Spiro derivatives as 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. TIFF2026502501000247.tif20161

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 for the treatment of M4-mediated diseases and disorders such as Parkinson's disease, schizophrenia, Alzheimer's disease and others described herein. [Means for solving the problem]

[0005] Formula (I):

[0006] [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein A contains one or two ring nitrogen atoms and one to three R A and each R is a 6- to 8-membered heterocycle optionally substituted with A independently, C 1~3 Alkyl, halogen, =O, OH, C 1~3 Hydroxyalkyl or C 1~3 haloalkyl; 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, NO2, -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; R 1 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, 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 substituted with 0, 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 is a halogen, C 0~6 Alkylene -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, C 1~6 Alkylene-OC 1~6 Alkyl, C 1~6 Alkylene-NHC(O)C 1~6 Alkyl, C 1~6Alkylene-C(O)NHC 1~6 Alkyl, C 0~6 Alkylene-Cyc, OC 0~6 Alkylene-Cyc, NH-Cyc, N(C 1~6 alkyl)-Cyc or C(O)Cyc; Cyc is C 3~12 Cycloalkyl, C 3~6 Heterocycloalkyl, C 5~12 Spirocycloalkyl, C 5~12 Heterospirocycloalkyl, C 6~10 aryl, a 3- to 12-membered heterocycle, or a 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl contains 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; and Cyc is 0, 1, 2, or 3 R 3a is substituted with a substituent; each R 3a are halogens, CN, OH, =O, =N(C 1~6 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-C(O)C 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 0~6Alkylene-COOH, C 0~6 Alkylene-CO2C 1~6 Alkyl, C 0~6 Alkylene-C 3~6 cycloalkyl and C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 alkylene-3 to 6-membered heterocycles; R 4 H, halogen, CN, OH, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 Alkoxy; 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, =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 substituted with 0, 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 is an alkyne, and Z is 0, 1, 2 or 3 C 1~6 Alkoxy or C3~6 substituted with cycloalkyl; provided that R 1 and R 4 are each H, m and p are each 1, and A is

[0007] [ka] and (a) R 2 is H, Y is CH2, n is 1, and R 3 But CH3, OCH3,

[0008] [ka] or (b) R 2 is F, YCH2, n is 1, and R 3 but,

[0009] [ka] or (c) R 2 is H, Y is a bond, n is 1, and R 3 but,

[0010] [ka] or (d) R 2 is H, Y is a bond, n is 2, and R 3 but,

[0011] [ka] If R 5 is not CO2CH2CH3 or CO2CH(CH3)3. In some embodiments, one or more H may be present in any of, but not limited to, R 1 Group, R 2 Group, R 3 Groups and / or R 4 Any D present in the group may be substituted.

[0012] Pharmaceutical compositions comprising the compounds as disclosed herein.Further provided herein is a method for treating an M4-mediated (or M4-associated) 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.

[0013] 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 in a variety of forms, the following description includes specific cases, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific cases described herein. DETAILED DESCRIPTION OF THE INVENTION

[0014] Formula (I):

[0015] [ka] Provided herein are compounds having the structure: or a pharmaceutically acceptable salt thereof. 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.

[0016] 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. 1~7Alkyl 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.

[0017] 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 an alkylene group having a number of carbon atoms, including all ranges and all subgroups as previously described for "alkyl" groups. C0 alkylene indicates a direct bond (i.e., no alkylene linker).

[0018] 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. 2~7Alkenyl 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.

[0019] 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.

[0020] 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 3~12Cycloalkyl refers to cycloalkyl groups having any number of ring carbon atoms, including all ranges (i.e., 3 to 12 carbon atoms), and all subgroups (e.g., 4 to 8, 3 to 7, 4 to 7, 3 to 6, 4 to 6, 3 to 5, 4 to 5, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Non-limiting examples of bridged cycloalkyl groups include:

[0021] [ka] Non-limiting examples of spirocycloalkyl groups include:

[0022] [ka] Non-limiting examples of fused cycloalkyl include:

[0023] [ka] (for example,

[0024] [ka] ) Unless otherwise indicated, a cycloalkyl group can be an unsubstituted cycloalkyl group or a substituted cycloalkyl group.

[0025] 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 3- to 12-membered ring having 1, 2, or 3 heteroatoms selected from N, O, and S. As another example, a heterocycle can be a 5- to 12- or 8- to 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 piperidine, piperazine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, oxazepane, thiazole, pyrrole, and pyridine. Non-limiting examples of heterocyclic groups include:

[0026] [ka] Examples include:

[0027] 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 3~6 Heterocycles may be optionally substituted with 1 to 3 groups independently selected from: heterocycles. Other contemplated substitutions are discussed in detail elsewhere in this disclosure.

[0028] 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.

[0029] 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.

[0030] [ka] TIFF2026502501000015.tif239165TIFF2026502501000016.tif175166. Unless otherwise specified, a heteroaryl group can be an unsubstituted heteroaryl group or a substituted heteroaryl group.

[0031] 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.

[0032] As used herein, the term "alkoxy" or "alkoxyl" refers to an "-O-alkyl" group.

[0033] 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, CHCl, and CHCF. Similarly, "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, e.g., OCF. And "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with one or more halogens.

[0034] 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). The number of heteroatoms in the heteroalkyl chain can be, for example, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1 or 2. Specific numbers of heteroatoms contemplated include 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 heteroatoms.

[0035] 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 (CO-NRSO2R), hydroxamic acid (CONROH), hydroxamate (CONROR), tetrazole, hydroxyisoxazole, isoxazol-3-one, and sulfonamide (SO2NR), where each R can independently represent hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0036] 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.

[0037] Compounds of the Disclosure Formula (I):

[0038] [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or N-oxide thereof, wherein: A contains one or two ring nitrogen atoms and one to three R A is a 6-8 membered heterocycle optionally substituted with Each R A independently, C 1~3 Alkyl, halogen, =O, OH, C 1~3 Hydroxyalkyl or C 1~3 is haloalkyl; 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, NO2, -N(R 6 )(R 7 ), C 1~6 Alkyl, C2~6 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; R 1 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 substituted with 0, 1, 2 or 3 substituents independently selected from halogen, CN, OH, ═O, SO and C1-3 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, C3~6 cycloalkyl or a 4-8 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 3 is a halogen, C 0~6 Alkylene -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, C 1~6 Alkylene-OC 1~6 Alkyl, C 1~6 Alkylene-NHC(O)C 1~6 Alkyl, C 1~6 Alkylene-C(O)NHC 1~6 Alkyl, C 0~6 Alkylene-Cyc, OC 0~6 Alkylene-Cyc, NH-Cyc, N(C 1~6 alkyl)-Cyc or C(O)Cyc; Cyc is C 3~12 Cycloalkyl, C 3~6 Heterocycloalkyl, C 5~12 Spirocycloalkyl, C 5~12 Heterospirocycloalkyl, C 6~10 aryl, a 4- to 12-membered heterocycle, or a 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl contains 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; and Cyc is 0, 1, 2, or 3 R 3a is substituted with a substituent; Each R 3a are halogens, CN, OH, =O, =N(C 1~6 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 0~6Alkylene-C(O)C 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-CO2C 1~6 Alkyl, C 0~6 Alkylene-C 3~6 cycloalkyl and C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 alkylene-3 to 6 membered heterocycle; R 4 H, halogen, CN, C 1~6 Alkyl, OH or C 1~6 is alkoxy; 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, =O, SO2, OH, C 0~6 Alkylene-NH2, C 0~6 Alkylene-NH(C 1~6 alkyl), C0~6 Alkylene-N(C 1~6 Alkyl)2, C 0~6 Alkylene-SO2C 1~6 Alkyl, C 1~6 Alkyl and C 1~6 substituted with 0, 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 is an alkyne, and Z is 0, 1, 2 or 3 C 1~6 Alkoxy or C 3~6 substituted with cycloalkyl; However, R 1 and R 4 are each H, m and p are each 1, and A is

[0039] [ka] and (a)R 2 is H, Y is CH2, n is 1, and R 3 But CH3, OCH3,

[0040] [ka] is, or (b)R 2 is F, Y is CH2, n is 1, and R 3 but,

[0041] [ka] is, or (c)R 2is H, Y is a bond, n is 1, and R 3 but,

[0042] [ka] is, or (d)R 2 is H, Y is a bond, n is 2, and R 3 but,

[0043] [ka] If R 5 is not CO2CH2CH3 or CO2CH(CH3)3. In some embodiments, one or more H may be present in any R 1 Group, R 2 Group, R 3 Groups and / or R 4 Any D present in the group may be substituted.

[0044] In various cases, the ring containing the Y substituent,

[0045] [ka] is somewhere on the ring, C 1~3 Alkyl, halogen, C 1~3 It is optionally substituted with haloalkyl, OH, or CN. In some cases, the ring containing the Y substituent is substituted with methyl, fluoro, CF, OH, or CN.

[0046] In various cases, A:

[0047] [ka] and X is N, CH, C(OH) or CF.

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

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

[0050] In various cases, Y is CH2, CHF, CF2, or C(OH)H. In some cases, Y is CH2. In some cases, m is 1. In some cases, n is 1. In some cases, p is 1.

[0051] In various cases, the compound has the formula (Ib):

[0052] [ka] In various cases, the compound has the structure of formula (Ic):

[0053] [ka] In various cases, the compound has the structure of formula (Id):

[0054] [ka] In various cases, the compound has the structure of formula (Ie):

[0055] [ka] It has the following structure.

[0056] In some cases, R 5 is the CO2Z bioequivalent,

[0057] [ka] is selected from the group consisting of:

[0058] In various cases, R 5 is CO2C 1~7 Alkyl,

[0059] [ka] In some cases, R 5 is CO2CH2CH3.

[0060] In various cases, R 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.

[0061] 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 a halogen.

[0062] In various cases, 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 some cases, at least one R 6 and R 7together 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.

[0063] In various cases, R 4 is H or a halogen.

[0064] In various cases, R 1 , R 2 and R 4 At least one of R is halogen. 1 , R 2 and R 4 At least one of is F.

[0065] In various cases, R 3 is C 0~6 Alkylene-Cyc, OC 0~6 Alkylene-Cyc, NH-Cyc, N(C 1~6 alkyl)-Cyc or C(O)Cyc, where Cyc is C 3~6 Cycloalkyl, C 6~10 aryl, a 4- to 8-membered heterocycle, or a 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl contains 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; and Cyc is 0, 1, 2, or 3 R 3a In various cases, R 3 is C 0~6 Alkylene-Cyc, OC 0~6 Alkylene-Cyc, NH-Cyc, N(C 1~6 alkyl)-Cyc or C(O)Cyc, where Cyc is C 3~12 Cycloalkyl, C 6~10 aryl, a 4- to 12-membered heterocycle, or a 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl contains 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; and Cyc is 0, 1, 2, or 3 R 3a In various cases, R 3 is -[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- to 10-membered heteroaryl, and one, two, or three R 3a In some cases, R 3 teeth,

[0066] [ka] TIFF2026502501000033.tif240166TIFF2026502501000034.tif78162 and 0, 1, 2 or 3 R 3a In various cases, R 3 teeth,

[0067] [ka] and 0, 1, 2 or 3 R 3a In some cases, R 3 is unsubstituted. In various cases, R 3 is one or two R 3a In some cases, R 3 is one R 3a In some 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, N(C 1~6 Alkyl)2, C 1~6 Alkylene-N(C 1~6 Alkyl)2, -SC 1~6 Alkyl, NHC(O)C 1~6Alkyl, C 1~6 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. In some cases, at least one R 3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2OCH3, CH2 OCH2CH3, F, CN, =O, SO2, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, CH2OCH3, CH2OCF3, SCH3, N(CH3)2, NHCOCH3, CD3,

[0068] [ka] In various cases, at least one R 3a is CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH or OCHF2.

[0069] Some illustrative examples of the compounds (or pharmaceutically acceptable salts thereof) disclosed herein are shown in Table A.

[0070] [Table 1] TIFF2026502501000038.tif234162TIFF2026502501000039.tif237161TIFF2026502501000040.tif249163TIFF2026502501000041.tif231161TIFF2026502501000042.tif229162TIFF2026502501000043.tif237161TIFF2026502501000044.tif235162TIFF2026502501000045.tif234161TIFF2026502501000046.tif224161TIFF2026502501000047.tif244162TIFF2026502501000048.tif251161TIFF2026502501000049.tif247161TIFF2026502501000050.tif244162TIFF2026502501000051.tif228161TIFF2026502501000052.tif238161TIFF2026502501000053.tif250161TIFF2026502501000054.tif235163TIFF2026502501000055.tif232162TIFF2026502501000056.tif247162TIFF2026502501000057.tif233162TIFF2026502501000058.tif243162TIFF2026502501000059.tif237163TIFF2026502501000060.tif241161TIFF2026502501000061.tif218162TIFF2026502501000062.tif214161TIFF2026502501000063.tif245162TIFF2026502501000064.tif241161TIFF2026502501000065.tif248161TIFF2026502501000066.tif227161TIFF2026502501000067.tif223162TIFF2026502501000068.tif251162TIFF2026502501000069.tif237161TIFF2026502501000070.tif235161TIFF2026502501000071.tif250161TIFF2026502501000072.tif238162TIFF2026502501000073.tif21 6162TIFF2026502501000074.tif244162TIFF2026502501000075.tif242161TIFF2026502501000076.tif239161T IFF2026502501000077.tif222162TIFF2026502501000078.tif236161TIFF2026502501000079.tif248163TIFF20 26502501000080.tif235161TIFF2026502501000081.tif250161TIFF2026502501000082.tif241162TIFF2026502 501000083.tif233161TIFF2026502501000084.tif227161TIFF2026502501000085.tif250163TIFF202650250100 0086.tif250161TIFF2026502501000087.tif240162TIFF2026502501000088.tif240161TIFF2026502501000089. tif237162TIFF2026502501000090.tif250161TIFF2026502501000091.tif239161TIFF2026502501000092.tif24 0161TIFF2026502501000093.tif221161TIFF2026502501000094.tif242162TIFF2026502501000095.tif142161.

[0071] 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, 3Isotopes 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.

[0072] The dashed lines and thick wedge bonds (i.e.,

[0073] [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.,

[0074] [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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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).

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] In some cases, hemisalts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts, or sesquifumarates.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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").

[0095] 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).

[0096] 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).

[0097] 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).

[0098] 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).

[0099] 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.

[0100] Pharmaceutical preparations Also provided herein is a pharmaceutical formulation 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."

[0101] "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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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. The pharmaceutical compositions may be mixed with starch, potato, or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. The pharmaceutical compositions, individually or collectively, may provide immediate, modified, or extended release of the compound(s). Examples of pharmaceutical compositions include, but are not limited to, immediate-release, modified-release, and extended-release dosage forms.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] Treatment methods The compounds disclosed herein can act on the M4 receptor. Muscarinic acetylcholine receptor M4 (also known as muscarinic 4 or CHRM4) is a protein in humans encoded by the CHRM4 gene. M4 receptors are primarily expressed in the brain. The 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).

[0122] 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).

[0123] 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).

[0124] 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.

[0125] 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.

[0126] 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.

[0127] Examples of mood (affective) disorders that can be treated in accordance with the present disclosure include, but are not limited to, bipolar disorder, 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] Schizophrenia or psychosis for which the compounds of the present disclosure 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 disorders due to general medical conditions 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 spectrum" disorders, For example, disorders associated with psychosis, including schizophrenia or schizotypal personality disorder, or 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.

[0142] 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. Patent No. 8,664,234.

[0143] Potential sleep disorders for which the compounds of the present disclosure 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 fall asleep; 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; increasing the amount and percentage of stage 2 sleep; promoting 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 disrupted breathing during sleep; and conditions resulting from reduced sleep quality.

[0144] Pain disorders in which the compounds of the present disclosure may be useful include neuropathic pain (e.g., post-herpetic neuralgia, nerve injury, "pain" e.g., vulvodynia, phantom limb pain, rhizomelic pain, 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, dental pain, 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.

[0145] Compounds of the present disclosure can be used to reduce tolerance and / or dependence on opioid treatment of pain, and for the treatment of, for example, alcohol, opioid and cocaine withdrawal syndromes.

[0146] 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, 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.

[0147] 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 can be synthesized according to any of Schemes 1 to 6.

[0148] [ka]

[0149] 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. NAr), 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 -R 3 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 G 1 -R 3 is an 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. 1 Removal 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). 1may be one of many other protecting groups suitable for amines, including carboxybenzyl (Cbz) or benzoyl (Bz) groups, which 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, 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 5 should be represented by the same moiety as desired in the final product or a protected variant thereof in dichloromethane or other suitable solvent. Chiral separation of the racemic mixture, for example, chiral chromatographic methods such as chiral HPLC or chiral supercritical fluid chromatography (SFC), can produce enantiomerically pure compounds of formula I'.

[0150] [ka]

[0151] Scheme 2 depicts an alternative synthetic route for the preparation of compounds of formula I and I'. With reference to Scheme 2a, compound IV (wherein R 1 , R 2 , R 3 , R 4 The R and A substituents should be represented by the same moieties as desired in the final product or a protected variation thereof. 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, fluoroaryl, or fluoroalkyl substituent, e.g., 4-methylphenyl, methyl, nonafluorobutyl; m, n, and p are independently represented by an integer selected from 1 or 2, and Y should be represented by the same moiety as desired in the final product in the presence of a base such as potassium carbonate or potassium phosphate tribasic in a suitable solvent, including, but not limited to, MeCN, DMSO, DMF, or THF. Referring 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. ) can similarly replace the arylalkyl / fluoroalkyl sulfonate on chiral compound VIII, where R 6 is an aryl, alkyl, fluoroaryl, or fluoroalkyl substituent, such as 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 to produce compound IX. The BOC group can be removed 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 4and 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. 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. 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 HPLC or 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 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. ) 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 R 1 , 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.

[0152] [ka]

[0153] 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 4 The substituents, as well as X, should be represented by the same moiety 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 1may 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.

[0154] [ka]

[0155] 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). NCoupling 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. 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 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. 5can 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.

[0156] [ka]

[0157] 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 to obtain enantiomerically pure compound XXIII (wherein R 6 is to be represented by an aryl, alkyl, fluoroaryl, or fluoroalkyl substituent, such as 4-methylphenyl, methyl, or nonafluorobutyl. Compound XXVII can be coupled with XXIV in the presence of a base such as potassium carbonate or potassium phosphate tribasic in a suitable solvent, including but not limited to MeCN, DMSO, DMF, or THF. Alternatively, compound XXVII can be obtained by double S reaction of enantiomerically pure amine XXV with dichloro XXVI. N It can be prepared by the reaction of 2. 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). 1can 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 or 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 2 is a sulfonate or halogen.) to afford compound XXIX. Subsequently, the tert-butoxycarbonyl (Boc) of compound XXIX 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), to afford enantiomeric compound XXX, followed by coupling to R in dichloromethane or other suitable solvent. 5 to 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 The protecting group P can be coupled to XXVI via a 2 reaction to form the cyclized 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 1may 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 6 is 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.

[0158] [ka]

[0159] Scheme 6 refers to a synthetic sequence for the preparation of compounds of formula Id. With reference to Scheme 6a, 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 halide / sulfonate-Z or Z-sulfate-Z in DMF or other suitable solvent to produce compounds 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 carbamates of formula Id, where Z should be represented by the same moiety as desired in the final product or a protected variant thereof. Another alternative method for the preparation of Formula Id is to use CDI instead of triphosgene and ZOH (where Z should be represented by the same moiety as desired in the final product or a protected variant thereof) to react with Compound XXX to synthesize the carbamate of Formula Id. In Scheme 6b, the tert-butoxycarbonyl (Boc) of Compound XXVII 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), to provide the enantiomeric Compound XXXI, which can then be subsequently treated in three reaction steps to afford Compound XXXII (where Z should be represented by the same moiety as desired in the final product or a protected variant thereof). These three methods are: 1) treatment with CO gas, a base such as DBU, and Z-sulfate-Z or halide / sulfonate-Z in a suitable solvent such as DMF; 2) using triphosgene and ZOH in a suitable solvent such as DCM and a base such as pyridine; 3) using CDI and ZOH in a suitable solvent such as THF. 1 Removal of the protecting group P in this case results in compound XXXIII. 1 refers to groups well known to those skilled in the art for amine protection. For example, P 1may be a carboxybenzyl (Cbz) that can be cleaved via H gas conditions in a suitable solvent, including but not limited to, treatment with a wet solution of 10% Pd / C in methanol (MeOH). Alternatively, P 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 XXXIII can be prepared by standard C-N coupling procedures, such as, but not limited to, Buchwald-Hartwig coupling and, when appropriate, S-coupling of the amine. N Using the Ar reaction, 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.) to give compounds of formula Id.

[0160] Embodiments of the present disclosure 1. Formula (I):

[0161] [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or said N-oxide. (In the formula, A contains 1 or 2 ring nitrogen atoms and 0, 1, 2 or 3 R A is a 6- to 8-membered heterocycle substituted with; Each R A independently, C 1~3 Alkyl, halogen, =O, OH, C 1~3 Hydroxyalkyl or C 1~3 is haloalkyl; 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, NO2, -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; R 1 is 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, and R 1 is substituted with 0, 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 is a halogen, C 0~6 Alkylene -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, C 1~6 Alkylene-OC 1~6 Alkyl, C 1~6 Alkylene-NHC(O)C 1~6 Alkyl, C 1~6 Alkylene-C(O)NHC 1~6 Alkyl, C 0~6 Alkylene-Cyc, OC 0~6 Alkylene-Cyc, NH-Cyc, N(C 1~6 alkyl)-Cyc or C(O)Cyc; Cyc is C 3~12 Cycloalkyl, C 3~6 Heterocycloalkyl, C 5~12 Spirocycloalkyl, C 5~12 Heterospirocycloalkyl, C 6~10 aryl, a 4- to 12-membered heterocycle, or a 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl contains 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; and Cyc is 0, 1, 2, or 3 R 3a is substituted with a substituent; Each R 3a are halogens, CN, OH, =O, =N(C 1~6 alkyl), SO2, C 1~6 Alkyl, C 2~10 Alkene, C 1~6Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylene-OC 1~6 Alkyl, C 0~6 Alkylene-C(O)C 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-CO2C 1~6 Alkyl, C 0~6 Alkylene-C 3~6 cycloalkyl and C containing 1, 2 or 3 heteroatoms selected from N, O and S 0~6 alkylene-3 to 6 membered heterocycle; R 4 H, halogen, CN, OH, C 1~6 Alkyl, C 1~6 -haloalkyl or C 1~6 is alkoxy; 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 8~14cycloalkyl, 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 substituted with 0, 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 and R 4 are each H, m and p are each 1, and A is

[0162] [ka] and (a)R 2 is H, Y is CH2, n is 1, and R 3 But CH3, OCH3,

[0163] [ka] is, or (b)R 2is F, Y is CH2, n is 1, and R 3 but,

[0164] [ka] is, or (c)R 2 is H, Y is a bond, n is 1, and R 3 but,

[0165] [ka] is, or (d)R 2 is H, Y is a bond, n is 2, and R 3 but

[0166] [ka] If R 5 provided that it is not CO2CH2CH3 or CO2CH(CH3)3.

[0167] 2.A is

[0168] [ka] and X is N, CH, C(OH) or CF, or a salt thereof.

[0169] 3. Formula (Ia):

[0170] [ka] or a pharmaceutically acceptable salt thereof.

[0171] 4. The compound of any one of embodiments 1-3, or a salt thereof, wherein Y is CH2, CHF, CF2, or C(OH)H.

[0172] 5. The compound of embodiment 4, or a salt thereof, wherein Y is CH2.

[0173] 6. The compound or salt thereof of any one of embodiments 1 to 5, wherein m is 1.

[0174] 7. The compound of any one of embodiments 1 to 6, or a salt thereof, wherein n is 1.

[0175] 8. The compound of any one of embodiments 1 to 7, or a salt thereof, wherein p is 1.

[0176] 9.Formula (Ib):

[0177] [ka] or a salt thereof.

[0178] 10.Formula (Ic):

[0179] [ka] 10. The compound of embodiment 9, having the structure:

[0180] 11. Formula (Id):

[0181] [ka] 10. The compound of embodiment 9, having the structure:

[0182] 12. Formula (Ie):

[0183] [ka] or a pharmaceutically acceptable salt thereof.

[0184] 13.R 5 is a CO2Z bioequivalent, and

[0185] [ka] 12. The compound of any one of embodiments 1 to 11, or a salt thereof, selected from the group consisting of:

[0186] 14.R 5 But CO2C 1~7 Alkyl,

[0187] [ka] 13. The compound of any one of embodiments 1 to 12, or a salt thereof, selected from the group consisting of:

[0188] 15.R 5 15. The compound of embodiment 14, or a salt thereof, wherein is CO2CH2CH3.

[0189] 16.R 1 H, halogen, CN, OH, -N(R 6 )(R 7 ), C 1~6 Alkyl or C 1~6 16. The compound or salt thereof of any one of embodiments 1-15, wherein:

[0190] 17.R 1 17. The compound of embodiment 16, or a salt thereof, wherein is H or halogen.

[0191] 18.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 18. The compound of any one of embodiments 1-17, or a salt thereof, which is haloalkoxy.

[0192] 19.R 2 But H, halogen, C 1~6 Alkyl, C 1~6Alkoxy, C 1~6 Haloalkyl or C 1~6 The compound of embodiment 18, or a salt thereof, wherein:

[0193] 20.R 2 20. The compound of embodiment 19, or a salt thereof, wherein is H or halogen.

[0194] 21.Each R 6 and R 7 However, independently, H, C 1~6 Alkyl or C(O)-C 1~6 21. The compound of any one of embodiments 1 to 20, or a salt thereof, wherein:

[0195] 22.Each R 6 and R 7 are independently H or C 1~6 22. The compound of embodiment 21, or a salt thereof, wherein R is alkyl.

[0196] 23. At least one R 6 and R 7 are taken together with the nitrogen to which they are attached to form a 4-10 membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N and O; or a salt thereof.

[0197] 24.R 4 24. The compound or salt thereof of any one of embodiments 1-23, wherein is H or halogen.

[0198] 25.R 1 , R 2 and R 4 25. The compound or salt thereof of any one of embodiments 1 to 24, wherein at least one of is halogen.

[0199] 26.R 1 , R 2 and R 4 26. The compound or salt thereof of any one of embodiments 1 to 25, wherein at least one of is F.

[0200] 27.R3 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, R 3 0, 1, 2 or 3 R 3a 27. The compound of any one of embodiments 1-26, or a salt thereof, substituted with:

[0201] 28.R 3 But C 3~6 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocycle; R 3 0, 1, 2 or 3 R 3a 28. The compound of embodiment 27, or a salt thereof, substituted with:

[0202] 29.R 3 but,

[0203] [ka] TIFF2026502501000119.tif244163TIFF2026502501000120.tif69162 and 0, 1, 2 or 3 R 3a 27. The compound of any one of embodiments 1-26, or a salt thereof, substituted with:

[0204] 30.R 3 but,

[0205] [ka] and 0, 1, 2 or 3 R 3a 30. The compound of embodiment 29, or a salt thereof, substituted with:

[0206] 31.R 3 The compound or salt thereof of any one of embodiments 1 to 30, wherein is unsubstituted.

[0207] 32.R 3 But one or two R 3a 31. The compound of any one of embodiments 1 to 30, or a salt thereof, substituted with:

[0208] 33.R 3 But one R 3a 33. The compound of embodiment 32, or a salt thereof, substituted with:

[0209] 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, N(C 1~6 Alkyl)2, C 1~6 Alkylene-N(C 1~6 Alkyl)2, -SC 1~6 Alkyl, NHC(O)C 1~6 Alkyl, C 1~6 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 of any one of embodiments 1 to 30, 32, and 33, or a salt thereof, wherein alkylene-3 to 6 membered heterocycle.

[0210] 35. At least one R 3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2OCH3, CH2 OCH2CH3, F, CN, =O, SO2, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, CH2OCH3, CH2OCF3, SCH3, N(CH3)2, NHCOCH3, CD3,

[0211] [ka] 35. The compound of embodiment 34, wherein:

[0212] 36. At least one R 3a 36. The compound of embodiment 35, or a salt thereof, wherein is CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH, or OCHF2.

[0213] 37. A compound as listed in Table A or a pharmaceutically acceptable salt thereof.

[0214] 38. The salt of embodiment 37, wherein the salt is selected from HCl, HCl·H2O, maleate, and maleate·H2O.

[0215] 39. A pharmaceutical formulation comprising a therapeutically effective amount of the compound of any one of embodiments 1-38 or a salt thereof, and a pharmaceutically acceptable excipient.

[0216] 40. 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 of any one of embodiments 1-38 or a salt thereof.

[0217] 41. The method of embodiment 40, wherein the M4-mediated (or M4-associated) disease or disorder is 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, 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-associated psychosis, 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.

[0218] 42. The method of embodiment 41, 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]

[0219] The following examples are offered for illustrative purposes and are not intended to limit the scope of the present disclosure.

[0220] As used throughout these examples, common organic abbreviations are defined as follows:

[0221] [Table 2]

[0222] 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). 1H 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 solvents used. In addition, chiral separations were performed to separate the enantiomers of certain compounds of the present invention by supercritical fluid chromatography (SFC). In some cases, the separated enantiomers are designated as peak 1 and peak 2 according to their order of elution. Based on their potency, chirality can be expressed 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.

[0223] 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.

[0224] 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 ACN (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.

[0225] LCMC Method 2: Instrument: SHIMADZU LC20-MS2020; Mobile phase: 0.8 mL / 4 L NH₃·H₂O in water (solvent A) and ACN (solvent B), using an elution gradient of 10% to 80% (solvent B) over 6 minutes and a hold 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.

[0226] 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.

[0227] HPLC Method 1: Instrument: SHIMADZU LC20-MS2020; Mobile phase: 0.2 mL / 1 L NH₃·H₂O in water (solvent A) and ACN (solvent B), using an elution gradient of 10% to 80% (solvent B) over 6 minutes and holding 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] Ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (P1), and ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (P1A)

[0232] [ka]

[0233] 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 (1A, 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 CHCOOH (13.2 g, 221 mmol) at 25 °C. The mixture was stirred at 25 °C for 60 min, then NaBH(OAc) (235 g, 1.10 mol) was added portionwise 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 tert-butyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 7.36-7.33 (m, 5H), 5.12 (s, 2H), 3.86-3.75 (m, 2H), 3.74 - 3.67 (m, 2H), 3.53 (t, J = 4.8 Hz, 4H), 2.57 (t, J = 8.0 Hz, 1H), 2.43 (s, 4H), 2.09 (dd, J = 6.8, 12.4 Hz, 1H), 1.96-1.78 (m, 3H), 1.70 (dd, J = 9.6, 12.4 Hz, 1H), 1.60-1.49 (m, 1H), 1.43 (s, 9H).

[0234] 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 benzyl 4-(2-azaspiro[3.4]octan-6-yl)-piperazine-1-carboxylate (340 g, crude, TFA salt), which was used directly in the next step without further purification. 1 H NMR (DMSO-d6 400 MHz) δ H = 7.47-7.30 (m, 5H), 5.17-5.05(m, 2H),4.25-4.05 (m, 2H), 3.98-3.71 (m, 4H), 3.65-3.53 (m, 1H), 3.51-3.35 (m, 2H), 3.20 (d, J = 5.2 Hz, 2H), 3.09-2.86 (m, 2H), 2.35 (dd, J = 8.4, 13.6 Hz, 1H), 2.10-1.96 (m, 3H), 1.85 (dd, J = 6.0, 8.4Hz, 1H), 1.79-1.69 m, 1H).LCMS [M+H] + 330.

[0235] 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 the phases were separated. The aqueous phase was extracted with DCM (2 x 600 mL), and the combined organic phases were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give ethyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 7.41-7.27 (m, 5H), 5.12 (s, 2H), 4.08 (q, J =7.1 Hz, 2H), 3.90-3.79 (m, 2H), 3.79-3.73 (m, 2H), 3.50 (t, J = 4.8 Hz, 4H), 2.60-2.49 (m, 1H), 2.40 (s, 4H), 2.08 (dd, J = 7.2, 12.8 Hz, 1H), 1.93-1.81 (m, 3H), 1.68 (dd, J = 9.6, 12.8 Hz, 1H), 1.58-1.46 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H).

[0236] Step 4. Synthesis of ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (P1): To a solution of ethyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (800 mg, 1.99 mmol) in EtOH (10 mL) was added wet Pd / C (80 mg, 10 wt%) under a N atmosphere. The suspension was degassed under vacuum and purged with H gas several times. The mixture was stirred under H gas (40 psi) at 50 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate, which was used directly for the next step. 1 H NMR (CDCl3 400 MHz) δ H = 4.09 (q, J = 7.2 Hz, 2H), 3.90-3.70 (m, 4H), 2.98-2.82 (m, 3H), 2.65-2.35 (m, 5H), 2.12-2.05 (m, 1H), 1.95-1.75 (m, 4H), 1.73-1.62 (m, 1H), 1.55-1.46 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H).

[0237] Step 5. Synthesis of ethyl (6R)-6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C3A) and ethyl (6S)-6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C3B): 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)). *Purification by LCMS [M+H] (50 mm, 10 μm); mobile phase: [0.1% NH₃H₂O, MeOH]; B%: 20% to 20%, min) gave 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, 95.9% purity. + 402.

[0238] Step 6. Synthesis of ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (P1A): 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 ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 4.08 (q, J = 7.2 Hz, 2H), 3.92-3.71 (m, 4H), 2.88 (t, J = 5.2 Hz, 4H), 2.58-2.33 (m, 5H), 2.15-2.03 (m, 1H), 1.97-1.75 (m, 3H), 1.71-1.63 (m, 1H), 1.57-1.43 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 268.

[0239] Ethyl (6R)-6-[4-(3-bromo-5-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (P2)

[0240] [ka]

[0241] A mixture of ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (1.27 g, 4.75 mmol), 3-bromo-2,5-difluoro-pyridine (921 mg, 4.75 mmol), and DIPEA (14.0 mL, 80.2 mmol) in pyridine (10.0 mL) was degassed, purged with N gas three times, and stirred at 120 °C under N gas for 12 h. The reaction mixture was concentrated under reduced pressure to remove volatile reagents. The residue was purified by silica gel flash chromatography (eluent: 0–10% MeOH / DCM) to give ethyl (6R)-6-[4-(3-bromo-5-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS m / z [M+H] + 443.

[0242] Ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P3)

[0243] [ka]

[0244] To a mixture of 3-bromo-2-fluoro-pyridine (1.65 g, 9.35 mmol) and ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (2.50 g, 9.35 mmol) in DMA (25.0 mL) was added KCO (2.58 g, 18.7 mmol) in one portion at 20 °C. The mixture was heated to 140 °C and stirred for 12 h. The mixture was cooled to 20 °C and concentrated under reduced pressure at 50 °C. Water (50 mL) was added to the remaining residue and extracted with DCM (4 × 50 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure at 50 °C. The residue was purified by silica gel chromatography (eluent of 0-5% MeOH / DCM) to give ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.22 (dd, J = 1.6 Hz, 4.8Hz, 1H), 8.77 (dd, J = 1.6 Hz, 8.0Hz, 1H), 6.76 (dd, J = 4.8 Hz, 7.6Hz, 1H), 5.30 (s, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95-3.74 (m, 4H), 3.43-3.27 (m, 4H), 2.68-2.60 (m, 4H), 2.14 (dd, J = 7.2 Hz, 12.8Hz, 1H), 1.99-1.88 (m, 2H), 1.88-1.71 (m, 2H), 1.60-1.52 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 423, 425.

[0245] 6-(4-(3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane (P4)

[0246] [ka]

[0247] Step 1: Synthesis of 2-(2-fluoropyridin-3-yl)pyrazine (C4): To a mixture of 2-chloropyrazine (1.56 mL, 17.5 mmol), (2-fluoro-3-pyridyl)boronic acid (2.46 g, 17.5 mmol), and NaCO (5.55 g, 52.4 mmol) in 1,4-dioxane (30.0 mL) and HO (6.00 mL), Pd(dppf)Cl (1.28 g, 1.75 mmol) was added in one portion at 20 °C and degassed several times under N gas. The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), and the organic layer was washed with water (2 × 50 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0-30% EtOAc / petroleum ether) to give 2-(2-fluoro-3-pyridyl)pyrazine. LCMS [M+H] + 176.

[0248] Step 2: Synthesis of tert-butyl 6-(4-(3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C5): A solution of 2-(2-fluoro-3-pyridyl)pyrazine (3.26 g, 18.6 mmol) and tert-butyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (5.50 g, 18.6 mmol) in DIPEA (10.0 mL) was stirred at 140 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with DCM (200 mL) and washed with water (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0–10% MeOH / DCM) to give tert-butyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate, which 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%: 35%–65%, 8 min) to give tert-butyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 9.24 (s, 1H), 8.65 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.86 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 7.01 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 3.82-3.68 (m, 4H), 3.15 (s, 4H), 2.60-2.39 (m, 5H), 2.06 (dd, J = 6.8 Hz, 12.4 HZ, 1H), 1.93-1.75 (m, 3H), 1.66-1.57 (m, 1H), 1.56-1.47 (m, 1H), 1.42 (s, 9H). LCMS [M+H] + 451.

[0249] Step 3: Synthesis of tert-butyl (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C5A) and tert-butyl (6S)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C5B): tert-Butyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (2.68 g, 5.95 mmol) was purified by prep-SFC. The sample was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm x 50 mm, 10 μm); mobile phase: [0.1% NH3HO ETOH]; B%: 30% to 30%, 7 min) to give peak 1, tert-butyl (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (1.18 g, 2.61 mmol, 43.8% yield, 99.5% purity) as an off-white solid, and peak 2, tert-butyl (6S)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. Peak 1: LCMS [M+H]+ 451. Peak 2: LCMS [M+H] + 451.

[0250] Step 4: Synthesis of 6-(4-(3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane (P4): To a solution of tert-butyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (6.30 g, 14.0 mmol) in DCM (30.0 mL) was added TFA (19.6 mL, 264 mmol). The mixture was stirred at 20 °C for 5 h. The mixture was adjusted to pH = 9 with 10% aqueous NaOH solution and then diluted with DCM (50 mL). The aqueous phase was extracted with DCM (2 × 30 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The organic layer was concentrated under reduced pressure to give 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane. 1 H NMR (CDCl3 400 MHz) δ H = 9.23 (d, J = 1.2 Hz, 1H), 8.73-8.57 (m, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.39-8.27 (m, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.08- 6.92 (m, 1H), 3.72-3.38 (m, 2H), 3.21-3.00 (m, 7H), 2.45 (d, J = 2.4 Hz, 5H), 2.24-2.15 (m, 1H), 2.10-2.02 (m, 1H), 1.96-1.88 (m, 1H), 1.77-1.68 (m, 1H), 1.65-1.54 (m, 1H), 1.48-1.36 (m, 1H). LCMS [M+H] + 351.

[0251] Ethyl 6-[4-(3-hydroxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P5)

[0252] [ka]

[0253] Step 1: Synthesis of tert-butyl 4-(3-hydroxypyridin-2-yl)piperazine-1-carboxylate (C6): A mixture of 2-fluoropyridin-3-ol (2.00 g, 17.7 mmol), tert-butyl piperazine-1-carboxylate (6.59 g, 35.4 mmol), and DIPEA (9.24 mL, 53.1 mmol) was degassed and purged with N gas three times. The mixture was then heated to 140 °C and stirred at 140 °C for 16 h under an atmosphere of N gas. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0–20% EtOAc / petroleum ether) to give tert-butyl 4-(3-hydroxy-2-pyridyl)piperazine-1-carboxylate. 1 H NMR (CDCl3400 MHz) δH = 7.96 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.22 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 7.03 (dd, J =4.8 Hz, 8.0 Hz, 1H), 3.67-3.59 (m, 4H), 3.09-2.98 (m, 4H), 1.50 (s, 9H). LCMS [M+H]+ 280.

[0254] Step 2: Synthesis of 2-(piperazin-1-yl)pyridin-3-ol (C7): To a solution of tert-butyl 4-(3-hydroxy-2-pyridyl)piperazine-1-carboxylate (3.00 g, 10.7 mmol) in MeOH (10.0 mL) was added HCl / MeOH (4 M, 15.0 mL). The mixture was stirred at 20 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give crude 2-(piperazin-1-yl)pyridin-3-ol. LCMS [M+H] + 180.

[0255] Step 3: Synthesis of tert-butyl 6-(4-(3-hydroxypyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C8): To a solution of 2-piperazin-1-ylpyridin-3-ol (1.90 g, 10.6 mmol, HCl salt) in DCE (20.0 mL) was added ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (2.09 g, 10.6 mmol), NaBH(OAc) (2.70 g, 12.7 mmol), CHCOOH (318 mg, 5.30 mmol), and EtN (4.43 mL, 31.8 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was added to saturated aqueous NaHCO (20 mL) and separated. The aqueous was extracted with EtOAc (3 × 150 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel flash chromatography (eluent: 0–10% MeOH / DCM) to give tert-butyl 6-[4-(3-hydroxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3400 MHz) δH = 7.95 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.19 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 6.99 (dd, J = 3.2 Hz, 4.4 Hz, 1H), 3.89-3.80 (m, 2H), 3.79-3.74 (m, 2H), 3.13 (t, J = 4.8 Hz, 4H), 2.77-2.60 (m, 5H), 2.20-2.10 (m, 1H), 2.00-1.75 (m, 4H), 1.65-1.55 (m, 1H), 1.46 (s, 9H).LCMS [M+H]+ 389.

[0256] Step 4: Synthesis of 2-(4-(2-azaspiro[3.4]octan-6-yl)piperazin-1-yl)pyridin-3-ol (C9): To a solution of tert-butyl 6-[4-(3-hydroxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (2.00 g, 5.15 mmol) in DCM (50.0 mL) was added TFA (5.72 mL, 77.2 mmol). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give 2-[4-(2-azaspiro[3.4]octan-6-yl)piperazin-1-yl]pyridin-3-ol. LCMS [M+H] 289.

[0257] Step 5: Synthesis of ethyl 6-(4-(3-((ethoxycarbonyl)oxy)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C10): To a solution of 2-[4-(2-azaspiro[3.4]octan-6-yl)piperazin-1-yl]pyridin-3-ol (1.60 g, 5.55 mmol) in DCM (10.0 mL) was added EtN (1.68 g, 16.6 mmol) and ethyl carbonochloridate (2.80 g, 25.8 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction mixture was quenched at 0° C. by the addition of water (10 mL) and then diluted with DCM (5 mL). The mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give ethyl 6-[4-(3-ethoxycarbonyloxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] 433.

[0258] Step 6: Synthesis of ethyl 6-[4-(3-hydroxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P5): A mixture of ethyl 6-[4-(3-ethoxycarbonyloxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (2.50 g, 5.78 mmol) and NaOH (1.20 g, 30.0 mmol) in EtOH (20.0 mL) and HO (10.0 mL) was heated to 60 °C and stirred at 60 °C for 16 hours. The mixture was cooled to 25 °C and concentrated in vacuo. DCM (200 mL) was then added to the mixture, which was then filtered. The filtrate was then concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0-10% MeOH / DCM) to give ethyl 6-[4-(3-hydroxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate: LCMS [M+H]+ 361.

[0259] 2-(5-Fluoro-2-piperazin-1-yl-3-pyridyl)-1,3,4-thiadiazole (P6)

[0260] [ka]

[0261] Step 1: Synthesis of tert-butyl 4-(5-fluoro-3-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (C11): A mixture of methyl 2-chloro-5-fluoro-pyridine-3-carboxylate (1.50 g, 7.91 mmol), tert-butyl piperazine-1-carboxylate (1.77 g, 9.50 mmol), and KCO (2.19 g, 15.8 mmol) in DMF (15.0 mL) was degassed and purged with N gas several times at 25 °C. The mixture was then heated to 120 °C and stirred at 120 °C for 12 hours under an atmosphere of N gas. The mixture was poured into HO (50 mL). The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with HO (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0-7% EtOAc / petroleum ether) to give tert-butyl 4-(5-fluoro-3-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate. LCMS [M+H] + 340.

[0262] Step 2: Synthesis of tert-butyl 4-[5-fluoro-3-(hydrazinecarbonyl)-2-pyridyl]piperazine-1-carboxylate (C12): To a solution of tert-butyl 4-(5-fluoro-3-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (1.81 g, 5.33 mmol) in EtOH (18.0 mL) was added NH2NH2·HO (4.71 g, 80.0 mmol, 85.0% purity) at 25 °C. The mixture was then heated to 80 °C and stirred at 80 °C for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by trituration with EtOAc / petroleum ether (1 / 1, 15 mL) at 25 °C and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 4-[5-fluoro-3-(hydrazinecarbonyl)-2-pyridyl]piperazine-1-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 10.10 (br s, 1H), 8.25 (d, J = 2.8 Hz, 1H), 8.10 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 3.66-3.56 (m, 4H), 3.13-3.02 (m, 4H), 1.51-1.45 (m, 9H).LCMS [M+H] + 340.

[0263] Step 3: Synthesis of tert-butyl 4-[5-fluoro-3-(formamidocarbamoyl)-2-pyridyl]piperazine-1-carboxylate (C13): To a solution of tert-butyl 4-[5-fluoro-3-(hydrazinecarbonyl)-2-pyridyl]piperazine-1-carboxylate (1.30 g, 3.83 mmol) in toluene (26.0 mL) was added HCOH (1.88 g, 38.3 mmol, 98% purity) at 25 °C under a N gas atmosphere. The mixture was then heated to 50 °C and 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 × 50 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel flash chromatography (eluent of 0-35% EtOAc / petroleum ether) to give tert-butyl 4-[5-fluoro-3-(formamidocarbamoyl)-2-pyridyl]-piperazine-1-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 13.15 (br d, J = 7.2 Hz, 1H), 9.04 (br d, J = 6.4 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.29-8.11 (m, 2H), 3.76 (br s, 4H), 3.08 (br s, 4H), 1.48 (s, 9H). LCMS [M+H] + 368.

[0264] Step 4: Synthesis of tert-butyl 4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazine-1-carboxylate (C14): To a solution of tert-butyl 4-[5-fluoro-3-(formamidocarbamoyl)-2-pyridyl]piperazine-1-carboxylate (1.00 g, 2.72 mmol) in toluene (50.0 mL) was added Lawesson's reagent (1.32 g, 3.27 mmol) at 25 °C under a N gas atmosphere. The mixture was then heated to 90 °C and stirred at 90 °C for 16 hours. The mixture was added to saturated aqueous NaHCO (60 mL) and stirred for 5 minutes. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent of 0-25% EtOAc / petroleum ether) to give tert-butyl 4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazine-1-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 9.28-9.13 (m, 1H), 8.39 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 8.34 (d, J = 2.8 Hz, 1H), 3.67-3.58 (m, 4H), 3.09-2.96 (m, 4H), 1.48 (s, 9H).LCMS [M+H] + 366.

[0265] Step 5: Synthesis of 2-(5-fluoro-2-piperazin-1-yl-3-pyridyl)-1,3,4-thiadiazole (P6): To a solution of tert-butyl 4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazine-1-carboxylate (100 mg, 274 μmol) in DCM (3.00 mL) was added HCl / EtOAc (4.00 M, 2.00 mL) at 25 °C under a nitrogen atmosphere. The mixture was then stirred at 25 °C for 12 hours. The mixture was adjusted to pH = 8 with saturated aqueous NaHCO and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a solid. 2-(5-Fluoro-2-piperazin-1-yl-3-pyridyl)-1,3,4-thiadiazole was used in the next step without further purification. LCMS [M+H] + 266.

[0266] Ethyl 6-(4-(3-bromopyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (P7)

[0267] [ka]

[0268] Step 1: Synthesis of 1-(3-bromopyridin-2-yl)piperazine (C15): A mixture of 3-bromo-2-chloropyridine (1.00 g, 5.20 mmol) and piperazine (537 mg, 6.24 mmol) in DMSO (20.0 mL) was stirred at 100 °C for 16 h. The mixtures were worked up together on separate scales. The residue was poured into water (150 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0–30% EtOAc / MeOH) to give 1-(3-bromo-2-pyridyl)piperazine. 1H NMR (CDCl3 400 MHz) δ H = 8.23 ​​(dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.79 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.78 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 3.35-3.27 (m, 4H), 3.10-3.01 (m, 4H).LCMS [M+H] + 242, 244.

[0269] Step 2: Synthesis of tert-butyl 6-(4-(3-bromopyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C16): To a mixture of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (409 mg, 1.82 mmol) and 1-(3-bromo-2-pyridyl)piperazine (550 mg, 1.82 mmol) in DCE (10.0 mL) was added HOAc (0.100 mL) and NaBH(OAc) (1.16 g, 5.45 mmol) in one portion. The mixture was stirred at 20 °C for 16 h. The residue was poured into saturated aqueous NaHCO (50 mL). The aqueous phase was extracted with DCM (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0–15% MeOH / DCM) to give tert-butyl 6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.23 ​​(dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.78 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.77 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 3.89-3.83 (m, 1H), 3.83-3.78 (m, 1H), 3.77-3.71 (m, 2H), 3.39 (br s, 4H), 2.65 (br s, 5H), 2.20-2.10 (m, 1H), 1.99-1.81 (m, 3H), 1.79-1.70 (m, 1H), 1.45 (s, 9H).LCMS [M+H] + 451, 453.

[0270] Step 3: Synthesis of 6-(4-(3-bromopyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane (C17): A mixture of tert-butyl 6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (850 mg, 1.88 mmol) in 1,4-dioxane (10.0 mL) was added in one portion to HCl / 1,4-dioxane (4 M, 4.00 mL) at 20° C. for 1 h. The mixture was concentrated to provide 6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane, which was used directly for the next step.

[0271] Step 4: Synthesis of ethyl 6-(4-(3-bromopyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (P7): To a mixture of 6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (1.00 g, 2.85 mmol, HCl salt) and EtN (1.44 g, 14.2 mmol) in DCM (10.0 mL), ethyl carbonochloridate (970 mg, 8.94 mmol) was added in one portion at 0 °C under a nitrogen atmosphere. The mixture was stirred at 20 °C for 2 h. The residue was poured into water (50 mL). The aqueous phase was extracted with DCM (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0–20% MeOH / DCM) to give ethyl 6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.23 ​​(dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.78 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.77 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.16-4.10 (m, 2H), 3.94-3.89 (m, 1H), 3.88-3.83 (m, 1H), 3.83-3.77 (m, 2H), 3.38 (br s, 4H), 2.64 (br s, 5H), 2.20-2.10 (m, 1H), 1.99-1.90 (m, 2H), 1.89-1.73 (m, 2H), 1.61-1.54 (m, 1H), 1.30-1.24 (m, 3H). LCMS [M+H] + 423, 425.

[0272] 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane (P8)

[0273] [ka]

[0274] Step 1: Synthesis of tert-butyl 4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazine-1-carboxylate (C18): A mixture of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate (200 mg, 514 μmol), 2-bromo-1,3-dimethyl-benzene (114 mg, 617 μmol), Pd(t-BuP) (26.3 mg, 51.4 μmol), CsCO (502 mg, 1.54 mmol), toluene (4.50 mL), and HO (0.500 mL) was added to a sealed tube under N gas in a glove box, then heated to 80 °C and stirred at 80 °C for 16 h. The mixture was then cooled to 25° C. and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0-8% EtOAc / petroleum ether) to give tert-butyl 4-[3-(2,6-dimethylphenyl)-2-pyridyl]-piperazine-1-carboxylate. LCMS [M+H]+ 368.

[0275] Step 2: Synthesis of 1-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazine (C19): A mixture of tert-butyl 4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazine-1-carboxylate (110 mg, 299 μmol) in EtOAc (5.00 mL) was added to the mixture at 20° C., and then HCl / EtOAc (4 M, 3.00 mL) was added to the mixture. The mixture was stirred at 20° C. for 4 hours. The mixture was concentrated in vacuo and used directly in the next step without further purification. LCMS [M+H] 268.

[0276] Step 3: Synthesis of tert-butyl 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C20): A mixture of 1-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazine (90.0 mg, 296 μmol, HCl salt) and EtN (150 mg, 1.48 mmol) in DCE (5.00 mL) was stirred for 10 minutes at 20° C. Then, tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (66.7 mg, 296 μmol) was added to the mixture and stirred for 20 minutes at 20° C. AcOH (12.8 mg, 214 μmol) and NaBH(OAc) (188 mg, 889 μmol) were then added to the mixture at 20° C. and stirred for 16 h at 20° C. An aqueous solution of NaHCO (10%, 25 mL) was then added to the mixture, and the mixture was extracted with DCM (50 mL × 2) and dried over anhydrous NaSO. The combined organic phase was concentrated under vacuum. The residue was purified by silica gel flash chromatography (eluent: 0–3% MeOH / DCM) to give tert-butyl 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] 477.

[0277] Step 4: Synthesis of 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane (P8): tert-Butyl 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (95.0 mg, 199 μmol) was dissolved in DCM (5.00 mL) to give a clear solution. TFA (0.250 mL, 3.39 mmol) was then added to the mixture, which was stirred at 20° C. for 2 hours. The mixture was concentrated in vacuo and used in the next step without further purification. LCMS [M+H] 377.

[0278] Ethyl (6R)-6-[4-[3-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridyl]-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P9)

[0279] [ka]

[0280] Step 1: Synthesis of ethyl 6-[4-(3-acetyl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C21): To a solution of ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (300 mg, 1.12 mmol) in DIPEA (10.0 mL) was added 1-(2-chloro-3-pyridyl)ethanone (175 mg, 1.12 mmol) in one portion at 20 °C. The mixture was heated to 130 °C and stirred for 16 hours. The mixture was cooled to 20 °C. The mixture was added to water (20 mL) and DCM (10 mL), stirred for 5 minutes, and separated. The aqueous phase was extracted with DCM (2 × 10 mL). The combined organic phase was concentrated under reduced pressure at 50 °C. The residue was purified by silica gel flash chromatography (eluent: 0-5% MeOH / DCM) to give ethyl 6-[4-(3-acetyl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.29 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.72 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.83 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.92 - 3.74 (m, 4H), 3.42-3.30 (m, 4H), 2.70-2.45 (m, 8H), 2.15-2.10 (m, 1H), 1.98-1.80 (m, 3H), 1.77-1.69 (m, 1H), 1.55-1.53 ​​(m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 387.

[0281] Step 2: Synthesis of ethyl (6R)-6-[4-[3-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridyl]-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P9): A mixture of ethyl (6R)-6-[4-(3-acetyl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (120 mg, 310 μmol) and 1,1-dimethoxy-N,N-dimethyl-methanamine (1.20 mL, 9.03 mmol) was heated to 100° C. and stirred for 16 hours at 100° C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-8% MeOH / DCM) to give ethyl (6R)-6-[4-[3-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 442.

[0282] Ethyl 6-[4-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P10)

[0283] [ka]

[0284] Step 1: Synthesis of tert-butyl 4-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine-1-carboxylate (C22): A mixture of 2-(5-chloro-2-fluoro-3-pyridyl)pyrazine (450 mg, 2.15 mmol) and tert-butyl 2,2,3,3,5,5,6,6-octadeuteriopiperazine-1-carboxylate (417 mg, 2.15 mmol) in pyridine (10.0 mL) and DIPEA (10.0 mL) was heated to 130° C. and stirred for 12 hours at 130° C. The reaction mixture was poured into water (50 mL) at 20° C. and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0-70% EtOAc / petroleum ether) to give tert-butyl 4-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine-1-carboxylate. LCMS [M+H] + 384.

[0285] Step 2: Synthesis of 1-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine (C23): To a solution of tert-butyl 4-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine-1-carboxylate (600 mg, 1.56 mmol) in 1,4-dioxane (10.0 mL) was added HCl / EtOAc (4 M, 4.00 mL) in one portion at 20° C. The mixture was stirred at 20° C. for 1 hour. The mixture was concentrated under reduced pressure to give 1-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine. The product was used directly for the next step without further purification. LCMS [M+H] + 284.

[0286] Step 3: Synthesis of ethyl 6-[4-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P10): To a solution of 1-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine (440 mg, 1.55 mmol) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (367 mg, 1.86 mmol) in DCE (5.00 mL) was added HOAc (9.31 mg, 155 μmol) in one portion at 0 °C under N. The mixture was stirred at 0°C for 30 minutes, and then NaBH(OAc)3 (986 mg, 4.65 mmol) was added at 0°C. The mixture was warmed to 20°C and stirred at 20°C for 16 hours. The reaction mixture was poured into water (50 mL) at 20°C and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-30% MeOH in DCM) to give ethyl 6-[4-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 465.

[0287] 3-(2-fluoropyridin-3-yl)isoxazole (P11) and 3-(2-fluoropyridin-3-yl)-4-methylisoxazole (P12)

[0288] [ka]

[0289] Step 1: Synthesis of (E)-2-fluoronicotinaldehyde oxime (C24): To a solution of 2-fluoropyridine-3-carbaldehyde (1.00 g, 7.99 mmol) in MeOH (2.00 mL) was added a solution of NHOH·HCl (833 mg, 12.0 mmol) and KOAc (1.18 g, 12.0 mmol) in HO (7.00 mL). The mixture was stirred at 15 °C for 4 h. The mixture was concentrated under reduced pressure to remove MeOH. The residue was then added to saturated aqueous NaCO (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0-20% EtOAc / petroleum ether) to give (3E)-2-fluoropyridine-3-carbaldehyde oxime. LCMS [M+H] + 141.

[0290] Step 2: Synthesis of (Z)-2-fluoro-N-hydroxynicotinimidoyl chloride (C25): (3E)-2-fluoropyridine-3-carbaldehyde oxime (900 mg, 6.42 mmol) was dissolved in MeCN (15.0 mL). Then, a solution of NCS (1.03 g, 7.71 mmol) in MeCN (15.0 mL) was added dropwise slowly at 15° C. After the addition, the reaction mixture was stirred at 15° C. for 3 hours. The mixture was used in the next step without workup.

[0291] Step 3: Synthesis of 3-(2-fluoropyridin-3-yl)-5-(trimethylsilyl)isoxazole (C26): To a solution of (3Z)-2-fluoro-N-hydroxy-pyridine-3-carboximidoyl chloride (1.10 g, 6.30 mmol) and ethynyl(trimethyl)silane (1.05 mL, 7.56 mmol) in MeCN (30.0 mL), TEA (965 μL, 6.93 mmol) was added, and the reaction mixture was stirred at 15 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0–30% EtOAc / petroleum ether) to give [3-(2-fluoro-3-pyridyl)isoxazol-5-yl]-trimethyl-silane. 1 H NMR (CDCl3 400 MHz) δ H = 8.60-8.41 (m, 1H), 8.30-8.25 (m, 1H), 7.32-7.28 (m, 1H), 6.91-6.88 (m, 1H), 0.38 (m, 9H). 19 F NMR (CDCl3 400 MHz) δ F = -68.19. LCMS [M+H] + 237.

[0292] Step 4: Synthesis of 3-(2-fluoropyridin-3-yl)isoxazole (P11): To a solution of [3-(2-fluoro-3-pyridyl)isoxazol-5-yl]-trimethyl-silane (100 mg, 423 μmol) in EtOH (1.00 mL) and MeCN (3.00 mL) was added CsF (46.8 μL, 1.27 mmol). The reaction was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was diluted with DCM (30 mL) and washed with water (20 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-50% EtOAc / petroleum ether) to give 3-(2-fluoro-3-pyridyl)isoxazole. LCMS [M+H] + 165.

[0293] Step 5: Synthesis of (E)-3-methoxy-3-oxoprop-1-en-1-yl 4-nitrobenzoate (C27): 4-Nitrobenzoic acid (3.00 g, 17.9 mmol) and methyl prop-2-ynoate (1.64 mL, 19.7 mmol) were dissolved in MeCN (30.0 mL), and N-methylmorpholine (990 μL, 8.98 mmol) was added. The mixture was then stirred at 40° C. for 16 hours. The mixture was concentrated under reduced pressure to remove MeCN. The residue was stirred in MTBE (100 mL) for 30 minutes at 20° C., and the mixture was then filtered. The collected filter cake was dried under reduced pressure to give [(E)-3-methoxy-3-oxoprop-1-enyl] 4-nitrobenzoate. 1 H NMR (CDCl3 400 MHz) δ H = 8.52 (d, J = 12.8 Hz, 1H), 8.37-8.30 (m, 4H), 5.98 (d, J = 12.4 Hz, 1H), 3.80 (s, 3H).

[0294] Step 6: Synthesis of methyl 3-(2-fluoropyridin-3-yl)isoxazole-4-carboxylate (C28): To a solution of (3Z)-2-fluoro-N-hydroxy-pyridine-3-carboximidoyl chloride (1.25 g, 7.16 mmol) in MeCN was added a solution of [(E)-3-methoxy-3-oxo-prop-1-enyl]4-nitrobenzoate (1.05 mL, 7.88 mmol) in DCM (20.0 mL). Then, TEA (1.10 mL, 7.88 mmol) was added in one portion. The mixture was stirred at 15 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-30% EtOAc / petroleum ether) to give methyl 3-(2-fluoro-3-pyridyl)isoxazole-4-carboxylate. LCMS [M+H] + 223.

[0295] Step 7: Synthesis of (3-(2-fluoropyridin-3-yl)isoxazol-4-yl)methanol (C29): A solution of methyl 3-(2-fluoro-3-pyridyl)isoxazole-4-carboxylate (690 mg, 3.11 mmol) in THF (20.0 mL) was cooled to −30° C. in a dry ice bath. Then, DIBAL-H in toluene (1 M, 12.4 mL) was added dropwise, and the mixture was stirred at −30° C. for 3 h. The reaction mixture was quenched at −30° C. to 20° C. by the addition of saturated aqueous NaHCO (20 mL). The mixture was then diluted with EtOAc (20 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give [3-(2-fluoro-3-pyridyl)isoxazol-4-yl]methanol, which was used in the next step without further purification. 1 H NMR (CDCl3 400 MHz) δ H = 8.60-8.53 (m, 1H), 8.41-8.31 (m, 1H), 8.16-8.10 (m, 1H), 7.37-7.34 (m, 1H), 4.71-4.65 (m, 2H). 19 F NMR (CDCl3 400 MHz) δ F = -67.89.

[0296] Step 8: Synthesis of 4-(bromomethyl)-3-(2-fluoropyridin-3-yl)isoxazole (C30): To a solution of [3-(2-fluoro-3-pyridyl)isoxazol-4-yl]methanol (348 mg, 1.79 mmol) in DME (6.00 mL) was added PBr (1.21 g, 4.48 mmol) dropwise at 0 °C. The mixture was then stirred at 20 °C for 6 h. The mixture was cooled to 0 °C and neutralized to pH = 7.0 with saturated aqueous NaHCO solution. DCM (20 mL) and HO (10 mL) were added to the mixture, stirred, and separated. The aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-30% EtOAc / petroleum ether) to give 4-(bromomethyl)-3-(2-fluoro-3-pyridyl)isoxazole. LCMS [M+H] + 257, 259.

[0297] Step 9: Synthesis of 3-(2-fluoropyridin-3-yl)-4-methylisoxazole (P12): A mixture of 4-(bromomethyl)-3-(2-fluoro-3-pyridyl)isoxazole (100 mg, 389 μmol) and 10% wet Pd / C (50.0 mg) in MeOH (4.00 mL). The mixture was degassed and purged with H gas three times. The mixture was stirred under H gas (15 psi) at 20 °C for 5 hours. The mixture was filtered and concentrated under reduced pressure to give 3-(2-fluoro-3-pyridyl)-4-methylisoxazole, which was used in the next step without further purification. LCMS [M+H] + 179.

[0298] 2-(5-Fluoro-2-(piperidin-4-yl)pyridin-3-yl)pyrazine (P13)

[0299] [ka]

[0300] Step 1: Synthesis of tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (C31): A mixture of 2,3-dibromo-5-fluoro-pyridine (500 mg, 1.96 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (606 mg, 1.96 mmol), NaCO (415 mg, 3.92 mmol) in 1,4-dioxane (10.0 mL) and HO (2.00 mL) was added to Pd(dppf)Cl (226 mg, 196 μmol) at 20 °C. The mixture was then purged with N three times at 20 °C. The mixture was stirred at 100° C. for 16 hours under N. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-30% EtOAc / petroleum ether) to give tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.40 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 2.4 Hz, 7.6 Hz, 1H), 5.98 (br s, 1H), 4.13-4.07 (m, 2H), 3.69-3.61 (m, 2H), 2.57-2.50 (m, 2H), 1.49 (s, 9H). LCMS [M+H-56] + 304.

[0301] Step 2: Synthesis of tert-butyl 4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (C32): A mixture of tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (280 mg, 783 μmol), tributyl(pyrazin-2-yl)stannane (289 mg, 783 μmol), Pd(PPh) (90.6 mg, 78.4 μmol), and CuI (14.9 mg, 78.4 μmol) in toluene (3.00 mL) was degassed and purged with N gas three times at 20 °C. The mixture was then heated to 110 °C and stirred at 110 °C for 16 hours under a N atmosphere. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-50% EtOAc / petroleum ether) to give tert-butyl 4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate. LCMS [M+H-100] + 257.

[0302] Step 3: Synthesis of tert-butyl 4-(5-fluoro-3-(pyrazin-2-yl)pyridin-2-yl)piperidine-1-carboxylate (C33): A mixture of tert-butyl 4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (124 mg, 347 umol) and wet Pd / C (50.0 mg, 10 wt%) in EtOH (5.00 mL) was degassed and purged with H gas three times, and then the mixture was stirred under H gas (40 psi) at 50 °C for 24 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-30% EtOAc / petroleum ether) to give tert-butyl 4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)piperidine-1-carboxylate. LCMS [M+H-100] + 259.

[0303] Step 4: Synthesis of 2-(5-fluoro-2-(piperidin-4-yl)pyridin-3-yl)pyrazine (P13): A mixture of tert-butyl 4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)piperidine-1-carboxylate (90.0 mg, 251 umol) and HCl / 1,4-dioxane (5.00 ml, 4M) was stirred at 20° C. for 2 hours under N2. The mixture was concentrated under reduced pressure to give 2-[5-fluoro-2-(4-piperidyl)-3-pyridyl]pyrazine, which was used directly in the next step without further purification. LCMS [M+H] + 259.

[0304] Example 1: Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(6-methoxy-2-methyl-3-pyridyl)-2-pyridyl]-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (1)

[0305] [ka]

[0306] Step 1: Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(6-methoxy-2-methyl-3-pyridyl)-2-pyridyl]-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (1): Dissolve ethyl (6R)-6-[4-(3-bromo-5-fluoro-2-pyridyl)piperazin-1-yl]octane in 1,4-dioxane (2.00 mL) and HO (0.500 mL). A mixture of [perazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate (40.0 mg, 90.6 μmol), (6-methoxy-2-methyl-3-pyridyl)boronic acid (22.7 mg, 136 μmol), Pd(dppf)Cl (6.63 mg, 9.06 μmol), and NaCO (28.8 mg, 272 μmol) was degassed and purged with N gas three times. The mixture was stirred at 90 °C for 2 hours under a N gas atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent and give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 53%–83%, 9 min) to give ethyl (6R)-6-[4-[5-fluoro-3-(6-methoxy-2-methyl-3-pyridyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.11 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 2.8 Hz, 8.0 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 3.88-3.78 (m, 2H), 3.74 (s, 2H), 3.03 (br s, 4H), 2.49 (br s, 1H), 2.34 (s, 7H), 2.06 (br dd, J = 6.8 Hz, 12.4 Hz, 1H), 1.95-1.74 (m, 4H), 1.56-1.46 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H). 19F NMR (CDCl3 400 MHz) δ F = -138.654. ​​LCMS [M+H] + 484.

[0307] Example 2: Synthesis of ethyl 6-(4-(3-(5-cyano-2-methylpyrimidin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (2)

[0308] [ka]

[0309] Step 1: Synthesis of 4-(2-fluoro-3-pyridyl)-2-methyl-pyrimidine-5-carbonitrile (C34): To a mixture of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (435 mg, 1.95 mmol), 4-chloro-2-methyl-pyrimidine-5-carbonitrile (200 mg, 1.30 mmol), and NaCO (414 mg, 3.91 mmol) in 1,4-dioxane (4.00 mL) and HO (0.50 mL) was added Pd(PPh) (150 mg, 130 μmol) in one portion at 20 °C. The mixture was degassed under vacuum and purged with N gas several times. The mixture was heated to 90 °C and stirred at 90 °C for 16 h. The reaction mixture was cooled to 20°C and DCM (20 mL) was added. The mixture was washed with brine (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0-10% EtOAc / petroleum ether) to give 4-(2-fluoro-3-pyridyl)-2-methyl-pyrimidine-5-carbonitrile. LCMS [M+H] + 215.

[0310] Step 2: Synthesis of ethyl 6-[4-[3-(5-cyano-2-methyl-pyrimidin-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (2): To a mixture of 4-(2-fluoro-3-pyridyl)-2-methyl-pyrimidine-5-carbonitrile (130 mg, 607 μmol) and ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (194 mg, 728 μmol), DIPEA (3.00 mL) and pyridine (3.00 mL) were added in one portion at 20 °C under a nitrogen atmosphere. The mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product as a brown oil. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 26%–56%, 8 min) to give ethyl 6-[4-[3-(5-cyano-2-methyl-pyrimidin-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.91 (s, 1H), 8.43 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.75 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 7.03 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.90-3.82 (m, 2H), 3.81-3.75 (m, 2H), 3.22-3.13 (m, 4H), 2.89 (s, 3H), 2.62-2.52 (m, 1H), 2.50-2.39 (m, 4H), 2.14-2.06 (m, 1H), 1.97-1.77 (m, 3H), 1.73-1.68 (m, 1H), 1.57-1.48 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 462.

[0311] Example 3: Synthesis of ethyl (6R)-6-[4-[3-(6-methylpyrazin-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (3)

[0312] [ka]

[0313] Synthesis of ethyl (6R)-6-[4-[3-(6-methylpyrazin-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (3): A mixture of 2-(2-fluoro-3-pyridyl)-6-methyl-pyrazine (50.0 mg, 264 μmol), ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (70.7 mg, 264 μmol), DIPEA (1.00 mL), and pyridine (1.00 mL) was heated to 130° C. and stirred for 16 hours at 130° C. The reaction mixture was concentrated in vacuo to give the crude product as a brown oil. The residue was purified by prep-HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 40%–70%, 7 min) to give ethyl (6R)-6-[4-[3-(6-methylpyrazin-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 9.03 (s, 1H), 8.36 (s, 1H), 8.31 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.87 (dd, J = 2.0 Hz, 7.6 Hz, 1H), 7.00 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.90 - 3.80 (m, 2H), 3.79 - 3.74 (m, 2H), 3.16 (t, J = 4.8 Hz, 4H), 2.64 (s, 3H), 2.60 - 2.38 (m, 5H), 2.12 - 2.04 (m, 1H), 1.96 - 1.78 (m, 3H), 1.73 - 1.65 (m, 1H), 1.57 - 1.46 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 437.

[0314] Example 4: Synthesis of ethyl (6R)-6-[4-[3-(1-methylpyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (4)

[0315]

Chem.

[0316] Synthesis of ethyl (6R)-6-[4-[3-(1-methylpyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (4): Ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane in 1,4-dioxane (2.00 mL) and HO (400 μL) To a mixture of octane-2-carboxylate (50.0 mg, 118 μmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (24.6 mg, 118 μmol), PdCl(dtbpf) (7.70 mg, 11.8 μmol) and KCO (32.7 mg, 236 μmol) were added in one portion at 20° C. The mixture was then degassed under vacuum and purged with N gas several times. The reaction mixture was heated to 100° C. and stirred at 100° C. for 16 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure at 50° C. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 26%–50%, 8 min) to give ethyl (6R)-6-[4-[3-(1-methylpyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.17 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.52 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.89 (dd, J = 5.2 Hz, 7.6 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.98 - 3.94 (m, 3H), 3.92 - 3.75 (m, 4H), 3.28 - 3.02 (m, 4H), 2.74 - 2.31 (m, 5H), 2.16 - 2.08 (m, 1H), 1.98 - 1.77 (m, 3H), 1.76 - 1.66 (m, 1H), 1.58 - 1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 425.

[0317] Example 5: Synthesis of ethyl (6R)-6-[4-[3-(2-isopropyltriazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (5)

[0318]

Chem.

[0319] Step 1: Synthesis of (R)-(2-(4-(2-(ethoxycarbonyl)-2-azaspiro[3.4]octan-6-yl)piperazin-1-yl)pyridin-3-yl)boronic acid (C35): Ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in 1,4-dioxane (5.00 mL) To a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (112 mg, 472 μmol), Pd(PPh3)4 (27.3 mg, 23.6 μmol) and KOAc (46.4 mg, 472 μmol) were added in one portion at 25°C. The mixture was then degassed under vacuum and purged with N2 gas several times. The reaction mixture was heated to 100°C and stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C. The reaction mixture was used directly in the next step without further purification.

[0320] Step 2: Synthesis of ethyl (6R)-6-[4-[3-(2-isopropyltriazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (5): A mixture of [2-[4-[(6R)-2-ethoxycarbonyl-2-azaspiro[3.4]octan-6-yl]piperazin-1-yl]-3-pyridyl]boronic acid (91.7 mg, 236 μmol) in 1,4-dioxane was added to 4-bromo-2-isopropyl-triazole (49.4 mg, 260 μmol), HO (500 μL), Pd(dppf)Cl (17.3 mg, 23.62 μmol), and KCO (65.3 mg, 472 μmol) at 25 °C. The mixture was then degassed under vacuum and purged with N2 gas several times. The reaction mixture was heated to 100°C and stirred at 100°C for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25°C, added to DCM (5 mL), and filtered. The filtrate was concentrated under reduced pressure at 50°C. The residue was purified by silica gel flash chromatography (eluent: 0-10% MeOH / DCM) to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex Gemini-NX 150 × 30 mm × 5 μm; mobile phase: [water (0.05% NH3HO)-ACN]; B%: 45%–75%, 7 min) to give ethyl (6R)-6-[4-[3-(2-isopropyltriazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.26 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 8.10 (s, 1H), 7.97 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.96 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.90-4.83 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.90-3.75 (m, 4H), 3.19-3.12 (m, 4H), 2.61-2.50 (m, 5H), 2.15-2.08 (m, 1H), 1.96-1.79 (m, 3H), 1.76-1.68 (m, 1H), 1.65-1.61 (m, 6H), 1.56-1.52 (m, 1H), 1.24 (m, 3H). LCMS [M+H] + 454.

[0321] Example 6: Synthesis of 2-pyrazin-2-yl-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (6)

[0322] [ka]

[0323] Synthesis of 2-(pyrazin-2-yl)-6-(4-(3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane (6): A solution of 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (50.0 mg, 143 μmol) and 2-chloropyrazine (15.3 μL, 171 μmol) in DIPEA (2.50 mL, 14.3 mmol) and pyridine (1.25 mL, 15.5 mmol) was stirred at 100° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 150 × 30 mm × 5 μm; mobile phase: [water (0.05% NH H O)-ACN]; B%: 23%–53%, 7 min) to give 2-pyrazin-2-yl-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane. 11H NMR (CDCl3, 400 MHz) δ H = 9.25 (d, J = 1.2 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.33 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 8.04 - 7.89 (m, 1H), 7.87 (dd, J = 2.0 Hz, 3.6 Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.75 (s, 1H), 7.02 (dd, J = 5.2 Hz, 7.6 Hz, 1H), 4.00 - 3.90 (m, 4H), 3.17 (t, J = 4.0 Hz, 4H), 2.63 - 2.57 (m, 1H), 2.48 (d, J = 4.0 Hz, 4H), 2.18 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.04 - 2.00 (m, 1H), 1.96 - 1.87 (m, 2H), 1.78 (dd, J = 9.6 Hz, 12.8 Hz, 1H), 1.57 - 1.50 (m, 1H). LCMS [M+H] + 429.

[0324] Example 7: Synthesis of 2,2-difluoroethyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (7)

[0325]

Chem.

[0326] Synthesis of 2,2-difluoroethyl 6-(4-(3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (7): A solution of 2,2-difluoroethanol (719 μL, 12.2 mmol), bis(trichloromethyl)carbonate (1.22 g, 4.11 mmol), and DMF (93.8 μL, 1.22 mmol) in DCM (6.00 mL) was cooled to 0° C. EtN (1.70 mL, 12.2 mmol) was added and stirred at 20° C. for 3 hours. Then, a solution of 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (100 mg, 285 μmol) and EtN (119 μL, 856 μmol) in DCM (4.00 mL) was added. The mixture was stirred at 20° C. for 2 hours. The mixture was diluted with DCM (20 mL), washed with saturated aqueous NaCO (20 mL), brine (20 mL), then dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-CAN]; B%: 35%–65%, 7 min) to give 2,2-difluoroethyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ Hδ = 9.23 (s, 1H), 8.67 (dd, J = 2.8 Hz, 1H), 8.46 (d, J = 2.8Hz, 1H), 8.33 (dd, J =2.0 Hz, 5.2 Hz, 1H), 7.87 (dd, J = 1.6Hz, 7.6Hz, 1H), 7.02 (dd, J = 4.8 Hz, 7.2 Hz, 1H), 6.06 - 5.77 (m, 1H), 4.26 - 4.18 (m, 2H), 3.92 - 3.81 (m, 4H), 3.16 (t, J = 4.8Hz, 4H), 2.55 - 2.45 (m, 5H), 2.08 (dd, J =4.8 Hz, 7.2 Hz, 1H), 1.95 - 1.79 (m, 3H), 1.72 - 1.67 (m, 1H), 1.53 - 1.49 (m, 1H). 19 19F NMR (CDCl3 400 MHz) δ F δ = -126.01. LCMS [M+H] + 459.

[0327] Examples 8, 9, and 10: Synthesis of but-2-ynyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (8), but-2-ynyl (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (9), and but-2-ynyl (6S)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (10)

[0328]

Chem.

[0329] Step 1: Synthesis of but-2-ynyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (8): A solution of but-2-yn-1-ol (21.0 mg, 300 μmol) and CDI (48.6 mg, 300 μmol) in DCM (2.00 mL) was stirred at 20° C. for 1 hour. Then, EtN (36.4 mg, 360 μmol) and 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (105 mg, 300 μmol) in DCM (1.00 mL) were added. The mixture was then stirred at 20° C. for 16 hours. The mixture was diluted with DCM (40 mL), washed with saturated aqueous NaHCO (20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (NHH O + NHHCO)-ACN]; B%: 37%–67%, 7 min) to give but-2-ynyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 9.24 (d, J = 1.2 Hz, 1H), 8.65 (dd, J = 1.6 Hz, 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.33 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.87 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.01 (dd, J = 5.2 Hz, 7.6 Hz, 1H), 4.65-4.60 (m, 2H), 3.93-3.82 (m, 2H), 3.80 (s, 2H), 3.15 (t, J = 4.8 Hz, 4H), 2.61-2.50 (m, 1H), 2.50-2.40 (m, 3H), 2.49-2.40 (m, 1H), 2.12-2.04 (m, 1H), 1.95-1.78 (m, 6H), 1.71-1.66 (m, 1H), 1.54-1.45 (m, 1H). LCMS [M+H] + 447.

[0330] Step 2: but-2-ynyl (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (9) and but-2-ynyl (6S)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (9) Synthesis of sylate (10): But-2-ynyl 6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (500 mg, 1.12 mmol) was purified by SFC (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3HO] EtOH]; B%: 40%-40%, min) to give peak 1 but-2-ynyl (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate and peak 2 but-2-ynyl (6S)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. Peak 1: 1 H NMR (CDCl3 400 MHz) δ H = 9.23 (br s, 1H), 8.65 (br s, 1H), 8.48 (br s, 1H), 8.33 (br d, J = 5.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.05-6.97 (m, 1H), 4.62 (br s, 2H), 3.94-3.73 (m, 4H), 3.16 (br s, 4H), 2.65-2.35 (m 5H), 2.07 (br s, 1H), 1.96-1.75 (m, 6H), 1.67 (br s, 1H), 1.53-1.44 (m, 1H).LCMS [M+H] + 447. Peak 2: 1 H NMR (CDCl3 400 MHz) δ H= 9.23 (br s, 1H), 8.66 (br s, 1H), 8.48 (br s, 1H), 8.33 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.87 (dd, J = 2.0 Hz, 7.6 Hz, 1H), 7.07-6.97 (m, 1H), 4.62 (d, J = 2.8 Hz, 2H), 3.94-3.75 (m, 4H), 3.16 (br s, 4H), 2.46 (br s, 5H), 2.08 (br s, 1H), 1.99-1.74 (m, 6H), 1.68 (br s, 1H), 1.53-1.44 (m, 1H). LCMS [M+H] + 447.

[0331] Examples 11 and 12: Synthesis of (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (11) and oxetan-3-yl-[(6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octan-2-yl]methanone (12)

[0332] [ka]

[0333] Step 1: Synthesis of (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (11): To a solution of tert-butyl (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 444 μmol) in DCM (4.00 mL), TFA (1.00 mL, 13.5 mmol) was added, and the mixture was stirred at 20 °C for 2 hours. The mixture was adjusted to pH = 9 with 10% aqueous NaOH. The mixture was extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure to give (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro-[3.4]octane. 1 H NMR (CDCl3 400 MHz) δ H= 9.24 (d, J = 1.2 Hz, 1H), 8.65 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.86 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 7.00 (dd, J = 4.8 Hz, 7.2 Hz, 1H), 3.74-3.30 (m, 4H), 3.15 (d, J = 4.4 Hz, 4H), 2.46 (s, 5H), 2.07-1.69 (m, 4H), 1.61 (dd, J = 10.0, 12.4Hz, 1H), 1.50-1.36 (m, 1H). LCMS [M+H] + 351.

[0334] Step 2: Synthesis of oxetan-3-yl-[(6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octan-2-yl]methanone (12): A mixture of oxetane-3-carboxylic acid (8.74 mg, 85.6 umol), EDCI (24.62 mg, 128.40 umol), HOBt (3.47 mg, 25.7 umol) and DIPEA (45.0 uL, 257 umol) in DMF (1.00 mL) was stirred at 20 °C for 0.5 h. Then, (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (30.0 mg, 85.6 μmol) was added to the mixture, and the mixture was stirred for 16 hours at 20° C. The mixture was purified by prep-HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 13% to 43%, 9 min) to give oxetan-3-yl-[(6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octan-2-yl]methanone. 1 H NMR (CDCl3 400 MHz) δ H= 9.24 (s, 1H), 8.66 (s, 1H), 8.48 (br s, 1H), 8.33 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 4.0 Hz, 1H), 4.94 - 4.84 (m, 2H), 4.72 (dd, J = 6.4, 8.0 Hz, 2H), 3.95 - 3.73 (m, 5H), 3.16 (br s, 4H), 2.67 - 2.32 (m, 5H), 2.17 - 1.99 (m, 1H), 1.97 - 1.78 (m, 3H), 1.75 - 1.66 (m, 1H), 1.54 - 1.43 (m, 1H). LCMS [M+H] + 435.

[0335] Example 13: Synthesis of ethyl 2-[(6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octan-2-yl]oxazole (13)

[0336]

Chem.

[0337] Synthesis of ethyl 2-[(6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octan-2-yl]oxazole (13): To a solution of (6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane (96.0 mg, 274 μmol) and 2-bromooxazole (48.6 mg, 329 μmol) in 1,4-dioxane (2.00 mL) was added t-BuONa (79.0 mg, 822 μmol), XantPhos (19.0 mg, 32.8 μmol), and Pd(dba) (25.1 mg, 27.4 μmol) at 20 °C. The mixture was degassed under vacuum and purged with N2 gas several times. The mixture was then stirred at 90 °C for 16 hours. The mixture was cooled to 20 °C. The reaction mixture was filtered, and the filter cake was washed with THF (15 mL). The filtrate was then concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 25% to 55%, 25 min) to give 2-[(6R)-6-[4-(3-pyrazin-2-yl-2-pyridyl)-piperazin-1-yl]-2-azaspiro[3.4]octan-2-yl]oxazole. 1 H NMR (CDCl3 400 MHz) δ H= 9.24 (s, 1H), 8.67-8.62 (m, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.33 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.87 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.19 (s, 1H), 7.01 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 6.78 (s, 1H), 4.01-3.93 (m, 2H), 3.93-3.88 (m, 2H), 3.17 (s, 4H), 2.60-2.43 (m, 5H), 2.16 (dd, J = 6.8 Hz, 12.8 Hz, 1H), 2.02-1.95 (m, 1H), 1.92-1.84 (m, 2H), 1.74 (d, J = 10.8 Hz, 1H), 1.52 (s, 1H). LCMS [M+H] + 418.

[0338] Example 14: Synthesis of 6R)-6-[4-[3-(4-ethoxycarbonylpyrazol-1-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate (14)

[0339]

Chem.

[0340] Synthesis of ethyl (6R)-6-[4-[3-(4-ethoxycarbonylpyrazol-1-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (14): Ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in DMF (1.00 mL) To a mixture of ethyl 1H-pyrazole-4-carboxylate (50.0 mg, 118 μmol), ethyl 1H-pyrazole-4-carboxylate (24.8 mg, 177 μmol), and (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (3.36 mg, 23.6 μmol), CuI (2.25 mg, 11.8 μmol) and KPO (75.2 mg, 354 μmol) were added in one portion at 20°C. The mixture was then degassed under vacuum and purged with N gas several times. The reaction mixture was heated to 130°C and stirred at 130°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to 25°C, DCM (3.00 mL) was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure at 50°C. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH3HO)-ACN]; B%: 32%–62%, 8 min) to give ethyl (6R)-6-[4-[3-(4-ethoxycarbonylpyrazol-1-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.50 (s, 1H), 8.29 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.10 (s, 1H), 7.72 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.97 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.88 - 3.72 (m, 4H), 3.05 - 2.94 (m, 4H), 2.58 - 2.39 (m, 5H), 2.09 (dd, J = 6.8 Hz, 12.8 Hz, 1H), 1.94 - 1.77 (m, 3H), 1.68 (dd, J = 9.6 Hz, 12.8 Hz, 1H), 1.52 - 1.47 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 483.

[0341] Example 15: Synthesis of ethyl 6-[4-[3-(cyclopropoxy)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (15)

[0342]

Chem.

[0343] Synthesis of ethyl 6-[4-[3-(cyclopropoxy)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (15): A mixture of ethyl 6-[4-(3-hydroxy-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (80.0 mg, 222 µmol), bromocyclopropane (269 mg, 2.22 mmol, 178 µL), and CsCO (217 mg, 666 µmol) in DMA (3.00 mL) was heated to 130 °C and stirred at 130 °C for 14 h. The mixture was cooled to 20 °C, and DCM (20.0 mL) was added to the mixture. The mixture was filtered and concentrated in vacuo to give the crude product (100 mg). 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%: 35%–61%, 8 min). The product-containing fractions were then combined, concentrated in vacuo, and freeze-dried to give ethyl 6-[4-[3-(cyclopropoxy)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 7.88 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.83 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95-3.87 (m, 1H), 3.86-3.82 (m, 1H), 3.81-3.75 (m, 2H), 3.74-3.68 (m, 1H), 3.60-3.16 (m, 4H), 2.81-2.41 (m, 5H), 2.20-2.09 (m, 1H), 2.02-1.88 (m, 2H), 1.87-1.65 (m, 2H), 1.62-1.58 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H), 0.85-0.75 (m, 4H). LCMS [M+H] + 401.

[0344] Examples 16, 17, and 18: Synthesis of ethyl 6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (16), ethyl (6S)-6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (17), and ethyl (6R)-6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (18)

[0345] [ka]

[0346] Step 1: Synthesis of ethyl 6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (16): A mixture of 2-(5-fluoro-2-piperazin-1-yl-3-pyridyl)-1,3,4-thiadiazole (60.0 mg, 226 μmol) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (37.2 mg, 188 μmol) in DCE (2.00 mL) was stirred at 20 °C for 1 hour. Then, AcOH (5.66 mg, 94.2 μmol) and NaBH(OAc) (120 mg, 565 μmol) were added to the reaction mixture. The mixture was stirred at 20 °C for 16 hours. The mixture was poured into saturated aqueous NaHCO3 (30 mL) and stirred for 5 minutes. The mixture was extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0–3% MeOH / DCM) to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: [water (NH3H2O)-ACN]; B%: 36%–66%, 8 min) to give ethyl 6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 9.21 (s, 1H), 8.33 (br d, J = 2.0 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.97-3.82 (m, 2H), 3.79 (s, 2H), 3.11 (br s, 4H), 2.66 (br s, 5H), 2.15 (br s, 1H), 2.03-1.83 (m, 3H), 1.76 (br s, 1H), 1.64-1.58 (m, 1H), 1.24 (t, J = 6.8 Hz, 3H). 19 F NMR (CDCl3 400 MHz) δ F = -132.678. LCMS [M+H] + 447.

[0347] Step 2: Synthesis of ethyl (6S)-6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (17) and ethyl (6R)-6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (18): Ethyl 6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (150 mg, 336 μmol) was purified by SFC (column: DAICEL CHIRALCEL Purification using OD-H (250 mm x 30 mm, 5 μm); mobile phase: [0.1% NH3HO EtOH]; B%: 30%-30%, min) gave peak 1, ethyl (6S)-6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate, and peak 2, ethyl (6R)-6-[4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. Peak 1: 1 H NMR (CDCl3 400 MHz) δH = 9.21 (singlet, 1H), 8.33 (doublet, J = 2.0 Hz, 2H), 4.10 (quartet, J = 7.2 Hz, 2H), 3.93 - 3.75 (multiplet, 4H), 3.10 (singlet, 4H), 2.65 (singlet, 5H), 2.13 (broad singlet, 1H), 2.01 - 1.78 (multiplet, 3H), 1.74 (singlet, 2H), 1.24 (triplet, J = 7.2 Hz, 3H). 19 19F NMR (CDCl3, 400 MHz) δ F = -132.66. LCMS [M + H] + 447. Peak 2: 1 1H NMR (CDCl3, 400 MHz) δ H = 9.21 (singlet, 1H), 8.33 (doublet, J = 2.0 Hz, 2H), 4.10 (quartet, J = 7.2 Hz, 2H), 3.93 - 3.75 (multiplet, 4H), 3.10 (singlet, 4H), 2.65 (singlet, 5H), 2.13 (broad singlet, 1H), 2.01 - 1.78 (multiplet, 3H), 1.74 (singlet, 2H), 1.24 (triplet, J = 7.2 Hz, 3H). 19 19F NMR (CDCl3, 400 MHz) δ F = -132.66. LCMS [M + H] + 447.

[0348] Example 19: Synthesis of ethyl 6-(4-(5'-fluoro-[3,3'-bipyridin]-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (19)

[0349]

Chemical Structure

[0350] Synthesis of ethyl 6-(4-(5'-fluoro-[3,3'-bipyridin]-2-yl)piperazin-1-yl)-2-azaspiro-[3.4]octane-2-carboxylate (19): Ethyl 6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in 1,4-dioxane (4.00 mL) and HO (1.00 mL) To a mixture of hydroxylate (50.0 mg, 118 μmol), (5-fluoro-3-pyridyl)boronic acid (33.3 mg, 236 μmol), and NaCO (37.6 mg, 354 μmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (7.70 mg, 11.8 μmol) was added in one portion at 20° C. under a nitrogen atmosphere. The mixture was then degassed under vacuum and purged with N gas several times. The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated. The crude product was purified by prep-HPLC (Column: Phenomenex Gemini-NX 80 × 40 mm × um. Conditions: water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN. Start B: 26; End B: 56. Gradient time (min): 8. Retention time at 100% B (min): 3. Flow rate (ml / min): 30) to give ethyl 6-[4-[3-(5-fluoro-3-pyridyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.66 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.73 (br d, J =9.6 Hz, 1H), 7.49 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 6.99 (dd, J =4.8 Hz, 7.2 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.92-3.86 (m, 1H), 3.86-3.80 (m, 1H), 3.80-3.74 (m, 2H), 3.20-3.10 (m, 4H), 2.65-2.34 (m, 5H), 2.10 (br dd, J = 7.2 Hz, 12.4 Hz, 1H), 1.97-1.78 (m, 3H), 1.74-1.65 (m, 1H), 1.55-1.45 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 440.

[0351] Example 20: Synthesis of ethyl 6-[4-[3-(cyclobutylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (20)

[0352]

Chem.

[0353] Synthesis of ethyl 6-[4-[3-(cyclobutylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (20): Ethyl 6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (50.0 mg, 118 μg) in 1,4-dioxane (3.00 mL) A mixture of (L7, 8.93 mg, 11.8 umol), cyclobutanamine (42.0 mg, 590 umol), t-BuONa (34.1 mg, 354 umol), 2-[bis(3,5-trifluoromethylphenylphosphino)-3,6-dimethoxy]-2,6-dimethylamino-1,1-biphenyl (L7, 8.93 mg, 11.8 umol), and Pd(dba) (10.8 mg, 11.8 umol). The mixture was degassed under vacuum and purged with N gas several times. The mixture was then heated to 100 °C and stirred at 100 °C for 16 h. The mixture was cooled to 20 °C, and DCM (5 mL) was added to the mixture. 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%: 48%–72%, 8 min). The product-containing fractions were then combined, concentrated in vacuo, and freeze-dried to give ethyl 6-[4-[3-(cyclobutylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 7.70 (d, J = 0.4 Hz, 1H), 6.86 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.33 - 4.21 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95 - 3.89 (m, 1H), 3.89 - 3.82 (m, 2H), 3.82 - 3.76 (m, 2H), 3.33 - 3.29 (m, 4H), 3.28 - 2.50 (m, 4H), 2.50 - 2.35 (m, 2H), 2.21 - 2.09 (m, 1H), 1.99 - 1.90 (m, 2H), 1.90 - 1.72 (m, 6H), 1.68 - 1.60 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H). LCMS [M+H] + 414.

[0354] Example 21: Synthesis of ethyl 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (21)

[0355]

Chem.

[0356] Synthesis of ethyl 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (21): A mixture of 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane (75.0 mg, 199 μmol, TFA salt) and TEA (60.5 mg, 598 μmol) in DCM (5.00 mL) was heated at 0-5°C. Ethyl carbonochloridate (340 mg, 3.13 mmol) was then added dropwise to the mixture at 0-5°C. The mixture was then warmed to 20°C and stirred at 20°C for 5 hours. The reaction was slowly quenched with aqueous NaHCO (10%, 25 mL) and then extracted with DCM (50 mL). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by pre-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%: 53%–77%, 8 min) to give ethyl 6-[4-[3-(2,6-dimethylphenyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.26 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.23 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.08 (m, 2H), 6.87 (dd, J = 4.8 Hz, 7.2 Hz, 1H), 4.08 (q, J = 3.2 Hz, 2H), 3.87 - 3.77 (m, 2H), 3.76 - 3.69 (m, 2H), 3.18 - 3.06 (m, 4H), 2.54 - 2.33 (m, 1H), 2.31 - 2.16 (m, 4H), 2.08 (s, 6H), 2.04 - 1.99 (m, 1H), 1.91 - 1.75 (m, 3H), 1.69 - 1.61 (m, 1H), 1.53 - 1.42 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 449.

[0357] Example 22: Synthesis of ethyl (6R)-6-[4-(6-fluoro-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (22)

[0358]

Chem.

[0359] Step 1: Synthesis of ethyl (6R)-6-[4-(3-bromo-6-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C36): To a solution of 3-bromo-2,6-difluoro-pyridine (100 mg, 516 μmol) in DMSO (3.00 mL) and K2CO3 (214 mg, 1.55 mmol), ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (152 mg, 567 μmol) was added in one portion at 20 °C under a nitrogen atmosphere. The mixture was degassed and purged with N2 gas several times. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (100 mL) at 20 °C and then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0-100% EtOAc / petroleum ether) to give ethyl (6R)-6-[4-(3-bromo-6-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 441, 443.

[0360] Step 2: Synthesis of ethyl (6R)-6-[4-(6-fluoro-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (22): To a solution of ethyl (6R)-6-[4-(3-bromo-6-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 227 μmol) in toluene (3.00 mL), Pd(PPh) (26.2 mg, 22.7 μmol) and CuI (14.9 mg, 78.4 μmol) in toluene (3.00 mL) was added tributyl(pyrazin-2-yl)stannane (100 mg, 272 μmol) in one portion at 20 °C under a nitrogen atmosphere. The mixture was heated to 110°C and stirred at 110°C for 12 hours. The reaction mixture was poured into water (100 mL) at 20°C and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 45%-75%, 7 min) to give ethyl (6R)-6-[4-(6-fluoro-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ Hδ = 9.11 (d, J = 1.2 Hz, 1H), 8.76 - 8.61 (m, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 6.56 (dd, J = 3.2 Hz, 8.0 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.90 - 3.69 (m, 4H), 3.30 - 3.05 (m, 4H), 2.73 - 2.32 (m, 5H), 2.07 (dd, J = 7.2, 12.4 Hz, 1H), 1.95 - 1.76 (m, 3H), 1.67 - 1.61 (m, 1H), 1.51 (s, 1H), 1.22 (t, J = 7.2 Hz, 3H). 19 19F NMR (CDCl3, 400 MHz) δ F δ = -67.666. LCMS [M+H] + 441.

[0361] Example 23: Synthesis of ethyl (6R)-6-[4-(3-isoxazol-5-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (23)

[0362]

Chem.

[0363] Synthesis of ethyl (6R)-6-[4-(3-isoxazol-5-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (23): A mixture of ethyl (6R)-6-[4-[3-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 226 μmol) in anhydrous MeOH (2.00 mL) was cooled to 0-5°C in an ice-water bath, and then a solution of amino hydrogen sulfate (28.2 mg, 249 μmol) in anhydrous MeOH (1.00 mL) was added dropwise at 0-5°C. The mixture was then allowed to warm to 20°C and stirred at 20°C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was added to saturated aqueous NH4Cl (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue as a brown oil. The residue was purified by prep-HPLC (Column: Xtimate C18 100 × 30 mm × 3 μm; Mobile phase: [water (0.225% FA)-ACN]; B%: 5%–35%, 8 min) to give ethyl (6R)-6-[4-(3-isoxazol-5-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.41-8.30 (m, 2H), 8.02 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 7.01 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 6.81 (s, 1H), 4.12 (q, J =7.2 Hz, 2H), 3.97-3.73 (m, 4H), 3.24 (br s, 4H), 2.59 (br s, 5H), 2.16 (br dd, J = 6.8 Hz, 12.4 Hz, 1H), 2.03-1.82 (m, 3H), 1.80-1.70 (br s, 1H), 1.57-1.49 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H). LCMS [M+H] +412.

[0364] Example 24: Synthesis of ethyl (6R)-6-[4-[3-[1-(2-methoxyethyl)pyrazol-4-yl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (24)

[0365] [ka]

[0366] Step 1: Synthesis of ethyl (6R)-6-[4-[3-(1H-pyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C37): Ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane in 1,4-dioxane (5.00 mL) and water (1.00 mL) To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (300 mg, 709 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (208 mg, 709 μmol), and K2CO3 (196 mg, 1.42 mmol), Pd(dppf)Cl2 (51.9 mg, 70.9 μmol) was added in one portion under a nitrogen atmosphere. The mixture was degassed under vacuum and purged with N2 gas several times. The mixture was then stirred at 100 °C for 4 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (3 × 15 mL). The filtrate was then concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluent: 0-5% MeOH / DCM) to give ethyl (6R)-6-[4-[3-(1H-pyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 411.

[0367] Step 2: Synthesis of ethyl (6R)-6-[4-[3-[1-(2-methoxyethyl)pyrazol-4-yl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (24): A mixture of ethyl (6R)-6-[4-[3-(1H-pyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (40 mg, 97.4 μmol), 1-bromo-2-methoxyethane (16.2 mg, 117 μmol), and CsCO (63.5 mg, 195 μmol) in DMF (2.00 mL) was stirred at 85 °C for 12 h under a N gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure 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%: 27%–57%, 7 min) to give ethyl (6R)-6-[4-[3-[1-(2-methoxyethyl)pyrazol-4-yl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.16 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.55 (dd, J = 2.0, 7.6 Hz, 1H), 6.90 (dd, J = 4.8 Hz, 7.2 Hz, 1H), 4.32 (t, J = 5.2 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.91-3.81 (m, 2H), 3.80-3.75 (m, 4H), 3.36 (s, 3H), 3.17 (s, 4H), 2.54 (s, 5H), 2.11 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 1.96-1.81 (m, 3H), 1.73 (s, 1H), 1.67 (s, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 469.

[0368] Examples 25 and 26: Synthesis of ethyl (6R)-6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (25) and ethyl (6S)-6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (26)

[0369] [ka]

[0370] Step 1: Synthesis of ethyl 6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C38): To a solution of ethyl 6-[4-(5-chloro-3-pyrazin-2-yl-2-pyridyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (400 mg, 860 μmol) in 1,4-dioxane (4.00 mL) was added a solution of KOH (145 mg, 2.58 mmol) in water (4.00 mL) in one portion at 20 °C under a nitrogen atmosphere. Then, di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]-phosphane (Me4-t-BuXphos, 82.7 mg, 172 μmol) and tris(dibenzylideneacetone)palladium (39.4 mg, 43.0 μmol) were added in one portion at 20° C. The mixture was degassed and purged with N2 gas several times at 25° C. The mixture was heated to 100° C. and stirred at 100° C. for 12 hours. The reaction mixture was poured into water (20 mL) at 20° C. and then extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-20% MeOH in DCM) to give ethyl 6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 447.

[0371] Step 2: Ethyl (6R)-6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (25) and ethyl (6S)-6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (26) Synthesis of [2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (26): Ethyl 6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate was purified by SFC (column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH3HO] Purification by elution with hexane (MeOH); B%: 30%-30%, min) afforded ethyl (6R)-6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (13.3 mg, 28.2 µmol, 25.2% yield, 94.7% purity) as a yellow solid and ethyl (6S)-6-[2,2,3,3,5,5,6,6-octadeuterio-4-(5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. Peak 1: 1 H NMR (CDCl3 400 MHz) δ H= 9.40 - 9.30 (m, 1H), 8.72 - 8.56 (m, 1H), 8.48 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.65 - 7.41 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.93 - 3.59 (m, 4H), 2.60 (s, 1H), 2.09 (dd, J = 6.8 Hz, 12.4 Hz, 1H), 1.98 - 1.66 (m, 4H), 1.56 (s, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 447. Peak 2: 1 H NMR (CDCl3 400 MHz) δ H = 9.40 - 9.30 (m, 1H), 8.72 - 8.56 (m, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.65 - 7.41 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.93 - 3.59 (m, 4H), 2.60 (s, 1H), 2.09 (dd, J = 6.8 Hz, 12.4 Hz, 1H), 1.98 - 1.66 (m, 4H), 1.56 (s, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 447.

[0372] Example 27: Synthesis of (6R)-ethyl 6-(4-(3-(1-hydroxyethyl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (27)

[0373]

Chem.

[0374] Synthesis of (6R)-ethyl 6-(4-(3-(1-hydroxyethyl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (27): To a mixture of ethyl (6R)-6-[4-(3-acetyl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 259 μmol) in MeOH (5.00 mL), NaBH (11.7 mg, 310 μmol) was added and stirred at 25° C. for 16 hours. The mixture was added with additional NaBH (11.7 mg, 310 μmol) and heated to 40° C., and the reaction mixture was stirred at 40° C. for 1 hour. The mixture was added to water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm, mobile phase: [water (10 mM NHHCO)-ACN]; B%: 30%–60%, 9 min) to give ethyl (6R)-6-[4-[3-(1-hydroxyethyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 HNMR (CDCl3 400 MHz) δ H = 8.29 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.06 (dd, J = 4.8 Hz, 7.2 Hz, 1H), 5.07 (q, J = 6.8 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.93-3.82 (m, 2H), 3.82-3.76 (m, 2H), 3.30-3.04 (m, 4H), 2.67 (br s, 5H), 2.17-2.09 (m, 1H), 1.95-1.70 (m, 5H), 1.54 (d, J = 4.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 389.

[0375] Example 28: Synthesis of ethyl (6R)-6-[4-(3-amino-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate (28)

[0376] [ka]

[0377] Step 1: Synthesis of ethyl (6R)-6-[4-(3-nitro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C39): To a solution of 2-fluoro-3-nitro-pyridine (300 mg, 2.11 mmol) and ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (677 mg, 2.53 mmol) in MeCN (5.00 mL) was added KCO (875 mg, 6.33 mmol) in one portion at 20 °C under a nitrogen atmosphere. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was added to water (20 mL) at 25 °C and then extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0-20% MeOH in DCM) to give ethyl (6R)-6-[4-(3-nitro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate. LCMS [M+H] + 390.

[0378] Step 2: Synthesis of ethyl (6R)-6-[4-(3-amino-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (28): To a solution of ethyl (6R)-6-[4-(3-nitro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (500 mg, 1.28 mmol) in MeOH (10.0 mL) was added Zn (1.67 g, 25.6 mmol) and saturated aqueous NH4Cl (10.0 mL) under a nitrogen atmosphere. The mixture was stirred at 25 °C for 16 h. The residue was filtered, and the filtrate was extracted with DCM (3 × 10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a black oil (360 mg). 320 mg of the black oil was used in the next step without further purification. 40.0 mg of the black oil was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; conditions: water (10 mM NHHCO)-ACN; start B: 27; end B: 57; gradient time (min): 9; 100% B retention time (min): 1.5; flow rate (ml / min): 30; injections: 2) to give ethyl (6R)-6-[4-(3-amino-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 7.75 (br d, J = 4.4 Hz, 1H), 6.95 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.88-6.81 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.06-3.96 (m, 1H), 3.94-3.87 (m, 1H), 3.80-3.75 (m, 2H), 3.74-3.49 (m, 4H), 3.48-2.61 (m, 6H), 2.44-1.73 (m, 6H), 1.70-1.61 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H).LCMS [M+H] + 360.

[0379] Examples 29 and 30: Synthesis of ethyl (6R)-6-[4-(3-acetamido-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (29) and ethyl (6R)-6-[4-[3-(ethoxycarbonylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (30)

[0380] [ka]

[0381] Step to the left: Synthesis of ethyl (6R)-6-[4-(3-acetamido-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (29): To a solution of ethyl (6R)-6-[4-(3-amino-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (50.0 mg, 139 μmol) and TEA (42.2 mg, 417 μmol) in DCM (3.00 mL) was added CHCOCl (13.1 mg, 167 μmol) in one portion at 20 °C under a nitrogen atmosphere. The mixture was stirred at 20 °C for 16 h. The residue was poured into water (10 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 × 10 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 prep-HPLC (Phenomenex Gemini-NX 80 × 30 mm × 3 μm column; conditions: water (10 mM NHHCO)-ACN; start B: 23; end B: 53; gradient time (min): 9; 100% B retention time (min): 1.5; flow rate (ml / min): 30; injections: 3) to give ethyl (6R)-6-[4-(3-acetamido-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.53 (br d, J = 7.2 Hz, 1H), 8.10-8.02 (m, 1H), 7.94-7.56 (m, 1H), 7.07-7.00 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.00-3.83 (m, 2H), 3.82-3.74 (m, 2H), 3.65-3.05 (m, 4H), 3.04-2.28 (m, 5H), 2.23 (s, 3H), 2.20-2.11 (m, 1H), 2.08-1.67 (m, 4H), 1.66-1.60 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 402.

[0382] Step to the right: Synthesis of ethyl (6R)-6-[4-[3-(ethoxycarbonylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (30): To a solution of ethyl (6R)-6-[4-(3-amino-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (50.0 mg, 139 μmol) and TEA (42.2 mg, 417 μmol) in DCM (3.00 mL) was added ethyl carbonochloridate (0.160 g, 1.47 mmol) in one portion at 20° C. under a nitrogen atmosphere. The mixture was stirred at 20° C. for 16 hours. LCMS showed starting material remained. Therefore, additional ethyl carbonochloridate (0.530 g, 4.88 mmol) was added at 20° C. The mixture was stirred at 20° C. for an additional 4 h. The mixture was poured onto water (10 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was further purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; conditions: water (10 mM NH4HCO3)-ACN; start B: 32; end B: 62; gradient time (min): 9; 100% B retention time (min): 1.5; flow rate (ml / min): 30; injections: 3) to give ethyl (6R)-6-[4-[3-(ethoxycarbonylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.40 - 8.20 (m, 1H), 8.02 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.26 - 7.17 (m, 1H), 7.02 (dd, J = 5.2 Hz, 8.0 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.94 - 3.69 (m, 4H), 3.07 (br t, J = 4.8 Hz, 4H), 2.80 - 2.40 (m, 5H), 2.14 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 1.99 - 1.81 (m, 3H), 1.81 - 1.76 (m, 1H), 1.65 - 1.53 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 432.

[0383] Example 31: Synthesis of ethyl 6-(4-(3-(isoxazol-3-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]-octane-2-carboxylate (31)

[0384]

Chem.

[0385] Synthesis of ethyl 6-(4-(3-(isoxazol-3-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (31): A solution of ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (70.0 mg, 262 μmol) and 3-(2-fluoro-3-pyridyl)isoxazole (43.0 mg, 262 μmol) in DIPEA (500 μL) and pyridine (250 μL) was stirred at 100° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 40%–70%, 7 min) to give ethyl 6-[4-(3-isoxazol-3-yl-2-pyridyl)-piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.46 (d, J = 1.6 Hz, 1H), 8.33 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.88 (dd, J = 2.0 Hz, 7.6 Hz, 1H), 6.95 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.90-3.75 (m, 4H), 3.18 (t, J = 4.8 Hz, 4H), 2.63-2.41 (m, 5H), 2.15-2.06 (m, 1H), 1.95-1.78 (m, 3H), 1.72-1.67 (m, 1H), 1.57-1.46 (m, 1H), 1.23 (t, J = 6.8 Hz, 3H). LCMS [M+H] + 412.

[0386] Example 32: Synthesis of ethyl 6-(4-(3-(4-methylisoxazol-3-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (32)

[0387] [ka]

[0388] Synthesis of ethyl 6-(4-(3-(4-methylisoxazol-3-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (32): A solution of ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 374 μmol) and 3-(2-fluoro-3-pyridyl)-4-methyl-isoxazole (66.6 mg, 374 μmol) in DIPEA (700 μL) and pyridine (350 μL) was stirred at 100° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 32%–62%, 9 min) to give ethyl 6-[4-[3-(4-methylisoxazol-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.34 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 8.27-8.23 (m, 1H), 7.60 (dd, J = 2.0 Hz, 7.6 Hz, 1H), 6.92 (dd, J = 4.8 Hz, 7.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.90 - 3.72 (m, 4H), 3.31-3.10 (m, 4H), 2.57-2.29 (m, 5H), 2.12-2.03 (m, 1H), 2.00-1.96 (m, 3H), 1.94-1.78 (m, 3H), 1.74-1.65 (m, 1H), 1.57-1.45 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 426.

[0389] Example 33: Synthesis of ethyl (6R)-6-[4-[3-(cyclobutylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate (33)

[0390] [ka]

[0391] Synthesis of ethyl (6R)-6-[4-[3-(cyclobutylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C40): 50.0 mg of ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in 1,4-dioxane (2.50 mL) A mixture of 2-[bis(3,5-trifluoromethylphenylphosphino)-3,6-dimethoxy]-2,6-dimethylamino-1,1-biphenyl (L7, 8.93 mg, 11.8 μmol), cyclobutanamine (84.0 mg, 1.18 mmol), t-BuONa (34.1 mg, 354 μmol), 2-[bis(3,5-trifluoromethylphenylphosphino)-3,6-dimethoxy]-2,6-dimethylamino-1,1-biphenyl (L7, 8.93 mg, 11.8 μmol), and Pd(dba) (10.8 mg, 11.8 μmol). The mixture was degassed under vacuum and purged with N gas several times. The mixture was then heated to 100°C and stirred at 100°C for 10 hours. The mixture was cooled to 20°C, and DCM (20 mL) was added to the mixture, which was then filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (eluent: 0-3.2% MeOH / DCM) to give ethyl (6R)-6-[4-[3-(cyclobutylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]-octane-2-carboxylate. LCMS [M+H] + 414.

[0392] Step 2: Synthesis of ethyl (6R)-6-[4-[3-[cyclobutyl(methyl)amino]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (33): A mixture of ethyl (6R)-6-[4-[3-(cyclobutylamino)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (40.0 mg, 96.7 μmol), NaH (19.3 mg, 484 μmol, 60% purity) in DMF (0.500 mL). The mixture was degassed under vacuum and purged with N gas several times. The mixture was stirred at 0 °C for 0.5 h. Then, a solution of MeI (16.5 mg, 116 μmol) in DMF (0.500 mL) was added dropwise to the mixture. The mixture was stirred at 0 °C for 1.5 hours. HO (5 mL) was added to the mixture, filtered, and concentrated under vacuum 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% NHHO)-ACN]; B%: 50% to 80%, 8 min). The fractions were then concentrated under vacuum and freeze-dried to give ethyl (6R)-6-[4-[3-[cyclobutyl-(methyl)amino]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (MeOD 400 MHz) δ H = 7.80 (dd, J = 1.2 Hz, 4.8 Hz, 1H), 7.10 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 6.85 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.95-3.75 (m, 5H), 3.66-3.39 (m, 4H), 2.75-2.60 (m, 8H), 2.28-2.15 (m, 3H), 2.03-1.85 (m, 5H), 1.83-1.70 (m, 3H), 1.64-1.55 (m, 1H), 1.24 (t, J = 6.8 Hz, 3H). LCMS [M+H] + 428.

[0393] Examples 34 and 235: Synthesis of ethyl (6R)-6-[4-[3-(5-oxopyrrolidin-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (34) and ethyl (6R)-6-[4-[3-(1-methyl-5-oxo-pyrrolidin-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (235)

[0394] [ka]

[0395] Step 1: Synthesis of ethyl (6R)-6-[4-[3-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2-pyridyl]-piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C41): Ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane in HO (2.00 mL) and 1,4-dioxane (10.0 mL) To a mixture of ethyl (E)-2-carboxylate (500 mg, 1.18 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (320 mg, 1.42 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd-118, 76.9 mg, 118 mmol), and K2CO3 (326 mg, 2.36 mmol). The mixture was degassed under reduced pressure and purged with N2 gas several times. The reaction mixture was stirred at 85 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-5% MeOH / DCM) to give ethyl (6R)-6-[4-[3-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 443.

[0396] Step 2: Synthesis of ethyl (6R)-6-[4-[3-[3-ethoxy-1-(nitromethyl)-3-oxo-propyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C42): To a mixture of ethyl (6R)-6-[4-[3-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (300 mg, 678 mmol) in CHNO (1.50 mL, 27.8 mmol), DBU (206 mg, 1.36 mmol) was added dropwise at 0° C. The mixture was then stirred at 20° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-10% MeOH / DCM) to give ethyl (6R)-6-[4-[3-[3-ethoxy-1-(nitromethyl)-3-oxo-propyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 504.

[0397] Step 3: Synthesis of ethyl (6R)-6-[4-[3-(5-oxopyrrolidin-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (34): To a mixture of ethyl (6R)-6-[4-[3-[3-ethoxy-1-(nitromethyl)-3-oxopropyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (160 mg, 318 μmol) in EtOH (8.00 mL), 10% wet Pd / C (30 mg) was added under N gas atmosphere at 20 °C. The mixture was then degassed under reduced pressure and purged with H gas several times. The mixture was then stirred at 60 °C for 24 h under H gas pressure (50 psi). The residue was purified by silica gel flash chromatography (eluent: 0–15% MeOH / DCM) and prep-HPLC (column: Boston Prime C18 150 × 30 mm × 5 um; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 20%–50%, 7 min) to give ethyl (6R)-6-[4-[3-(5-oxopyrrolidin-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.24 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.59 (dd, J = 1.2 Hz, 7.2 Hz, 1H), 7.00 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 5.97 (s, 1H), 4.15-3.99 (m, 3H), 3.93-3.76 (m, 5H), 3.32(dd, J = 6.8 Hz, 9.6 Hz, 1H), 3.19-3.02 (m, 4H), 2.83-2.74 (m, 1H), 2.73-2.52 (m, 5H), 2.40 (dd, J = 8.0 Hz, 16.8 Hz, 1H), 2.13 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.02-1.76 (m, 4H), 1.65-1.56 (m, 1H), 1.23 (t, J = 6.8 Hz, 3H). LCMS [M+H]+ 428.

[0398] Step 4: Synthesis of ethyl (6R)-6-[4-[3-(1-methyl-5-oxo-pyrrolidin-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (235): To a mixture of ethyl (6R)-6-[4-[3-(5-oxopyrrolidin-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (50.0 mg, 117 umol) in DMF (1.50 mL), NaH (14.0 mg, 351 umol, 60% purity) was added at 0 °C and stirred under N gas for 30 min at 0 °C. CHI (16.6 mg, 117 μmol) was then added to the mixture at 0° C., and the reaction was warmed to 20° C. and stirred at 20° C. for 1 h. HO (5 mL) was then added dropwise, and the mixture was extracted with DCM (3 × 5 mL) and concentrated under reduced pressure to provide the crude material. The crude material was purified by prep-HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (NH3HO + NH4HCO3)-ACN]; B%: 30%-60%, 7 min) to give ethyl (6R)-6-[4-[3-(1-methyl-5-oxo-pyrrolidin-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.24 (dd, J = 2.0 Hz, 4.8 Hz, 1H), 7.52 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 7.00 (dd, J = 4.4 Hz, 7.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.94 - 3.76 (m, 6H), 3.30 (dd, J = 6.0 Hz, 9.6 Hz, 1H), 3.25 - 2.95 (m, 4H), 2.93 - 2.82 (m, 4H), 2.81 - 2.50 (m, 5H), 2.45 (dd, J = 6.4 Hz, 16.8 Hz, 1H), 2.21 - 2.10 (m, 1H), 1.99 - 1.64 (m, 5H), 1.24 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 442.

[0399] Example 35: Synthesis of (R)-ethyl 6-(4-(3-(1-methylpiperazin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (35)

[0400]

Chem.

[0401] Step 1: Synthesis of (R)-ethyl 6-(4-(1'-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)-piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C43): Ethyl (6R)-6-[4-(3-bromo-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in 1,4-dioxane (4.00 mL) and HO (1.00 mL) To a mixture of 1,3,2-dioxaborolan-2-yl (100 mg, 236 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (105 mg, 472 μmol), and NaCO (75.1 mg, 709 μmol), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (Pd(dtbpf)Cl, 15.4 mg, 23.6 μmol) was added in one portion at 20 °C under a N gas atmosphere. The mixture was then degassed under vacuum and purged with N gas several times. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (eluent: 0-10% MeOH / DCM) to give ethyl (6R)-6-[4-[3-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate. LCMS [M+H] + 440.

[0402] Step 2: Synthesis of (R)-ethyl 6-(4-(3-(1-methylpiperazin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (35): To a solution of ethyl (6R)-6-[4-[3-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 227 μmol) in THF (5.00 mL) was added Pd / C (wet) (10.0 mg, 10.0% purity) under an N gas atmosphere. The suspension was degassed and purged with H gas three times. The mixture was stirred under H gas (15 psi) at 20 °C for 16 h. The reaction mixture was filtered, and the filter was concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 32% to 62%, 7 min) to give ethyl (6R)-6-[4-[3-(1-methyl-4-piperidyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.17 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.51 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.94 (dd, J = 4.8 Hz, 7.2 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.94 - 3.84 (m, 2H), 3.84 - 3.78 (m, 2H), 3.12 (t, J = 4.8 Hz, 4H), 3.02 (br d, J = 11.2 Hz, 2H), 2.87 - 2.76 (m, 1H), 2.63 (br s, 5H), 2.36 (s, 3H), 2.16 (dd, J = 6.8 Hz, 12.8 Hz, 1H), 2.11 - 2.02 (m, 2H), 2.00 - 1.90 (m, 2H), 1.86 (br dd, J = 5.2 Hz, 13.6 Hz, 1H), 1.80 - 1.69 (m, 5H), 1.64 - 1.55 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 442.

[0403] Examples 36, 236, and 237: Synthesis of ethyl 6-(4-(5-fluoro-3-(pyrazin-2-yl)pyridin-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (36), ethyl (6R)-6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (236), and ethyl (6S)-6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (237)

[0404]

Chem.

[0405] Step 1: Synthesis of ethyl 6-(4-(5-fluoro-3-(pyrazin-2-yl)pyridin-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (36): A mixture of 2-[5-fluoro-2-(4-piperidyl)-3-pyridyl]pyrazine (90.0 mg, 348 µmol) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (75.6 mg, 383 µmol) in DCE (2.00 mL) was added to TEA (176 mg, 1.74 mmol), and the mixture was stirred at 20 °C for 2 h. Then, NaBH(OAc) (221 mg, 1.05 mmol) and HOAc (20.9 mg, 348 µmol) were added at 20 °C. The mixture was stirred at 20°C for 18 hours under a N2 gas atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 100 x 40 mm x 3 µm; mobile phase: [water (TFA)-ACN]; B%: 5% to 35%, 8 min) to give ethyl 6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.63 (s, 1H), 8.80-8.75 (m, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.8 Hz, 1H), 7.79 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.97-3.83 (m, 4H), 3.65 (br d, J = 12.0 Hz, 2H), 3.58-3.53 (m, 1H), 3.04-2.94 (m, 2H), 2.48-2.40 (m, 1H), 2.35-1.98 (m, 9H), 1.85-1.76 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H). 19 F NMR (CDCl3 400 MHz) δ F = -77.130, -131.279.LCMS [M+H] + 440.

[0406] Step 2: Synthesis of ethyl (6R)-6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (236) and ethyl (6S)-6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (237): Ethyl 6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 228 μmol) was purified by SFC (column: DAICEL CHIRALPAK) Purification by IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 55%-55%, 9 min) gave ethyl (6R)-6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro-[3.4]octane-2-carboxylate. Peak 1, 1 H NMR (CDCl3 400 MHz) δ H = 8.73-8.68 (m, 2H), 8.64 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), 7.42 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.94-3.78 (m, 2H), 3.78-3.72 (m, 2H), 3.15-2.98 (m, 2H), 2.92-2.75 (m, 1H), 2.67-2.41 (m, 1H), 2.17-2.02 (m, 3H), 2.00-1.65 (m, 9H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 440. and ethyl (6S)-6-[4-(5-fluoro-3-pyrazin-2-yl-2-pyridyl)-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate were obtained. Peak 2, 1 H NMR (CDCl3 400 MHz) δ H= 8.71 (s, 2H), 8.64 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 3.2 Hz, 1H), 7.48-7.35 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.94-3.79 (m, 2H), 3.76 (s, 2H), 3.31-2.71 (m, 3H), 2.70-2.42 (m, 1H), 2.30-2.05 (m, 3H), 2.03-1.64 (m, 9H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 440.

[0407] Example 37: Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(4-hydroxybut-1-ynyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (238)

[0408]

Chem.

[0409] Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(4-hydroxybut-1-ynyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (238): Ethyl (6R)-6-[4-(3-bromo-5-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in toluene (2.00 mL) and HO (1.00 mL) To a mixture of 1-azaspiro[3.4]octane-2-carboxylate (100 mg, 227 μmol), buta-3-yn-1-ol (31.8 mg, 453 μmol, 34.3 μL), CuI (4.32 mg, 22.7 μmol), and triethanolamine (45.7 mg, 453 μmol), Pd(PPh)Cl (15.9 mg, 22.7 μmol) was added at 20 °C. The mixture was then degassed under vacuum and purged with N gas several times. The reaction mixture was heated to 110 °C and stirred at 110 °C for 12 hours under N gas. The mixture was cooled to 20 °C and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: 0–10%, MeOH / DCM) and further purified by prep-HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 um; mobile phase: [water (NH3HO)-ACN]; B%: 22%–52%, 8 min) to give ethyl (6R)-6-[4-[5-fluoro-3-(4-hydroxybut-1-ynyl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.03 (d, J = 3.2 Hz, 1H), 7.35 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.92-3.76 (m, 6H), 3.50 (br s, 4H), 2.74 (t, J = LCMS [M+H] + 431.

[0410] Example 38: Synthesis of ethyl (6R)-6-[4-(3-ethynyl-5-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (239) and ethyl (6R)-6-[4-[5-fluoro-3-(1H-triazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (240)

[0411] [ka]

[0412] Step 1: Synthesis of (R)-ethyl 6-(4-(5-fluoro-3-formylpyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C44): A mixture of 2-chloro-5-fluoro-pyridine-3-carbaldehyde (1.00 g, 6.27 mmol) and KCO (866 mg, 6.27 mmol) was stirred in 1,4-dioxane (40.0 mL). Then, ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (2.18 g, 8.15 mmol) was added, and the mixture was stirred at 20 °C for 16 hours. The mixture was diluted with EtOAc (100 mL), filtered, concentrated, and purified by flash silica gel chromatography (eluent: 0-10% MeOH / DCM) to give (R)-ethyl 6-(4-(5-fluoro-3-formylpyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate. LCMS [M+H] + 391.

[0413] Step 2: Synthesis of (R)-ethyl 6-(4-(3-ethynyl-5-fluoropyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (239): A mixture of ethyl (6R)-6-[4-(5-fluoro-3-formyl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 256 μmol) and KCO (70.8 mg, 512 μmol) was stirred in MeOH (3.00 mL). Then, a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (54.1 mg, 281 μmol) in MeOH (3.00 mL) was added, and the mixture was stirred at 25 °C for 5 hours. The mixture was diluted with water (3 mL) and concentrated. Water (5 mL) was added to the resulting residue again, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by prep-HPLC (column: Waters xbridge 150 × 25 mm 10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 36%–66%, 8 min) to give ethyl (6R)-6-[4-(3-ethynyl-5-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.09 (d, J = 2.8 Hz, 1H), 7.45 (dd, J = 3.2 Hz, 8.0 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.95-3.90 (m, 1H), 3.89-3.85 (m, 1H), 3.84-3.78 (m, 2H), 3.62-3.52 (m, 4H), 3.51 (s, 1H), 2.75-2.55 (m, 5H), 2.17 (dd, J = 6.8 Hz, 12.4 Hz, 1H), 2.03-1.91 (m, 2H), 1.91-1.84 (m, 1H), 1.82-1.71 (m, 1H), 1.69-1.62 (m, 1H), 1.26 (t, J = 6.8 Hz, 3H). LCMS [M+H]+ 387.

[0414] Step 3: Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(1H-triazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (240): A mixture of ethyl (6R)-6-[4-(3-ethynyl-5-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (48.0 mg, 124 µmol), TMSN3 (71.5 mg, 621 µmol), CuSO4·5HO (3.10 mg, 12.4 µmol), and sodium ascorbate (4.92 mg, 24.8 µmol) in t-BuOH (4.00 mL) and HO (1.00 mL) was degassed and purged with N2 gas three times. The mixture was then stirred at 80 °C for 18 h under N2 gas. The mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (column: Welch Ultimate C18 150 × 25 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 6% to 36%, 10 min) to give ethyl (6R)-6-[4-[5-fluoro-3-(1H-triazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.23 ​​(br s, 1H), 8.18-8.09 (m, 1H), 7.90-7.80 (m, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.97-3.74 (m, 4H), 3.35-3.18 (m, 4H), 3.00-2.72 (m, 5H), 2.26-2.14 (m, 1H), 2.10-1.74 (m, 5H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 430.

[0415] Example 39: Synthesis of ethyl (6R)-6-[4-[3-(1,4-dimethylpyrazol-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (241) and ethyl (6R)-6-[4-[3-(2,4-dimethylpyrazol-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (242)

[0416] [ka]

[0417] Step 1: Synthesis of (R)-ethyl 6-(4-(3-propionylpyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C45): A solution of 1-(2-chloro-3-pyridyl)propan-1-one (500 mg, 2.95 mmol) in DIPEA (1.50 mL) and pyridine (0.500 mL) was mixed with ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (828 mg, 3.10 mmol) in one portion at 20 °C under N gas. The mixture was heated to 130 °C and stirred at 130 °C for 12 h. The reaction mixture was then poured into aqueous HCl (2 M, 30 mL) at 20 °C and extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by flash silica gel chromatography (eluent of MeOH in DCM 0–10%) to give ethyl (6R)-6-[4-(3-propanoyl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.27 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.63 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 6.82 (dd, J = 5.6 Hz, 7.2 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.93-3.71 (m, 4H), 3.34 (br t, J = 4.8 Hz, 4H), 2.96 (q, J = 7.2 Hz, 2H), 2.65-2.53 (m, 5H), 2.12 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.00-1.80 (m, 3H), 1.79-1.67 (m, 1H), 1.55-1.50 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 401.

[0418] Step 2: Synthesis of (R,Z)-ethyl 6-(4-(3-(3-(dimethylamino)-2-methylacryloyl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C46): A solution of ethyl (6R)-6-[4-(3-propanoyl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 250 μmol) in MeCN (2.00 mL) was mixed with 1,1-dimethoxy-N,N-dimethyl-methanamine (149 mg, 1.25 mmol) in one portion at 20 °C under N gas. The mixture was heated to 115 °C and stirred at 115 °C for 30 h. The reaction mixture was concentrated to give ethyl (6R)-6-[4-[3-[(Z)-3-(dimethylamino)-2-methyl-prop-2-enoyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. The crude product was used directly for the next step without further purification. LCMS [M+H] + 456.

[0419] Step 3: Ethyl (6R)-6-[4-[3-(1,4-dimethylpyrazol-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro-[3.4]octane-2-carboxylate (241) and ethyl (6R)-6-[4-[3-(2,4-dimethylpyrazol-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (24 Synthesis of 2): To a solution of ethyl (6R)-6-[4-[3-[(Z)-3-(dimethylamino)-2-methyl-prop-2-enoyl]-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (400 mg, 878 μmol) in MeOH (5.00 mL) was added methylhydrazine hydrate (2.77 g, 17.3 mmol) in one portion at 20° C. under N gas. The mixture was heated to 70° C. and stirred at 70° C. for 12 hours. The reaction mixture was poured into water (20.0 mL) at 25° C. and then extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (eluent: 0-10% MeOH in DCM) to give a mixture of products. The crude product was purified by SFC ([0.1% NH3HO EtOH]; B%: 30%-30%, 9 min) to give ethyl (6R)-6-[4-[3-(1,4-dimethylpyrazol-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. Peak 1, 1 H NMR (CDCl3 400 MHz) δ H= 8.31 (dd, J = 2.0, 4.8 Hz, 1H), 7.43-7.26 (m, 2H), 6.91 (dd, J=5.2, 7.6 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.96-3.51 (m, 7H), 3.13 (br s, 4H), 2.80-2.14 (m, 5H), 2.13-2.04 (m, 1H), 1.97 (s, 3H), 1.94-1.73 (m, 4H), 1.56-1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 439. and ethyl (6R)-6-[4-[3-(2,4-dimethylpyrazol-3-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate were obtained. Peak 2, 1 H NMR (CDCl3 400 MHz) δ H = 8.22 (dd, J = 2.0, 5.2 Hz, 1H), 7.52 (dd, J = 2.0, 7.2 Hz, 1H), 7.17 (s, 1H), 6.83 (dd, J = 4.8, 7.6 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.90-3.64 (m, 7H), 3.16 (t, J = 4.8 Hz, 4H), 2.54-2.30 (m, 5H), 2.10-2.02 (m, 1H), 1.97 (s, 3H), 1.96-1.94 (m, 1H), 1.90-1.80 (m, 2H), 1.72-1.60 (m, 1H), 1.56-1.44 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H). LCMS [M+H] + 439.

[0420] Example 40: Synthesis of 6(R)-(4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane hydrochloride (243)

[0421] [ka]

[0422] Step 1: Synthesis of (R)-6-(4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane hydrochloride (243): To a solution of tert-butyl (6R)-6-[4-[3-(1-methylpyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (250 mg, 552 μmol) in 2-MeTHF (2.00 mL) was added HCl / HO (6 M in HO, 0.900 mL) in one portion at 20° C. The mixture was stirred at 20° C. for 3 hours. The reaction mixture was extracted with EtOAc (3×5 mL). The aqueous phase was concentrated under reduced pressure. The residue was freeze-dried to give (6R)-6-[4-[3-(1-methylpyrazol-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane. 1 H NMR (methanol-d 4400 MHz) δ H = 8.37 (s, 1H), 8.35-8.20 (m, 2H), 8.08 (s, 1H), 7.53 (dd, J = 6.4 Hz, 7.6 Hz, 1H), 4.35-3.77 (m, 10H), 3.75-3.57 (m, 4H), 3.55-3.37 (m, 2H), 2.63 (dd, J = 8.4 Hz, 13.6 Hz, 1H), 2.40-2.21 (m, 3H), 2.12-1.92 (m, 2H). LCMS [M+H] + 353.

[0423] Example 41: Synthesis of ethyl (R)-6-(4-(6-fluoro-5-hydroxy-3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (244)

[0424] [ka]

[0425] Step 1: Synthesis of 5-bromo-6-fluoro-2-nitropyridin-3-ol (C48): Aliquots of concentrated HSO (13.0 mL) and KNO (470 mg, 4.65 mmol) were mixed in one portion at room temperature and stirred for 30 minutes. 5-Bromo-6-fluoro-pyridin-3-ol (500 mg, 2.60 mmol) was then added in one portion, and the mixture was stirred at room temperature for 16 hours. The mixture was slowly poured into cold water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 5-bromo-6-fluoro-2-nitro-pyridin-3-ol. 1 H NMR (CDCl3 400 MHz) δ H = 10.21 (s, 1H), 8.00 (d, J = 6.4 Hz, 1H).

[0426] Step 2: Synthesis of 3-(benzyloxy)-5-bromo-6-fluoro-2-nitropyridine (C49): To a solution of 5-bromo-6-fluoro-2-nitro-pyridin-3-ol (530 mg, 2.24 mmol) in DMF (5.00 mL) was added NaH (134 mg, 3.35 mmol, 60% purity) in one portion at 0 °C under N gas and stirred at 0 °C for 30 minutes. Next, BnBr (765 mg, 4.47 mmol) was added in one portion at 0 °C, and the mixture was then warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture was poured into water (30 mL) and then extracted with EtOAc (3 × 30 mL). The combined organic layers were 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 0-20% EtOAc / petroleum ether) to give 5-benzyloxy-3-bromo-2-fluoro-6-nitro-pyridine. 1 H NMR (CDCl3 400 MHz) δ H = 7.86 (d, J = 6.4 Hz, 1H), 7.48-7.31 (m, 5H), 5.25 (s, 2H). LCMS m / z [M+H]+ 327, 329.

[0427] Step 3: Synthesis of ethyl (R)-6-(4-(5-(benzyloxy)-3-bromo-6-nitropyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C50): A solution of 5-benzyloxy-3-bromo-2-fluoro-6-nitro-pyridine (500 mg, 1.53 mmol) in DMSO (20.0 mL) was mixed with ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (409 mg, 1.53 mmol) and KCO (634 mg, 4.59 mmol) in one portion. The mixture was stirred at room temperature for 12 hours. The mixture was then poured into water (30 mL), extracted with EtOAc (3 × 20 mL), and washed with brine (50 mL). The mixture was then dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-10% MeOH / DCM) to give ethyl (6R)-6-[4-(5-benzyloxy-3-bromo-6-nitro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS m / z [M+H] + 574, 576.

[0428] Step 4: Synthesis of ethyl (R)-6-(4-(5-(benzyloxy)-6-nitro-3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C51): A solution of ethyl (6R)-6-[4-(5-benzyloxy-3-bromo-6-nitro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (250 mg, 435 μmol) and tributyl(pyrazin-2-yl)stannane (193 mg, 522 μmol) in toluene (10.0 mL) was mixed in one portion with CuI (8.29 mg, 43.5 μmol) and Pd(PPh) (25.1 mg, 21.8 μmol). The mixture was degassed under vacuum, purged with N gas three times, and stirred at 110 °C for 16 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-10% MeOH / DCM) to give ethyl (6R)-6-[4-(5-benzyloxy-6-nitro-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS m / z [M+H] + 574.

[0429] Step 5: Synthesis of ethyl (R)-6-(4-(5-(benzyloxy)-6-fluoro-3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C52): To a solution of ethyl (6R)-6-[4-(5-benzyloxy-6-nitro-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (80.0 mg, 139 μmol) in DMSO (2.00 mL) was added a solution of TBAF in THF (1 M, 1.00 mL) in one portion. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2 × 20 mL), 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: 0–12% MeOH / DCM) to give ethyl (6R)-6-[4-(5-benzyloxy-6-fluoro-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS m / z [M+H] + 547.

[0430] Step 6: Synthesis of ethyl (R)-6-(4-(6-fluoro-5-hydroxy-3-(pyrazin-2-yl)pyridin-2-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (244): To a solution of ethyl (6R)-6-[4-(5-benzyloxy-6-fluoro-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (70.0 mg, 128.06 μmol) in THF (10.0 mL) was added dry Pd / C (20 mg, 10% w / w) in one portion. The mixture was degassed and purged with H gas three times. The mixture was stirred under H gas (40 psi) at 30 °C for 16 hours. The reaction mixture was filtered and concentrated to provide a residue. The residue was purified by flash silica gel chromatography (eluent: 0–10% MeOH / DCM) and further purified by prep-HPLC (column: Phenomenex C18, 80 × 40 mm × 3 um; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; gradient: 19%–49% B over 8 min) to give ethyl (6R)-6-[4-(6-fluoro-5-hydroxy-3-pyrazin-2-yl-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CD3CN 400 MHz) δ H = 9.27 (d, J = 1.6 Hz, 1H), 8.62 (dd, J = 1.6 Hz, 2.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 10.8 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 3.82-3.61 (m, 4H), 2.92 (t, J = 4.8 Hz, 4H), 2.61-2.38 (m, 5H), 2.06-2.01 (m, 1H), 1.88-1.76 (m, 3H), 1.62 (dd, J = 9.2 Hz, 12.8 Hz, 1H), 1.50-1.38 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H). 19 F NMR (CD3CN 400 MHz) δF = -89.28. LCMS m / z [M+H] + 457.

[0431] Example 42: Synthesis of ethyl (R)-6-(4-fluoro-4-(5-fluoro-3-(pyrazin-2-yl)pyridin-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (245) and ethyl (S)-6-(4-fluoro-4-(5-fluoro-3-(pyrazin-2-yl)pyridin-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (246)

[0432] [ka]

[0433] Step 1: Synthesis of tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-4-hydroxy-piperidine-1-carboxylate (C53): A mixture of 2,3-dibromo-5-fluoro-pyridine (3.50 g, 13.7 mmol) in DCM (35.0 mL) was mixed with n-BuLi in n-hexane (2.5 M, 6.09 mL) at −70° C. under N gas and stirred at −70° C. for 10 minutes. Then, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.19 g, 11.0 mmol) in DCM (20.0 mL) was added dropwise to the mixture at −70° C., and the mixture was stirred at −70° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: 0-13% EtOAc / petroleum ether) to give tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-4-hydroxy-piperidine-1-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.39 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 2.4 Hz, 7.2 Hz, 1H), 4.21-3.97 (m, 2H), 3.45-3.15 (m, 2H), 2.85-2.73 (m, 2H), 1.49 (s, 9H), 1.45-1.36 (m, 2H). LCMS m / z [M+H-100] + 275, 277.

[0434] Step 2: Synthesis of tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-4-fluoro-piperidine-1-carboxylate (C54): A mixture of tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-4-hydroxy-piperidine-1-carboxylate (700 mg, 1.87 mmol) in DCM (7.00 mL) was mixed with DAST (756 mg, 4.69 mmol) at 0 ° C. and stirred at 25 ° C. for 12 hours. The mixture was added to saturated aqueous NaHCO (50 mL) and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: 0-7% EtOAc / petroleum ether) to give tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-4-fluoro-piperidine-1-carboxylate. LCMS m / z [M+H-56] + 321, 323.

[0435] Step 3: Synthesis of tert-butyl 4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-piperidine-1-carboxylate (C55): A mixture of tert-butyl 4-(3-bromo-5-fluoro-2-pyridyl)-4-fluoro-piperidine-1-carboxylate (340 mg, 901 μmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (225 mg, 1.08 mmol) in 1,4-dioxane (5.00 mL) and HO (0.700 mL) was mixed with Pd(dppf)Cl (66.0 mg, 90.1 μmol) and NaCO (191 mg, 1.80 mmol). The mixture was degassed under vacuum, purged with N gas three times, and stirred for 12 h at 100° C. The mixture was concentrated and purified by flash silica gel chromatography (eluent: 0–49% EtOAc / petroleum ether) to give tert-butyl 4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]piperidine-1-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H = 8.33 (d, J = 2.8 Hz, 1H), 7.56-7.54 (m, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.30 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 4.02-3.86 (m, 5H), 3.34-3.04 (m, 2H), 2.11-2.00 (m, 4H), 1.45 (s, 9H). 19 F NMR (CDCl3 400 MHz) δ F = -129.12, -150.16. LCMS m / z [M+H-56] + 323.

[0436] Step 4: Synthesis of 5-fluoro-2-(4-fluoro-4-piperidyl)-3-(1-methylpyrazol-4-yl)pyridine (C56): A mixture of tert-butyl 4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]piperidine-1-carboxylate (390 mg, 1.03 mmol) in EtOAc (1.00 mL) was mixed with HCl / EtOAc (4 M, 5.00 mL) and stirred at 20 ° C. for 1 hour. The mixture was concentrated to give 5-fluoro-2-(4-fluoro-4-piperidyl)-3-(1-methylpyrazol-4-yl)pyridine, which was used in the next step without purification. LCMS m / z [M + H] + 279.

[0437] Step 5: Synthesis of tert-butyl 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (C57): A mixture of 5-fluoro-2-(4-fluoro-4-piperidyl)-3-(1-methylpyrazol-4-yl)pyridine (324 mg, 1.03 mmol, HCl) in DCE (10.0 mL) was mixed with TEA (521 mg, 5.15 mmol) and tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (255 mg, 1.13 mmol). The mixture was stirred at 25 °C for 1 h, then NaBH(OAc) (654.48 mg, 3.09 mmol) and AcOH (30.9 mg, 515 μmol) were added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was mixed with saturated aqueous NaHCO (50 mL) and extracted with DCM (3 × 10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to provide a residue. The residue was purified by flash silica gel chromatography (eluent: 0–5% MeOH / DCM) to give tert-butyl 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate.1 H NMR (CDCl3 400 MHz) δ H = 8.33 (d, J = 2.8 Hz, 1H), 7.57-7.49 (m, 2H), 7.29 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 3.96 (s, 3H), 3.85-3.68 (m, 4H), 2.84-2.72 (m, LCMS m / z [M+H] + 488.

[0438] Step 6: Synthesis of 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane (C58): A mixture of tert-butyl 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 410 μmol) in DCM (2.00 mL) was mixed with TFA (614 mg, 5.38 mmol) and stirred at 20 ° C. for 12 hours. The mixture was concentrated to provide 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane, which was used for the next step without further purification. LCMS m / z [M+H] + 388.

[0439] Step 7: Synthesis of ethyl 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (C59): A mixture of 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane (205 mg, 409 μmol, TFA), TEA (124 mg, 1.23 mmol) in DCM (3.00 mL) was mixed with ethyl carbonochloridate (160 mg, 1.47 mmol) and added dropwise at 0° C. The mixture was then warmed to 20° C. and stirred at 20° C. for 4 hours. The reaction was slowly quenched with saturated aqueous NaHCO3 (10 mL) and then extracted with DCM (3 x 5 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (eluent: 0-7% MeOH / DCM) to give ethyl 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS m / z [M+H] + 460.

[0440] Step 8: Synthesis of ethyl (6R)-6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (245) and ethyl (6S)-6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (246): Ethyl 6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate was purified by SFC (column: DAICEL CHIRALPAK) Purification by AD (250 mm x 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3HO)]; B%: 20%, isocratic elution mode) gave ethyl (6R)-6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate. Peak 1: 1 H NMR (CDCl3 400 MHz) δ H = 8.32 (d, J = 2.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.29 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.91-3.72 (m, 4H), 2.92-2.73 (m, 2H), 2.69-2.55 (m, 1H), 2.47-2.01 (m, 7H), 1.98-1.67 (m, 4H), 1.64-1.48 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H). 19 F NMR (CDCl3 400 MHz) δ F = -75.75, -129.31.LCMS m / z [M+H] +460. and ethyl (6S)-6-[4-fluoro-4-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate. Peak 2: 1 H NMR (CDCl3 400 MHz) δ H = 8.32 (d, J = 2.8 Hz, 1H), 7.59-7.48 (m, 2H), 7.29 (dd, J = 2.8 Hz , 9.2 Hz, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.96 (s, 3H), 3.91-3.72 (m, 4H), 2.86-2.72 (m, 2H), 2.66-2.54 (m, 1H), 2.42-2.02 (m, 7H), 1.96-1.72 (m, 1H), 1.96-1.72 (m, 3H), 1.60-1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). 19 F NMR (CDCl3 400 MHz) δ F = -75.76, -129.40.LCMS m / z [M+H] + 460.

[0441] Example 43: Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(4-fluorotetrahydropyran-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (247)

[0442] [ka]

[0443] Step 1: Synthesis of ethyl (6R)-6-[4-[3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C60): Ethyl (6R)-6-[4-(3-bromo-5-fluoro-2-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in 1,4-dioxane (8.00 mL) and HO (2.00 mL). A mixture of 2-azaspiro[3.4]octane-2-carboxylate (230 mg, 521 μmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (132 mg, 628 μmol), CsCO (340 mg, 1.04 mmol), and Pd(dppf)Cl (77.0 mg, 105 μmol) was degassed and purged with N gas three times. The mixture was then stirred under N gas at 100° C. for 3 hours. The mixture was concentrated to provide a residue. The residue was purified by flash silica gel chromatography (eluent: 0–10% MeOH / DCM) to give ethyl (6R)-6-[4-[3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (DMSO-d 6400 MHz) δ H = 8.11 (d, J = 3.2 Hz, 1H), 7.39 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 6.03 (br s, 1H), 4.21 (br d, J = 2.4 Hz, 2H), 3.98 (q, J = 7.2 Hz, 2H), 3.81-3.77 (m, 2H), 3.77-3.63 (m, 4H), 3.10 (br s, 4H), 2.48-2.43 (m, 7H), 2.08-2.00 (m, 1H), 1.83-1.72 (m, 3H), 1.66-1.59 (m, 1H), 1.48-1.40 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 445.

[0444] Step 2: Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(4-hydroxytetrahydropyran-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C61): Ethyl (6R)-6-[4-[3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate in i-PrOH (10.0 mL) To a mixture of [(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese (40.8 mg, 67.4 μmol), tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese (100 mg, 224 μmol), phenylsilane (97.3 mg, 899 μmol) in DCE (4.00 mL) was added at 0° C. The mixture was then stirred at room temperature under O gas (15 psi) for 16 hours. The mixture was concentrated to provide a residue. The residue was purified by flash silica gel chromatography (eluent: 0-8% MeOH / DCM) to give ethyl (6R)-6-[4-[5-fluoro-3-(4-hydroxytetrahydropyran-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. LCMS m / z [M+H] + 463.

[0445] Step 3: Synthesis of ethyl (6R)-6-[4-[5-fluoro-3-(4-fluorotetrahydropyran-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (247): A mixture of ethyl (6R)-6-[4-[5-fluoro-3-(4-hydroxytetrahydropyran-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (95.0 mg, 205 μmol) in DCM (10.0 mL) was degassed and purged with N gas three times. Then, DAST (170 mg, 1.06 mmol) in DCM (3.00 mL) was added dropwise to the mixture at 0 ° C., and the mixture was stirred under N gas for 2 hours at 0 ° C. The pH was adjusted to 7-8 with saturated aqueous NaHCO, and the organic layer was then washed with HO (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated to provide a residue. The residue was purified by prep-HPLC (column: Waters Xbridge, 150 × 25 mm × 5 um; mobile phase: [water (NHHO)-ACN]; gradient: 36% to 66% B over 10 min) and lyophilized to give ethyl (6R)-6-[4-[5-fluoro-3-(4-fluorotetrahydropyran-4-yl)-2-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate. 1 H NMR (CDCl3 400 MHz) δ H= 8.24 (d, J = 2.8 Hz, 1H), 7.62 (dd, J = 2.8 Hz, 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.96-3.91 (m, 2H), 3.91-3.87 (m, 2H), 3.87-3.82 (m, 2H), 3.80 (s, 2H), 2.96 (br s, 4H), 2.81-2.70 (m, 1H), 2.68-2.63 (m, 2H), 2.62-2.54 (m, 2H), 2.18-2.07 (m, 2H), 1.98-1.89 (m, 2H), 1.88-1.79 (m, 2H), 1.79-1.72 (m, 2H), 1.71-1.51 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 465.

[0446] Examples 37-234 were synthesized using the methodology described above for Examples 1-36 and similar starting materials as listed in Table 1. Table 1 also lists the specific methods used, as well as characterization data for these examples. Peak 1 or Peak 2 indicates the order of elution on chiral HPLC / SFC.

[0447] [Table 3] TIFF2026502501000173.tif220161TIFF2026502501000174.tif228161TIFF2026502501000175.tif222161TIFF2026502501000176.tif217161TIFF2026502501000177.tif222161TIFF2026502501000178.tif212161TIFF2026502501000179.tif221161TIFF2026502501000180.tif221161TIFF2026502501000181.tif221161TIFF2026502501000182.tif226161TIFF2026502501000183.tif226161TIFF2026502501000184.tif221161TIFF2026502501000185.tif221161TIFF2026502501000186.tif231161TIFF2026502501000187.tif231161TIFF2026502501000188.tif217161TIFF2026502501000189.tif212161TIFF2026502501000190.tif231161TIFF2026502501000191.tif227161TIFF2026502501000192.tif231161TIFF2026502501000193.tif228161TIFF2026502501000194.tif226161TIFF2026502501000195.tif232161TIFF2026502501000196.tif218161TIFF2026502501000197.tif222161TIFF2026502501000198.tif218161TIFF2026502501000199.tif222161TIFF2026502501000200.tif222161TIFF2026502501000201.tif225161TIFF2026502501000202.tif218161TIFF2026502501000203.tif224161TIFF2026502501000204.tif219161TIFF2026502501000205.tif222161TIFF2026502501000206.tif217161TIFF2026502501000207.tif218161TIFF2026 502501000208.tif226161TIFF2026502501000209.tif221161TIFF2026502501000210.tif21 7161TIFF2026502501000211.tif231161TIFF2026502501000212.tif222161TIFF202650250 1000213.tif231161TIFF2026502501000214.tif217161TIFF2026502501000215.tif232161.

[0448] 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.

[0449] 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.

[0450] [Table 4] TIFF2026502501000217.tif228161TIFF2026502501000218.tif228161TIFF2026502501000219.tif22816 1TIFF2026502501000220.tif228161TIFF2026502501000221.tif228161TIFF2026502501000222.tif22816 1TIFF2026502501000223.tif228161TIFF2026502501000224.tif228161TIFF2026502501000225.tif22816 1TIFF2026502501000226.tif228161TIFF2026502501000227.tif228161TIFF2026502501000228.tif70161

Claims

1. Formula (I): 【Chemistry 1】 or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or said N-oxide. (In the formula, A is a 6- to 8-membered heterocycle containing 1 or 2 ring nitrogen atoms and 0, 1, 2, or 3 R Ａ is substituted with; Each R Ａ are independently １～３ Alkyl, halogen, ═O, OH, C １～３ Hydroxyalkyl or C １～３ haloalkyl; Y is a bond, S, O, 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, NO ２ , -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 substituted with 0, 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 a halogen, C ０～６ Alkylene -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, C １～６ Alkylene -O-C １～６ Alkyl, C １～６ Alkylene-NHC(O)C １～６ Alkyl, C １～６ Alkylene-C(O)NHC １～６ Alkyl, C ０～６ Alkylene-Cyc, O—C ０～６ Alkylene-Cyc, NH-Cyc, N(C １～６ alkyl)-Cyc or C(O)Cyc; Cyc is C ３～１２ Cycloalkyl, C ３～６ Heterocycloalkyl, C ５～１２ Spirocycloalkyl, C ５～１２ Heterospirocycloalkyl, C ６～１０ aryl, a 4- to 12-membered heterocycle, or a 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl contains 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; and Cyc is 0, 1, 2, or 3 R ３ａ is substituted with a substituent; Each R ３ａ is halogen, CN, OH, =O, =N(C １～６ 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 -C(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-CO ２ C １～６ Alkyl, C ０～６ Alkylene-C ３～６ cycloalkyl 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, OH, C １～６ Alkyl, C １～６ -haloalkyl or C １～６ is alkoxy; 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 substituted with 0, 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 0, 1, 2 or 3 C １～６ Alkoxy or C ３～６ substituted with cycloalkyl; However, R １ and R ４ are each H, m and p are each 1, and A is 【Chemistry 2】 and (a) R ２ is H and Y is CH ２ where n is 1 and R ３ But CH ３ , OCH ３ , 【Transformation 3】 is, or (b) R ２ is F and Y is CH ２ where n is 1 and R ３ but, 【Chemistry 4】 is, or (c) R ２ is H, Y is a bond, n is 1, and R ３ but, 【Transformation 5】 is, or (d) R ２ is H, Y is a bond, n is 2, and R ３ but, 【Transformation 6】 If R ５ is CO ２ CH ２ CH ３ or CO ２ CH (CH ３ ) ３ provided that it is not.)

2. A is, 【Transformation 7】 and X is N, CH, C(OH) or CF, or a salt thereof.

3. Formula (Ia): 【Transformation 8】 3. The compound of claim 2 having the structure: or a pharmaceutically acceptable salt thereof.

4. Y is CH ２ , CHF, CF ２ or C(OH)H, or a salt thereof.

5. Y is CH ２ The compound or salt thereof according to claim 4, wherein:

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

7. The compound or salt thereof according to any one of claims 1 to 6, wherein n is 1.

8. The compound or salt thereof according to any one of claims 1 to 7, wherein p is 1.

9. Formula (Ib): 【Chemistry 9】 The compound according to claim 1 or a salt thereof, having the structure:

10. Formula (Ic): 【Chemistry 10】 The compound according to claim 9, having the structure:

11. Formula (Id): 【Chemistry 11】 The compound according to claim 9, having the structure:

12. Formula (Ie): 【Chemistry 12】 2. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt thereof.

13. R ５ CO ２ Z bioisosteres, and 【Chemistry 13】 The compound or salt thereof according to any one of claims 1 to 11, selected from the group consisting of:

14. R ５ But CO ２ C １～７ Alkyl, 【Chemistry 14】 The compound or salt thereof according to any one of claims 1 to 12, selected from the group consisting of:

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

16. R １ H, halogen, CN, OH, -N(R ６ ) (R ７ ), C １～６ Alkyl or C １～６ The compound or salt thereof according to any one of claims 1 to 15, which is alkoxy.

17. R １ The compound or salt thereof according to claim 16, wherein is H or a halogen.

18. 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 thereof according to any one of claims 1 to 17, which is haloalkoxy.

19. R ２ H, halogen, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl or C １～６ 19. The compound or salt thereof of claim 18, which is haloalkoxy.

20. R ２ The compound or salt thereof according to claim 19, wherein is H or a halogen.

21. Each R ６ and R ７ However, independently, H, C １～６ Alkyl or C(O)-C １～６ The compound or salt thereof according to any one of claims 1 to 20, which is alkyl.

22. Each R ６ and R ７ are independently H or C １～６ 22. The compound or salt thereof according to claim 21, wherein the compound is alkyl.

23. At least one R ６ and R ７ and R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocycle containing 0 to 2 additional ring heteroatoms independently selected from N and O, or a salt thereof.

24. R ４ The compound or salt thereof according to any one of claims 1 to 23, wherein is H or halogen.

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

26. R １ , R ２ and R ４ The compound or salt thereof 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, R ３ is 0, 1, 2 or 3 R ３ａ The compound or salt thereof according to any one of claims 1 to 26, substituted with

28. R ３ But C ３～６ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocycle; R ３ is 0, 1, 2 or 3 R ３ａ 28. The compound of claim 27, or a salt thereof, substituted with:

29. R ３ but, 【Chemistry 15】 【change】 and 0, 1, 2 or 3 R ３ａ The compound or salt thereof according to any one of claims 1 to 26, substituted with

30. R ３ but, 【Chemistry 16】 and 0, 1, 2 or 3 R ３ａ 30. The compound of claim 29, or a salt thereof, substituted with:

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

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

33. R ３ But one R ３ａ 33. The compound of claim 32, or a salt thereof, 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, N(C １～６ alkyl) ２ , C １～６ Alkylene-N(C １～６ alkyl) ２ , -S-C １～６ Alkyl, NHC(O)C １～６ Alkyl, C １～６ 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 thereof according to any one of claims 1 to 30, 32 and 33, which is an 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 ,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 、N(CH ３ ) ２ ,NHCH ３ 、CD ３ 、 【Chemistry 17】 35. The compound according to claim 34, or a salt thereof, 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 thereof according to claim 35, wherein:

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

38. The salt may be an HCl salt, an HCl salt.H ２ O, maleate, and maleate·H ２ 38. The salt of claim 37, wherein the salt is selected from:

39. A pharmaceutical formulation comprising a therapeutically effective amount of a compound according to any one of claims 1 to 38 or a salt thereof, and a pharmaceutically acceptable excipient.

40. 40. 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 of any one of claims 1 to 38, or a salt thereof.

41. 41. The method of claim 40, wherein the M4-mediated (or M4-associated) disease or disorder is 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, 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-associated psychosis, 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.

42. 42. The method of claim 41, 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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