-1-carboxylate (476 mg, 1.30 mmol, 95.6% yield, 99.0% purity) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H = 8.26 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.54 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 4.20 (br s, 2H), 3.37-3.26 (m, 1H), 2.74 (br s, 2H), 2.46 (s, 3H), 1.87 (d, J = 12.8 Hz, 2H), 1.63-1.52 (m, 2H), 1.47 (s, 9H). LCMS m / z [M+H] + 362.

[0330] Step 4: Synthesis of 5-fluoro-2-(4-methyltriazol-1-yl)-3-(4-piperidyl)pyridine (C44) To a solution of tert-butyl 4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]piperidine-1-carboxylate (476 mg, 1.32 mmol) in DCM (5.00 mL) was added dropwise HCl / 1,4-dioxane (4 M, 2.00 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 5-fluoro-2-(4-methyltriazol-1-yl)-3-(4-piperidyl)pyridine (300 mg, 990 μmol, 75.2% yield, 98.2% purity, HCl salt) as a yellow oil. 1H NMR (MeOD 400 MHz) δ H = 8.43 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 7.97 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 3.50 (br d, J = 12.8 Hz, 2H), 3.25-3.16 (m, 1H), 3.10-3.01 (m, 2H), 2.46 (s, 3H), 2.19-2.11 (m, 2H), 2.06-1.95 (m, 2H). LCMS m / z [M+H] + 262.

[0331] Step 5: Synthesis of tert-butyl 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (C45) To a mixture of 5-fluoro-2-(4-methyltriazol-1-yl)-3-(4-piperidyl)pyridine (300 mg, 1.01 mmol, HCl salt) in DCE (5.00 mL) was added TEA (420 μL, 3.02 mmol), followed by tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (227 mg, 1.01 mmol). The mixture was stirred at room temperature for 0.5 h. HOAc (28.8 μL, 504 μmol) and NaBH(OAc) (641 mg, 3.02 mmol) were added. The mixture was stirred at room temperature for 11.5 h. The reaction mixture was poured into 10% aqueous NaHCO (15 mL) and then extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (450 mg, 956 μmol, 83.3% yield) as a yellow oil. LCMS m / z [M+H] + 471.

[0332] Step 6: Synthesis of ethyl 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (C46) To a solution of tert-butyl 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (450 mg, 956 μmol) in DCM (5.00 mL), TFA (1.20 mL, 16.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (463 mg, crude, TFA salt) as a yellow oil, which was used in the theoretical amount in the next step.

[0333] Step 7: Synthesis of 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (C47) A mixture of 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane (463 mg, 956 μmol, TFA salt) in DCM (4.00 mL) was added dropwise to TEA (666 μL, 4.78 mmol) at 0 °C. Ethyl carbonochloridate (690 mg, 6.36 mmol) was then added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was slowly quenched with saturated aqueous NaHCO (20 mL) at 0 °C and then extracted with DCM (3 × 5 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-5% MeOH / DCM) to give ethyl 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (250 mg, 551 μmol, 51.0% yield, 97.5% purity) as a yellow oil. LCMS m / z [M+H] + 443.

[0334] Step 8: Synthesis of ethyl (6R)-6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A23) and ethyl (6S)-6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (A24) Ethyl 6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (120 mg, 271 μmol) was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO₂-EtOH (0.1% NH₃HO)]; B%: 55%, isocratic elution mode) to give peak 1 ethyl (6R)-6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (37.1 mg, 81.6 μmol, 30.1% yield, 97.4% purity) as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H = 8.23 ​​(d, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.60 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.89-3.80 (m, 2H), 3.80-3.74 (m, 2H), 3.18-2.99 (m, 3H), 2.62-2.52 (m, 1H), 2.45 (s, 3H), 2.16-2.07 (m, 1H), 2.05-1.75 (m, 8H), 1.75-1.78 (m, 2H), 1.58-1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 443. Peak 2 Ethyl (6S)-6-[4-[5-fluoro-2-(4-methyltriazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (46.9 mg, 106 μmol, 39.1% yield, 100% purity) was obtained as an off-white solid. 1 H NMR (CDCl3 400 MHz) δ H=8.23 (d, J = 2.8 Hz, 1H), 7.86 (s, 1H), 7.61 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.90-3.81 (m, 2H), 3.80-3.74 (m, 2H), 3.17-2.99 (m, 3H), 2.64-2.52 (m, 1H), 2.46 (s, 3H), 2.16-2.07 (m, 1H), 2.03-1.75 (m, 8H), 1.74-1.68 (m, 2H), 1.56-1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 443.

[0335] Using the methodology described above for Examples A1-A24 and starting materials similar to those listed in the table, compounds A25-A293 were synthesized as listed in the table below.

[0336] [Table 3] TIFF2025532632000099.tif249161TIFF2025532632000100.tif251161TIFF2025532632000101.tif250161TIFF2025532632000102.tif242161TIFF202 5532632000103.tif249161TIFF2025532632000104.tif244163TIFF2025532632000105.tif242161TIFF2025532632000106.tif242161TIFF2025532632 000107.tif243162TIFF2025532632000108.tif247162TIFF2025532632000109.tif246161TIFF2025532632000110.tif247162TIFF2025532632000111. tif243162TIFF2025532632000112.tif247161TIFF2025532632000113.tif247161TIFF2025532632000114.tif247162TIFF2025532632000115.tif17161

[0337] Example #20: Biological Assays FLIPR assay Fluo8, an intracellular calcium-sensitive dye that exhibits an increase in fluorescence intensity upon calcium binding, was used in a fluorescence imaging plate reader (FLIPR) assay. Stimulation of Gq-coupled G protein-coupled receptors (GPCRs) results in calcium efflux from the endoplasmic reticulum to the cytoplasm (Berridge, 1993); therefore, this assay is suitable for evaluating M1, M3, and M5 receptors. CHO-K1 cells overexpressing M1, M3, or M5 muscarinic acetylcholine receptors (mAChRs) were dispensed into 384-well plates at 15,000 cells per well in a 30 μl volume and grown overnight at 37°C in a 5% CO2 atmosphere. Ten μl of Fluo8 solution per well was added to each well and incubated for 30 minutes at 37°C in a 5% CO2 atmosphere. Compounds diluted in Hank's balanced salt solution (HBSS) were transferred to the cell assay plate at 10 μl per well and then read on the FLIPR instrument. The resulting data for each receptor subtype yielded EC 50 and E max The figures were calculated.

[0338] Results for selected compounds provided herein are shown in the table below.

[0339] cAMP assay M2 and M4 mACh receptors are G receptors that, when activated, cause a decrease in cAMP. iM2 or M4 are receptor-coupled receptors. An assay was developed to measure the potency and efficacy of compounds at M2 or M4 mAChRs using M2- or M4-overexpressing CHO-K1 cell lines. Time-resolved fluorescence resonance energy transfer (TR-FRET) technology was used, in which a signal is generated as a result of energy transfer when a donor molecule is in close proximity to an acceptor molecule when the molecule is bound to a molecule of interest. cAMP detection is a competitive binding assay, in which cAMP produced by the cells competes with a labeled donor molecule for binding to an anti-cAMP acceptor antibody. Because basal levels of cAMP in CHO-K1 cell lines are low, forskolin was used to increase cAMP levels, allowing for the assessment of agonist activity at the mAChR of interest.

[0340] Results for selected compounds provided herein are shown in the table below.

[0341] [Table 4] TIFF2025532632000117.tif232161TIFF2025532632000118.tif232161TIFF20255326320 00119.tif232161TIFF2025532632000120.tif232161TIFF2025532632000121.tif229161

Claims

1. Formula (I): 【Chemical 1】 or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide thereof. (In the formula, A is a 6- to 8-membered heterocycle containing one or two ring nitrogen atoms and is selected from the group consisting of halogen, OH, and C. １～３ optionally substituted with 1 to 3 substituents independently selected from alkyl; Y is a bond, O, S, or CH ２ , CHF, CF ２ or C(OH)H; m is 1 or 2; n is 1 or 2; p is 1 or 2; R １ is H, halogen, CN, OH, -N(R ６ ) (R ７ ), C １～６ Alkyl, C ２～６ Heteroalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkoxy, -[O] ０～１ -C ３～６ cycloalkyl, -[O] ０～１ -C ６～１０ aryl, -[O] ０～１ -4 to 8-membered heterocycle or -[O] ０～１ - 5- to 10-membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R １ But C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkoxy, -[O] ０～１ -C ３～６ cycloalkyl, -[O] ０～１ -C ６～１０ aryl, -[O] ０～１ -4 to 8 membered heterocycle, -[O] ０～１ -5 to 10 membered heteroaryl, -NH-C ３～６ Cycloalkyl, —NH—C ６～１０ Aryl, —NH-4- to 8-membered heterocycle, —NH-5- to 10-membered heteroaryl, —N(C １～６ alkyl)-C ３～６ Cycloalkyl, —N(C １～６ alkyl)-C ６～１０ Aryl, —N(C １～６ alkyl)-4 to 8-membered heterocycle or -N(C １～６ alkyl)-5 to 10-membered heteroaryl, R １ is halogen, CN, OH, =O, SO ２ and C １ ~ ３ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R ２ is H, halogen, CN, OH, -N(R ６ ) (R ７ ), C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Heteroalkyl, C ３～６ cycloalkyl or a 4-8 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R ３ is halogen, CN, OH, -N(R ６ ) (R ７ ), C １～６ Alkyl, C ２～６ Heteroalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkoxy, -[O] ０～１ -C ３～６ cycloalkyl, -[O] ０～１ -C ６～１０ aryl, -[O] ０～１ -4 to 8 membered heterocycle, or -[O] ０～１ -5 to 10 membered heteroaryl, -NH-C ３～６ Cycloalkyl, —NH—C ６～１０ Aryl, —NH-4- to 8-membered heterocycle, —NH-5- to 10-membered heteroaryl, —N(C １～６ alkyl)-C ３～６ Cycloalkyl, —N(C １～６ alkyl)-C ６～１０ Aryl, —N(C １～６ alkyl)-4 to 8 membered heterocycle, or -N(C １～６ alkyl)-5 to 10-membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; ３～６ Cycloalkyl, —C ６～１０ The aryl, 4- to 8-membered heterocycle, or 5- to 10-membered heteroaryl may have 0, 1, 2, or 3 R ３ａ is substituted with a substituent; Each R ３ａ is halogen, CN, OH, =O, =N(C １～３ alkyl), SO ２ , C １～６ Alkyl, C ２～１０ Alkene, C １～６ Hydroxyalkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylene -O-C １～６ Alkyl, C ０～６ Alkylene-NH ２ , C ０～６ Alkylene-NH(C １～６ alkyl), C ０～６ Alkylene-N(C １～６ alkyl) ２ , -S-C １～６ Alkyl, C ０～６ Alkylene-SO ２ C １～６ Alkyl, C ０～６ Alkylene -C(O)NH ２ , C ０～６ Alkylene -C(O)NH(C １～６ alkyl), C ０～６ Alkylene -C(O)N(C １～６ alkyl) ２ , C ０～６ Alkylene-NHC(O)C １～６ Alkyl, C ０～６ Alkylene-COOH, C ０～６ Alkylene-C ３～６ Cycloalkyl, C １～６ Alkylene -O-C １～６ Alkylene Si(C １～３ alkyl) ３ and C containing 1, 2 or 3 heteroatoms selected from N, O and S ０～６ alkylene-3-6 membered heterocycle; R ４ is H, halogen, CN or OH; R ５ is -CO ２ -Z or a biological equivalent thereof; Each R ６ and R ７ are independently H, C １～６ Alkyl, C(O)-C １～６ Alkyl, spiro or bicyclic C ８～１４ cycloalkyl, an 8-14 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R ６ or R ７ When is other than H, it is halogen, CN, ═O, SO ２ , O.H., C. ０～６ Alkylene-NH ２ , C ０～６ Alkylene-NH(C １～６ alkyl), C ０～６ Alkylene-N(C １～６ alkyl) ２ , C ０～６ Alkylene-SO ２ C １～６ Alkyl, C １～６ Alkyl and C １～６ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy; R ６ and R ７ together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N, O and S; Z is C １～７ Alkyl, C １～７ Haloalkyl, C ３～６ Cycloalkyl or C ２～６ alkyne, Z is C １～６ Alkoxy or C ３～６ optionally substituted with cycloalkyl; However, R １ , R ２ and R ４ are each H, and Y is CH ２ wherein m, n and p are each 1, and A is 【Chemistry 2】 and R ３ is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy, or 【Chemistry 3】 If R ５ is CO ２ CH ２ CH ３ provided that it is not.)

2. A is, 【Chemistry 4】 and X is N, C(F), C(OH) or CH.

3. Formula (Ia): 【Chemistry 5】 3. The compound or salt of claim 2, having the structure:

4. Formula (Ib): 【Chemistry 6】 4. The compound or salt of claim 3 having the structure:

5. Y is CH ２ , CHF, CF ２ or C(OH)H.

6. Y is CH ２ The compound or salt of claim 5,

7. The compound or salt according to any one of claims 1 to 3, 5 and 6, wherein m is 1.

8. The compound or salt according to any one of claims 1 to 3 and 5 to 7, wherein n is 1.

9. The compound or salt according to any one of claims 1 to 3 and 5 to 8, wherein p is 1.

10. Formula (Ic): 【Chemistry 7】 5. The compound or salt of claim 4 having the structure:

11. Formula (Id): 【Chemistry 8】 5. The compound or salt of claim 4 having the structure:

12. R ５ CO ２ Z bioisosteres, 【Chemistry 9】 The compound or salt according to any one of claims 1 to 11, selected from the group consisting of:

13. Formula (Ie): 【Chemistry 10】 2. The compound or salt of claim 1 having the structure:

14. R ５ But CO ２ C １～７ Alkyl, 【Chemistry 11】 The compound or salt according to any one of claims 1 to 11 and 13, selected from the group consisting of:

15. R ５ CO ２ CH ２ CH ３ 15. The compound or salt of claim 14, wherein:

16. R ４ The compound or salt according to any one of claims 1 to 15, wherein is H or a halogen.

17. R １ H, halogen, CN, OH, -N(R ６ ) (R ７ ), C １～６ Alkyl or C １～６ 17. The compound or salt of any one of claims 1 to 16, which is alkoxy.

18. R １ 18. The compound or salt of claim 17, wherein is H or a halogen.

19. R ２ H, halogen, CN, OH, -N(R ６ ) (R ７ ), C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy or C １～６ 19. The compound or salt of any one of claims 1 to 18, which is haloalkoxy.

20. R ２ H, halogen, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl or C １～６ 20. The compound or salt of claim 19, which is haloalkoxy.

21. R ２ 21. The compound or salt of claim 20, wherein is H or a halogen.

22. Each R ６ and R ７ However, independently, H, C １～６ Alkyl or C(O)-C １～６ 22. The compound or salt of any one of claims 1 to 21, which is alkyl.

23. Each R ６ and R ７ are independently H or C １～６ 23. The compound or salt of claim 22, wherein the compound or salt is alkyl.

24. At least one R ６ and R ７ together with the nitrogen to which they are attached form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N and O.

25. R １ , R ２ , R ３ and R ４ The compound or salt according to any one of claims 1 to 24, wherein at least one of is a halogen.

26. R １ , R ２ , R ３ and R ４ The compound or salt according to any one of claims 1 to 25, wherein at least one of is F.

27. R ３ But - [O] ０～１ -C ３～６ cycloalkyl, -[O] ０～１ -C ６～１０ aryl, -[O] ０～１ -4 to 8-membered heterocycle or -[O] ０～１ - 5 to 10 membered heteroaryl, and 1, 2 or 3 R ３ａ 27. The compound or salt of any one of claims 1 to 26, optionally substituted with:

28. R ３ But C ３～６ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocycle, and one, two, or three R ３ａ 28. The compound or salt of any one of claims 1 to 27, optionally substituted with:

29. R ３ but, 【Chemistry 12】 【change】 and one, two or three R ３ａ 29. The compound or salt of any one of claims 25 to 28, optionally substituted with:

30. R ３ but, 【Chemistry 13】 and one, two or three R ３ａ 30. The compound or salt of claim 29, optionally substituted with:

31. R ３ 31. The compound or salt of any one of claims 1 to 30, wherein is unsubstituted.

32. R ３ But one or two R ３ａ 31. The compound or salt of any one of claims 1 to 30, substituted with:

33. R ３ But one R ３ａ 33. The compound or salt of any one of claims 1 to 30 and 32, substituted with:

34. At least one R ３ａ But halogen, CN, OH, ═O, SO ２ , C １～６ Alkyl, C ２～１０ Alkene, C １～６ Hydroxyalkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylene -O-C １～６ Alkyl, C ０～６ Alkylene-N(C １～６ alkyl) ２ , -S-C １～６ Alkyl, C ０～６ Alkylene-NHC(O)C １～６ alkyl or C containing 1, 2 or 3 heteroatoms selected from N, O and S ０～６ The compound or salt according to any one of claims 1 to 30, 32 and 33, which is alkylene-3 to 6-membered heterocycle.

35. At least 1 person ３ａ が、CH ３ 、H ２ CH ３ , HH(H) ３ ) ２ 、H ２ HH(H) ３ ) ２ 、CF ３ 、\HF ２ 、H ２ CH ２ F、CH ２ CHF ２ 、H ２ O, C (C) ３ ) ２ OH、CHH ２ OCH ３ 、H ２ CH ２ OCH ３ 、H ２ OCH ２ CH ３ 、F、CN、=O、SO ２ 、OH、OCH ３ ,OCH ２ CH ３ ,OCH(CH ３ ) ２ 、OCHF ２ ,H ２ OCH ３ ,H ２ OCF ３ 、SCH ３ 、NH ２ 、N(CH ３ ) ２ ,NHCH ３ 、CD ３ 、 【Chemistry 14】 35. The compound or salt of claim 34, wherein:

36. At least one R ３ａ But CH ３ , C.H. ２ CH ３ ,F,CN,OH,OCH ３ , C.F. ３ , C.H. ２ OH or OCHF ２ 36. The compound or salt of claim 35, wherein:

37. Formula (If): 【Chemistry 15】 (In the formula, R １ is a halogen; R ３ is -[O] ０～１ -C ３～６ cycloalkyl, -[O] ０～１ -C ６～１０ aryl, -[O] ０～１ -4 to 8-membered heterocycle or -[O] ０～１ - 5- to 10-membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2, or 3 ring heteroatoms selected from N, O, and S; R ３ is 0, 1, 2 or 3 R ３ａ is substituted with a substituent; R ５ is CO ２ Z or a biological equivalent thereof; Z is C １～７ Alkyl, C １～７ Haloalkyl, C ３～６ Cycloalkyl or C ２～６ Alkyne, C １～６ Alkoxy or C ３～６ Optionally substituted with cycloalkyl.

2. The compound or salt of claim 1 having the structure:

38. R １ 38. The compound or salt of claim 37, wherein is Cl or F.

39. R ３ is a 5- to 6-membered heterocycle containing one ring heteroatom selected from S and O, or a 5- to 6-membered heteroaryl containing two or three ring heteroatoms independently selected from N and S, and R ３ but halogens, CN, OH and C １～６ 0, 1 or 2 R independently selected from alkyl ３ａ 39. The compound or salt of claim 37 or 28, which is substituted with a substituent.

40. R ５ CO ２ C １～７ 40. The compound or salt of claim 37, 38 or 39, which is alkyl.

41. R ５ CO ２ 41. The compound or salt of claim 40, which is Et.

42. A compound as listed in Table A or a pharmaceutically acceptable salt thereof.

43. 43. A pharmaceutical formulation comprising a therapeutically effective amount of a compound or salt according to any one of claims 1 to 42, and a pharmaceutically acceptable excipient.

44. 43. A method for treating an M4-mediated (or M4-associated) disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound or salt according to any one of claims 1 to 42.

45. M4-mediated (or M4-associated) diseases or disorders include Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders (e.g., mild cognitive deficit), 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's syndrome), cerebral amyloid angiopathy, Alzheimer's disease psychosis, dementia-related psychosis, bipolar I 45. The method of claim 44, wherein the cause is selected from the group consisting of bipolar disorder, bipolar II disorder, bipolar depression, missed and / or manic episodes associated with bipolar disorder, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, and atherosclerosis.

46. 46. ​​The method of claim 45, wherein the M4-mediated (or M4-associated) disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, and sleep disorders.

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