M4 activators / modulators and uses thereof

Abstract

The present disclosure provides compounds of Formula I: (I) or an N-oxide thereof or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein: A, Y, m, n, p, R1, R2, R3, R3a, R4, R5, R6, R7 and Z are as described herein; the present disclosure provides processes for preparing such compounds, N-oxides, or salts; intermediates useful for the preparation of such compounds, N-oxides, or salts; the present invention relates to compounds, N-oxides, or salts, and compositions containing such compounds, N-oxides, or salts, and their use for the treatment of M4-mediated (or M4-related) disorders, including, for example, Alzheimer's disease, Parkinson's disease, schizophrenia (e.g., their cognitive and negative symptoms), pain, addiction, and sleep disorders.

Description

Technical Field

[0001] The present disclosure generally relates to novel pyridine azaspiro compounds which are agonists / activators / modulators of the muscarinic M4 receptor and can be used for treating M4-mediated diseases and disorders, but not limited to schizophrenia, Alzheimer's disease, dementia-related psychosis, dementia with Lewy Bodies, Parkinson's disease, and related memory and executive function disorders, bipolar disorder, agitation, and related psychosis. Background Art

[0002] Patients suffering from schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's Disease, depression, and various other neurological / neurodegenerative diseases often suffer from behavioral and cognitive impairments, leading to debilitating disruptions to their daily lives. For many years, numerous pharmacological treatments have been discovered that provide some improvement in behavioral and cognitive function. However, the improvements are at best modest, and typically, the potential dose-limiting side effects associated with these treatments (including extrapyramidal side effects and metabolic side effects) result in partial responsiveness and non-compliance.

[0003] Muscarinic acetylcholine receptors (mAChRs) are a viable mechanism for treating such diseases. Five mAChR subtypes (M1-M5) have been identified, which are part of the G protein-coupled receptor (GPCR) superfamily. These subtypes are widely distributed in the peripheral and central nervous systems (CNS), and the M1 and M4 subtypes are mainly expressed in the CNS. The M4 agonist HTL0016878 for treating the main symptoms of Alzheimer's disease entered Phase 2 clinical trials.

[0004] Therefore, there is a need for agonists of the muscarinic M4 receptor for treating M4-mediated diseases and disorders such as Parkinson's disease, schizophrenia, Alzheimer's disease, and other diseases and disorders described herein. Summary of the Invention

[0005] The present invention provides a compound having the structure of formula (I) or its N-oxide or a pharmaceutically acceptable salt of the compound or its N-oxide:

[0006]

[0007] wherein A is a 6-8 membered heterocycle containing 1 or 2 ring nitrogen atoms and optionally substituted with 1 to 3 C 1-3 alkyl groups; Y is a bond, S, CH2, CHF, CF2 or C(OH)H; m is 1 or 2; n is 1 or 2; p is 1 or 2; R 1is H, halogen, CN, OH, –N(R 6 )(R 7 )、C 1-6 alkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4- to 8-membered heterocycle, -[O] 0-1 -5- 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, -N(C 1-6 alkyl)-5- to 10-membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and when 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 or -[O] 0-1 -5- to 10-membered heteroaryl, R 1 is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OH, =O, SO2 and C 1-3 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, C 3-6 cycloalkyl or a 4- to 8-membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 3 is halogen, CN, OH, –N(R6 )(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 - 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 - 8 - membered heterocycle or -N(C 1-6 alkyl)-5 - 10 - membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and when R 3 is -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4 - 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 - 8 - membered heterocycle or -N(C 1-6 alkyl)-5 - 10 - membered heteroaryl, it is optionally substituted by 1, 2 or 3 R 3a substituents; each R 3a is independently selected from halogen, 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, C1-6 Alkylene-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, -S-C 1-6 Alkyl, C 0-6 Alkylene-SO2C 1-6 Alkyl, C 0-6 Alkylene-C(O)NH2, C 0-6 Alkylene-C(O)NH(C 1-6 Alkyl), C 0-6 Alkylene-C(O)N(C 1-6 Alkyl)2, C 0-6 Alkylene-NHC(O)C 1-6 Alkyl, C 0-6 Alkylene-COOH and C with 1, 2 or 3 heteroatoms selected from N, O and S 0-6 Alkylene-3-6 membered heterocycle; R 4 Is H, halogen, CN or OH; R 5 Is -CO2-Z or its bioisostere; each R 6 And R 7 Independently is H, C 1-6 Alkyl, C(O)-C 1-6 Alkyl, spiro or bicyclic C 8-14 Cycloalkyl, 8-14 membered heterocycle with 1, 2 or 3 ring heteroatoms selected from N, O and S, and when R 6 Or R 7 Is not H, it may optionally be substituted by 1, 2 or 3 substituents independently selected from: halogen, CN, OH, =O, SO2, C 0-6 Alkylene-NH2, C 0-6 Alkylene-NH(C 1-6 Alkyl), C 0-6 Alkylene-N(C 1-6 Alkyl)2, C 0-6 Alkylene-SO2C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, or R 6 And R 7 Together with the nitrogen to which they are attached form a 4-10 membered heterocycle with 0-2 additional ring heteroatoms independently selected from N, O and S; and Z is C 1-7 Alkyl, C 1-7 Halogenated alkyl, C 3-6 Cycloalkyl or C 2-6Alkynyl, and Z is optionally substituted with C 1-6 alkoxy or C 3-6 cycloalkyl; provided that when R 1 , R 2 and R 4 are each H, Y is CH2, m, n and p are each 1, A is and R 3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy or then R 5 is not CO2CH2CH3.

[0008] Also provided herein are pharmaceutical compositions comprising a compound as disclosed herein. Also provided are methods of treating M4-mediated (or M4-related) diseases or disorders in a subject associated with abnormal M4 receptor activity, the methods comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein.

[0009] Other aspects and advantages will be apparent to those of ordinary skill in the art upon review of the following detailed description in conjunction with the accompanying drawings. While the compounds and methods disclosed herein admit of various forms, the following description includes specific instances, and it is to be understood that the disclosure is illustrative and not intended to limit the invention to the specific instances described herein. Detailed Description

[0010] Provided herein are compounds having the structure of formula (I):

[0011] or an N-oxide thereof or a pharmaceutically acceptable salt of the compound or its N-oxide. Also provided herein are compounds that act on the M4 receptor. The compounds described herein can be used to treat M4-mediated diseases or M4-related diseases.

[0012] Chemical Definition

[0013] As used herein, the term "alkyl" refers to straight-chain and branched-chain saturated hydrocarbon groups containing from 1 to 30 carbon atoms (e.g., from 1 to 20 carbon atoms or from 1 to 10 carbon atoms). The term C n means that the alkyl group has "n" carbon atoms. For example, C6 alkyl refers to an alkyl group having 6 carbon atoms. C 1-7An alkyl group refers to an alkyl group having a carbon atom number covering the entire range (i.e., 1 to 7 carbon atoms) and all subgroups (e.g., 2 - 6, 2 - 5, 3 - 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 tert-butyl (1,1-dimethylethyl). Unless otherwise specified, an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.

[0014] As used herein, the term "alkylene" refers to a divalent saturated aliphatic group. The term C n means an alkylene group having "n" carbon atoms. For example, C1 alkylene is CH2. For example, C 1-6 alkylene refers to an alkylene group having a carbon atom number covering the entire range and all subgroups as previously described for the "alkyl" group.

[0015] As used herein, the terms "olefin" or "alkenyl" are defined the same as "alkyl", except that they contain at least one carbon-carbon double bond and have 2 to 30 carbon atoms, such as 2 to 20 carbon atoms or 2 to 10 carbon atoms. The term C n means an alkenyl group having "n" carbon atoms. For example, C4 alkenyl refers to an alkenyl group having 4 carbon atoms. C 2-7 alkenyl refers to an alkenyl group having a carbon atom number covering the entire range (i.e., 2 to 7 carbon atoms) and all subgroups (e.g., 2 - 6, 2 - 5, 3 - 6, 2, 3, 4, 5, 6, and 7 carbon atoms). Particularly contemplated alkenyl groups include vinyl, 1-propenyl, 2-propenyl, and butenyl. Unless otherwise specified, an alkenyl group can be an unsubstituted alkenyl group or a substituted alkenyl group. Unless otherwise specified, an alkenyl group can be a cis-alkenyl or a trans-alkenyl.

[0016] As used herein, the terms "alkyne" or "alkynyl" are defined the same as "alkyl", except that they contain at least one carbon-carbon triple bond and have 2 to 30 carbon atoms, such as 2 to 20 carbon atoms or 2 to 10 carbon atoms. The term C n means an alkynyl group having "n" carbon atoms. For example, C4 alkynyl refers to an alkynyl group having 4 carbon atoms. C 2-7 alkynyl refers to an alkynyl group having a carbon atom number covering the entire range (i.e., 2 to 7 carbon atoms) and all subgroups (e.g., 2 - 6, 2 - 5, 3 - 6, 2, 3, 4, 5, 6, and 7 carbon atoms). Particularly contemplated alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, and butynyl. Unless otherwise specified, an alkynyl group can be an unsubstituted alkynyl group or a substituted alkynyl group.

[0017] As used herein, the term "cycloalkyl" specifically refers to a non-aromatic ring in which each atom of the ring is carbon, i.e., a carbocyclic ring, and can be monocyclic, bicyclic, bridged, fused, or spiro. The term C n means that the cycloalkyl group has "n" ring carbon atoms. For example, C5 cycloalkyl refers to a cycloalkyl group having 5 ring carbon atoms in the ring. C 3-8 Cycloalkyl refers to cycloalkyl groups having a full range (i.e., 3 to 8 carbon atoms) and all subgroups (e.g., 4 - 8, 3 - 7, 4 - 7, 3 - 6, 4 - 6, 3 - 5, 4 - 5, 3, 4, 5, 6, 7, and 8 carbon atoms) of ring carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Non-limiting examples of bridged cycloalkyl groups include Non-limiting examples of spirocycloalkyl groups include Unless otherwise specified, the cycloalkyl group can be an unsubstituted cycloalkyl group or a substituted cycloalkyl group.

[0018] 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, the heterocycles of the present disclosure can be monocyclic, bicyclic, bridged, fused, or spiro. For example, the heterocycle can be a 4 - 8 membered monocyclic, bicyclic, bridged, fused, or spiro ring having 1 or 2 or 3 heteroatoms selected from N, O, and S. Again, the heterocycle can be an 8 - 10 membered bicyclic, bridged, fused, or spiro group having 1 or 2 or 3 heteroatoms selected from N, O, and S in the bicyclic ring. Non-limiting examples of heterocyclic groups include azepane, aziridine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, dihydrofuran, dihydropyran, morpholine, oxazepane, thiazole, pyrrole, pyridone, and pyridine. Non-limiting examples of heterocyclic groups include

[0019]

[0020] The cycloalkyl and heterocyclic groups can be saturated or partially unsaturated ring systems (e.g., having double or triple bonds), but these groups are not aromatic. The cycloalkyl and heterocyclic groups can be optionally substituted with, for example, 1 to 3 groups independently selected from: 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 0-6Alkylene-SO2 alkyl, halogen, OH, NHC 1-3 Alkylene-aryl, OC 1-3 Alkylene-aryl, C 1-3 Alkylene-aryl and C having 1-3 heteroatoms selected from N, O, and S 0-6 Alkylene-C 3-6 Heterocycle. Specific substitutions of these groups are described elsewhere in this disclosure.

[0021] As used herein, the term "aryl" refers to an aromatic ring in which each atom of the ring is carbon and can 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, phenanthryl, biphenylyl, indanyl, indenyl, anthryl, fluorenyl, tetrahydroacenaphthylenyl. Unless otherwise specified, an aryl can be an unsubstituted aryl group or a substituted aryl group.

[0022] As used herein, the term "heteroaryl" refers to an aromatic heterocycle and can be a monocyclic or polycyclic (e.g., fused bicyclic and fused tricyclic) aromatic ring system in which 1 to 4 (e.g., 1 to 3) ring atoms are selected from oxygen, nitrogen, and sulfur and the remaining ring atoms are carbon, and the ring system is attached to the remainder of the molecule through any ring atom. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, dioxolyl, furyl, thienyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, benzofuryl, benzothiazolyl, triazinyl, triazolyl, purinyl, pteridinyl, indolyl, 3H-indolyl, phthalazinyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyridopyridyl, indolyl, 3H-indolyl, pteridinyl, and quinoxalinyl. Non-limiting examples of heteroaryl groups include

[0023]

[0024]

[0025] Unless otherwise specified, a heteroaryl group can be an unsubstituted heteroaryl group or a substituted heteroaryl group.

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

[0027] As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by one or more halogen atoms.

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

[0029] As used herein, the term "halogen" is defined as fluorine, chlorine, bromine, and iodine. Thus, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. In some cases, the haloalkyl group is a perhaloalkyl group, i.e., all hydrogen atoms of the alkyl group have been replaced by halogen atoms. Some non-limiting examples of haloalkyl groups include CF3, CHF2, CH2F, CCl3, CI3, and CH2CF3. Similarly, "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, such as OCF3.

[0030] As used herein, the term "heteroalkyl" refers to an alkyl chain interrupted by one or more heteroatoms selected from N, O, and S and having 2 to 30 carbon atoms (e.g., 2 to 20 carbon atoms or 2 to 10 carbon atoms). The term C n means that the heteroalkyl group has "n" carbon atoms. For example, C6 heteroalkyl refers to an alkyl group having 6 carbon atoms and the carbon chain is interrupted by one or more heteroatoms. C 2-6 heteroalkyl refers to an alkyl group having a carbon atom number covering the entire range (i.e., 2 to 6 carbon atoms) and all subgroups (e.g., 2-5, 3-6, 3-5, 4-6, 2, 3, 4, 5, and 6 carbon atoms).

[0031] As used herein, the term "bioisostere" refers to a molecule obtained by the exchange of one atom or a group of atoms with another or another group of broadly similar atoms. For example, an ester group can be replaced by one of the bioisosteres of the following esters, including but not limited to acylsulfonamide (CONR—SO2R), hydroxamic acid (CONROH), hydroxamate (CONROR), tetrazole, hydroxyisoxazole, isoxazol-3-one, and sulfonamide (SO2NR), where each R can independently represent hydrogen, alkyl, fluoroalkyl, carbocyclic group, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkyl alkyl, heteroaryl, or heteroaryl alkyl.

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

[0033] Compounds of the present disclosure

[0034] Compounds having the structure of formula (I) are disclosed herein: or an N-oxide thereof or a pharmaceutically acceptable salt of the compound or its N-oxide, wherein:

[0035] A is a 6-8 membered heterocycle containing 1 or 2 ring nitrogen atoms and optionally substituted by 1 to 3 substituents independently selected from halogen, OH, and C 1-3 alkyl;

[0036] Y is a bond, S, O, CH2, CHF, CF2, or C(OH)H;

[0037] m is 1 or 2;

[0038] n is 1 or 2;

[0039] p is 1 or 2;

[0040] R 1 is H, halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4-8 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 3-6Cycloalkyl, -N(C 1-6 alkyl)-C 6-10 aryl, -N(C 1-6 alkyl)-4-8 membered heterocycle or -N(C 1-6 alkyl)-5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and when 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 -4-8 membered heterocycle or -[O] 0-1 -5-10 membered heteroaryl, R 1 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OH, =O, SO2 and C 1-3 alkyl,

[0041] R 2 is H, halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-6 cycloalkyl or a 4-8 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S;

[0042] R 3 is halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4-8 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, and the C 3-6 cycloalkyl, C 6-10An aryl, 4- to 8-membered heterocycle, or 5- to 10-membered heteroaryl is substituted with 0, 1, 2, or 3 R 3a substituents;

[0043] Each R 3a is independently selected from halogen, CN, OH, =O, =N(C 1-3 alkyl), C 1-6 alkyl, C 2-10 alkene, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylene-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, -S-C 1-6 alkyl, C 0-6 alkylene-SO2C 1-6 alkyl, C 0-6 alkylene-C(O)NH2, C 0-6 alkylene-C(O)NH(C 1-6 alkyl), C 0-6 alkylene-C(O)N(C 1-6 alkyl)2, C 0-6 alkylene-NHC(O)C 1-6 alkyl, C 0-6 alkylene-COOH, C 0-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-O-C 1-6 alkyleneSi(C 1-3 alkyl)3 and a C 0-6 alkylene-3- to 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0044] R 4 is H, halogen, CN, or OH;

[0045] R 5 is -CO2-Z or a bioisostere thereof;

[0046] Each R 6 and R 7 are independently H, C 1-6 alkyl, C(O)-C 1-6 alkyl, spiro or bicyclic C 8-14A cycloalkyl group, an 8-14 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S, and when R 6 or R 7 is not H, it may optionally be substituted with 1, 2 or 3 substituents independently selected from the following: halogen, CN, =O, SO2, OH, C 0-6 alkyl-NH2, C 0-6 alkyl-NH(C 1-6 alkyl), C 0-6 alkyl-N(C 1-6 alkyl)2, C 0-6 alkyl-SO2C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkoxy, or

[0047] 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; and

[0048] Z is C 1-7 alkyl, C 1-7 haloalkyl, C 3-6 cycloalkyl or C 2-6 alkyne, and Z is optionally substituted with C 1-6 alkoxy or C 3-6 cycloalkyl;

[0049] Provided that when R 1 , R 2 and R 4 are each H, Y is CH2, m, n and p are each 1, A is and R 3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy or then R 5 is not CO2CH2CH3.

[0050] In the compounds of formula (I), A can be a 6-8 membered heterocycle containing 1 or 2 ring nitrogen atoms and optionally substituted with 1 to 3 C 1-3 alkyl groups. In each case, A is where X is N, CH, CF or C(OH). In each case, A is In the compounds of formula (I), X can be N or CH. In each case, X is N. In each case, X is CH.

[0051] In some cases, the compound has the structure of formula (Ia):

[0052]

[0053] In some cases, the compound has the structure of formula (Ib):

[0054]

[0055] In various cases, Y can be a bond, S, CH2, CHF, CF2 or C(OH)H. In various cases, Y is CH2, CHF, CF2 or C(OH)H. In some cases, Y is CH2.

[0056] In various cases, m can be 1 or 2. In various cases, m is 1.

[0057] In various cases, n can be 1 or 2. In various cases, n is 1.

[0058] In various cases, p can be 1 or 2. In various cases, p is 1.

[0059] In some cases, the compound has the structure of formula (Ic):

[0060]

[0061] In some cases, the compound has the structure of formula (Id):

[0062]

[0063] In various cases, R 5 is -CO2-Z or a bioisostere thereof. In various cases, R 5 is a CO2Z bioisostere selected from the following:

[0064] In various cases, R 5 is selected from CO2-C 1-7 alkyl,

[0065] In some cases, R 5 is CO2-C 1-7 alkyl. In some cases, R 5 is CO2CH2CH3.

[0066] In some cases, the compound has the structure of formula (Ie):

[0067]

[0068] In various cases, R 4 can be H, halogen, CN or OH. In various cases, R 4 is H or halogen. In some cases, R 4 is H.

[0069] In various cases, R 1 can be H, halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4-8-membered heterocycle or -[O] 0-1 -5-10-membered heteroaryl, where the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and when 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 -4-8-membered heterocycle or -[O] 0-1 -5-10-membered heteroaryl, R 1 can optionally be substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OH, =O, SO2 and C 1-3 alkyl. In various cases, R 1 is R 1 is H, halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl or C 1-6 alkoxy. In some cases, R 1 is H or halogen.

[0070] In various cases, R 2 can be H, halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C1-6 Halogenated alkoxy, C 2-6 heteroalkyl, C 3-6 ycloalkyl or a 4- to 8-membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S. In each case, 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 halogenated alkoxy. In some cases, R 2 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 halogenated alkoxy. In some cases, R 2 is H or halogen. In some cases, R 2 is H. In some cases, R 2 and R 4 each is H.

[0071] In each case, each R 6 and R 7 can independently be H, C 1-6 alkyl, C(O)-C 1-6 alkyl, spiro or bicyclic C 8-14 cycloalkyl, an 8- to 14-membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S, and when R 6 or R 7 is not H, it can optionally be substituted with 1, 2 or 3 substituents independently selected from: halogen, CN, OH, =O, SO2, C 0-6 alkylene-NH2, C 0-6 alkylene-NH(C 1-6 alkyl), C 0-6 alkylene-N(C 1-6 alkyl)2, C 0-6 alkylene-SO2C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkoxy, or R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 10-membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N, O and S. In each case, each R 6 and R 7 independently is H, C 1-6 alkyl or C(O)-C 1-6Alkyl. In some cases, each R 6 and R 7 are independently H or C 1-6 alkyl. In various cases, at least one R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 10-membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N and O.

[0072] In various cases, R 3 can be halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4- to 8-membered heterocycle or -[O] 0-1 -5- to 10-membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and when R 3 is -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4- to 8-membered heterocycle or -[O] 0-1 -5- to 10-membered heteroaryl, it is optionally substituted by 1, 2 or 3 R 3a substituents. In various cases, R 3 is -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4- to 8-membered heterocycle or -[O] 0-1 -5- to 10-membered heteroaryl, and is optionally substituted by 1, 2 or 3 R 3a . In many cases, at least one of R 1 , R 2 , R 3 and R 4 is halogen. In some cases, at least one of R 1 , R 2 , R 3 and R 4 is F. In various cases, R 3For

[0073]

[0074] and optionally substituted by 1, 2 or 3 R 3a substituents.

[0075] In some cases, R 3 is

[0076]

[0077] and optionally substituted by 1, 2 or 3 R 3a substituents. In some cases, R 3 is C 3-6 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 8-membered heterocycle, optionally substituted by 1, 2 or 3 R 3a substituents. In some cases, R 3 is a 5- to 6-membered heterocycle containing 1 ring heteroatom selected from S and O, or a 5- to 6-membered heteroaryl containing 2 or 3 ring heteroatoms independently selected from N and S, and optionally substituted by 1 or 2 R 1-6 substituents independently selected from halogen, CN, OH and C 3a alkyl substituents.

[0078] In the compounds of formula (I), R 3 may optionally be substituted by 1, 2 or 3 R 3a groups. In many cases, R 3 is unsubstituted. In many cases, R 3 is substituted by 1 or 2 R 3a substituents. In some cases, R 3 is substituted by 1 R 3a substituent. In the compounds of formula (I), each R 3a may independently be selected from halogen, 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-0-C 1-6 alkyl, C 0-6 alkylene-NH2, C 0-6 alkylene-NH(C 1-6 alkyl), C 0-6Alkylene-N(C 1-6 alkyl)2, -S-C 1-6 alkyl, C 0-6 alkylene-SO2C 1-6 alkyl, C 0-6 alkylene-C(O)NH2, C 0-6 alkylene-C(O)NH(C 1-6 alkyl), C 0-6 alkylene-C(O)N(C 1-6 alkyl)2, C 0-6 alkylene-NHC(O)C 1-6 alkyl, C 0-6 alkylene-COOH and C 0-6 alkylene-3-6 membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S. In each case, at least one R 3a is halogen, 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-0-C 1-6 alkyl, C 0-6 alkylene-N(C 1-6 alkyl)2, -S-C 1-6 alkyl, C 0-6 alkylene-NHC(O)C 1-6 alkyl or C 0-6 alkylene-3-6 membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S. In many cases, at least one R 3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, F, CN, =O, SO2, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, SCH3, N(CH3)2, NHCOCH3, CD3, In some cases, at least one R 3a is CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH or OCHF2.

[0079] In some cases, the compound has the structure of formula (If):

[0080]

[0081] wherein R 1 is halogen; R 3 is -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4- to 8-membered heterocycle or -[O] 0-1 -5- to 10-membered heteroaryl, wherein said heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and R 3 is substituted with 0, 1, 2 or 3 R 3a substituents; R 5 is -CO2-Z or a bioisostere thereof, and Z is C 1-7 alkyl, C 1-7 haloalkyl, C 3-6 cycloalkyl or C 2-6 alkynyl, and is optionally substituted with C 1-6 alkoxy or C 3-6 cycloalkyl. In some cases, R 1 is Cl or F. In some cases, R 3 is a 5- to 6-membered heterocycle containing 1 ring heteroatom selected from S and O, or a 5- to 6-membered heteroaryl containing 2 or 3 ring heteroatoms independently selected from N and S, and is substituted with 0, 1 or 2 R 1-6 substituents independently selected from halogen, CN, OH and C 3a alkyl. In various cases, R 5 is CO2C 1-7 alkyl.

[0082] Examples of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If) according to the present disclosure are shown in Table A.

[0083] Table A

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] The present disclosure also includes all pharmaceutically acceptable isotopically labeled compounds identical to those described herein, wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominating in nature. Examples of isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen such as 2 H, 3 H; isotopes of carbon such as 11 C, 13 C and14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O, 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S. Isotope-labeled compounds can include combinations of two or more of the same or different isotopes described above. Certain isotope-labeled compounds of the present disclosure, for example those incorporating radioactive isotopes, can be used in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotopes tritium, i.e., 3 H or "T", and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and facile means of detection. Replacement with heavier isotopes (such as deuterium (i.e., 2 H or "D")) may provide certain therapeutic advantages due to higher metabolic stability (e.g., extended in vivo half-life or reduced dosage requirements) and may thus be preferred in certain instances. Replacement with positron-emitting isotopes (such as 11 C, 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotope-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the attached protocols and / or examples and preparations, using appropriate isotope-labeled reagents in place of the previously employed unlabeled reagents. Pharmaceutically acceptable solvates according to the present disclosure include those in which the crystallization solvent can be replaced by an isotope, such as D2O, acetone-d6, or DMSO-d6.

[0112] A chemical structure having one or more stereocenters depicted by a dashed and bold wedge bond (i.e., and ) is intended to indicate the absolute stereochemistry of the stereocenters present in the chemical structure. Bonds represented by simple lines do not indicate a stereochemical preference. Bonds represented by a dashed or bold straight bond (i.e., and ) The keys indicated are intended to indicate the relative stereochemistry of the stereocenters present in the chemical structure. Unless otherwise indicated to the contrary, a chemical structure that includes one or more stereocenters exemplified herein but not indicating absolute or relative stereochemistry encompasses all possible stereoisomeric forms (e.g., diastereomers, enantiomers) of the compound and mixtures thereof. A structure having a single bold or wedged dashed line and at least one additional simple line encompasses a single enantiomeric series of all possible diastereomers. Similarly, a chemical structure having an alkenyl group is intended to encompass both the cis and trans orientations, or when substituted, the E-isomer and Z-isomer of the chemical structure.

[0113] Pharmaceutically acceptable salts and co-crystals

[0114] As used herein, the phrase “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 side effects such as toxicity, irritation, allergic response, etc. and are commensurate with a reasonable benefit / risk ratio.

[0115] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. 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.

[0116] As used herein, “Formula (I)”, “Formula (Ia)”, “Formula (Ib)”, “Formula (Ic)”, “Formula (Id)” and “Formula (Ie)” are also defined to include all forms of the compounds of the present disclosure, including but not limited to their hydrates, solvates, isomers (including, for example, rotamers), crystalline and non-crystalline forms, polymorphs, polycrystalline forms, metabolites, prodrugs. For example, the compounds or their pharmaceutically acceptable salts disclosed herein can exist in unsolvated form and in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. Generally, for the purposes of the present disclosure, the solvated form is considered equivalent to the unsolvated form.

[0117] The compounds of the present disclosure can exist as inclusion compounds or other complexes (e.g., co-crystals). Included within the scope of the present disclosure are complexes such as inclusion compounds, drug-host inclusion complexes, where the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of the present disclosure containing two or more organic and / or inorganic components, which can be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64(8), 1269 - 1288, Haleblian (August 1975). Co-crystals are generally defined as crystalline complexes of neutral molecular components held together by non-covalent interactions, but can 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 M. J. Zaworotko, Chem. Commun. 2004, 17, 1889 - 1896. For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Sci. 1975, 64, 1269 - 1288.

[0118] In some cases, the compounds of the present disclosure can exist as atropisomers (e.g., one or more atropisomers) and / or be isolated as atropisomers. 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 by 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.

[0119] When any racemate crystallizes, there can be two different types of crystals. The first type is the racemic compound (true racemate) mentioned above, where a homogeneous form of crystals containing equimolar amounts of the two enantiomers is produced. The second type is a racemic mixture or conglomerate, where crystals of two forms are produced in equimolar amounts, each form containing a single enantiomer.

[0120] The compounds of the present disclosure may also exist as their N-oxides or pharmaceutically acceptable salts of the compounds or N-oxides.

[0121] 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 have the formula R3N + -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 amine or a heteroaromatic amine (e.g., R3N together form 1-alkylpiperidine, 1-alkylpyrrolidine, 1-benzylpyrrolidine or pyridine). For example, imine nitrogen, especially heterocyclic imine nitrogen or heteroaromatic imine nitrogen, or pyridine-type nitrogen (=N-) atoms, such as the nitrogen atoms in pyridine, pyridazine or pyrazine, can be N-oxidized to form N-oxides containing ≡N + -O – groups. Thus, the compounds according to the present disclosure containing 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 poly-N-oxides or mixtures thereof, depending on the number of nitrogen atoms suitable for forming stable N-oxides).

[0122] As used herein, the term "N-oxide" 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 the amine compound can form mono-N-oxides) or poly-N-oxides (e.g., bis-N-oxides), or mixtures in any ratio thereof.

[0123] As described above, the compounds of the present disclosure (or their N-oxides) may exist in the form of pharmaceutically acceptable salts derived from inorganic acids or organic acids. Depending on the particular compound, the salts of the compound may be advantageous due to one or more physical properties of the salt, such as enhanced drug stability at different temperatures and humidities, or desired solubility in water or oil. In some cases, the salts of the compound may also be used as aids in the separation, purification and / or resolution of the compound.

[0124] When it is intended to administer a salt to a patient (as opposed to, for example, use in an in vitro environment), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to salts prepared by combining a compound of the present disclosure with an acid whose anions are generally considered suitable for human consumption or a base whose cations are generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present disclosure because they have higher water solubility relative to the parent compound.

[0125] When possible, suitable pharmaceutically acceptable acid addition salts of the compounds of the present disclosure include those derived from inorganic acids and organic acids, inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid, and sulfuric acid, and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic 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, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids.

[0126] Specific examples of suitable organic acids include, but are not limited to, acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoate), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonic acid, alginic acid, β-hydroxybutyric acid, galactonic acid, galacturonic acid, adipic acid, alginic acid, butyric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, dodecylsulfuric acid, saccharic acid, glycerophosphoric acid, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmitic acid, pectic acid, 3-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, and undecanoic acid.

[0127] In addition, when the compounds of the present disclosure bear an acidic moiety, suitable pharmaceutically acceptable salts thereof may 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, the base salts are formed from bases that form non-toxic salts, including aluminum salts, arginine salts, benzathine salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, meglumine salts, ethanolamine salts, tromethamine salts, and zinc salts.

[0128] Organic salts can be prepared from secondary, tertiary, or quaternary amines, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. The basic nitrogen-containing group can be quaternized with reagents such as lower alkyl (C1-Cs) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides); dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate); long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides); aralkyl halides (e.g., benzyl and phenethyl bromides), etc.

[0129] In some cases, hemisalts of acids and bases can also be formed, such as hemisulfates and hemicalcium salts, or sequifumarate.

[0130] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present disclosure are known to those skilled in the art.

[0131] The compounds of the present disclosure can exist as a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and can exhibit physical properties of a solid or a liquid depending on temperature. Typically, such materials do not produce a characteristic X-ray diffraction pattern and, although exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change occurs from an apparently solid material to a material with liquid properties, which change is characterized by a change in state, typically a second-order change ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and produces a characteristic X-ray diffraction pattern with defined peaks. Such materials will also exhibit the properties of a liquid upon sufficient heating, but the change from solid to liquid is characterized by a phase change, typically a first-order phase change ("melting point").

[0132] When subjected to suitable conditions, the compounds of the present disclosure may also exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state is an intermediate between the true crystalline state and the true liquid state (melt or solution). Mesomorphism due to temperature change is described as "thermotropic", and mesomorphism due to the addition of a second component (such as water or another solvent) is described as "lyotropic". Compounds having the potential to form lyotropic mesophases are described as "amphiphilic" and are composed of molecules having ionic (such as -COO'Na*, -COOK*, or -SO3s'Na*) or non-ionic (such as -N"N*(CHs)3) polar head groups. See more information in Crystals and the Polarizing Microscope, N.H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970).

[0133] The present disclosure also relates to prodrugs of the compounds of the present disclosure. Thus, when certain derivatives of the compounds of the present disclosure, which may themselves have little or no pharmacological activity, are administered in vivo or on the body, they can be converted into the compounds of formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (edited by E.B. Roche, American Pharmaceutical Association).

[0134] Prodrugs according to the present disclosure can be prepared, for example, 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", as described, for example, in Design of Prodrugs, H. Bundgaard (Elsevier, 1985) or in Prodrugs: Challenges and Reward, 2007 Edition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134 - 175 (Springer, 2007).

[0135] In addition, certain compounds of the present disclosure may themselves act as prodrugs of other compounds of the present disclosure. The present disclosure also encompasses compounds of the present disclosure containing protecting groups. Those skilled in the art will also understand that the compounds of the present disclosure can also be prepared with certain protecting groups, which can be used for purification or storage and can be removed before administration to a patient. The protection and deprotection of functional groups are described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3rd Edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

[0136] Also included within the scope of the present disclosure are metabolites of the compounds of the present disclosure, i.e., compounds formed in the body after administration of the drug.

[0137] Other acids and bases, although not themselves pharmaceutically acceptable, can also be used to prepare salts that can be used as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts or base addition salts.

[0138] It should be understood that the compounds disclosed herein can exist as mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of the free form of the compound and pharmaceutically acceptable salts are also contemplated.

[0139] Pharmaceutical formulations

[0140] Also provided herein are pharmaceutical formulations comprising an effective amount of a compound of the present disclosure and one or more pharmaceutically acceptable excipients. As used herein, the term "formulation" may be used interchangeably with "composition".

[0141] "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 a disease or condition and / or substantially reduce the chance of a disease or condition in a subject. As used herein, the terms "patient" and "subject" may be used interchangeably and mean an animal, such as a dog, cat, cow, horse, and sheep (i.e., non-human animals) and a human. A particular patient or subject is a mammal (e.g., a human). The terms "patient" and "subject" include male and female.

[0142] As used herein, the term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), appropriately selected according to the intended form of administration and in accordance with conventional pharmaceutical practice.

[0143] The compounds of the present disclosure can be administered alone or as part of a pharmaceutically acceptable composition or formulation. Additionally, these compounds can be administered all at once, such as by rapid bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, such as using transdermal delivery. It should also be noted that the dosage of the compound can vary over time.

[0144] If desired, the compounds and other pharmaceutically active compounds disclosed herein can be administered to a subject or patient by any suitable route, such as orally, topically, rectally, parenterally (e.g., subcutaneous injection, intravenous, intramuscular, intraosseous, and intrathecal injection or infusion techniques), or as a buccal, inhaled, or nasal spray. Administration can provide a systemic effect (e.g., enteral or parenteral). All methods available to those skilled in the art for administering pharmaceutical active agents are contemplated. In some cases, the disclosed formulations can be administered orally or topically.

[0145] Suitable oral compositions or formulations according to the present disclosure include, but are not limited to, tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions or formulations suitable for oral use can be prepared by any method known in the art for manufacturing pharmaceutical compositions.

[0146] 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, the liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, 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 the inert diluent, oral compositions may also include adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0147] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate dibasic and / or with: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution 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; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0148] Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, lozenges, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be compositions that release the active ingredient only or preferentially in a certain part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0149] The active compound can also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms of tablets, lozenges, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. As is conventional practice, such dosage forms may also contain other substances in addition to the inert diluent, 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 form may also contain buffering agents. They may optionally contain opacifying agents and may also be compositions that release the active ingredient only or preferentially in a certain part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0150] The pharmaceutical compositions and formulations described herein can also be administered topically or transdermally, particularly when the treatment target includes diseases of regions or organs that are easily accessible for topical application, including the eye, skin, or lower intestine. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application to the lower intestine can be achieved, for example, in the form of 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.

[0151] For topical application, the pharmaceutical composition can be formulated as a suitable ointment, cream, lotion, or gel containing the active ingredient suspended or dissolved in one or more carriers, as well as any desired preservatives or buffering agents that may be required. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, polyethylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated as 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0152] Ophthalmic formulations, otic drops, and eye drops are also encompassed within the scope of the present disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0153] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are commonly used as solvents or suspending media. For this purpose, any mild non-volatile oil can be employed, including synthetic mono- or di-glycerides of fatty acids. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0154] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0155] To prolong the action of the compounds described herein, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Depot injection formulations are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactic acid-polyglycolide. The rate of release of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0156] Compositions for rectal or vaginal administration are specifically suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol or suppository wax), which are solids at ambient temperature but liquids at body temperature and thus melt in the rectal or vaginal cavity and release the active compound.

[0157] The sterile injectable form of the compositions described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. Additionally, a sterile non-volatile oil is commonly used as a solvent or suspending medium. For this purpose, any mild non-volatile oil can be employed, including synthetic mono- or di-glycerides of fatty acids. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables, such as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span and other emulsifying agents or bioavailability enhancers, which are commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms, can also be used for formulating purposes.

[0158] The pharmaceutical composition can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline with benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0159] The compounds for use in the methods of the present disclosure can be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit doses for the subject being treated, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect, optionally together with a suitable pharmaceutical carrier. The unit dosage form can be a single daily dose or one of multiple daily doses (e.g., about 1 to 4 times or more per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

[0160] For oral administration, the composition can be provided in the form of tablets containing 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, and 500 mg of the active ingredient for adjusting the dose of the patient according to the symptoms. The drug generally contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of the active ingredient. Intravenous, during a constant rate infusion, the dose can range from about 0.1 mg / kg / minute to about 10 mg / kg / minute.

[0161] Treatment methods

[0162] The compounds disclosed herein (e.g., the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), and formula (Id)) and their pharmaceutically acceptable salts can act on the M4 receptor. The muscarinic acetylcholine receptor M4 (also known as muscarinic 4 or CHRM4) is a protein encoded by the CHRM4 gene in humans. The M4 receptor is mainly 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 (about 46%), where M4 is the major muscarinic subtype. M4 is expressed sporadically in the periphery (e.g., testis, skin, and colon).

[0163] The M4 receptor couples to G q / iThe protein is coupled and acts as an inhibitory autoreceptor 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 cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related central nervous system pathologies"; FASEB Journal, 2004; 18:1410-1412), and acts as a postsynaptic regulatory receptor in the striatum, neocortex, and hippocampus (Levey et al.; Identification and localization of muscarinic acetylcholine receptor proteins in 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).M4 receptors have also been found presynaptically on glutamatergic synapses from the cortex to the striatum (Pancani, T. et al., “Allosteric activation of M4 improve behavioral and physiological alterations in early symptomatic YAC128 mice”, Proceedings of the National Academy of Sciences of the United States of America, November 10, 2015; 112(45):14078 - 83) and on hippocampal glutamatergic neurons where M4 regulates glutamate release presynaptically. The highest expression of M4 receptors is found in the striatum, where M4 receptors also modulate dopaminergic neurotransmission and are co - expressed with D1 dopamine receptors in a subpopulation of spiny neurons in the striatum, which contains GABA as the major 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).

[0164] It has been hypothesized that the administration of a selective M4 agonist will provide 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 view is further supported by studies demonstrating that M4 receptors regulate the kinetics of dopaminergic and cholinergic neurotransmission and that hyperdopaminergic states result in loss of M4 function (Tzavara et al., 2004).

[0165] The compounds of the present disclosure may also be used to treat / alleviate 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; Vol. 2014.10, pp. 183-191). These behavioral symptoms include, but are not limited to, agitation, vocal outbursts, compulsivity, anxiety, irritability, aggression, disorientation, hallucinations, delusions, illusions, suspicion, apathy, depression, disinhibition, motor abnormalities, and obsessive-compulsive behaviors, as well as sleep disorders (Dillon, Carol et al., “Behavioral symptoms related to cognitive impairment”, Neuropsychiatric Disease and Treatment; 2013:91443-1455). By treating / alleviating the above-described behavioral symptoms, it is believed that the compounds of the present disclosure will also enhance cognition.

[0166] In view of the foregoing, the compounds of the present disclosure can be used to treat schizophrenia and Alzheimer's disease. The compounds of the present disclosure can also be used to treat Parkinson's disease, Huntington's disease, addiction, substance use disorders, depression, and epilepsy. The compounds of the present disclosure can also be used to treat Alzheimer's disease psychosis.

[0167] It is believed that the M4 selective activators of the present disclosure may also have a wide range of other therapeutic applications for treating central nervous system conditions or diseases, including neurological disorders, neurodegenerative disorders, and / or mental disorders. Neurological disorders, neurodegenerative disorders, and / or mental disorders include, but are not limited to, (1) mood [affective] disorders; (2) neurological, stress-related, and somatoform disorders, including anxiety disorders; (3) disorders including symptoms of cognitive deficits in mammals (including humans); (4) disorders including attention deficit, executive function deficits (working memory deficits), impulse control dysfunction, extrapyramidal symptoms, disorders based on basal ganglia, hippocampal, and prefrontal cortex dysfunction; (5) behavioral and emotional disorders that typically occur in childhood and adolescence; (6) psychological developmental disorders; (7) generalized atrophy primarily affecting the central nervous system; (8) extrapyramidal and movement disorders; (9) behavioral syndromes related to physiological disorders and physical factors; (10) disorders of adult personality and behavior; (11) schizophrenia and other mental disorders; (12) mental and behavioral disorders caused by the use of psychoactive substances; (13) sexual dysfunction including hypersexuality; (14) mental retardation; (15) factitious disorders, such as acute hallucinatory mania; (16) episodic and paroxysmal disorders, epilepsy; (17) narcolepsy; (18) dementia, and (19) amyotrophic lateral sclerosis.

[0168] Examples of mood (affective) disorders treatable according to the present disclosure include, but are not limited to, bipolar type I disorder, hypomania (manic and mixed forms), bipolar type II disorder; depressive disorders, such as single episode depression or recurrent major depressive disorder, chronic depression, psychotic depression, mild depressive disorder, postpartum-onset depression, depressive disorder with psychotic symptoms; persistent mood [affective] disorders, such as cyclothymic temperament, dysthymia, euthymia; premenstrual syndrome (PMS) and premenstrual dysphoric disorder.

[0169] Examples of neurological, stress-related, and somatoform disorders treatable according to the present disclosure include, but are not limited to, anxiety disorders, social anxiety disorder, generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social phobia, chronic anxiety disorder; obsessive-compulsive disorder; reactions to severe stress and adjustment disorders, such as post-traumatic stress disorder (PTSD), acute stress disorder, other neurological disorders such as depersonalization-derealization syndrome.

[0170] As used herein, the phrases "cognitive deficit" and "disorders including symptoms of cognitive deficits" refer to below-normal or suboptimal functioning in one or more cognitive aspects (such as memory, intelligence, learning, and logical ability, or attention and executive function (working memory)) in a particular individual compared to other individuals in the same general age group.

[0171] Examples of "disorders comprising cognitive deficit symptoms" treatable according to 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, Lewy body dementia, stroke, frontotemporal dementia, progressive supranuclear palsy, Huntington's disease, HIV disease (HIV-related dementia), traumatic brain injury, and substance abuse; mild cognitive impairment, ADHD, Asperger's syndrome, and age-related memory impairment; cognitive decline or delirium post-operative or associated with intensive care treatment.

[0172] Examples of disorders typically first diagnosed in infancy, childhood, and adolescence treatable according to the present disclosure include, but are not limited to, hyperkinetic disorders, including disorders of activity and attention, attention deficit / hyperactivity disorder (ADHD), hyperkinetic 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 multiple motor tic disorder (Gilles de la Tourette's syndrome), substance-induced tic disorder; autistic disorder; Batten disease, excessive masturbation, nail biting, nose picking, and thumb sucking.

[0173] Examples of psychological developmental disorders treatable according to the present disclosure include, but are not limited to, pervasive developmental disorders, including but not limited to Asperger's syndrome and Rett syndrome, autistic disorder, childhood autistic disorder and hyperkinetic disorder associated with mental retardation and stereotyped movements, specific motor function developmental disorder, specific academic skill developmental disorder.

[0174] Examples of generalized atrophy primarily affecting the central nervous system treatable according to the present disclosure include, but are not limited to, generalized atrophy in multiple sclerosis primarily affecting the basal ganglia, including Huntington's disease and amyotrophic lateral sclerosis.

[0175] Examples of extrapyramidal and movement disorders having basal ganglia dysfunction and / or degeneration treatable according to the present disclosure include, but are not limited to, Huntington's disease; Parkinson's disease; secondary parkinsonism, such as postencephalitic parkinsonism; parkinsonism included in other disorders; Niemann-Pick disease, Lewy body disease; basal ganglia degenerative diseases; other extrapyramidal and movement disorders, including tremors, essential tremor and drug-induced tremors, myoclonus, chorea and drug-induced chorea, drug-induced tics and tics of organic origin, drug-induced acute dystonia, drug-induced tardive dyskinesia, myospasm and disorders associated with myospastic states or weakness (including tremors); mental deficiencies (including spastic states, Down syndrome and fragile X chromosome syndrome), levodopa-induced movement disorders; restless legs syndrome and stiff person syndrome.

[0176] Other examples of movement disorders having basal ganglia dysfunction and / or degeneration treatable according to the present disclosure include, but are not limited to, dystonia, including but not limited to focal dystonia, multifocal or segmental dystonia, torsion dystonia, hemidystonia, generalized and tardive dystonia (induced by psychopharmacological drugs). Focal dystonia includes cervical dystonia (torticollis), blepharospasm (eyelid spasm), limb dystonia (limb spasm, such as writer's cramp), or mandibular dystonia and spasmodic dysphonia (vocal cord spasm); neuroleptic-induced movement disorders, including but not limited to neuroleptic malignant syndrome (NMS), neuroleptic-induced parkinsonism, neuroleptic-induced early-onset or acute movement disorders, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and neuroleptic-induced tremors.

[0177] Examples of behavioral syndromes related to physiological disorders and physical factors according to the present disclosure include, but are not limited to, non-organic sleep disorders, including but not limited to non-organic hypersomnia, non-organic disorders of the sleep-wake schedule (circadian rhythm sleep disorders), insomnia, somnambulism and sleep deprivation; mental and behavioral disorders associated with the puerperium, including postpartum and puerperal depression; eating disorders, including but not limited to anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified, overeating, obesity, compulsive eating disorder and pica.

[0178] Examples of adult personality and behavioral disorders treatable according to the present disclosure include, but are not limited to, personality disorders, including, but not limited to, emotionally unstable, borderline, obsessive-compulsive, compulsive, dependent, and passive-aggressive personality disorders; habit and impulse disorders (impulse control disorders), including intermittent explosive disorder, pathological gambling, pathological fire-setting (pyromania), pathological stealing (kleptomania), trichotillomania; Munchausen syndrome.

[0179] Examples of schizophrenia and other mental disorders treatable according to the present disclosure include, but are not limited to, different types of persistent or intermittent schizophrenia (e.g., delusional, hebephrenic, catatonic, undifferentiated, residual, and schizophreniform disorders); schizotypal disorders (such as borderline, latent, prepsychotic, prodromal, pseudoneurotic, pseudopsychotic schizophrenia, and schizotypal personality disorder); persistent delusional disorder; acute, transient, and persistent psychotic disorders; induced delusional disorder; different types of schizoaffective disorders (e.g., bipolar or mixed); puerperal psychosis and other and unspecified non-organic psychoses, such as social withdrawal in schizophrenia.

[0180] Examples of mental and behavioral disorders due to the use of psychoactive substances treatable according to the present disclosure include, but are not limited to, mental and behavioral disorders due to the use of alcohol, opioids, cannabinoids, sedatives or hypnotics, cocaine; mental and behavioral disorders due to the use of other stimulants (including caffeine), mental and behavioral disorders due to drug dependence and abuse (e.g., narcotic dependence, alcoholism, amphetamine and methamphetamine dependence, opioid dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndromes and relapse prevention), use of hallucinogens, tobacco (nicotine), volatile solvents, and mental and behavioral disorders due to multiple drug use and use of other psychoactive substances, including the following subtype symptoms: harmful use, dependence syndrome, withdrawal state, and withdrawal state with delirium.

[0181] Examples of dementia treatable according to the present disclosure include, but are not limited to, vascular dementia, dementia caused by Creutzfeld-Jacob disease, HIV, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Alzheimer's type dementia.

[0182] The compounds, their N-oxides and pharmaceutically acceptable salts of the foregoing disclosure may be useful for schizophrenia or psychosis including one or more of the following conditions: schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychostimulants and cocaine) psychosis / psychotic disorder, psychosis associated with an affective disorder, brief reactive psychosis, schizoaffective psychosis, "schizophrenia spectrum" disorders such as schizoid or schizotypal personality disorder, or diseases associated with psychosis (such as major depressive disorder, bipolar disorder, Alzheimer's disease and post-traumatic stress syndrome), including positive and negative symptoms of schizophrenia and other psychoses; 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 general medical conditions or substance abuse); delirium, amnestic disorder or age-related cognitive decline.

[0183] In addition to the central nervous system disorders mentioned above, the compounds of the present disclosure may also be used to treat other M4-mediated (or M4-related) disorders, such as, but not limited to, addiction (e.g., substance addiction such as opioid, cocaine or alcohol addiction), pain (e.g., acute pain, inflammatory pain and neuropathic pain) and sleep disorders (such as sleep disorders associated with REM sleep regulation, e.g., sleep disorders associated with the onset of REM sleep). Additional M4-mediated (or M4-related) disorders or conditions that may be treated with the compounds of the present disclosure include dry mouth, cognitive disorders (e.g., mild cognitive impairment), movement disorders, 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, Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism and atherosclerosis. See, for example, US8,664,234.

[0184] Potential sleep disorders for which the compounds, their N-oxides, and pharmaceutically acceptable salts of the foregoing disclosure may be useful include: improving sleep quality; enhancing sleep maintenance; increasing the value calculated by dividing the time the subject sleeps by the time the subject attempts to sleep; reducing sleep latency or onset time (the time required to fall asleep); decreasing the difficulty of falling asleep; increasing sleep continuity; reducing the number of awakenings during sleep; reducing nocturnal awakenings; reducing the time spent awake after initial sleep onset; increasing total sleep amount; reducing fragmentation of sleep; altering the timing, frequency, or duration of REM sleep episodes; altering the timing, frequency, or duration of slow-wave (i.e., stage 3 or 4) sleep episodes; increasing the amount and percentage of stage 2 sleep; promoting slow-wave sleep; enhancing EEG-delta activity during sleep; increasing daytime alertness; reducing daytime sleepiness; treating or reducing excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy; sleep interruption; sleep apnea; wakefulness; nocturnal myoclonus; REM sleep interruption; jet lag; shift worker sleep disorder; sleep abnormality; night terrors; insomnia associated with depression, affective / mood disorders, and somnambulism and enuresis, and sleep disorders associated with aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity and mental and physical disorders associated with transmeridian travel and shift work; conditions caused by drugs that cause reduced REM sleep as a side effect; syndromes characterized by non-restorative sleep and myalgia or sleep apnea associated with respiratory disorders during sleep; and conditions caused by decreased sleep quality.

[0185] Pain disorders for which the compounds, their N-oxides, and pharmaceutically acceptable salts of the present disclosure may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, "dynias", e.g., vulvodynia, phantom limb pain, avulsion of roots, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndrome (which may be substantially caused by any injury at any level of the nervous system); post-surgical pain syndrome (e.g., post-mastectomy syndrome, post-thoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia); perioperative pain (general surgery, gynecological pain), chronic pain, dysmenorrhea, and pain associated with angina, 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.

[0186] The compounds, their N-oxides and pharmaceutically acceptable salts of the foregoing disclosure can be used to reduce tolerance to and / or dependence on opioid treatment of pain, and can be used to treat withdrawal syndromes such as alcohol, opioid and cocaine.

[0187] In various cases, M4-mediated (or M4-related) diseases or disorders can be selected from: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders (such as mild cognitive impairment), Parkinson's disease, Parkinson's disease - levodopa-induced dyskinesia, Huntington's disease, movement disorders, tardive dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism and atherosclerosis. In some cases, M4-mediated (or M4-related) diseases or disorders are selected from Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease - levodopa-induced dyskinesia and sleep disorders.

[0188] Synthesis of the compounds of the present disclosure

[0189] The compounds of the present disclosure can be synthesized by any method known in the art. For example, the compounds of the present disclosure (compounds of formula (I)) can be synthesized according to Schemes 1, 2, 3, 4, 5 and 6.

[0190] Scheme 1

[0191]

[0192] Scheme 1 involves a synthetic sequence for preparing compounds of formula I and formula I'. According to Scheme 1, compound II can be coupled with heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl and heteroalkyl boronic acids, borate esters or potassium trifluoroborates via Suzuki-Miyaura coupling reaction. The scope of the reaction type is not limited to Suzuki-Miyaura, but includes Stille, Negishi, Hiyama and decarboxylative couplings; Sonogashira coupling with alkyne / silyl alkyne; and nucleophilic aromatic substitution of amines and alcohols (S N Ar), where R 1 、R 2 、R 3 、R 4 and A substituents should be represented by the same moieties required in the final product or its protected variants to via reaction with G1 coupling reaction or S N Ar reaction to produce Compound III, while G 1 is a boronic acid / ester / trifluoroborate, stannane, magnesium, zinc, carboxylic acid, carboxylic acid ester or alcohol / amine; or a terminal alkyne / silyl alkyne, using standard selections of metal source, ligand and base, coupling in a standard solvent / cosolvent, which is but not limited to DMF, acetonitrile, 1,4-dioxane, THF, pyridine, toluene, ethanol, n-butanol, tert-butanol. Examples of Pd / ligand / base combinations in the coupling reaction include but are not limited to tetrakis(triphenylphosphine)palladium(0) plus sodium carbonate and tris(dibenzylideneacetone)dipalladium(0) plus dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl plus potassium carbonate. In the S N Ar reaction, examples of the base include but are not limited to triethylamine, N,N-diisopropylethylamine, K2CO3, Cs2CO3, K3PO4, K3PO4, H2O, tBuOK and NaH. Removal of the protecting group P 1 gives Compound IV. The protecting group P 1 in this case refers to groups for amine protection well-known to those skilled in the art. For example, P 1 can 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). Alternatively, P 1 can be one of many other protecting groups suitable for amines, including carboxybenzyl (Cbz) or benzoyl (Bz) groups, and can be cleaved under standard conditions known to those skilled in the art. Compound IV can be coupled with Compound V (where m, n and p independently represent integers selected from 1 or 2) to produce the racemic Compound VI using standard reductive amination procedures, such as but not limited to the combination of sodium cyanoborohydride and titanium(IV) ethoxide or sodium triacetoxyborohydride in a suitable solvent. The protecting group Boc can be cleaved via acidic conditions in a suitable solvent, including but not limited to treatment with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM), followed by treatment with R 5 in dichloromethane or other suitable solvents to obtain a carbamate or carbamate bioisostere (where R 5(should be represented by the same moiety required in the final product or its protected variant) to produce the compound of formula I as a racemic mixture. Chiral separation of the racemic mixture, such as chiral chromatography methods such as chiral HPLC or chiral supercritical fluid chromatography (SFC), can produce the compound of formula I' that is enantiomerically enriched or enantiomerically pure (e.g., %ee is at least 98%). An enantiomerically enriched compound is a compound in which the enantiomeric excess (%ee) is at least 80% (i.e., the enantiomeric ratio of one enantiomer to the other is 9:1). The %ee of the enantiomerically enriched compound can be at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. The measurement of %ee can be carried out using known laboratory techniques.

[0193] Scheme 2

[0194]

[0195] Scheme 2 relates to an alternative synthetic route for preparing the compounds of formula I and formula I'. Referring to Scheme 2a, compound IV (wherein R 1 、R 2 、R 3 、R 4 and the A substituent should be represented by the same moiety required in the final product or its protected variant), can displace the sulfonate ester of the enantiomerically pure compound VII in the presence of a base such as potassium carbonate or tripotassium phosphate in a suitable solvent, wherein R 5 of formula VII should be represented by the same moiety required in the final product or its protected variant, wherein R 6 is an aryl, alkyl or fluoroalkyl substituent, such as 4-methylphenyl, methyl, nonafluorobutyl; and m, n and p independently represent an integer selected from 1 or 2, and Y should be represented by the same moiety required in the final product, and the solvent includes but is not limited to DMSO, DMF, MeCN or THF. Referring to Scheme 2b, compound IV (wherein R 1 、R 2 、R 3 、R 4 and A should be represented by the same moiety required in the final product or its protected variant), can similarly displace the arylalkyl / fluoroalkyl sulfonate ester on the chiral compound VIII to produce compound IX, wherein R 6 is an aryl, alkyl or fluoroalkyl substituent, such as 4-methylphenyl, methyl, nonafluorobutyl; and m, n and p independently represent an integer selected from 1 or 2, and Y should be represented by the same moiety required in the final product. The Boc group is removed, which can be cleaved via acidic conditions in a suitable solvent, which includes but is not limited to trifluoroacetic acid in dichloromethane (DCM), and then with R 5Process to obtain a carbamate or carbamate bioisostere (wherein R 5 should be represented by the same moiety required in the final product or its protected variant), to generate the compound of formula I' as a single enantiomer. Alternatively, as shown in Scheme 2c, compound IV (wherein R 1 , R 2 , R 3 , R 4 and the A substituent should be represented by the same moiety required in the final product or its protected variant), can be coupled with compound X (wherein R 5 should be represented by the same moiety required in the final product or its protected variant, m, n and p are independently represented by an integer selected from 1 or 2, and Y should be represented by the same moiety required in the final product), to generate the compound of general formula I as a racemic mixture using standard reductive amination procedures, such as but not limited to the combination of sodium cyanoborohydride and titanium(IV) ethoxide or sodium triacetoxyborohydride in a suitable solvent. The chiral separation of the racemate of formula I can be accomplished by chiral SFC to provide the compound of formula I' as a single enantiomer. In Scheme 2d, compound XI (wherein R 1 , R 2 , R 3 and R 4 should be represented by the same moiety required in the final product or its protected variant, wherein G 2 is a sulfonate or halogen), can be coupled with the enantiopure compound XII (wherein A and R 5 of formula XII should be represented by the same moiety required in the final product or its protected variant, m, n and p independently represent an integer selected from 1 or 2, and Y should be represented by the same moiety required in the final product), to generate the compound of formula I' using standard coupling procedures, such as but not limited to the Suzuki-Miyaura coupling or Buchwald-Hartwig coupling reaction and the S N Ar reaction of amines. Additionally, referring to Scheme 2e, the enantiopure compound XIII can be coupled with heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl and heteroalkyl boronic acids, boronic esters or potassium trifluoroborates via the Suzuki-Miyaura coupling reaction. The scope of reaction types is not limited to Suzuki-Miyaura, but includes Stille, Negishi, Hiyama and decarboxylative couplings; Sonogashira coupling with alkynes / silylalkynes; and nucleophilic aromatic substitution (S N Ar) of amines and alcohols, to generate the compound of formula I' as a single enantiomer, wherein R 1 , R 2 , R 3 , R 4 , R5 The A substituent and the A' substituent should be represented by the same moiety as required in the final product or its protected variant, m, n, and p independently represent an integer selected from 1 or 2, and Y should be represented by the same moiety as required in the final product.

[0196] Scheme 3

[0197]

[0198] Scheme 3 relates to a synthetic sequence for preparing compounds of formula Ia. According to Scheme 3, compound XIV can be coupled with heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl, and heteroalkyl boronic acids, boronic esters, or potassium trifluoroborates via a Suzuki-Miyaura coupling reaction. The scope of the reaction type is not limited to Suzuki-Miyaura, but includes Stille, Negishi, Hiyama, and decarboxylative couplings; Sonogashira coupling with alkynes / silylalkynes; and nucleophilic aromatic substitution of amines and alcohols (S N Ar), and via a coupling reaction or S N Ar reaction, using standard selections of metal sources, ligands, and bases, compound XV is generated in a standard solvent (such as but not limited to DMF, acetonitrile, 1,4-dioxane, THF, pyridine, toluene, ethanol, n-butanol, tert-butanol), where R 1 、R 2 、R 3 and R 4 substituents and Y should be represented by the same moiety as required in the final product or its protected variant. Examples of Pd / ligand / base combinations in the coupling reaction include but are not limited to tetrakis(triphenylphosphine)palladium(0) plus potassium carbonate and tris(dibenzylideneacetone)dipalladium(0) plus dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl plus potassium carbonate. In the S N Ar reaction, examples of bases include but are not limited to triethylamine, N,N-diisopropylethylamine, K2CO3, Cs2CO3, K3PO4, tBuOK, and NaH. Removal of the protecting group P 1 gives compound XVI. The protecting group P 1 in this case refers to groups for amine protection well-known to those skilled in the art. For example, P 1 can 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). Alternatively, P 1can be one of many other protecting groups suitable for amines, including the carboxybenzyl (Cbz) or benzoyl (Bz) groups, and can be cleaved under standard conditions known to those skilled in the art. Compound XVI can be coupled with compound V (where m, n, and p independently represent an integer selected from 1 or 2, and Y should be represented by the same moiety required in the final product) to generate the racemic compound XVII using standard reductive amination procedures such as but not limited to the combination of sodium cyanoborohydride with titanium(IV) ethoxide or sodium triacetoxyborohydride in a suitable solvent, followed by deprotection of the Boc-protecting group and treatment with R 5 to produce a carbamate or carbamate bioisostere (where R 5 should be represented by the same moiety required in the final product or its protected variant) to generate a compound of formula Ia.

[0199] Scheme 4

[0200]

[0201] Scheme 4 relates to a synthetic sequence for preparing a compound of formula Ib. Referring to Scheme 4, compound XVIII can be coupled with a heteroaryl, aryl, alkenyl, heterocycloalkyl, cycloalkyl, spiroheteroalkyl, spiroalkyl, alkyl, and heteroalkyl boronic acid, boronate, or potassium trifluoroborate via a Suzuki-Miyaura coupling reaction. The scope of the reaction type is not limited to Suzuki-Miyaura, but includes Stille, Negishi, Hiyama, and decarboxylative couplings; Sonogashira coupling with alkynes / silylalkynes; and nucleophilic aromatic substitution of amines and alcohols (S N Ar), and via a coupling reaction or S N Ar reaction, using standard selections 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, tert-butanol) to generate compound XIX, where R 1 、R 2 、R 3 and R 4 substituents should be represented by the same moiety required in the final product or its protected variant. Examples of Pd / ligand / base combinations in the coupling reaction include but are not limited to tetrakis(triphenylphosphine)palladium(0) plus sodium carbonate and tris(dibenzylideneacetone)dipalladium(0) plus dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl plus potassium carbonate. In the S N Ar reaction, examples of bases include but are not limited to triethylamine, N,N-diisopropylethylamine, K2CO3, Cs2CO3, K3PO4, tBuOK, and NaH. Removal of the protecting group P 1 gives compound XX. The protecting group P 1In this context, it refers to a group for amine protection well-known to those skilled in the art. For example, P 1 can 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). Alternatively, P 1 can be one of many other protecting groups suitable for amines, including carboxybenzyl (Cbz) or benzoyl (Bz) groups, and can be cleaved under standard conditions known to those skilled in the art. Compound XX can be coupled with compound XXI to generate the racemic compound XXII 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, and subsequently the Boc group is deprotected and treated with R 5 to produce a carbamate or carbamate bioisostere in dichloromethane or other suitable solvents (where R 5 should be represented by the same moiety required in the final product or its protected variant) to generate a compound of formula Ib.

[0202] Scheme 5

[0203]

[0204] Scheme 5 relates to an alternative synthetic route for preparing a compound of formula Ic. Referring to Scheme 5a, compound XXVII can be prepared via two synthetic methods. One synthetic method is the enantiomeric compound XXIII, where R 6 should be represented by an aryl, alkyl or fluoroalkyl substituent, such as 4-methylphenyl, methyl or nonafluorobutyl, which can be coupled with XXIV in the presence of a base such as potassium carbonate or tripotassium phosphate in a suitable solvent, including but not limited to MeCN, DMSO, DMF or THF. Additionally, an alternative route is completed by the coupling of compounds XXV and XXVI. Removal of the protecting group P 1 gives compound XXVIII. The protecting group P 1 in this context refers to a group for amine protection well-known to those skilled in the art. For example, P 1 can be carboxybenzyl (Cbz), which can be cleaved via H2 gas conditions in a suitable solvent, including but not limited to treatment with a solution of wet 10% Pd / C in methanol (MeOH). Alternatively, P 1 can be one of many other protecting groups suitable for amines, including benzyl (Bn) or benzoyl (Bz) groups, and can be cleaved under standard conditions known to those skilled in the art. Compound XXVIII can be coupled with compound XI (where R 1 、R 2 、R 3and R 4 should be represented by the same moiety required in the final product or its protected variant, wherein G 1 is a sulfonate or halogen), to use standard C-N coupling procedures such as, but not limited to, Buchwald-Hartwig coupling reaction and S of amine when appropriate N Ar reaction to produce a compound of formula 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 provide the enantiomeric compound XXX,, and then further treated with R 5 in dichloromethane or other suitable solvents to produce a carbamate or carbamate bioisostere, wherein R 5 should be represented by the same moiety required in the final product or its protected variant to produce a compound of formula Ic. Alternatively, as shown in Scheme 5b, compound XXXI (wherein R 1 、R 2 、R 3 and R 4 should be represented by the same moiety required in the final product or its protected variant), can be coupled with XXVI by double S N 2 cyclization to produce compound XIX. Removal of the protecting group P 1 gives compound XX. The protecting group P 1 in this case refers to a group for amine protection well known to those skilled in the art. For example, P 1 can 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). Alternatively, P 1 can be one of many other protecting groups suitable for amines, including carboxybenzyl (Cbz) or benzoyl (Bz) groups, and can be cleaved under standard conditions known to those skilled in the art. Compound XX can displace the sulfonate of enantiopure compound XXIII, wherein R 6 is an aryl, alkyl or fluoroalkyl substituent such as 4-methylphenyl, methyl, nonafluorobutyl; for example 4-methylphenyl or methyl in the presence of a base such as potassium carbonate in a suitable solvent (including but not limited to DMSO, DMF or THF), to produce 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 provide the enantiomeric compound XXX,, and then further treated with R 5 in dichloromethane or other suitable solvents to produce a carbamate or carbamate bioisostere, wherein R5 should be represented by the same moiety required in the final product or its protected variants to generate the compounds of formula Ic.

[0205] Scheme 6

[0206]

[0207] Scheme 6 relates to the synthetic sequence for preparing the compounds of formula Id. Referring to Scheme 6, compound XXX (wherein R 1 , R 2 , R 3 and R 4 substituents should be represented by the same moiety required in the final product or its protected variants), can subsequently be treated with CO2 gas, a base such as DBU and Z-sulfate-Z or halide / sulfonate-Z (wherein Z should be represented by the same moiety required in the final product or its protected variants) in DMF or other suitable solvent to generate the compounds of formula Id. An alternative synthetic route for preparing the compounds of formula Id is to use triphosgene and ZOH, in a suitable solvent such as DCM and a base such as pyridine (wherein Z should be represented by the same moiety required in the final product or its protected variants), to react with compound XXX to synthesize the carbamate of formula Id.

[0208] Embodiments of the present disclosure

[0209] 1. A compound having the structure of formula (I):

[0210]

[0211] or its N-oxide or a pharmaceutically acceptable salt of said compound or its N-oxide, wherein:

[0212] A is a 6-8 membered heterocycle containing 1 or 2 ring nitrogen atoms and optionally substituted with 1 to 3 substituents independently selected from halogen, OH and C 1-3 alkyl;

[0213] Y is a bond, O, S, CH2, CHF, CF2 or C(OH)H;

[0214] m is 1 or 2;

[0215] n is 1 or 2;

[0216] p is 1 or 2;

[0217] R 1 is H, halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 heteroalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -[O] 0-1 -C 3-6 Cycloalkyl, -[O] 0-1 -C 6-10 Aryl, -[O] 0-1 -4 - 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, and when 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 - 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 - 8-membered heterocycle or -N(C 1-6 Alkyl)-5 - 10-membered heteroaryl, R 1 is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OH, =O, SO2 and C 1-3 Alkyl,

[0218] R 2 is H, halogen, CN, OH, –N(R 6 )(R 7 )、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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;

[0219] R 3 is halogen, CN, OH, –N(R 6 )(R 7 ), C1-6 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 - 8 - membered heterocycle or -[O] 0-1 -5 - 10 - membered heteroaryl, -NH - C 3-6 Cycloalkyl, -NH - C 6-10 Aryl, -NH - 4 - 8 - membered heterocycle, -NH - 5 - 10 - membered heteroaryl, -N(C 1-6 Alkyl)-C 3-6 Cycloalkyl, -N(C 1-6 Alkyl)-C 6-10 Aryl, -N(C 1-6 Alkyl)-4 - 8 - membered heterocycle or -N(C 1-6 Alkyl)-5 - 10 - membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and the C 3-6 Cycloalkyl, C 6-10 Aryl, 4 - 8 - membered heterocycle or 5 - 10 - membered heteroaryl is substituted by 0, 1, 2 or 3 R 3a Substituents;

[0220] Each R 3a Independently selected from halogen, CN, OH, =O, =N(C 1-3 Alkyl), SO2, C 1-6 Alkyl, C 2-10 Olefin, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylene - 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, -S - C 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 0-6Alkylene-C(O)N(C 1-6 alkyl)2, C 0-6 alkylene-NHC(O)C 1-6 alkyl, C 0-6 alkylene-COOH, C 0-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-O-C 1-6 alkyleneSi(C 1-3 alkyl)3 and C 0-6 alkylene-3-6 membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0221] R 4 is H, halogen, CN or OH;

[0222] R 5 is -CO2-Z or a bioisostere thereof;

[0223] Each R 6 and R 7 is independently H, C 1-6 alkyl, C(O)-C 1-6 alkyl, spiro or bicyclic C 8-14 cycloalkyl, 8-14 membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S, and when R 6 or R 7 is not H, it may optionally be substituted by 1, 2 or 3 substituents independently selected from: halogen, CN, OH, =O, SO2, C 0-6 alkylene-NH2, C 0-6 alkylene-NH(C 1-6 alkyl), C 0-6 alkylene-N(C 1-6 alkyl)2, C 0-6 alkylene-SO2C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkoxy, or

[0224] 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; and

[0225] Z is C 1-7 alkyl, C 1-7 haloalkyl, C 3-6 cycloalkyl or C 2-6 alkyne, and Z is optionally substituted by C 1-6 alkoxy or C 3-6 cycloalkyl;

[0226] The condition is that when R 1 , R 2 and R 4 are each H, Y is CH2, m, n and p are each 1, and A is and R 3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy or then R 5 is not CO2CH2CH3.

[0227] 2. The compound or salt according to embodiment 1, wherein A is and X is N, CF, C(OH) or CH.

[0228] 3. The compound or salt according to embodiment 2, the compound or salt having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof:

[0229]

[0230] 4. The compound or salt according to embodiment 3, the compound or salt having the structure of formula (Ib):

[0231]

[0232] 5. The compound or salt according to any one of embodiments 1 to 3, wherein Y is CH2, CHF, CF2 or C(OH)H.

[0233] 6. The compound or salt according to embodiment 5, wherein Y is CH2.

[0234] 7. The compound or salt according to any one of embodiments 1 to 3, 5 and 6, wherein m is 1.

[0235] 8. The compound or salt according to any one of embodiments 1 to 3 and 5 to 7, wherein n is 1.

[0236] 9. The compound or salt according to any one of embodiments 1 to 3 and 5 to 8, wherein p is 1.

[0237] 10. The compound or salt according to embodiment 4, the compound or salt having the structure of formula (Ic):

[0238]

[0239] 11. The compound or salt according to embodiment 4, the compound or salt having the structure of formula (Id):

[0240]

[0241] 12. A compound or salt according to any one of embodiments 1 to 11, wherein R 5 is a CO2Z bioisostere and is selected from

[0242] 13. A compound or salt according to embodiment 1, wherein the compound or salt has the structure of formula (Ie), or a pharmaceutically acceptable salt thereof:

[0243]

[0244] 14. A compound or salt according to any one of embodiments 1 to 11 and 13, wherein R 5 is selected from CO2C 1-7 alkyl,

[0245] 15. A compound or salt according to embodiment 14, wherein R 5 is CO2CH2CH3.

[0246] 16. A compound or salt according to any one of embodiments 1 to 15, wherein R 4 is H or a halogen.

[0247] 17. A compound or salt according to any one of embodiments 1 to 16, wherein R 1 is H, a halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl or C 1-6 alkoxy.

[0248] 18. A compound or salt according to embodiment 17, wherein R 1 is H or a halogen.

[0249] 19. A compound or salt according to any one of embodiments 1 to 18, wherein R 2 is H, a halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.

[0250] 20. A compound or salt according to embodiment 19, wherein R 2 is H, a halogen, C 1-6 alkyl, C1-6 Alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy.

[0251] 21. The compound or salt according to embodiment 20, wherein R 2 is H or halogen.

[0252] 22. The compound or salt according to any one of embodiments 1 to 21, wherein each R 6 and R 7 is independently H, C 1-6 alkyl, or C(O)-C 1-6 alkyl.

[0253] 23. The compound or salt according to embodiment 22, wherein each R 6 and R 7 is independently H or C 1-6 alkyl.

[0254] 24. The compound or salt according to any one of embodiments 1 to 21, wherein at least one R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 10-membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N and O.

[0255] 25. The compound or salt according to any one of embodiments 1 to 24, wherein at least one of R 1 , R 2 and R 4 is halogen.

[0256] 26. The compound or salt according to embodiment 25, wherein at least one of R 1 , R 2 and R 4 is F or Cl.

[0257] 27. The compound or salt according to any one of embodiments 1 to 26, wherein R 3 is -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4- to 8-membered heterocycle, or -[O] 0-1 -5- to 10-membered heteroaryl, and is optionally substituted by 1, 2, or 3 R 3a .

[0258] 28. The compound or salt according to any one of embodiments 1 to 27, wherein R 3 is C 3-6A cycloalkyl group, a 5- to 10-membered heteroaryl group, or a 4- to 8-membered heterocyclic ring, optionally substituted by 1, 2, or 3 R 3a substituents.

[0259] 29. The compound or salt according to any one of embodiments 25 to 28, wherein R 3 is

[0260]

[0261] and is optionally substituted by 1, 2, or 3 R 3a substituents.

[0262] 30. The compound or salt according to embodiment 29, wherein R 3 is and is optionally substituted by 1, 2, or 3 R 3a substituents.

[0263] 31. The compound or salt according to any one of embodiments 1 to 30, wherein R 3 is unsubstituted.

[0264] 32. The compound or salt according to any one of embodiments 1 to 30, wherein R 3 is substituted by 1 or 2 R 3a substituents.

[0265] 33. The compound or salt according to any one of embodiments 1 to 30 and 32, wherein R 3 is substituted by 1 R 3a substituent.

[0266] 34. The compound or salt according to any one of embodiments 1 to 30, 32, and 33, wherein at least one R 3a is halogen, 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-O-C 1-6 alkyl, C 0-6 alkylene-N(C 1-6 alkyl)2, -S-C 1-6 alkyl, C 0-6 alkylene-NHC(O)C 1-6alkyl or C having 1, 2 or 3 heteroatoms selected from N, O and S 0-6 alkylene-3- to 6-membered heterocycle.

[0267] 35. The compound or salt according to embodiment 34, wherein at least one R 3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CHF2, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, F, CN, ═O, SO2, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, CH2OCH3, CH2OCF3, SCH3, NH2, N(CH3)2, NHCOCH3, CD3,

[0268] 36. The compound or salt according to embodiment 35, wherein at least one R 3a is CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH or OCHF2.

[0269] 37. The compound or salt according to embodiment 1, the compound or salt having the structure of formula (If), or a pharmaceutically acceptable salt thereof:

[0270]

[0271] wherein

[0272] R 1 is halogen;

[0273] R 3 is -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4- to 8-membered heterocycle or -[O] 0-1 -5- to 10-membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and R 3 is substituted with 0, 1, 2 or 3 R 3a substituents;

[0274] R 5 is CO2Z. or a bioisostere thereof; and

[0275] Z is C 1-7 alkyl, C 1-7 haloalkyl, C 3-6 cycloalkyl or C2-6 alkyne and optionally substituted by C 1-6 alkoxy or C 3-6 cycloalkyl.

[0276] 38. The compound or salt according to embodiment 37, wherein R 1 is Cl or F.

[0277] 39. The compound or salt according to embodiment 37 or 28, wherein R 3 is a 5- or 6-membered heterocycle containing 1 ring heteroatom selected from S and O, or a 5- or 6-membered heteroaryl containing 2 or 3 ring heteroatoms independently selected from N and S, and R 3 is substituted by 0, 1 or 2 R 1-6 substituents independently selected from halogen, CN, OH and C 3a alkyl.

[0278] 40. The compound or salt according to embodiment 37, 38 or 39, wherein R 5 is CO2C 1-7 alkyl.

[0279] 41. The compound or salt according to embodiment 40, wherein R 5 is CO2Et.

[0280] 42. A compound as described in Table A or a pharmaceutically acceptable salt thereof.

[0281] 43. A pharmaceutical formulation comprising a therapeutically effective amount of the compound or salt according to any one of embodiments 1 to 42 and a pharmaceutically acceptable excipient.

[0282] 44. A method for treating an M4-mediated (or M4-related) disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound or salt according to any one of embodiments 1 to 42.

[0283] 45. The method according to embodiment 44, wherein the M4-mediated (or M4-related) disease or disorder is selected from: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive disorder (e.g., mild cognitive impairment), Parkinson's disease, Parkinson's disease-Levodopa-induced dyskinesia, Huntington's disease, movement disorder, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, Alzheimer's psychosis, dementia-related psychosis, bipolar type I disorder, bipolar type II disorder, bipolar depression, missed diagnosis and / or manic episode associated with bipolar disorder, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorder, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

[0284] 46. The method according to embodiment 45, wherein the M4-mediated (or M4-related) disease or disorder is selected from Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease-Levodopa-induced dyskinesia, and sleep disorder.

[0285] Examples

[0286] The following examples are provided for illustration and are not intended to limit the scope of the disclosure.

[0287] As used throughout these examples, common organic abbreviations are defined as follows:

[0288]

[0289]

[0290] An inert atmosphere (nitrogen or argon) is typically required, especially in cases where oxygen or moisture-sensitive reagents such as dry Pd / C, intermediates, and / or inert conditions are employed. Commercial solvents and reagents are typically used without further purification. Anhydrous solvents are used where appropriate, typically from WuXi-EHS, which meet the following QC specifications for water: a) for N,N-dimethylformamide, <50 ppm; b) for dichloromethane, toluene, and tetrahydrofuran, <100 ppm; c) for methanol, ethanol, 1,4-dioxane, and diisopropylamine <200 ppm. Products are typically dried under vacuum and then subjected to further reaction or biological testing. Mass spectrometry data are reported by liquid chromatography-mass spectrometry (LCMS) and high performance liquid chromatography (HPLC). 11H NMR spectra were recorded at 400 MHz on a Bruker instrument. Chemical shifts (δ) for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm) relative to the residual peak from the deuterated solvent employed. In addition, chiral separation was carried out by supercritical fluid chromatography (SFC) to separate enantiomers of certain compounds of the present disclosure. In some examples, the separated enantiomers were designated as peak 1 and peak 2 according to their elution order. Based on their potencies, chirality can be achieved as the (R)-isomer or the (S)-isomer. LCMS was generally carried out after reactions via detectable intermediates and allowed to proceed to complete conversion before addition of subsequent reagents.

[0291] For synthetic reference procedures in other embodiments or methods, reaction conditions (reaction time and temperature) may vary. For some compounds, microwave-mediated reactions were carried out in a Biotage Initiator microwave reactor. Generally, reactions were monitored by thin layer chromatography or mass spectrometry and workup was carried out when appropriate. Purification can vary between experiments: generally, solvents and solvent ratios for eluents / gradients were selected to provide appropriate Rf or retention times. All starting materials in these preparations and examples are commercially available or can be prepared by methods known in the art or as described herein.

[0292] LCMC Method 1: Instrument: SHIMADZU LC20-MS2010; Mobile phase: 1.5 mL / 4L aqueous solution of TFA (Solvent A) and acetonitrile solution of 0.75 mL / 4L TFA (Solvent B), using an elution gradient of 5%-95% (Solvent B) within 0.7 minutes and held at 95% for 0.4 minutes at a flow rate of 1.5 mL / min; Column: MERCK, RP-18e 25-2mm; Wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0293] LCMC Method 2: Instrument: SHIMADZU LC20-MS2020; Mobile phase: 0.8 mL / 4L aqueous solution of NH3·H2O (Solvent A) and acetonitrile (Solvent B), using an elution gradient of 10%-80% (Solvent B) within 6 minutes and held at 80% for 0.5 minutes at a flow rate of 0.8 mL / min; Column: Titank C18; 5um; 2.1×50mm; Wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0294] LCMC Method 3: Instrument: SHIMADZU LCMS-2020; Mobile phase: From an aqueous solution of 5% ACN (0.01875% TFA) (0.0375% TFA) to an aqueous solution of 95% ACN within 0.60 minutes, flow rate set at 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, flow rate set at 2.0 mL / min; return to an aqueous solution of 5% ACN and hold for 0.02 min, flow rate set at 2.0 mL / min; Column: EVO C18 2.1×30 mm, 5um. Column temperature: 50 °C.

[0295] HPLC Method 1: Instrument: SHIMADZU LC20-MS2020; Mobile phase: 0.2 ML / 1L aqueous solution of NH3·H2O (Solvent A) and acetonitrile (Solvent B), use an elution gradient of 10% - 80% (Solvent B) within 6 minutes and hold at 80% for 2 minutes at a flow rate of 0.8 mL / min; Column: Titank C18, 5μm, 2.1×50 mm; Wavelength: UV 220 nm, 215 nm and 254 nm; Column temperature: 50 °C.

[0296] HPLC Method 2: Instrument: SHIMADZU LC-20AD; Mobile phase: From an aqueous solution of 10% ACN (0.018% TFA) (0.037% TFA) to an aqueous solution of 80% ACN within 3.00 minutes, flow rate set at 1.5 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate set at 1.5 mL / min; return to an aqueous solution of 10% ACN and hold for 0.30 min, flow rate set at 2.0 mL / min; Column: Kinetex C18 LC column 4.6×50 mm, 5um. Wavelength: UV 220 nm and 254 nm. Column temperature: 50 °C.

[0297] SFC Method 1: Instrument: CAS-SH-ANA-SFC-G (Agilent1260 with DAD detector); Column: ChiralPak AD-3 150×4.6 mm I.D., 3um; Mobile phase: A: CO2, B:

[0298] Methanol (0.05% DEA) isocratic: 40% B; Flow rate: 2.5 mL / min, Column temperature: 40 °C; Back pressure: 100 bar.

[0299] SFC Method 2: Instrument: CAS-SH-ANA-SFC-L (Waters UPCC with PDA detector); Column: Chiralcel OD-3 I.D., 3 um. Mobile phase: A: CO2, B: methanol (0.05% DEA) Gradient: from 5% to 40% B in 4 min and from 40% to 5% B in 0.2 min, then hold 5% B for 1.8 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C; Back pressure: 1500 psi.

[0300] Example #1: Synthesis of Ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate P1) Synthesis

[0301]

[0302] Step 1: Synthesis of tert-butyl 6-(4-benzyloxycarbonylpiperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C1) At 25 °C, add CH3COOH (13.2 g, 221 mmol) to a mixture of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (commercially available, 100 g, 444 mmol), benzyl piperazine-1-carboxylate (commercially available, 117 g, 532 mmol) and molecular sieve (67.5 g) in DCE (2.30 L). Stir the mixture at 25 °C for 60 min, then add NaBH(OAc)3 (235 g, 1.10 mol) in portions and stir at 25 °C for 15 h. Pour the mixture into saturated aqueous NaHCO3 (1.70 L), stir for 10 min and separate. Extract the aqueous phase with DCM (3 × 800 mL). Wash the combined organic phases with brine (1.20 L), dry over anhydrous Na2SO4, filter and concentrate in vacuo at 50 °C. Grind the crude product with petroleum ether (1.80 L) at 25 °C for 60 min. Filter the suspension and dry the cake in vacuo at 50 °C to obtain intermediate C1.

[0303] Step 2: Synthesis of benzyl 4-(2-azaspiro[3.4]oct-6-yl)piperazine-1-carboxylate (C2) Add TFA (286 g, 2.51 mol) 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). Stir the mixture at 25 °C for 12 h. Concentrate the reaction mixture under reduced pressure at 50 °C to obtain intermediate C2 (TFA salt), which is used directly in the next step without further purification. LCMS [M+H] + 330.

[0304] Step 3: Synthesis of Ethyl 6-(4-(benzyloxycarbonyl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C3) At 25 °C, NaHCO3 (541 g, 6.45 mol) was added to a mixture of 4-(2-azaspiro[3.4]oct-6-yl)piperazine-1-carboxylic acid benzyl ester (220 g, 496 mmol, TFA salt) in DCM (1.50 L) and H2O (750 mL). The reaction mixture was stirred at 25 °C for 10 min and ethyl chloroformate (178 g, 1.64 mol) was added dropwise at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (500 mL), stirred at 25 °C for 30 min, and separated. The aqueous phase was extracted with DCM (2 × 600 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the intermediate C3.

[0305] Step 4: (6R)-Ethyl 6-(4-(benzyloxycarbonyl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate and (6S)-Ethyl 6-(4-(benzyloxycarbonyl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (C4A and C4B)

[0306] The racemic mixture of ethyl 6-(4-(benzyloxycarbonyl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (430 g, 1.07 mol) was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm * 50 mm, 10 um); mobile phase: [0.1% NH3H2O MeOH]; B%: 20%, min) to give intermediate C4A and intermediate C4B. LCMS [M+H] + 402.

[0307] Step 5: Synthesis of (6R)-Ethyl 6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (P1)

[0308] At 20 °C, wet 10% Pd / C (15.0 g) was added to a solution of (6R)-ethyl 6-(4-(benzyloxycarbonyl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (120 g, 299 mmol) in MeOH (1200 mL). The suspension was degassed under vacuum and purged with H2 gas several times. The mixture was stirred at 25 °C under H2 gas (15 psi) for 16 h. The reaction mixture was filtered and washed with MeOH (2 × 1,000 mL). The filtrate was concentrated to give the intermediate P1.

[0309] Example #2: Synthesis of Ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane- 2-carboxylate (Intermediate P2)

[0310]

[0311] Step 1: Synthesis of Ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P2) and Ethyl (6R)-6-[4-(6-bromo-5-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C5A) To a mixture of 2-bromo-3,5-difluoro-pyridine (5.00 g, 25.7 mmol), K2CO3 (7.13 g, 51.5 mmol) in DMF (100 mL) was added Ethyl (6R)-6-piperazin-1-yl-2-azaspiro[3.4]octane-2-carboxylate (7.24 g, 27.0 mmol). The mixture was then heated to 110 °C and stirred at 110 °C for 22 h under a N2 atmosphere. The mixture was cooled to 25 °C and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 3% MeOH / DCM) to give a mixture of P2 and C5A.

[0312] Step 2: Ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (P2)

[0313] The mixture of P2 and C5A was further separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 um); mobile phase: [0.1% NH3H2O ETOH]; B%: 35% - 35%, B3.5; 60 min) to give the intermediate P2. 1 1H NMR (CDCl3 400 MHz) δ H = 7.97 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.98 - 3.84 (m, 2H), 3.82 - 3.77 (m, 2H), 3.16 (brs, 4H), 2.72 (brs, 5H), 2.20 - 2.15 (m, 1H), 2.05 - 1.75 (m, 5H), 1.24 (t, J = 6.8 Hz, 3H). 19 19F NMR (CDCl3 400 MHz) δ F = -128.178.

[0314] Example #3: Synthesis of Ethyl (6R)-6-[4-[2-(5-methoxy-3-pyridinyl)-3-pyridinyl]piperazin-1-yl]-2-aza spiro[3.4]octane-2-carboxylate (A1)

[0315]

[0316] Step 1: Synthesis of Ethyl (6R)-6-[4-(2-chloro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C6) A mixture of 2-chloro-3-iodo-pyridine (373 mg, 1.56 mmol), intermediate P1 (500 mg, 1.87 mmol), Pd2(dba)3 (143 mg, 156 μmol), XantPhos (180 mg, 312 μmol), and t-BuONa (225 mg, 2.34 mmol) in 1,4-dioxane (10.0 mL) was degassed in vacuo and purged with N2 gas several times. The reaction mixture was heated to 110 °C and stirred at 110 °C for 16 h under a N2 atmosphere. The mixture was cooled to 20 °C, and dichloromethane (50 mL) was added to the mixture. The mixture was filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: dichloromethane solution of 0 - 10% methanol) to give intermediate C6. LCMS m / z [M+H]+ 379.

[0317] Step 2: Synthesis of Ethyl (6R)-6-[4-[2-(5-methoxy-3-pyridinyl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A1) A mixture of intermediate C6 (50.0 mg, 132 μmol), (5-methoxy-3-pyridinyl)boronic acid (40.4 mg, 264 μmol), Na2CO3 (42.0 mg, 396 μmol), and PdCl2(dtpbf) (8.60 mg, 13.2 μmol) in 1,4-dioxane (4.00 mL) and H2O (1.00 mL) was degassed in vacuo and purged with N2 several times. The reaction mixture was heated to 85 °C and stirred at 85 °C for 16 h under a N2 atmosphere. The mixture was filtered and concentrated in vacuo to give the crude product. The crude product was purified by preparative 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 A1. 1 HNMR (CDCl3 400 MHz) δH = 8.90 (s, 1H), 8.41 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 7.50 - 7.34 (m, 1H), 7.26 - 7.22 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.98 - 3.82 (m, 5H), 3.80 - 3.74 (m, 2H), 3.28 - 2.86 (m, 4H), 2.83 - 2.25 (m, 5H), 2.21 - 1.80 (m, 5H), 1.57 - 1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 452。

[0318] Example #4: Synthesis of Ethyl (6R)-6-[4-[5-fluoro-2-(6-fluoro-3-pyridinyl)-3-pyridinyl]piperazin-1-yl]-2-aza spiro[3.4]octane-2-carboxylate (A2)

[0319]

[0320] Step 1: Synthesis of Ethyl (6R)-6-[4-[5-Fluoro-2-(6-fluoro-3-pyridinyl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A2) The mixture of intermediate P2 (40.0 mg, 90.6 μmol), 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30.3 mg, 136 μmol), Pd(dppf)Cl2 (6.63 mg, 9.06 μmol) and Na2CO3 (28.8 mg, 272 μmol) in 1,4-dioxane (2.00 mL) and H2O (0.500 mL) was degassed and purged with N2 gas three times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150×25 mm×5 μm; mobile phase: [water (FA)-ACN]; B%: 7% - 37%, 10 min) to obtain A2. 1 1H NMR (CDCl3 400 MHz) δ H = 8.86 (d, J = 2.4 Hz, 1H), 8.32 (dt, J = 2.4 Hz, 8.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.17 - 7.10 (m, 1H), 7.01 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.92 - 3.74 (m, 4H), 3.04 - 2.78 (m, 4H), 2.76 - 2.34 (m, 5H), 2.17 - 1.66 (m, 6H), 1.23 (t, J = 7.2 Hz, 3H). 1919F NMR (CDCl3, 400 MHz) δ F = -68.347, -126.520. LCMS m / z [M+H] + 458

[0321] Example #5: Synthesis of Ethyl (6R)-6-[4-(2-pyrrolidin-1-yl-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]oct ane-2-carboxylate (A3)

[0322]

[0323] Step 1: Synthesis of Ethyl (6R)-6-[4-(2-Pyrrolidin-1-yl-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A3) A mixture of intermediate C6 (29.0 mg, 76.5 μmol) and pyrrolidine (10.9 mg, 153 μmol, 12.8 μL) in DIPEA (0.500 mL) was heated to 100 °C and stirred for 16 h. The mixture was then stirred at 120 °C - 130 °C for an additional 32 h. The mixture was then cooled to 20 °C and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40 mm×3 μm; mobile phase: [water (0.05% NH3·H2O + 10 mM NH4HCO3) - ACN]; B%: 40% - 70%, 8 min) to give A3. 1 1H NMR (CDCl3, 400 MHz) δ H = 7.93 - 7.88 (m, 1H), 7.19 - 7.14 (m, 1H), 6.64 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.94 - 3.83 (m, 2H), 3.82 - 3.76 (m, 2H), 3.56 - 3.50 (m, 4H), 3.11 - 2.79 (m, 4H), 2.78 - 2.36 (m, 5H), 2.21 - 2.10 (m, 1H), 2.02 - 1.64 (m, 9H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 414

[0324] Example #6: Synthesis of Ethyl 6-(4-(2-(azetidin-1-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4] octane-2-carboxylate (A4)

[0325]

[0326] Step 1: Synthesis of tert-butyl 4-(2-fluoro-3-pyridyl)piperazine-1-carboxylate (C7) To a mixture of 3-bromo-2-fluoropyridine (2.00 g, 11.4 mmol), tert-butyl piperazine-1-carboxylate (2.54 g, 13.6 mmol), tert-butyl piperazine-1-carboxylate (2.54 g, 13.6 mmol) and tBuONa (1.64 g, 17.1 mmol) in toluene (30.0 mL) was added Pd2(dba)3 (520 mg, 568 μmol) and XantPhos (658 mg, 1.14 mmol). The mixture was degassed under vacuum and purged with N2 gas several times. Then the reaction mixture was heated to 100 °C and stirred at 100 °C under N2 atmosphere for 16 h. The mixture was cooled to 25 °C, and then H2O (50 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (4 × 50 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: 0 - 20% ethyl acetate / petroleum ether) to give the intermediate C7. LCMS m / z 282 [M+H] + . 1 H NMR (CDCl3 400 MHz) δ H = 7.82 - 7.74 (m, 1H), 7.25 - 7.20 (m, 1H), 7.14 - 7.10 (m, 1H), 3.62 - 3.58 (m, 4H), 3.10 - 3.00 (m, 4H), 1.48 (s, 9H). LCMS m / z [M+H] + 282.

[0327] Step 2: Synthesis of 1-(2-fluoro-3-pyridyl)piperazine (C8) To a mixture of intermediate C7 (2.19 g, 7.78 mmol) in EA (25.0 mL) was added a solution of HCl in EA (4 M, 15.0 mL). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated in vacuo to give the crude C8HCl salt, which was used in the next step without further purification.

[0328] Step 3: Synthesis of Ethyl 6-[4-(2-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C9) A mixture of intermediate C8 (1.69 g, 7.76 mmol, HCl salt) and Et3N (3.93 g, 38.8 mmol) in DCE (20.0 mL) was stirred at 25 °C for 10 minutes. Then ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (3.06 g, 15.5 mmol) and AcOH (233 mg, 3.88 mmol) were added to the mixture. The mixture was stirred at 25 °C for 20 min. Then NaBH(OAc)3 (4.94 g, 23.3 mmol) was added to the mixture at 25 °C and stirred at 25 °C for 16 h. Saturated aqueous NaHCO3 solution (80 mL) was added to the mixture, and then the mixture was extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: dichloromethane solution of 0 - 5% methanol) to give intermediate C9. LCMS m / z [M+H] + 363.

[0329] Step 4: Synthesis of Ethyl 6-[4-[2-(azetidin-1-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A4) A mixture of intermediate C9 (100 mg, 276 μmol), Cs2CO3 (360 mg, 1.10 mmol) and azetidine (77.4 mg, 828 μmol, HCl salt) in DMA (5.00 mL) was heated to 130 °C - 140 °C and stirred at 130 °C - 140 °C for 26 h. The mixture was cooled to 25 °C. Then H2O (20 mL) was added to the mixture. The aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with H2O (3 × 50 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40 mm×3 μm; mobile phase: [water (0.05% NH3H2O)-ACN]; B%: 33% - 59%, 8 min) to give A4. 1 HNMR (CDCl3 400 MHz) δ H= 7.88 (dd, J = 1.6 Hz, 5.2 Hz, 1H), 7.09 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 6.62 (dd, J = 5.2 Hz, 7.6 Hz, 1H), 4.14 - 4.02 (m, 6H), 3.90 - 3.81 (m, 2H), 3.80 - 3.72 (m, 2H), 3.09 - 2.78 (m, 4H), 2.75 - 2.37 (m, 5H), 2.27 - 2.18 (m, 2H), 2.16 - 2.08 (m, 1H), 1.94 - 1.78 (m, 3H), 1.76 - 1.68 (m, 1H), 1.62 - 1.49 (m, 1H), 1.22 (t, J = 6.8 Hz, 3H). LCMS m / z [M+H] + 400。

[0330] Example #7: Synthesis of Ethyl (R)-6-(4-(2-cyclobutoxypyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane- 2-carboxylate (A5)

[0331]

[0332] Step 1: Synthesis of 2-(cyclobutyloxy)-3-iodopyridine (C10) A mixture of 2-fluoro-3-iodopyridine (100 mg, 448 μmol), cyclobutanol (32.3 mg, 448 μmol) and Cs2CO3 (292 mg, 897 μmol) in DMSO (1.00 mL) was heated to 90 °C and stirred at ~90 °C - 100 °C for 17 h. The reaction mixture was cooled to 20 °C. Then H2O (10 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent: petroleum ether) to give the intermediate C10. LCMS m / z [M+H] + 276。

[0333] Step 2: Synthesis of Ethyl (6R)-6-[4-[2-(Cyclobutoxy)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A5) To a mixture of Intermediate P1 (38.5 mg, 144 μmol), Intermediate C10 (33.0 mg, 120 μmol) and t-BuONa (23.1 mg, 240 μmol) in 1,4-dioxane (0.500 mL) was added XPhos (11.4 mg, 24.0 μmol) and Pd(OAc)2 (5.39 mg, 24.0 μmol). Then the mixture was degassed under vacuum and purged with N2 gas several times. The mixture was heated to 90 °C and stirred for 16 h. The mixture was cooled to 20 °C, filtered and concentrated in vacuo, and purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40 mm×3 μm; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 40%-70%, 8 min) to give A5. 1 1H NMR (CDCl3 400 MHz) δ H = 7.75 (d, J = 4.0 Hz, 1H), 7.07 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.80 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 5.29 - 5.19 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95 - 3.84 (m, 2H), 3.83 - 3.77 (m, 2H), 3.33 - 3.01 (m, 4H), 2.95 - 2.55 (m, 5H), 2.54 - 2.43 (m, 2H), 2.25 - 2.05 (m, 3H), 2.03 - 1.77 (m, 5H), 1.75 - 1.65 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 415.

[0334] Example #8: Synthesis of Ethyl (R)-6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro [3.4]octane-2-carboxylate (A6)

[0335]

[0336] Step 1: Synthesis of 2-(3,5-difluoropyridin-2-yl)pyrazine (C11) A mixture of 2-bromo-3,5-difluoro-pyridine (50.0 mg, 258 μmol), tributyl(pyrazin-2-yl)-stannane (142 mg, 387 μmol), CuI (4.91 mg, 25.8 μmol), and Pd(PPh3)4 (29.8 mg, 25.8 μmol) in toluene (2.00 mL) was degassed and purged with N2 several times at 20 °C. Then the mixture was heated to 110 °C and stirred at 110 °C for 12 h. The mixture was cooled to 20 °C and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (eluent: dichloromethane solution of 0 - 3% methanol) to obtain intermediate C11. 1 HNMR (CDCl3 400 MHz) δ H = 9.24 (s, 1H), 8.74 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.45 - 7.35 (m, 1H). LCMS m / z [M + H] + 194.

[0337] Step 2: Synthesis of ethyl (R)-6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (A6) A mixture of intermediate P1 (69.2 mg, 259 μmol), intermediate C11 (50.0 mg, 259 μmol), and DIPEA (0.500 mL, 2.87 mmol) in pyridine (0.500 mL) was stirred at 130 °C for 24 h. The mixture was concentrated in vacuo and purified by flash silica gel chromatography and preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: [water (NH3·H2O + NH4HCO3)-ACN]; B%: 40% - 70%, 7 min) to obtain A6. 1 HNMR (CDCl3 400 MHz) δ H = 9.23 (s, 1H), 8.73 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 7.16 (br d, J = 10.0 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.88 - 3.74 (m, 4H), 2.91 (br s, 4H), 2.63 - 2.38 (m, 5H), 2.12 - 2.03 (m, 1H), 1.95 - 1.75 (m, 3H), 1.70 - 1.60 (m, 1H), 1.52 - 1.42 (br s, 1H), 1.23 (t, J = 7.2 Hz, 3H). 1919F NMR (CDCl3 400 MHz) δ F = -124.49. LCMS m / z [M+H] + 441.

[0338] Example #9: Synthesis of Ethyl (6R)-6-[4-(5-fluoro-2-tetrahydropyran-4-yl-3-pyridinyl)piperazin-1-yl]-2-azaspiro [3.4]octane-2-carboxylate (A7)

[0339]

[0340] Step 1: Synthesis of Ethyl (6R)-6-[4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (C12) A mixture of Ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 227 μmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (71.4 mg, 340 μmol), Pd(dppf)Cl2 (16.6 mg, 22.7 μmol) and Na2CO3 (72.0 mg, 680 μmol) in 1,4-dioxane (2.00 mL) and H2O (0.250 mL) was degassed and purged with N2 several times at 20 °C. Then the mixture was heated to 90 °C and stirred at 90 °C for 12 h. The mixture was cooled to 20 °C and concentrated in vacuo, and purified by flash silica gel chromatography (eluent: 0 - 5% MeOH / DCM) to give the crude product. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm; mobile phase: [water (NH3·H2O + NH4HCO3)-ACN]; B%: 40% - 70%, 7 min) to give C12 (19.8 mg, 42.3 μmol, yield 18.7%, purity 94.9%). 1 1H NMR (CDCl3 400 MHz) δ H= 8.08 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 6.36 (br s, 1H), 4.33 (d, J = 2.8 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.95 - 3.72 (m, 6H), 3.03 (br s, 4H), 2.70 - 2.49 (m, 7H), 2.14 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.02 - 1.79 (m, 3H), 1.77 - 1.71 (m, 1H), 1.62 - 1.49 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 445。

[0341] Step 2: Synthesis of Ethyl (6R)-6-[4-(5-Fluoro-2-tetrahydropyran-4-yl-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A7) At 20 °C under N2, wet Pd / C (50.0 mg, 10.0% purity) was added to a solution of ethyl (6R)-6-[4-[2-(3,6-Dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (50.0 mg, 112 μmol) in EtOH (5.00 mL), and the mixture was degassed and purged with H2 three times. Then the mixture was stirred at 40 °C under H2 (15 psi) for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo and purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 40% - 70%, 7 min) to give Compound 7 (27.0 mg, 58.1 μmol, yield 51.7%, purity 96.1%). 1 H NMR (CDCl3 400 MHz) δ H = 8.20 (br s, 1H), 7.11 (br d, J = 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 4H), 3.96 - 3.77 (m, 4H), 3.53 (br t, J = 11.6 Hz, 2H), 3.32 (br t, J = 12.4 Hz, 1H), 2.90 (br s, 4H), 2.66 (br s, 5H), 2.18 - 1.69 (m, 6H), 1.58 (s, 4H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 447。

[0342] Example #10: Synthesis of Ethyl (6R)-6-[4-(5-fluoro-2-thiazol-4-yl-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A8)

[0343]

[0344] To a mixture of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 227 μmol), tributyl(thiazol-4-yl)stannane (127 mg, 340 μmol) in toluene (1.00 mL) was added CuI (4.32 mg, 22.7 μmol) and Pd(PPh3)4 (26.2 mg, 22.7 μmol). The mixture was degassed under vacuum and purged with N2 gas several times. The reaction mixture was stirred at 110 °C for 12 h under a N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–5% MeOH / DCM) and further purified by preparative HPLC (column: Welch Xtimate C18, 150×30 mm×5 μm; mobile phase: [water (FA)-ACN]; gradient: 0% - 40% B in 9 min) to give ethyl (6R)-6-[4-(5-fluoro-2-thiazol-4-yl-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as a yellow oil (52.0 mg, 117 μmol, yield 51.5%, purity 100%). 1 1H NMR (CDCl3 400 MHz) δ H = 8.92 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.19 - 7.09 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.95 - 3.73 (m, 4H), 3.04 (br s, 4H), 2.90 - 2.70 (m, 5H), 2.23 - 2.11 (m, 1H), 2.03 - 1.90 (m, 3H), 1.88 - 1.78 (m, 1H), 1.77 - 1.68 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 446.

[0345] Example #11: Synthesis of Ethyl (6R)-6-[4-[5-fluoro-2-(tetrahydropyran-4-ylamino)-3-pyridinyl]piperazin-1-yl]- 2-azaspiro[3.4]octane-2-carboxylate (A9)

[0346]

[0347] A mixture of tetrahydropyran-4-amine (68.8 mg, 680 μmol), ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (150 mg, 340 μmol), Pd2(dba)3 (31.1 mg, 34.0 μmol), t-BuONa (98.0 mg, 1.02 mmol), and 2-[bis(3,5-trifluoromethylphenyl)phosphino]-3,6-dimethoxy-2,6-dimethylamino-1,1-biphenyl (L7, 25.7 mg, 34.0 μmol) in 1,4-dioxane (2.00 mL) was degassed under vacuum and purged with N2 gas three times. Then the mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–3% MeOH / DCM) and further purified by preparative HPLC (column: Boston Prime C18, 150×30 mm×5 μm; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 52%–82%, 7 min) to give ethyl (6R)-6-[4-[5-fluoro-2-(tetrahydropyran-4-ylamino)-3-pyridyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid (28.7 mg, 61.7 μmol, yield 14.0%, purity 99.3%). 1 H NMR (CDCl3 400 MHz) δH = 7.73 (s, 1H), 6.94 (dd, J = 2.4 Hz, 9.2 Hz, 1H), 4.83 (d, J = 7.2 Hz, 1H), 4.18 - 4.03 (m, 3H), 4.01 - 3.77 (m, 6H), 3.58 (t, J = 10.8 Hz, 2H), 2.89 (brs, 4H), 2.70 - 2.55 (m, 5H), 2.20 - 2.10 (m, 1H), 2.05 (d, J = 11.2 Hz, 2H), 1.98 - 1.80 (m, 3H), 1.78 - 1.66 (m, 1H), 1.56 - 1.46 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 462。

[0348] Example #12: Synthesis of Ethyl (6R)-6-[4-[5-fluoro-2-(4-methylpyrazol-1-yl)-3-pyridinyl]piperazin-1-yl]-2- azaspiro[3.4]octane-2-carboxylate (A10)

[0349]

[0350] To a mixture of ethyl (6R)-6-[4-(2-bromo-5-fluoro-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (30.0 mg, 68.0 μmol), 4-methyl-1H-pyrazole (8.37 mg, 102 μmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (9.67 mg, 68.0 μmol) in DMF (1.00 mL) was added CuI (13.0 mg, 68.0 μmol) and K3PO4 (43.3 mg, 204 μmol) in one portion. The mixture was degassed under vacuum and purged with N2 gas several times. The reaction mixture was stirred at 130 °C for 12 h under a N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18, 80×40 mm×3 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; gradient: 39%-69% B in 8 min) to give ethyl (6R)-6-[4-[5-fluoro-2-(4-methylpyrazol-1-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid (9.40 mg, 21.2 μmol, yield 31.3%, purity 100%). 1 HNMR (CD3OD 400 MHz) δ H = 8.09 - 7.83 (m, 2H), 7.60 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.93 - 3.70 (m, 4H), 2.75 (d, J = 4.4 Hz, 4H), 2.69 - 2.45 (m, 5H), 2.20 (s, 3H)), 2.18 - 2.11 (m, 1H), 1.99 - 1.81 (m, 3H), 1.70 (dd, J = 9.6 Hz, 12.8 Hz, 1H), 1.57 - 1.46 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 443。

[0351] Example #13: (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-1-piperidinyl]-2-azaspiro [3.4]Ethyl octane-2-carboxylate (A11) and (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-1-piperidinyl]-2- Synthesis of ethyl azaspiro[3.4]octane-2-carboxylate (A12)

[0352]

[0353] Step 1: Synthesis of 5-fluoro-2-(pyrazin-2-yl)pyridin-3-amine (C13)

[0354] A mixture of 2-bromo-5-fluoro-pyridin-3-amine (1.00 g, 5.24 mmol), tributyl(pyrazin-2-yl)stannane (1.93 g, 5.24 mmol), CuI (99.7 mg, 524 μmol) and Pd(PPh3)4 (605 mg, 524 μmol) in toluene (20.0 mL) was degassed under reduced pressure and purged with N2 gas three times. Then the mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to remove toluene. The residue was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0 - 17% ethyl acetate / petroleum ether) to give 5-fluoro-2-pyrazin-2-yl-pyridin-3-amine as an off-white solid (700 mg, 3.52 mmol, yield 67.1%, purity 95.5%). LCMS m / z [M+H] + 191。

[0355] Step 2: Synthesis of 2-(3-bromo-5-fluoropyridin-2-yl)pyrazine (C14)

[0356] To a solution of 5-fluoro-2-pyrazin-2-yl-pyridin-3-amine (700 mg, 3.68 mmol) in water (4.00 mL) at 0 °C was added dropwise a solution of HBr in H2O (4.00 mL, purity 48%). The mixture was stirred at 0 °C for 0.5 h. Then a solution of NaNO2 (279 mg, 4.05 mmol) in water (2.00 mL) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for another 0.5 h. The mixture was added to a solution of CuBr (581 mg, 4.05 mmol) in water (2.00 mL) at 60 °C. The mixture was stirred at 60 °C for 2 h. The mixture was poured into a saturated aqueous NaHCO3 solution (100 mL) and stirred for 5 min. The mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0 - 11% ethyl acetate / petroleum ether) to give 2-(3-bromo-5-fluoro-2-pyridinyl)pyrazine as an off-white solid (580 mg, 2.09 mmol, yield 56.8%, purity 91.5%). LCMS m / z [M+H] + 254,256。

[0357] Step 3: Synthesis of tert-butyl 5-fluoro-2-(pyrazin-2-yl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (C15)

[0358] 2-(3-Bromo-5-fluoro-2-pyridyl)pyrazine (580 mg, 2.28 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (706 mg, 2.28 mmol), Pd(PPh3)4 (264 mg, 228 μmol) and Na2CO3 (726 mg, 6.85 mmol) in a mixture of water (1.00 mL) and 1,4-dioxane (8.00 mL) were degassed under reduced pressure and purged with N2 gas three times. Then the mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The mixture was filtered and the organic phase was concentrated under reduced pressure to give a residue. The residue was diluted with water (80 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-14% ethyl acetate / petroleum ether) to give tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow oil (840 mg, 1.87 mmol, yield 81.9%, purity 79.3%). 1 HNMR (CDCl3 400 MHz) δ H = 9.10 (s, 1H), 8.67 - 8.42 (m, 3H), 7.37 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 5.60 (s, 1H), 3.97 (s, 2H), 3.51 (t, J = 5.2 Hz, 2H), 2.15 (s, 2H), 1.48 (s, 9H). LCMS m / z [M + H] + 357。

[0359] Step 4: Synthesis of 5-fluoro-2-(pyrazin-2-yl)-1',2',3',6'-tetrahydro-3,4'-bipyridine (C16)

[0360] To a solution of tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 2.24 mmol) in DCM (12.0 mL) was added HCl / 1,4-dioxane (4 M, 4.00 mL). The mixture was stirred at room temperature for 12 h. The mixture was adjusted to pH = 8 with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (3 × 40 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-[5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-2-pyridyl]-pyrazine as a yellow oil (510 mg, crude). The crude product was used in the next step without further purification. LCMS m / z [M + H] + 257。

[0361] Step 5: Synthesis of ethyl 6-(5-fluoro-2-(pyrazin-2-yl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)-2-aza Spiro[3.4]octane-2-carboxylate (C17)

[0362] A mixture of 2-[5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-2-pyridinyl]pyrazine (510 mg, 1.99 mmol) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (432 mg, 2.19 mmol) in DCE (16.0 mL) was stirred at room temperature for 1 hour. Then NaBH(OAc)3 (1.27 g, 5.97 mmol) and AcOH (12.0 mg, 199 μmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was poured into saturated aqueous NaHCO3 (80 mL) and stirred for 5 min. The mixture was extracted with DCM (3 × 60 mL). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 4% MeOH / DCM) to give ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-3,6-dihydro-2H-pyridin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as a yellow oil (600 mg, 1.35 mmol, yield 67.6%, purity 98.1%). The yellow oil (100 mg) was purified by preparative HPLC (column: Boston Prime C18, 150 × 30 mm × 5 μm; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 45% - 75%, 7 min) to give ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-3,6-dihydro-2H-pyridin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as a yellow oil (41.1 mg, 93.9 μmol, yield 41.1%, purity 100%). 1 HNMR (CDCl3 400 MHz) δ H = 9.03 (s, 1H), 8.81 - 8.30 (m, 3H), 7.47 - 7.33 (m, 1H), 5.58 (s, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.96 - 3.83 (m, 2H), 3.84 - 3.74 (s, 2H), 3.09 (br s, 2H), 2.80 - 2.40 (m 3H), 2.30 - 2.05 (m, 3H), 2.02 - 1.80 (m, 3H), 1.89 - 1.60 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 438。

[0363] Step 6: Synthesis of (R)-6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperidin-1-yl)-2-azaspiro[3.4] Ethyl octane-2-carboxylate (A11) and (S)-6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperidin-1-yl)-2-aza Spiro[3.4]octane-2-carboxylate (A12)

[0364] Ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-3,6-dihydro-2H-pyridin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 457 μmol), Pd / C (50.0 mg, 10% c purity) in EtOH (6.00 mL) was degassed under reduced pressure and purged with H2 gas three times, and then the mixture was stirred at 40 °C under a H2 atmosphere (40 psi) for 48 hours. The mixture was filtered and the organic phase was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 5% MeOH / DCM) and further separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O MeOH]; B%:: 50% - 50%) to give ethyl (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate as a yellow oil (14.7 mg, 33.2 μmol, yield 14.6%, purity 99.4%). 1 H NMR (CDCl3 400 MHz) δ H = 9.07 (s, 1H), 8.70 - 8.52 (m, 2H), 8.43 (d, J = 2.4 Hz, 1H), 7.68 - 7.38 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.98 - 3.80 (m, 2H), 3.77 (s, 2H), 3.45 - 2.88 (m, 3H), 2.81 - 2.29 (m, 2H), 2.27 - 2.07 (m, 1H), 2.05 - 1.62 (m, 10H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 440. Ethyl (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate as a yellow oil (15.7 mg, 33.6 μmol, yield 14.8%, purity 93.9%). 1 HNMR (CDCl3 400 MHz) δ H= 9.08 (s, 1H), 8.68 - 8.54 (m, 2H), 8.44 (d, J = 2.8 Hz, 1H), 7.71 - 7.39 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 4.02 - 3.81 (m, 2H), 3.77 (s, 2H), 3.51 - 2.84 (m, 3H), 2.83 - 2.30 (m, 2H), 2.23 - 2.14 (m, 1H), 2.11 - 1.62 (m, 10H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 440。

[0365] Example #14: (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy-1-piperidinyl]-2-aza Spiro[3.4]octane-2-carboxylate (A13) and (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy- 1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (A14)

[0366]

[0367] Step 1: Synthesis of tert-butyl 4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (C18) Synthesis

[0368] To a solution of tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-3,6-dihydro-2H-pyridine-1-carboxylate (400 mg, 1.12 mmol) in i-PrOH (20.0 mL) and DCM (4.00 mL) was added phenylsilane (486 mg, 4.49 mmol) and tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-en-1-yloxy]manganese (204 mg, 337 μmol). The reaction mixture was stirred at room temperature under an O2 atmosphere (15 psi) for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 30% ethyl acetate / petroleum ether) to afford tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxypiperidine-1-carboxylate as a yellow oil (60.0 mg, 160 μmol, 14.3% yield). 1 H NMR (CD3OD 400 MHz) δ H = 9.05 - 8.85 (m, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.63 - 8.60 (m, 1H), 8.52 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 3.89 (d, J = 12.8 Hz, 2H), 3.24 - 3.07 (m, 2H), 1.97 - 1.74 (m, 4H), 1.44 (s, 9H). LCMS m / z [M + H - 56] + 319。

[0369] Step 2: Synthesis of 4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)piperidin-4-ol (C19)

[0370] To a solution of tert-butyl 4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy-piperidine-1-carboxylate (60.0 mg, 160 μmol) in DCM (8.00 mL) was added HCl / 1,4-dioxane (4 M, 4.00 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)piperidin-4-ol (50.0 mg, crude, HCl salt) as a yellow solid. The crude product was used in the next step without further purification. LCMS m / z [M+H] + 275。

[0371] Step 3: Synthesis of ethyl 6-(4-(5-fluoro-2-(pyrazin-2-yl)pyridin-3-yl)-4-hydroxypiperidin-1-yl)-2-azaspiro [3.4]octane-2-carboxylate (C20)

[0372] A mixture of 4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)piperidin-4-ol (50.0 mg, 161 μmol, HCl salt), ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (31.7 mg, 161 μmol), and Et3N (48.8 mg, 483 μmol) in DCE (10.0 mL) was stirred at room temperature for 1 h. Then AcOH (9.66 mg, 16.1 μmol) and NaBH(OAc)3 (102 mg, 483 μmol) were added in one portion. The reaction mixture was stirred at room temperature for 11 h. The mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–6% MeOH / DCM) to give ethyl 6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (36.0 mg, 79.0 μmol, yield 49.1%) as a yellow oil. 1 1H NMR (CD3OD 400 MHz) δ H = 9.10 - 8.90 (m, 1H), 8.81 - 8.51 (m, 3H), 7.91 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 4.11 - 4.03 (m, 2H), 3.94 - 3.75 (m, 4H), 3.07 - 2.85 (m, 3H), 2.80 - 2.60 (m, 2H), 2.35 - 2.15 (m, 1H), 2.12 - 2.02 (m, 2H), 2.00 - 1.73 (m, 6H), 1.66 - 1.47 (m, 1H), 1.25 - 1.20 (m, 3H). LCMS m / z [M+H]+ 456。

[0373] Step 4: Synthesis of (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy-1-piperidinyl]-2-azaspiro [3.4]octane-2-carboxylate (A13) and (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy-1-piper idinyl]-2-azaspiro[3.4]octane-2-carboxylate (A14)

[0374] The yellow oil was purified by SFC (column: DAICEL CHIRALPAK IC, (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 55%%, isocratic elution mode) to obtain ethyl (6S)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid (6.50 mg, 13.7 μmol, purity 95.9%). 1 HNMR (CDCl3 400 MHz) δ H = 9.37 (s, 1H), 8.70 (d, J = 2.8 Hz, 1H), 8.56 - 8.45 (m, 2H), 7.65 (dd, J = 2.4 Hz, 10.2 Hz, 1H), 7.44 (br s, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.91 - 3.72 (m, 4H), 2.89 - 2.38 (m, 5H), 2.17 - 2.05 (m, 1H), 1.98 - 1.74 (m, 7H), 1.73 - 1.66 (m, 1H), 1.57 - 1.46 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 456. Peak 2 was ethyl (6R)-6-[4-(5-fluoro-2-pyrazin-2-yl-3-pyridinyl)-4-hydroxy-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid (6.60 mg, 13.2 μmol, purity 91.4%). 1 HNMR (CDCl3 400 MHz) δ H = 9.37 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.55 - 8.46 (m, 2H), 7.65 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 7.44 (br s, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.91 - 3.72 (m, 4H), 2.89 - 2.34 (m, 5H), 2.17 - 2.06 (m, 1H), 1.97 - 1.79 (m, 6H), 1.76 - 1.63 (m, 2H), 1.57 - 1.41 (m, 1H), 1.23 (t, J = 6.8 Hz, 3H). LCMS m / z [M+H] + 456。

[0375] Example #15: (6R)-6-[4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridinyl)piperazin-1-yl]-2-aza Ethyl spiro[3.4]octane-2-carboxylate (A15) and (6S)-6-[4-(5-chloro-2-(tetrahydropyran-4-yl)-3-pyridinyl)piperazin-1- yl]-2-azaspiro[3.4]octane-2-carboxylate (A16) synthesis

[0376]

[0377] Step 1: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-pyridinyl)piperazine-1-carboxylate (C21)

[0378] A mixture of tert-butyl piperazine-1-carboxylate (4.43 g, 23.8 mmol), 2-bromo-5-chloro-3-fluoropyridine (5.00 g, 23.8 mmol) and K2CO3 (6.57 g, 47.5 mmol) in DMSO (50.0 mL) was stirred at 110 °C for 36 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 3% ethyl acetate / petroleum ether) to give tert-butyl 4-(5-chloro-3-fluoropyridin-2-yl)piperazine-1-carboxylate as a yellow oil (3.89 g, 10.2 mmol, yield 42.9%, purity 82.7%). 1 H NMR (CDCl3 400 MHz) δ H = 8.04 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 3.74 - 3.50 (m, 4H), 3.11 - 2.90 (m, 4H), 1.48 (s, 9H). LCMS m / z [M+H] + 376, 378.

[0379] Step 2: Synthesis of tert-butyl 4-[5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinyl]piperazine-1-carboxylate (C22)

[0380] A solution of tert-butyl 4-(2-bromo-5-chloro-3-pyridyl)piperazine-1-carboxylate (1.00 g, 2.65 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (558 mg, 2.65 mmol), Pd(dppf)Cl2 (194 mg, 265 μmol) and Na2CO3 (563 mg, 5.31 mmol) in 1,4-dioxane (10.0 mL) and water (2.50 mL) was degassed and purged with N2 gas three times. The reaction mixture was stirred at 90 °C for 12 h under a N2 atmosphere. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 30% ethyl acetate / petroleum ether) to give tert-butyl 4-[5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridyl]piperazine-1-carboxylate as a colorless oil (775 mg, 1.82 mmol, yield 68.7%, purity 89.4%). LCMS m / z [M+H] + 380。

[0381] Step 3: Synthesis of tert-butyl 4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazine-1-carboxylate (C23)

[0382] To a solution of tert-butyl 4-[5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (775 mg, 2.04 mmol) in EtOAc (8.00 mL) was added PtO2 (100 mg, 440 μmol). The reaction mixture was degassed under vacuum and purged with H2 gas several times and stirred at room temperature under a H2 atmosphere (15 psi) for 12 h. The mixture was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 30% ethyl acetate / petroleum ether) to give tert-butyl 4-(5-chloro-2-tetrahydropyran-4-yl-3-pyridyl)piperazine-1-carboxylate as a colorless oil (357 mg, 874 μmol, yield 42.8%, purity 93.5%). 1 H NMR (CDCl3 400 MHz) δ H = 8.31 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 4.17 - 4.06 (m, 4H), 3.60 (brs, 4H), 3.39 - 3.33 (m, 1H), 2.82 (t, J = 4.4 Hz, 4H), 2.13 - 2.06 (m, 2H), 1.59 (d, J = 12.8 Hz, 2H), 1.49 (s, 9H). LCMS m / z [M+H] + 383。

[0383] Step 4: Synthesis of 1-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazine (C24)

[0384] HCl / EtOAc (4 M, 3.00 mL) was added to tert-butyl 4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazine-1-carboxylate (357 mg, 935 μmol) in DCM (3.00 mL), and then the mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give 1-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazine (298 mg, 935 μmol, 100% yield, HCl salt) as a yellow oil, which was used in the next step without purification as the theoretical amount.

[0385] Step 5: Synthesis of ethyl 6-[4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazin-1-yl]-2-azaspiro octane-2-carboxylate (C25)

[0386] A mixture of 1-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazine (298 mg, 935 μmol, HCl salt), ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (184 mg, 935 μmol) and TEA (473 mg, 4.67 mmol) in DCE (3.00 mL) was stirred at room temperature for 1 h. Then AcOH (56.1 mg, 935 μmol) and NaBH(OAc)3 (594 mg, 2.80 mmol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 3% methanol / dichloromethane) to give ethyl 6-[4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (176 mg, 349 μmol, 37.3% yield, 91.8% purity) as a white solid. LCMS m / z [M+H] + 463.

[0387] Step 6: Synthesis of (6R)-6-[4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)piperazin-1-yl]-2-azaspiro [3.4]octane-2-carboxylate (A15) and (6S)-6-[4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl)

[0388] piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A16)

[0389] Ethyl (6R)-6-[4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (176 mg, 380 μmol) was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3·H2O)]; B%: 60%, isocratic elution mode) to give ethyl (6R)-6-[4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid (25.7 mg, 54.3 μmol, yield 14.3%, purity 97.8%). 1 H NMR (CDCl3 400 MHz) δ H = 8.29 (s, 1H), 7.34 (s, 1H), 4.10 (q, J = 7.2 Hz, 4H), 3.99 - 3.76 (m, 4H), 3.52 (t, J = 11.6 Hz, 2H), 3.39 - 3.24 (m, 1H), 3.22 - 2.24 (m, 9H), 2.23 - 2.10 (m, 1H), 2.11 - 1.98 (m, 3H), 1.97 - 1.62 (m, 4H), 1.61 - 1.59 (m, 1H), 1.52 - 1.50 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 463. Ethyl (6S)-6-[4-(5-chloro-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid (27.3 mg, 56.8 μmol, yield 14.9%, purity 96.3%). 1 H NMR (CDCl3 400 MHz) δ H = 8.29 (s, 1H), 7.34 (s, 1H), 4.10 (q, J = 7.2 Hz, 4H), 3.99 - 3.75 (m, 4H), 3.52 (t, J = 11.6 Hz, 2H), 3.37 - 3.25 (m, 1H), 3.21 - 2.41 (m, 9H), 2.20 - 2.10 (m, 1H), 2.12 - 1.98 (m, 3H), 1.98 - 1.62 (m, 4H), 1.62 - 1.59 (m, 1H), 1.52 - 1.50 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 463.

[0390] Example #16: Synthesis of (6R)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1- yl]-2-azaspiro[3.4]octane-2-carboxylate (A17) and (6S)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4- yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A18)

[0391]

[0392] Step 1: Synthesis of tert-butyl 4-(2-bromo-5-fluoropyridin-3-yl)piperazine-1-carboxylate (C26)

[0393] To a solution of 2-bromo-3,5-difluoropyridine (10.0 g, 51.6 mmol) in DMSO (100 mL) was added tert-butyl piperazine-1-carboxylate (11.5 g, 61.9 mmol) and K2CO3 (14.3 g, 103 mmol) in one portion. The mixture was stirred at 110 °C for 12 h. The reaction mixture was cooled to room temperature. H2O (300 mL) was added to the mixture. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with 3% aqueous LiCl solution (250 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0 - 18% ethyl acetate / petroleum ether) to give tert-butyl 4-(2-bromo-5-fluoro-3-pyridyl)piperazine-1-carboxylate as an off-white solid (8.00 g, 22.2 mmol, yield 43.1%). 1 HNMR (CDCl3 400 MHz) δ H = 7.97 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 3.67 - 3.57 (m, 4H), 3.09 - 2.91 (m, 4H), 1.46 (s, 9H). LCMS m / z [M + H] + 360, 362.

[0394] Step 2: Synthesis of tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (C27)

[0395] tert-Butyl 4-(2-bromo-5-fluoro-3-pyridyl)piperazine-1-carboxylate (1.00 g, 2.78 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (700 mg, 3.33 mmol), K2CO3 (767 mg, 5.55 mmol) and Pd(dppf)Cl2 (203 mg, 278 μmol) in a mixture of 1,4-dioxane (10.0 mL) and water (1.00 mL) were degassed under vacuum and purged with N2 gas several times. The reaction mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–14% ethyl acetate / petroleum ether) to give tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridyl]piperazine-1-carboxylate as an off-white solid (930 mg, 2.56 mmol, 92.2% yield). 1 1H NMR (CD3OD 400 MHz) δ H = 8.05 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 6.35 - 6.25 (m, 1H), 4.32 (q, J = 2.4 Hz, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.66 - 3.46 (m, 4H), 3.07 - 2.91 (m, 4H), 2.67 - 2.55 (m, 2H), 1.47 (s, 9H). LCMS m / z [M+H] + 364。

[0396] Step 3: Synthesis of tert-butyl 4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazine-1-carboxylate (C28)

[0397] At 0 °C, phenylsilane (715 mg, 6.60 mmol) was added to a mixture of tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-3-pyridyl]piperazine-1-carboxylate (1.20 g, 3.30 mmol) and tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-en-oxy]-manganese (39.9 mg, 66.0 μmol) in DCM (1.00 mL) and i-PrOH (8.00 mL). The mixture was stirred at room temperature under an O2 atmosphere (15 psi) for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–26% ethyl acetate / petroleum ether) to give tert-butyl 4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate as an off-white solid (430 mg, 1.13 mmol, 61.4% yield). LCMS m / z [M+H] + 382。

[0398] Step 4: Synthesis of 4-(5-fluoro-3-(piperazin-1-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (C29)

[0399] HCl / 1,4-dioxane (4 M, 1.96 mL) was added to a solution of tert-butyl 4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (150 mg, 393 μmol) in DCM (6.00 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoro-3-piperazin-1-yl-2-pyridyl)tetrahydropyran-4-ol as an off-white solid (130 mg, crude, HCl salt). The crude product was used in the next step without further purification. LCMS m / z [M+H] + 282。

[0400] Step 5: Synthesis of ethyl 6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazin-1-yl)-2-aza spiro[3.4]octane-2-carboxylate (C30)

[0401] A mixture of 4-(5-fluoro-3-piperazin-1-yl-2-pyridinyl)tetrahydropyran-4-ol (130 mg, 409 μmol, HCl salt), ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (80.7 mg, 409 μmol), and Et3N (124 mg, 1.23 mmol) in DCE (10.0 mL) was stirred at room temperature for 1 hour. Then AcOH (2.46 mg, 40.91 μmol) and NaBH(OAc)3 (260 mg, 1.23 mmol) were added in one portion. The reaction mixture was stirred at room temperature for 11 hours. The mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography (eluent: 0 - 7% MeOH / DCM) to give ethyl 6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (140 mg, 303 μmol, 74.0% yield) as a colorless oil. LCMS m / z [M+H] + 463。

[0402] Step 6: (6R)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2- Ethyl azaspiro[3.4]octane-2-carboxylate (A17) and (6S)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A18) Synthesis of Ethyl azaspiro[3.4]octane-2-carboxylate (A17) and (6S)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (A18)

[0403] A sample of ethyl 6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (140 mg, 303 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD, 250 mm × 30 mm, 10 μm; mobile phase: [CO2 - MeOH(0.1% NH3H2O)]; B%: 25%, isocratic elution mode) to give peak 1, and (6R)-ethyl 6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (24.1 mg, 51.3 μmol, purity 98.5%) as an off-white solid. 1 1H NMR (CD3OD 400 MHz) δ H= 8.37 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 2.4 Hz, 10.0 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 4.00 - 3.89 (m, 3H), 3.88 - 3.77 (m, 5H), 3.24 - 2.59 (m, 8H), 2.57 - 2.39 (m, 3H), 2.25 - 2.16 (m, 1H), 2.04 - 1.86 (m, 3H), 1.80 - 1.71 (m, 1H), 1.64 - 1.52 (m, 3H), 1.23 (t, J = 6.8 Hz, 3H). LCMS m / z [M+H] + 463, found 463. Peak 2 was ethyl (6S)-6-[4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid (25.0 mg, 54.1 μmol, 17.9% yield). 1 H NMR (CD3OD 400 MHz) δ H = 8.37 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.8 Hz, 9.6 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 4.01 - 3.78 (m, 8H), 3.20 - 2.85 (m, 6H), 2.83 - 2.64 (m, 2H), 2.61 - 2.37 (m, 3H), 2.22 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.09 - 1.84 (m, 3H), 1.77 (dd, J = 9.2 Hz, 12.8 Hz, 1H), 1.69 - 1.48 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 463.

[0404] Example #17: (6R)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]- Ethyl 2-azaspiro[3.4]octane-2-carboxylate (A19) and (6S)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]- Ethyl 2-azaspiro[3.4]octane-2-carboxylate (A20)

[0405]

[0406] Step 1: Synthesis of tert-butyl 4-(5-fluoro-2-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazine-1-carboxylate (C31) (C31)

[0407] To a solution of tert-butyl 4-[5-fluoro-2-(4-hydroxytetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (200 mg, 524 μmol) in DCM (8.00 mL) was added dropwise DAST (338 mg, 2.10 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 14% ethyl acetate / petroleum ether) to give tert-butyl 4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate as a colorless oil (170 mg, 443 μmol, yield 84.6%). 1 1H NMR (CD3OD 400 MHz) δ H = 8.27 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 2.4 Hz, 10.0 Hz, 1H), 3.96 - 3.81 (m, 4H), 3.56 (br s, 4H), 2.90 (t, J = 4.8 Hz, 4H), 2.51 - 2.25 (m, 4H), 1.48 (s, 9H). LCMS m / z [M + H] + 384。

[0408] Step 2: Synthesis of 1-(5-fluoro-2-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazine (C32)

[0409] To a solution of tert-butyl 4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazine-1-carboxylate (170 mg, 443 μmol) in DCM (8.00 mL) was added HCl / 1,4-dioxane (4 M, 3.00 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridyl]piperazine as an off-white solid (140 mg, crude, HCl salt). The crude product was used in the next step without further purification. 1 1H NMR (CD3OD 400 MHz) δ H = 8.41 (d, J = 2.4 Hz, 1H), 7.89 (br d, J = 9.6 Hz, 1H), 3.99 - 3.79 (m, 4H), 3.44 - 3.34 (m, 4H), 3.26 - 3.15 (m, 4H), 2.57 - 2.18 (m, 4H). LCMS m / z [M + H] + 284。

[0410] Step 3: Synthesis of Ethyl 6-(4-(5-fluoro-2-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-3-yl)piperazin-1-yl)-2-azaspiro [3.4]octane-2-carboxylate (C33)

[0411] A mixture of 1-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazine (140 mg, 438 μmol, HCl salt), ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (86.4 mg, 438 μmol), and Et3N (133 mg, 1.31 mmol) in DCE (10.0 mL) was stirred at room temperature for 1 h. Then, AcOH (2.63 mg, 43.8 μmol) and NaBH(OAc)3 (278 mg, 1.31 mmol) were added in one portion. The mixture was stirred at room temperature for 11 h. The mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–3% MeOH / DCM) to give ethyl 6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (130 mg, 280 μmol, yield 63.9%) as a colorless oil. 1 1H NMR (CDCl3 400 MHz) δ H = 8.30 - 8.15 (m, 1H), 7.38 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.01 - 3.70 (m, 8H), 2.95 (brs, 4H), 2.78 - 2.22 (m, 9H), 2.21 - 2.07 (m, 1H), 2.02 - 1.71 (m, 4H), 1.70 - 1.62 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 465.

[0412] Step 4: Synthesis of (6R)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-aza Spiro[3.4]octane-2-carboxylate (19) and (6S)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl] Piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate (20)

[0413] Ethyl (6R)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate sample (130 mg, 280 μmol) was separated by SFC (column: DAICEL CHIRALPAK IG, 250 mm × 30 mm, 10 μm; mobile phase: [CO2-MeOH(0.1% NH3H2O)]; B%: 60%, isocratic elution mode) to obtain (6R)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid in peak 1 (26.0 mg, 51.1 μmol, yield 29.7%, purity 91.2%). 1 H NMR (CDCl3 400 MHz) δ H = 8.29 - 8.18 (m, 1H), 7.38 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.99 - 3.72 (m, 8H), 3.06 - 2.87 (m, 4H), 2.85 - 2.45 (m, 5H), 2.45 - 2.24 (m, 4H), 2.14 (dd, J = 6.8 Hz, 12.4 Hz, 1H), 2.03 - 1.79 (m, 3H), 1.78 - 1.66 (m, 1H), 1.59 - 1.51 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 465. Ethyl (6S)-6-[4-[5-fluoro-2-(4-fluorotetrahydropyran-4-yl)-3-pyridinyl]piperazin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate as an off-white solid in peak 2 (27.1 mg, 51.8 μmol, yield 30.1%, purity 88.7%). 1 H NMR (CDCl3 400 MHz) δ H = 8.29 - 8.18 (m, 1H), 7.38 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.98 - 3.73 (m, 8H), 3.03 - 2.84 (m, 4H), 2.82 - 2.45 (m, 5H), 2.45 - 2.22 (m, 4H), 2.14 (dd, J = 7.2 Hz, 12.8 Hz, 1H), 2.03 - 1.79 (m, 3H), 1.77 - 1.67 (m, 1H), 1.57 - 1.47 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 465.

[0414] Example #18: (6S)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]-1-piperidinyl]- Ethyl 2-azaspiro[3.4]octane-2-carboxylate (A21) and (6R)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]-1-piperidinyl]- Ethyl 2-azaspiro[3.4]octane-2-carboxylate (A22)

[0415]

[0416] Step 1: Synthesis of methyl 3-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-5-fluoropyridine-2-carboxylate (C34) (C34)

[0417] To a solution of methyl 3-bromo-5-fluoro-pyridine-2-carboxylate (3.50 g, 15.0 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.09 g, 16.4 mmol) in H2O (4.00 mL) and 1,4-dioxane (32.0 mL) was added Na2CO3 (3.17 g, 29.9 mmol) and Pd(dppf)Cl2 (1.09 g, 1.50 mmol) in one portion. The mixture was degassed under vacuum and purged with N2 gas three times. The mixture was stirred at 80 °C for 16 h. The mixture was poured into water (30 mL) and stirred for 5 min. The mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–16% ethyl acetate / petroleum ether) to give methyl 3-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-5-fluoro-pyridine-2-carboxylate (6.50 g, 19.3 mmol, 96.4% yield) as a colorless oil. LCMS m / z [M+H] + 337。

[0418] Step 2: Synthesis of methyl 3-(1-tert-butoxycarbonyl-4-piperidinyl)-5-fluoropyridine-2-carboxylate (C35)

[0419] Under an Ar atmosphere, dry Pd / C (300 mg, 10% w / w) was added to a solution of methyl 3-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-5-fluoro-pyridine-2-carboxylate (3.00 g, 8.92 mmol) in MeOH (30.0 mL). The suspension was degassed and purged with H2 gas three times. The mixture was stirred at 45 °C under a H2 atmosphere (45 psi) for 72 h. The mixture was filtered and the cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–25% ethyl acetate / petroleum ether) to give methyl 3-(1-tert-butoxycarbonyl-4-piperidinyl)-5-fluoro-pyridine-2-carboxylate (2.00 g, 5.91 mmol, 66.3% yield) as a colorless oil. LCMS m / z [M+H] + 339。

[0420] Step 3: Synthesis of tert-butyl 4-[5-fluoro-2-(hydrazinocarbonyl)-3-pyridinyl]piperazine-1-carboxylate (C36)

[0421] To a solution of methyl 3-(1-tert-butoxycarbonyl-4-piperidinyl)-5-fluoro-pyridine-2-carboxylate (2.00 g, 5.91 mmol) in EtOH (20.0 mL) was added NH2NH2·H2O (6.00 g, 102 mmol, purity 85%) in one portion. Then the mixture was stirred at 60 °C for 6 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 3% methanol / dichloromethane) to give tert-butyl 4-[5-fluoro-2-(hydrazinecarbonyl)-3-pyridyl]piperidine-1-carboxylate (1.44 g, 4.26 mmol, yield 72.0%) as a colorless oil. LCMS m / z [M - Boc] + 239.

[0422] Step 4: Synthesis of tert-butyl 4-[5-fluoro-3-(1,3,4-thiadiazol-2-yl)-2-pyridinyl]piperazine-1-carboxylate (C37) (C37)

[0423] To a solution of tert-butyl 4-[5-fluoro-2-(hydrazinecarbonyl)-3-pyridyl]piperidine-1-carboxylate (1.44 g, 4.26 mmol) in toluene (15.0 mL) was added HCO2H (2.09 g, 42.6 mmol). The solution was degassed under vacuum and purged with N2 gas three times, then the mixture was stirred at 50 °C for 1 h. The mixture was adjusted to pH = 8 with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil. The oil was purified by flash silica gel chromatography (eluent: 0 - 78% methanol / dichloromethane) to give tert-butyl 4-[5-fluoro-2-(formylamino-carbonyl)-3-pyridyl]piperidine-1-carboxylate (980 mg, 2.67 mmol, yield 62.8%) as a colorless oil. LCMS m / z [M - Boc] + 267.

[0424] Step 5: Synthesis of tert-butyl 4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]piperazine-1-carboxylate (C38) (C38)

[0425] To a solution of tert-butyl 4-[5-fluoro-2-(formamidocarbamoyl)-3-pyridinyl]piperidine-1-carboxylate (200 mg, 546 μmol) in toluene (2.00 mL) and pyridine (0.500 mL) was added Lawesson's reagent (265 mg, 655 μmol) in one portion. The reaction mixture was stirred at 90 °C for 12 h. The mixture was poured into water (5 mL) and stirred for 5 min. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 19% ethyl acetate / petroleum ether) to give tert-butyl 4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]piperidine-1-carboxylate as an off-white solid (140 mg, 384 μmol, 70.4% yield). 1 HNMR (CDCl3 400 MHz) δ H = 9.16 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.37 - 4.10 (m, 2H), 3.09 - 2.84 (m, 2H), 1.95 (d, J = 12.8 Hz, 2H), 1.65 - 1.55 (m, 2H), 1.49 (s, 9H). LCMS m / z [M - Boc] + 265。

[0426] Step 6: Synthesis of 2-[5-fluoro-3-(piperidin-4-yl)-2-pyridinyl]-1,3,4-thiadiazole (C39)

[0427] To a solution of tert-butyl 4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]piperidine-1-carboxylate (140 mg, 384 μmol) in DCM (1.50 mL) was added HCl / 1,4-dioxane (4 M, 1.50 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give 2-[5-fluoro-3-(4-piperidinyl)-2-pyridinyl]-1,3,4-thiadiazole as an off-white solid (115 mg, crude, HCl salt), which was used without purification in the next step. LCMS m / z [M + H] + 265。

[0428] Step 7: (6S)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]piperidin-1-yl]-2-aza spiro[3.4]octane-2-carboxylic acid ethyl ester (A21) and (6R)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridin yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester (A22) synthesis

[0429] To a mixture of 2-[5-fluoro-3-(piperidin-4-yl)-2-pyridinyl]-1,3,4-thiadiazole (115 mg, 382 μmol, HCl salt) in DCE (1.50 mL) was added TEA (193 mg, 1.91 mmol) and ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (75.4 mg, 382 μmol) in one portion. Then, the mixture was stirred at room temperature for 2 h. NaBH(OAc)3 (243 mg, 1.15 mmol) and AcOH (2.30 mg, 38.2 μmol) were added to the mixture in one portion. The mixture was stirred at room temperature for 32 h. The mixture was poured into saturated aqueous NaHCO3 (5 mL) and extracted with DCM (3 × 10 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 5% methanol / dichloromethane) and further separated by SFC (column: DAICEL CHIRALCEL OD-H, 250 mm × 30 mm, 5 μm; mobile phase: [CO2 - i-PrOH(0.1% NH3H2O)]; B%: 45%, isocratic elution mode) to give ethyl (6S)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (21.7 mg, 48.7 μmol, yield 24.1%) as an off-white solid in peak 1. 1 HNMR(CDCl3 400 MHz) δ H = 9.15 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 4.25 (t, J = 11.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.92 - 3.76 (m, 4H), 3.11 (t, J = 10.4 Hz, 2H), 2.73 - 2.58 (m, 1H), 2.26 - 2.12 (m, 3H), 2.02 - 1.90 (m, 4H), 1.88 - 1.71 (m, 4H), 1.62 - 1.53 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 446. Ethyl (6R)-6-[4-[5-fluoro-2-(1,3,4-thiadiazol-2-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (18.5 mg, 41.5 μmol, yield 20.6%) as an off-white solid in peak 2. 1 H NMR(CDCl3 400 MHz) δ H= 9.15 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 2.4 Hz, 10.0 Hz, 1H), 4.25 (t, J = 11.2 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.92 - 3.75 (m, 4H), 3.11 (t, J = 10.4 Hz, 2H), 2.73 - 2.59 (m, 1H), 2.28 - 2.11 (m, 3H), 2.01 - 1.89 (m, 4H), 1.88 - 1.71 (m, 4H), 1.62 - 1.52 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H). LCMS m / z [M+H] + 446. Subsequently, chirality was set based on potency.

[0430] Example #19: (6R)-6-[4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]piperidin-1-yl]-2- azaspiro[3.4]octane-2-carboxylic acid ethyl ester (A23) and (6S)-6-[4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridin yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester (A24) synthesis

[0431]

[0432] Step 1: Synthesis of 3-bromo-5-fluoro-2-(1H-1,2,4-triazol-1-yl)pyridine (C41)

[0433] A mixture of 1,1 - dimethoxypropan - 2 - one (618 mg, 5.24 mmol) and 4 - methylbenzenesulfonylhydrazide (975 mg, 5.24 mmol) in DMSO (10.0 mL) was stirred at room temperature for 1 hour. Then 3 - bromo - 5 - fluoropyridin - 2 - amine (1.00 g, 5.24 mmol) was added to the mixture. The reaction mixture was stirred at 90 °C for 15 hours. The reaction mixture was cooled to room temperature. Water (20 mL) was added and the mixture was stirred for 15 min. The mixture was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0 - 40% ethyl acetate / petroleum ether) to give 3 - bromo - 5 - fluoro - 2 - (4 - methyl - 1,2,3 - triazol - 1 - yl)pyridine as a yellow oil (428 mg, 1.49 mmol, yield 28.4%, purity 89.4%). LCMS m / z [M+H] + 257, 259.

[0434] Step 2: Synthesis of tert-butyl 4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]-3,6-dihydro-2H-pyridine-1-carboxylate (C42) Step 3: Synthesis of tert-butyl 4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]piperidine-1-carboxylate (C43)

[0435] 3-Bromo-5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)pyridine (428 mg, 1.66 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (515 mg, 1.66 mmol), Pd(dppf)Cl2 (122 mg, 167 μmol), and Na2CO3 (353 mg, 3.33 mmol) in a mixture of 1,4-dioxane (5.00 mL) and H2O (1.00 mL) were degassed under vacuum and purged with N2 gas three times. The reaction mixture was then stirred at 90 °C for 12 h under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–40% ethyl acetate / petroleum ether) to give tert-butyl 4-[5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-pyridinyl]-3,6-dihydro-2H-pyridine-1-carboxylate (490 mg, 1.31 mmol, yield 78.5%, purity 95.9%) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H = 8.31 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 7.48 (dd, J = 2.8 Hz, 8.0 Hz, 1H), 5.73 (s, 1H), 4.02 (br s, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.43 (s, 3H), 1.94 (br s, 3H), 1.47 (s, 9H). LCMS m / z [M+H] + 360.

[0436] Step 4: Synthesis of 5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-(piperidin-4-yl)pyridine (C44) Step 5: Synthesis of tert-butyl 6-[4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]piperidin-1-yl]-2-azaspiro

[0437] To a solution of tert-butyl 4-[5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-pyridinyl]-3,6-dihydro-2H-pyridine-1-carboxylate (490 mg, 1.36 mmol) in MeOH (5.00 mL) was added dry Pd / C (300 mg, 10% w / w). The mixture was degassed and purged with H2 gas three times. The reaction was stirred at 30 °C for 16 h under a H2 atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 4-[5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-pyridinyl]piperidine-1-carboxylate (476 mg, 1.30 mmol, yield 95.6%, purity 99.0%) as a yellow oil. 1 H NMR (CDCl3 400 MHz) δ H= 8.26 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.54 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 4.20 (br s, 2H), 3.37 - 3.26 (m, 1H), 2.74 (br s, 2H), 2.46 (s, 3H), 1.87 (d, J = 12.8 Hz, 2H), 1.63 - 1.52 (m, 2H), 1.47 (s, 9H). LCMS m / z [M + H] + 362。

[0438] [3.4]octane-2-carboxylate (C45)

[0439] To a solution of tert-butyl 4-[5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-pyridinyl]piperidine-1-carboxylate (476 mg, 1.32 mmol) in DCM (5.00 mL) was added dropwise HCl / 1,4-dioxane (4 M, 2.00 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford 5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-(piperidin-4-yl)pyridine as a yellow oil (300 mg, 990 μmol, yield 75.2%, purity 98.2%, HCl salt). 1 H NMR (MeOD 400 MHz) δ H = 8.43 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 7.97 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 3.50 (br d, J = 12.8 Hz, 2H), 3.25 - 3.16 (m, 1H), 3.10 - 3.01 (m, 2H), 2.46 (s, 3H), 2.19 - 2.11 (m, 2H), 2.06 - 1.95 (m, 2H). LCMS m / z [M + H] + 262。

[0440] Step 6: Synthesis of ethyl 6-[4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]piperidin-1-yl]-2-azaspiro [3.4]octane-2-carboxylate (C46)

[0441] To a mixture of 5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-(piperidin-4-yl)pyridine (300 mg, 1.01 mmol, HCl salt) in DCE (5.00 mL) was added TEA (420 μL, 3.02 mmol), and then tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (227 mg, 1.01 mmol) was added. The mixture was stirred at room temperature for 0.5 h. HOAc (28.8 μL, 504 μmol) and NaBH(OAc)3 (641 mg, 3.02 mmol) were added. The mixture was stirred at room temperature for 11.5 h. The reaction mixture was poured into 10% aqueous NaHCO3 (15 mL), and then extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 6-[4-[5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (450 mg, 956 μmol, 83.3% yield) as a yellow oil. LCMS m / z [M+H] + 471。

[0442] Step 7: Synthesis of 6-[4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]piperidin-1-yl]-2-azaspiro [3.4]octane-2-carboxylic acid ethyl ester (C47)

[0443] To a solution of tert-butyl 6-[4-[5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (450 mg, 956 μmol) in DCM (5.00 mL) was added dropwise TFA (1.20 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give 6-[4-[5-fluoro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylic acid (463 mg, crude, TFA salt), which was used in the next step in the theoretical amount.

[0444] Step 8: (6R)-6-[4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]piperidin-1-yl]-2-aza spiro[3.4]octane-2-carboxylic acid ethyl ester (A23) and (6S)-6-[4-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)-3-pyridinyl]piperidin-1-

[0445] To a mixture of 6-[4-[5-fluoro-2-(4-methyl-1,2,3-triazol-1-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane (463 mg, 956 μmol, TFA salt) in DCM (4.00 mL) was added dropwise TEA (666 μL, 4.78 mmol) at 0 °C. Then ethyl chloroformate (690 mg, 6.36 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched slowly with saturated aqueous NaHCO3 (20 mL) at 0 °C and then extracted with DCM (3 × 5 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0 - 5% MeOH / DCM) to give ethyl 6-[4-[5-fluoro-2-(4-methyl-1,2,3-triazol-1-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (250 mg, 551 μmol, yield 51.0%, purity 97.5%) as a yellow oil. LCMS m / z [M+H] + 443。

[0446] yl]-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester (A24) synthesis Example #20: Biological assay FLIPR assay

[0447] Ethyl 6-[4-[5-fluoro-2-(4-methyl-1,2,3-triazol-1-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (120 mg, 271 μmol) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2 - EtOH (0.1% NH3H2O)]; B%: 55%, isocratic elution mode) to give (6R)-ethyl 6-[4-[5-fluoro-2-(4-methyl-1,2,3-triazol-1-yl)-3-pyridinyl]-1-piperidinyl]-2-azaspiro[3.4]octane-2-carboxylate (37.1 mg, 81.6 μmol, yield 30.1%, purity 97.4%) as an off-white solid in peak 1. 1 H NMR (CDCl3 400 MHz) δ H= 8.23 (d, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.60 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.89 - 3.80 (m, 2H), 3.80 - 3.74 (m, 2H), 3.18 - 2.99 (m, 3H), 2.62 - 2.52 (m, 1H), 2.45 (s, 3H), 2.16 - 2.07 (m, 1H), 2.05 - 1.75 (m, 8H), 1.75 - 1.78 (m, 2H), 1.58 - 1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 443. The peak 2 is ethyl (6S)-6-[4-[5-fluoro-2-(4-methyl-1,2,3-triazol-1-yl)-3-pyridyl]-1-piperidyl]-2-azaspiro[3.4]octane-2-carboxylate (46.9 mg, 106 μmol, yield 39.1%, purity 100%). 1 H NMR (CDCl3 400 MHz) δ H = 8.23 (d, J = 2.8 Hz, 1H), 7.86 (s, 1H), 7.61 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.90 - 3.81 (m, 2H), 3.80 - 3.74 (m, 2H), 3.17 - 2.99 (m, 3H), 2.64 - 2.52 (m, 1H), 2.46 (s, 3H), 2.16 - 2.07 (m, 1H), 2.03 - 1.75 (m, 8H), 1.74 - 1.68 (m, 2H), 1.56 - 1.47 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS m / z [M + H] + 443.

[0448] Using the methods described above for Examples A1 - A24 and similar starting materials shown in the table, compounds A25 - A293 were synthesized as shown in the following table.

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470] cAMP assay

[0471] ​

[0472] Fluorescence imaging plate reader (FLIPR) assays were performed using the intracellular calcium-sensitive dye Fluo 8, which exhibits increased fluorescence intensity upon calcium binding. Stimulation of Gq-coupled G-protein-coupled receptors (GPCRs) causes calcium efflux from the endoplasmic reticulum to the cytoplasm (Berridge, 1993), making this assay 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 a volume of 30 μl per well at 15,000 cells per well and allowed to grow overnight in a 37 °C, 5% CO2 atmosphere. Fluo-8 solution, 10 μl per well, was added to each well and incubated for 30 minutes in a 37 °C, 5% CO2 atmosphere. Compounds diluted in Hank's balanced salt solution (HBSS) were transferred to the cell assay plates at 10 μl per well and then read on a FLIPR instrument. EC 50 and E max values were calculated from the resulting data for each receptor subtype.

[0473] Results for the selected compounds provided herein are shown in the table below.

[0474] ​

[0475] M2 and M4 mACh receptors are G i -coupled receptors that cause a decrease in cAMP upon activation. Assays were developed to measure the potency and efficacy of compounds on M2 or M4 mAChRs using CHO-K1 cell lines overexpressing M2 or M4. Time-resolved fluorescence resonance energy transfer (TR-FRET) technology was used, where a signal is generated as a result of energy transfer when the donor molecule is in close proximity to the receptor molecule if the molecule has bound to the molecule of interest. cAMP detection is a competitive binding assay where cAMP produced by the cells competes with a labeled donor molecule for binding to an anti-cAMP receptor antibody. Due to the low basal level of cAMP in the CHO-K1 cell line, forskolin was used to increase the cAMP level to enable evaluation of agonist activity at the mAChR of interest.

[0476] Results for the selected compounds provided herein are shown in the table below.

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485] I.A. indicates EC50 > 10 μM; N / A indicates not tested or not available;

[0486] “+” means 100 to 499.9 nM; “++” means 20 to 99.9 nM; and “+++” means < 20 nM;

[0487] “*” means 80% to 100%; “**” means 50% to 79.9%; and “***” means 19% to 49.9%;

[0488] And “****” means < 19%.

Claims

1. A compound having the structure of formula (I): or its N-oxide or a pharmaceutically acceptable salt of the compound or its N-oxide, wherein: A is a 6- to 8-membered heterocycle containing 1 or 2 ring nitrogen atoms and optionally substituted with 1 to 3 substituents independently selected from halogen, OH, and C 1-3 alkyl; Y is a bond, O, S, CH2, CHF, CF2 or C(OH)H; m is 1 or 2; n is 1 or 2; p is 1 or 2; R 1 is H, halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -[O] 0-1 -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, wherein each of the heterocycle and heteroaryl contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and when 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- 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 optionally substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OH, =O, SO2 and C 1-3 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, C 3-6 cycloalkyl or a 4- to 8-membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S; R 3 is halogen, CN, OH, –N(R 6 )(R 7 ), C 1-6 alkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 -4-8 membered heterocycle or -[O] 0-1 -5-10 membered heteroaryl, -NH-C 3-6 cycloalkyl, -NH-C 6-10 aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C 1-6 alkyl)-C 3-6 cycloalkyl, -N(C 1-6 alkyl)-C 6-10 aryl, -N(C 1-6 alkyl)-4-8 membered heterocycle or -N(C 1-6 alkyl)-5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each contain 1, 2 or 3 ring heteroatoms selected from N, O and S, and the C 3-6 cycloalkyl, -C 6-10 aryl, 4-8 membered heterocycle or 5-10 membered heteroaryl is substituted with 0, 1, 2 or 3 R 3a substituents; Each R 3a is independently selected from halogen, CN, OH, =O, =N(C 1-3 alkyl), SO2, C 1-6 alkyl, C 2-10 alkene, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylene-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, -S-C 1-6 alkyl, C 0-6 alkylene-SO2C 1-6 alkyl, C 0-6 alkylene-C(O)NH2, C 0-6 alkylene-C(O)NH(C 1-6 alkyl), C 0-6 alkylene-C(O)N(C 1-6 alkyl)2, C 0-6 alkylene-NHC(O)C 1-6 alkyl, C 0-6 alkylene-COOH, C 0-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-O-C 1-6 alkyleneSi(C 1-3 alkyl)3 and C 0-6 alkylene-3-6 membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S; R 4 is H, halogen, CN or OH; R 5 is -CO2-Z or its bioisostere; Each R 6 and R 7 is independently H, C 1-6 alkyl, C(O)-C 1-6 alkyl, spiro or bicyclic C 8-14 cycloalkyl, an 8- to 14-membered heterocycle containing 1, 2 or 3 ring heteroatoms selected from N, O and S, and when R 6 or R 7 is not H, it may optionally be substituted with 1, 2 or 3 substituents independently selected from: 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 alkoxy, or R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 10-membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N, O, and S; and Z is C 1-7 alkyl, C 1-7 haloalkyl, C 3-6 cycloalkyl or C 2-6 alkyne, and Z is optionally substituted by C 1-6 alkoxy or C 3-6 cycloalkyl; Provided that when R 1 , R 2 and R 4 are each H, Y is CH2, m, n and p are each 1, A is and R 3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy or , then R 5 is not CO2CH2CH3.

2. The compound or salt according to claim 1, wherein A is and X is N, C(F), C(OH) or CH.

3. The compound or salt according to claim 2, wherein the compound or salt has the structure of formula (Ia), or a pharmaceutically acceptable salt thereof:

4. The compound or salt according to claim 3, wherein the compound or salt has the structure of formula (Ib):

5. The compound or salt according to any one of claims 1 to 3, wherein Y is CH2, CHF, CF2 or C(OH)H.

6. The compound or salt according to claim 5, wherein Y is CH2.

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

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

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

10. The compound or salt according to claim 4, wherein the compound or salt has the structure of formula (Ic):

11. The compound or salt according to claim 4, wherein the compound or salt has the structure of formula (Id):

12. The compound or salt according to any one of claims 1 to 11, wherein R 5 is a CO2Z bioisostere and is selected from 13. The compound or salt according to claim 1, wherein the compound or salt has the structure of formula (Ie), or a pharmaceutically acceptable salt thereof:

14. A compound or salt according to any one of claims 1 to 11 and 13, wherein R 5 is selected from CO2C 1-7 alkyl, 15. The compound or salt according to claim 14, wherein R 5 is CO2CH2CH3.

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

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

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

19. The compound or salt according to any one of claims 1 to 18, wherein 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 haloalkoxy.

20. The compound or salt according to claim 19, wherein R 2 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy.

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

22. The compound or salt according to any one of claims 1 to 21, wherein each R 6 and R 7 is independently H, C 1-6 alkyl or C(O)-C 1-6 alkyl.

23. The compound or salt according to claim 22, wherein each R 6 and R 7 is independently H or C 1-6 alkyl.

24. The compound or salt according to any one of claims 1 to 21, wherein at least one R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 10-membered heterocycle containing 0-2 additional ring heteroatoms independently selected from N and O.

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

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

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

28. The compound or salt according to any one of claims 1 to 27, wherein R 3 is C 3-6 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 8-membered heterocycle, optionally substituted by 1, 2 or 3 R 3a substituents.

29. A compound or salt according to any one of claims 25 to 28, wherein R 3 is and optionally substituted by one, two or three R 3a groups.

30. The compound or salt according to claim 29, wherein R 3 is and optionally substituted by one, two or three R 3a groups.

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

32. The compound or salt according to any one of claims 1 to 30, wherein R 3 is substituted by one or two R 3a substituents.

33. The compound or salt according to any one of claims 1 to 30 and 32, wherein R 3 is substituted by one R 3a group.

34. A compound or salt according to any one of claims 1 to 30, 32 and 33, wherein at least one R 3a is halogen, 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-O-C 1-6 alkyl, C 0-6 alkylene-N(C 1-6 alkyl)2, -S-C 1-6 alkyl, C 0-6 alkylene-NHC(O)C 1-6 alkyl or C 0-6 alkylene-3- to 6-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S.

35. The compound or salt according to claim 34, wherein at least one R 3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CHF2, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, F, CN, =O, SO2, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, CH2OCH3, CH2OCF3, SCH3, NH2, N(CH3)2, NHCOCH3, CD3, 36. The compound or salt according to claim 35, wherein at least one R 3a is CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH or OCHF2.

37. The compound or salt according to claim 1, wherein the compound or salt has the structure of formula (If), or a pharmaceutically acceptable salt thereof: wherein R 1 is a halogen; R 3 is -[O] 0-1 -C 3-6 cycloalkyl, -[O] 0-1 -C 6-10 aryl, -[O] 0-1 a 4 - 8 - membered heterocycle or -[O] 0-1 a 5 - 10 - membered heteroaryl, where each of the heterocycle and heteroaryl contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and R 3 is substituted with 0, 1, 2 or 3 R 3a substituents; R 5 is CO2Z or a bioisostere thereof; and Z is C 1-7 alkyl, C 1-7 haloalkyl, C 3-6 cycloalkyl or C 2-6 alkyne, and optionally substituted by C 1-6 alkoxy or C 3-6 cycloalkyl.

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

39. The compound or salt according to claim 37 or 28, wherein R 3 is a 5- to 6-membered heterocycle containing 1 ring heteroatom selected from S and O, or a 5- to 6-membered heteroaryl containing 2 or 3 ring heteroatoms independently selected from N and S, and R 3 is substituted with 0, 1 or 2 R 1-6 substituents independently selected from halogen, CN, OH and C 3a alkyl.

40. A compound or salt according to claim 37, 38 or 39, wherein R 5 is CO2C 1-7 alkyl.

41. The compound or salt according to claim 40, wherein R 5 is CO2Et.

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

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

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

45. The method according to claim 44, wherein the M4-mediated (or M4-related) disease or disorder is selected from: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive disorder (e.g., mild cognitive impairment), Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, movement disorder, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, Alzheimer's disease psychosis, dementia-related psychosis, bipolar type I disorder, bipolar type II disorder, bipolar depression, missed diagnosis and / or manic episode associated with bipolar disorder, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorder, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

46. The method according to claim 45, wherein the M4-mediated (or M4-related) disease or disorder is selected from Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, and sleep disorder.

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