Positive allosteric modulators of the muscarinic acetylcholine receptor m1

Abstract

Described are 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones and 2,3,4,5-tetrahydro-6H-benzo[b][1,5]oxazocin-6-ones that have an additional fused or bridged ring and are positive allosteric modulators of muscarinic acetylcholine receptor M1 (mAChR M1), pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating neurological disorders, psychiatric disorders, or a combination thereof.

Description

POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M1 RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 641,188, filed May 1, 2024, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure relates to compounds, compositions, and methods for treating muscarinic acetylcholine receptor M1 related diseases and / or disorders, such as neurological and psychiatric disorders. BACKGROUND

[0003] Positive allosteric modulators are compounds that bind to a site distinct from that of the orthosteric agonist binding site of a target protein. These modulators enhance the affinity or efficacy of an orthosteric agonist. For example, a selective muscarinic M1positive allosteric modulator would result in an increased affinity at the orthosteric binding site for acetylcholine (ACh), the endogenous agonist for the muscarinic M1 receptor, or an increase in the efficacy induced by ACh. In some systems, the compound may also have an intrinsic activity to activate the receptor in the absence of orthosteric ligand. Positive allosteric modulation (potentiation), therefore, can be an attractive mechanism for enhancing appropriate physiological receptor activation.

[0004] Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or the muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist ACh. Acetylcholinesterase (AChE) inhibitors, which inhibit the hydrolysis of ACh, have been approved in the United States for use in the palliative, but not disease-modifying, treatment of the cognitive deficits in Alzheimer’s disease (AD) patients.

[0005] mAChRs are members of the family A GPCRs, and include five subtypes, designated M1, M2, M3, M4, and M5. M1, M3and M5mainly couple to Gq and activate phospholipase C, whereas M2 and M4 mainly couple to Gi / o and associated effector systems. These five distinctmAChR subtypes have been identified in the mammalian central nervous system where they are prevalent and differentially expressed. M1-M5 mAChRs have varying roles in cognitive, sensory, motor and autonomic functions. Activation of various muscarinic receptors, particularly the M1subtype, has been proposed as a mechanism to enhance cognition in disorders such as AD and schizophrenia (as well as negative symptoms). Thus, selective positive allosteric modulators of mAChR subtypes that regulate processes involved in cognitive function could prove superior to AChE inhibitors for treatment of AD and related disorders as these compounds may exhibit improved selectivity for specific mAChRs.

[0006] Efforts to create selective M1agonists have been largely unsuccessful, in part due to the high conservation of the orthosteric ACh binding site. As a result, mAChR agonists in clinical studies induce the same adverse effects of AChE inhibitors by activation of peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and to further explore the therapeutic utility of mACh receptors in AD, schizophrenia and other disorders, there exists a need to develop compounds that are highly selective modulators of M1 and other individual mAChR subtypes. Accordingly, allosteric modulation may be an advantageous pathway because allosteric sites on mAChRs are less highly conserved.

[0007] Despite advances in muscarinic receptor (mAChR) research, there remains a scarcity of compounds that are potent, efficacious and selective positive allosteric modulators of the M1 mAChR that are also effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity, or other neurologic diseases in which the muscarinic M1receptor may be involved. SUMMARY

[0008] In one aspect, disclosed are compounds of formula (I), or pharmaceutically acceptable salts thereof,wherein m is 0 or 1; n is 0, 1, 2, 3, or 4; R1is selected from the group consisting of H, C1-4alkyl, C1-4fluoroalkyl, –C1-6alkylene–X1, G1, and –C1-4alkylene–G1; X1is selected from the group consisting of –OR1a, –NR1aR1b, –S(O)2R1a, and –C(O)NR1aR1b; R1aand R1bare independently selected from the group consisting of H, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, and –C1-3alkylene–C3-4cycloalkyl; G1is selected from the group consisting of phenyl, a 5- to 12-membered heteroaryl containing 1- 3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, and a C3- 8cycloalkyl, wherein each is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, C1-4alkyl, C1-4fluoroalkyl, OH, –OC1-4alkyl, –OC1-4fluoroalkyl, C3-4cycloalkyl, and –C1-3alkylene–C3-4cycloalkyl, wherein the heteroatoms contained in the heteroaryl and heterocyclyl are independently selected from the group consisting of O, N, and S; R2, at each occurrence, is independently selected from the group consisting of C1-4alkyl and –C1- 3alkylene–OC1-4alkyl; or two R2, together with the atom(s) to which each is attached, form a C3-6cycloalkane or oxo; or wherein alternatively, R1and one R2, together with the atoms to which each is attached, form a 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle beingoptionally substituted with 1-4 R3asubstituents independently selected from the group consisting of C1-4alkyl and halogen; or wherein alternatively, R1and one R2substituted on a non-adjacent carbon atom, together link to form a first C2-3alkylene bridge, the first C2-3alkylene bridge being optionally substituted with 1-4 R3bsubstituents independently selected from the group consisting of C1-4alkyl and halogen, wherein optionally one R3band a second R2together link to form a second C2-3alkylene bridge; R4is selected from the group consisting of H, C1-4alkyl, halogen, C2-4alkenyl, C1-4fluoroalkyl, CN, NO2, NH2, NHC(O)C1-4alkyl, –OR4a, C3-4cycloalkyl, –CH2OR4a, and –CH2NR4aR4b, wherein R4aand R4bare independently H or C1-4alkyl, or alternatively, R4aand R4b, together with the nitrogen to which each attaches, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, wherein the heterocyclyl is optionally substituted with a first substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, C1-2fluoroalkyl, phenyl, and pyridyl, and optionally substituted with a second substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, and C1-2fluoroalkyl, and optionally substituted with third and fourth substituents independently selected from the group consisting of halogen and C1-4alkyl; R5is selected from the group consisting of H, C1-4alkyl, halogen, C1-4fluoroalkyl, CN, –OR5a, C3-4cycloalkyl, –CH2OR5a, and –CH2NR5aR5b, wherein R5aand R5bare independently H or C1-4alkyl, or alternatively, R5aand R5b, together with the nitrogen to which each attaches, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, wherein the heterocyclyl is optionally substituted with a first substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, C1- 2fluoroalkyl, phenyl, and pyridyl, and optionally substituted with a second substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, and C1-2fluoroalkyl, and optionally substituted with third and fourth substituents independently selected from the group consisting of halogen and C1-4alkyl; or alternatively, R4and R5, together with the atoms to which each attaches, form a 5- to 7- membered carbocyclic ring; Z1is CR6or N;R6is H or C1-4alkyl; R7aand R7bare independently selected from the group consisting of H and C1-4alkyl; R8is selected from the group consisting of:Z4is CH, CR9, or N; Z5is CH, CR9, or N; wherein 0-2 of Z2, Z3, Z4, and Z5are N; Z6is CH, CR9, or N; Z7is CH, CR14, or N; Z8is C or N;ring 6-membered fully or partially unsaturated heterocyclic ring t R14and / or R15, wherein the heterocyclic ring contains 1-3 heteroatoms independently selected from the group consisting of N, O, and S; ring 6-membered fully or partially unsaturated heterocyclic R14and / or R15, wherein the heterocyclic ring containsa 2 additional heteroatoms independently selected from the group consisting of N, O, and S; R9, at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OC1-4alkyl, and –OC1-4fluoroalkyl; R10is selected from the group consisting of G10, –C(O)NR10aR10b, halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OR10a, –SR10a, –N(R10a)C(O)R10b, –N(R10b)C(O)R10a, –N(R10b)C(O)OR10a, –CO2R10a, –C(O)R10a, –S(O)2NR10aR10b, –S(O)2R10a, –C1-3alkylene–OR10b, and H; R10ais selected from the group consisting of H, C1-4alkyl, C1-4fluoroalkyl, –C1-4alkylene–O–C1-4alkyl, –C1-4alkylene–C(O)N(C1-4alkyl)2, G12, and –C1-4alkylene–G12; R10bis selected from the group consisting of H and C1-4alkyl; G10and G12are independently selected from the group consisting of a 5- to 10-membered heteroaryl containing 1-3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, phenyl, and C3-6cycloalkyl, the heteroatoms being independently selected from the group consisting of N, O, and S, wherein each is optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, C1-4alkyl, C1-4fluoroalkyl, –OR11a, –C(O)NR11aR11b, –C1-4alkylene–OR11a, G11, and –C1-3alkylene–G11, and optionally substituted with 1-3 additional substituents independently selected from the group consisting of halogen, oxo, and C1-4alkyl; R11aand R11bare independently selected from the group consisting of hydrogen and C1-4alkyl;G11is C3-6cycloalkyl or 3- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S; R14, at each occurrence is independently selected from the group consisting of halogen, C1-4alkyl, –OC1-4alkyl, and C3-4cycloalkyl; R15is oxo; R16is phenyl or pyridyl; o is 0, 1, or 2; and q is 0 or 1.

[0009] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] In another aspect, the invention provides a method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0011] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a disorder associated with muscarinic acetylcholine receptor activity.

[0012] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of a disorder associated with muscarinic acetylcholine recepter activity.

[0013] In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.

[0014] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, with minimal to substantially no M1 agonist activity compared to acetylcholine. The relative absence of M1agonist activity is expected to avoid or reduce cholinergic adverse effect liability at therapeutic concentrations and / or doses.DETAILED DESCRIPTION

[0015] Disclosed herein are positive allosteric modulators of the M1 muscarinic acetylcholine receptor M1(mAChR M1). The modulators can have the structure of formula (I). Compounds of formula (I) exhibit high affinity for mAChR M1, and can also exhibit selectivity over other muscarinic acetylcholine receptors. Compounds of formula (I) can be used to treat or prevent diseases and disorders associated with mAChR M1by modulating mAChR M1activity. mAChR M1has been implicated in a number of different diseases and disorders including, but not limited to, neurological and psychiatric disorders.

[0016] Since the orthosteric binding sites of the mAChR isoforms are highly conserved, selective modulators of the mAChRs that bind at the orthosteric site remain elusive. One strategy to selectively bind and modulate the mAChRs includes identifying allosteric sites which may be amenable to modulation by a small molecule. In particular, positive allosteric modulation of mAChR M1can result in potentiation of the mAChR M1receptor and provide therapeutic benefits for disorders associated with mAChR M1 dysfunction. 1. Definitions

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0018] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and“consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0019] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0020] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0021] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “C1-6alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-4alkyl” means a straight or branched chain saturated hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0022] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.

[0023] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched saturated chain hydrocarbon, for example, of 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, - CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0024] The term “alkenylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon having at least one carbon-carbon double bond.

[0025] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][1,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6- membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0026] The term “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl”is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl), or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0027] The term “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic all-carbon ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl”is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0028] The term “deuterioalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more hydrogen atoms in the alkyl are the isotope deuterium, i.e.,2H. Representative examples of deuterioalkyl include CD3, CH2CD3, and CD2CD3.

[0029] The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a fluoro group. Representative examples of fluoroalkyl include CH2F, CHF2, CF3, and CH2CF3.

[0030] The term “fluorodeuterioalkyl,” as used herein, means a fluoroalkyl group, as defined herein, in which one or more hydrogen atoms in the fluoroalkyl are the isotope deuterium, i.e.,2H. Representative examples of fluorodeuterioalkyl include CD2F, CDF2, and CD2CF3.

[0031] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0032] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0033] The term "halodeuterioalkyl," as used herein, means a haloalkyl, as defined herein, in which one or more hydrogen atoms in the haloalkyl are the isotope deuterium, i.e.,2H. Representative examples of halodeuterioalkyl include CD2F, CDF2, CD2CF3, CD2Cl, CDCl2, and CD2CCl3.

[0034] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatom- containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaryl (bicyclic heteroaryl). The term “heteroaryl”is used herein to refer to a heteroarene when present as a substituent, the term "heteroarene" being used in cases of ring fusion. The monocyclic heteroaryl are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g.1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8- to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., "fully aromatic" 10π electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1- yl), a monocyclic heteroaryl ring fused to a monocyclic 5- to 6-membered heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic 5- to 6-membered heteroarene (e.g., quinolin-5-yl, indol-4-yl). A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclic heteroaromatic ring system having four double bonds and at least one heteroatomcontributing a lone electron pair to a fully aromatic 10π electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ring system composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl.

[0035] The term “heterocycle” or “heterocyclic," as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term “heterocyclyl”is used herein to refer to a heterocycle when present as a substituent. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2- thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3- dihydrobenzothien-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6- azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2- oxaspiro[3.3]heptanyl, and 3-oxaspiro[5.5]undecanyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1- azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom.

[0036] The term “hydroxyl” or “hydroxy,” as used herein, means an -OH group.

[0037] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., "C1-4alkyl," "C3-6cycloalkyl," "C1-4alkylene"). These designations are used as generally understood by those skilled in the art. For example, the representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. As used herein, “Cmto Cn,” “Cm-Cn” or “Cm-n” in which “m” and “n” are integers refers to the number of carbon atoms in the relevant group. That is, the group can contain from “m” to “n”, inclusive, carbon atoms. Thus, for example, a “C1to C6alkyl” group refers to all alkyl groups having from 1 to 6 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH)3CH2- , CH3CH(CH)3CH2- and (CH3)3C-. Thus, "C3alkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "C1-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "C1-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched). If no “m” and “n” are designated with regard to a group, the broadest range described in these definitions is to be assumed.

[0038] A dashed bond, , represents an optional unsaturation between the atoms forming the bond. This bond may be unsaturated (e.g. C=C, C=N, C=O) or saturated (e.g. C-C, C-N, C-O). When a dashed bond is present in a ring system it may form part of an aromatic ring system.

[0039] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups may include, for example, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0040] As used herein, an "optional substituent" is a substituent that may or may not be present on another molecular group, such as a ring (e.g., phenyl) or chain (e.g., alkyl). A groupthat is "optionally substituted" with a substituent means the group is either unsubstituted or substituted with the substituent.

[0041] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0042] In accordance with established chemical drawing conventions, it is also understood that in chemical structures, hydrogen atoms are implied on carbon atoms where a substituent is not explicitly depicted, so as to fulfil the valency requirement of carbon for an octet of electrons (https: / / en.wikipedia.org / wiki / Skeletal_formula). Forare equivalent depictions of an isopropyl group.Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3, or 4, solvent or water molecules.

[0044] As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

[0045] The terms, “polymorphs” and “polymorphic forms” refer to crystalline forms of the same molecule, and different polymorphs may have different physical properties such as, forexample, melting temperatures, heats of fusion, solubilities, dissolution rates and / or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice. Polymorphs of a molecule can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation. Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X- ray diffractometry, vibrational spectroscopy, e.g., IR and Raman spectroscopy, solid state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.

[0046] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0047] The following abbreviations may be used herein: AcOH acetic acid Ac2O acetic anhydride AIBN azobisisobutyronitrile aq aqueous atm atmosphere(s) B2pin2bis(pinacolato)diboron CDCl3chloroform-d CD3OD methanol-d4 CD3COOD acetic acid-d4 Celite® diatomaceous earth conc. concentrated Cpd compound CypMgBr cyclopropylmagnesium bromide DCE dichloroethane DCl hydrochloric acid-dDCM dichloromethane d doublet dd doublet of doublets DtBAD di-tert-butyl azodicarboxylate Deoxo-Fluor bis(2-methoxyethyl)amino]sulfur trifluoride DIPEA / DIEA diisopropylethylamine DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMF•DMA N,N-dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide DMSO-d6dimethylsulfoxide-d6(deuterated dimethylsulfoxide) D2O deuterium oxide (deuterated or heavy water) dppf 1,1'-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane ES-MS electrospray mass spectrometry EtOAc ethyl acetate EtOH ethanol Et3N triethylamine eq. / equiv equivalents h or hr hour(s) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz hertz iPA / iPrOH isopropyl alcohol KOAc potassium acetate LCMS liquid chromatography-mass spectrometry M molarity (for concentration)mCPBA 3-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeI methyl iodide MeOH methanol MHz megahertz min minute(s) mw microwave NaHMDS sodium bis(trimethylsilyl)amide NaOAc sodium acetate NaOD sodium deuteroxide NaSMe sodium methanthiolate n-BuLi n-butyllithium NBS N-bromoosuccinimide NCS N-chlorosuccinimide NMP N-methyl-2-pyrrolidone PCy3tricyclohexylphosphine Pd(OAc)2 palladium(II)acetate Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2(1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride Ph phenyl (PhSO2)2NF N-fluorobenzenesulfonimide ppm parts per million RockPhos Palladacycle Gen-3 [(2-Di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate Rochelle salt potassium sodium tartrate tetrahydrate RP reverse phase r.t. / rt / RT room temperature s singletsat. saturated soln. solution STAB sodium triacetoxy borohydride T3P 1-propanephosphonic anhydride TBAF tetrabutylammonium fluoride TBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran XantPhos 9,9-dimethyl-4,5-bis(di-tert-butylphosphino)xanthene XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 2. Compounds

[0048] Throughout the embodiments and description of the compounds of the invention, all instances of haloalkyl may be fluoroalkyl (e.g., any C1-4haloalkyl may be C1-4fluoroalkyl).

[0049] Where heterocyclic and heteroaromatic ring systems are defined to "contain" or as "containing" specified heteroatoms (e.g., 1-3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atoms of the heterocyclic and heteroaromatic ring systems that are not one of the specified heteroatoms are carbon atoms.

[0050] In the following, numbered embodiments of the invention are disclosed (e.g., E1, E1.1, E2, E3, E3.1, E4, E4.1, E4.2, etc.). In the numbered embodiments, the reference to a range of preceding embodiments in multiple dependent format (e.g., "the compound of any of E1-E3") is a reference, in the alternative, to each embodiment sequentially listed herein in the recited range. For example, the range "any of E1-E4.1 or E4.6-E4.7" means "any of E1, E1.1, E2, E3, E3.1, E4, E4.1, E4.6, or E4.7."

[0051] E1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein m is 0 or 1; n is 0, 1, 2, 3, or 4; R1is selected from the group consisting of H, C1-4alkyl, C1-4fluoroalkyl, –C1-6alkylene–X1, G1, and –C1-4alkylene–G1; X1is selected from the group consisting of –OR1a, –NR1aR1b, –S(O)2R1a, and –C(O)NR1aR1b; R1aand R1bare independently selected from the group consisting of H, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, and –C1-3alkylene–C3-4cycloalkyl; G1is selected from the group consisting of phenyl, a 5- to 12-membered heteroaryl containing 1- 3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, and a C3-8cycloalkyl, wherein each is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, C1-4alkyl, C1-4fluoroalkyl, OH, –OC1-4alkyl, –OC1-4fluoroalkyl, C3-4cycloalkyl, and –C1-3alkylene–C3-4cycloalkyl, wherein the heteroatoms contained in the heteroaryl and heterocyclyl are independently selected from the group consisting of O, N, and S; R2, at each occurrence, is independently selected from the group consisting of C1-4alkyl and –C1- 3alkylene–OC1-4alkyl; or two R2, together with the atom(s) to which each is attached, form a C3-6cycloalkane or oxo; or wherein alternatively, R1and one R2, together with the atoms to which each is attached, form a 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle beingoptionally substituted with 1-4 R3asubstituents independently selected from the group consisting of C1-4alkyl and halogen; or wherein alternatively, R1and one R2substituted on a non-adjacent carbon atom, together link to form a first C2-3alkylene bridge, the first C2-3alkylene bridge being optionally substituted with 1-4 R3bsubstituents independently selected from the group consisting of C1-4alkyl and halogen, wherein optionally one R3band a second R2together link to form a second C2-3alkylene bridge; R4is selected from the group consisting of H, C1-4alkyl, halogen, C2-4alkenyl, C1-4fluoroalkyl, CN, NO2, NH2, NHC(O)C1-4alkyl, –OR4a, C3-4cycloalkyl, –CH2OR4a, and –CH2NR4aR4b, wherein R4aand R4bare independently H or C1-4alkyl, or alternatively, R4aand R4b, together with the nitrogen to which each attaches, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, wherein the heterocyclyl is optionally substituted with a first substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, C1-2fluoroalkyl, phenyl, and pyridyl, and optionally substituted with a second substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, and C1-2fluoroalkyl, and optionally substituted with third and fourth substituents independently selected from the group consisting of halogen and C1-4alkyl; R5is selected from the group consisting of H, C1-4alkyl, halogen, C1-4fluoroalkyl, CN, –OR5a, C3-4cycloalkyl, –CH2OR5a, and –CH2NR5aR5b, wherein R5aand R5bare independently H or C1-4alkyl, or alternatively, R5aand R5b, together with the nitrogen to which each attaches, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, wherein the heterocyclyl is optionally substituted with a first substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, C1- 2fluoroalkyl, phenyl, and pyridyl, and optionally substituted with a second substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, and C1-2fluoroalkyl, and optionally substituted with third and fourth substituents independently selected from the group consisting of halogen and C1-4alkyl; or alternatively, R4and R5, together with the atoms to which each attaches, form a 5- to 7- membered carbocyclic ring; Z1is CR6or N;R6is H or C1-4alkyl; R7aand R7bare independently selected from the group consisting of H and C1-4alkyl; R8is selected from the group consisting of:Z4is CH, CR9, or N; Z5is CH, CR9, or N; wherein 0-2 of Z2, Z3, Z4, and Z5are N; Z6is CH, CR9, or N; Z7is CH, CR14, or N; Z8is C or N;ring 6-membered fully or partially unsaturated heterocyclic ring t R14and / or R15, wherein the heterocyclic ring contains 1-3 heteroatoms independently selected from the group consisting of N, O, and S; ring 6-membered fully or partially unsaturated heterocyclic R14and / or R15, wherein the heterocyclic ring containsa 2 additional heteroatoms independently selected from the group consisting of N, O, and S; R9, at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OC1-4alkyl, and –OC1-4fluoroalkyl; R10is selected from the group consisting of G10, –C(O)NR10aR10b, halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OR10a, –SR10a, –N(R10a)C(O)R10b, –N(R10b)C(O)R10a, –N(R10b)C(O)OR10a, –CO2R10a, –C(O)R10a, –S(O)2NR10aR10b, –S(O)2R10a, –C1-3alkylene–OR10b, and H; R10ais selected from the group consisting of H, C1-4alkyl, C1-4fluoroalkyl, –C1-4alkylene–O–C1-4alkyl, –C1-4alkylene–C(O)N(C1-4alkyl)2, G12, and –C1-4alkylene–G12; R10bis selected from the group consisting of H and C1-4alkyl; G10and G12are independently selected from the group consisting of a 5- to 10-membered heteroaryl containing 1-3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, phenyl, and C3-6cycloalkyl, the heteroatoms being independently selected from the group consisting of N, O, and S, wherein each is optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, C1-4alkyl, C1-4fluoroalkyl, –OR11a, –C(O)NR11aR11b, –C1-4alkylene–OR11a, G11, and –C1-3alkylene–G11, and optionally substituted with 1-3 additional substituents independently selected from the group consisting of halogen, oxo, and C1-4alkyl; R11aand R11bare independently selected from the group consisting of hydrogen and C1-4alkyl;G11is C3-6cycloalkyl or 3- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S; R14, at each occurrence is independently selected from the group consisting of halogen, C1-4alkyl, –OC1-4alkyl, and C3-4cycloalkyl; R15is oxo; R16is phenyl or pyridyl; o is 0, 1, or 2; and q is 0 or 1.

[0052] E1.1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R2, at each occurrence, is independently selected from the group consisting of C1-4alkyl and –C1- 3alkylene–OC1-4alkyl; or two R2, together with the atom(s) to which each is attached, form a C3-6cycloalkane; or wherein alternatively, R1and one R2, together with the atoms to which each is attached, form a 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle being optionally substituted with 1-4 R3asubstituents independently selected from the group consisting of C1-4alkyl and halogen; or wherein alternatively, R1and one R2substituted on a non-adjacent carbon atom, together link to form a first C2-3alkylene bridge, the first C2-3alkylene bridge being optionally substituted with 1-4 R3bsubstituents independently selected from the group consisting of C1-4alkyl and halogen, wherein optionally one R3band a second R2together link to form a second C2-3alkylene bridge; R4is selected from the group consisting of H, C1-4alkyl, halogen, cyano, C2-4alkenyl, C1- 4fluoroalkyl, CN, NO2, NH2, NHC(O)C1-4alkyl, and C3-4cycloalkyl; R5is selected from the group consisting of C1-4alkyl, halogen, C1-4fluoroalkyl, CN, and C3-4cycloalkyl; R6is H; and. ompound of E1 or E1.1, or a pharmaceutically acceptable salt thereof, wherein m is 1. When m is 1, formula (I) has (I-a).

[0054] E3. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4; and R1and one R2, together with the atoms to which each is attached, form a 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle being optionally substituted with 1-4 R3asubstituents independently selected from the group consisting of C1-4alkyl and halogen; or wherein alternatively, R1and one R2substituted on a non-adjacent carbon atom, together link to form a first C2-3alkylene bridge, the first C2-3alkylene bridge being optionally substituted with 1-4 R3bsubstituents independently selected from the group consisting of C1-4alkyl and halogen, wherein optionally one R3band a second R2together link to form a second C2-3alkylene bridge.

[0055] E3.1. The compound of E3, or a pharmaceutically acceptable salt thereof, wherein each other occurrence of R2is independently selected from the group consisting of C1-4alkyl and –C1-3alkylene–OC1-4alkyl; wherein two R2, together with the atom(s) to which each is attached, alternatively form a C3-6cycloalkane or oxo.

[0056] E4. The compound of E3 or E3.1, or a pharmaceutically acceptable salt thereof, wherein R1and one R2, together with the atoms to which each is attached, form the 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle being optionally substituted with 1-4 R3asubstituents independently selected from the group consisting of C1-4alkyl and halogen.

[0057] E4.1. The compound of E4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (V): a straight chain C1-2alkylene,with an oxygen or nitrogen atom.

[0058] E4.2. The compound of E4.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula or CF2.

[0059] E4.3. The or a

[0060] E4.4. The compound of E4.2 or E4.3, or a pharmaceutically acceptable salt thereof, wherein L1Ais CH2.

[0061] E4.5. The compound of E4.2 or E4.3, or a pharmaceutically acceptable salt thereof, wherein L1Ais CF2.

[0062] E4.6. The compound of E4.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula or NR3a; and R3ais C1-4alkyl.

[0063] E4.7. The compound of E4.6, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (V- b1), and / or thecompound has formula .

[0064] E4.8.or a pharmaceutically acceptable salt thereof, wherein R3ais methyl.

[0065] E4.9. The compound of any of E4.6-E4.8, or a pharmaceutically acceptable salt thereof, wherein L1Bis O.

[0066] E4.10. The compound of any of E4.6-E4.8, or a pharmaceutically acceptable salt thereof, wherein L1Bis NH.

[0067] E4.11. The compound of any of E4.6-E4.8, or a pharmaceutically acceptable salt thereof, wherein L1Bis NR3a.

[0068] E4.12. The compound of any of E4.1-E4.11, or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

[0069] E5. The compound of E3, or a pharmaceutically acceptable salt thereof, wherein R1and one R2substituted on a non-adjacent carbon atom, together link to form the firstC2-3alkylene bridge, the first C2-3alkylene bridge being optionally substituted with 1-4 R3bsubstituents independently selected from the group consisting of C1-4alkyl and halogen, wherein optionally one R3band a second R2together link to form a second C2-3alkylene bridge.

[0070] E5.1. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein the compound has formula L2is the first C2-3alkylene bridge

[0071] E5.2. The compound of E5.1, or a pharmaceutically acceptable salt thereof, wherein the first C2-3alkylene bridge at L2is a C2alkylene bridge, optionally substituted with the 1-4 R3bsubstituents.

[0072] E5.3. The compound of E5.1, or a pharmaceutically acceptable salt thereof, wherein the first C2-3alkylene bridge at L2is a C3alkylene bridge, optionally substituted with the 1-4 R3bsubstituents.

[0073] E5.4. The compound of any of E1-E3.1 or E5-E5.3, of a pharmaceutically acceptable salt thereof, wherein the first alkylene bridge is optionally substituted with 1 R3bsubstituent.

[0074] E5.5. The compound of any of E1-E3.1 or E5-E5.4, or a pharmaceutically acceptable salt thereof, wherein R3bis C1-4alkyl.

[0075] E5.6. The compound of E5.5, or a pharmaceutically acceptable salt thereof, wherein R3bis methyl.

[0076] E5.7. The compound of any of E1-E3.1 or E5-E5.3, of a pharmaceutically acceptable salt thereof, wherein the first alkylene bridge is unsubstituted.

[0077] E5.8. The compound of any of E5.1-E5.7, or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

[0078] E5.9. The compound of any of E5.1-E5.7, or a pharmaceutically acceptable salt thereof, wherein n1 is 1.

[0079] E5.10. The compound of any of E1-E3.1, E5.1-E5.7, or E5.9, or a pharmaceutically acceptable salt thereof, wherein R2is C1-4alkyl.

[0080] E5.11. The compound of E5.10, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

[0081] E5.12. The compound of any of E1-E3.1, E5-E5.4, or E5.9, or a pharmaceutically acceptable salt thereof, wherein one R3band a second R2together link to form the second C2-3alkylene bridge.

[0082] E5.13. The compound of E5.12, or a pharmaceutically acceptable salt thereof, wherein the second C2-3alkylene bridge is a C2alkylene bridge.

[0083] E5.14. The compound of E5.7 or E5.8, or a pharmaceutically acceptable salt

[0084] E5.15. The compound of E5.7 or E5.8, or a pharmaceutically acceptable saltthereof, wherein the compound has e).

[0086] E5.17. The compound of any of E5.7 or E5.9-E5.11, or a pharmaceutically acceptable salt thereof, wherein the compound hasf) and / or the compound has formula .

[0087] E5.18. The compound of any of E5.7 or E5.9-E5.11, or a pharmaceuticallyacceptable salt thereof, wherein the compound has (VI-j).

[0089] E5.20. The compound of any of E5.4-E5.6 or E5.8, or a pharmaceutically acceptable salt thereof, wherein the compound has (VI-k).

[0090] E5.21. The compound of any of E5.4-E5.6 or or a acceptable salt thereof, wherein the compound has l).

[0091] E5.22. The compound of any of E5.4-E5.6 or E5.8, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VI-m):n): ):3): e salt thereof, wherein the compound has formula .

[0093] E6. Theacceptable salt thereof, wherein R4is selected from the group consisting of H, C1-4alkyl, and halogen.

[0094] E6.1. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein R4is H.

[0095] E6.2. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein R4is C1-4alkyl.

[0096] E6.3. The compound of E6.2, or a pharmaceutically acceptable salt thereof, wherein R4is CH3.

[0097] E6.4. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein R4is halogen.

[0098] E6.5. The compound of E6.4, or a pharmaceutically acceptable salt thereof, wherein R4is chloro.

[0099] E7. The compound of any of E1-E6.5, or a pharmaceutically acceptable salt thereof, wherein R5is C1-4alkyl.

[0100] E7.1. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R5is CH3.

[0101] E8. The compound of any of E1-E7.1, or a pharmaceutically acceptable salt thereof, wherein Z1is CR6.

[0102] E8.1. The compound of any of E1-E8, or a pharmaceutically acceptable salt thereof, wherein R6is H (i.e., Z1is CH).

[0103] E9. The compound of any of E1-E8.1, or a pharmaceutically acceptable salt thereof, wherein R7aand R7bare H.

[0104] E10. The compound of any of E1-E9, or a pharmaceutically acceptable salt thereof, .

[0105] E11.of E1-E10, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group ,nd ptable salt thereof, wherein p is 0.

[0107] E11.2. The compound of E11, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0108] E11.3. The compound of E11, or a pharmaceutically acceptable salt thereof, wherein p is 2.

[0109] E11.4. The compound of E11, or a pharmaceutically acceptable salt thereof, wherein p is 3.

[0110] E11.5. The compound of E11, or a pharmaceutically acceptable salt thereof, wherein p is 4.

[0111] E11.6. The compound of any of E11-E11.3, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group ,, lt . of E1-E10 or E12, or a pharmaceutically acceptablesalt thereof, wherein Z3is CH.

[0114] E12.2. The compound of any of E1-E10 or E12, or a pharmaceutically acceptable salt thereof, wherein Z3is CR9.

[0115] E12.3. The compound of any of E1-E10 or E12, or a pharmaceutically acceptable salt thereof, wherein Z3is N.

[0116] E13. The compound of any of E1-E12 or E12.2, or a pharmaceutically acceptable salt thereof, wherein R9, at each occurrence, is independently selected from the group consisting of halogen, C1-4alkyl, and –OC1-4alkyl.

[0117] E13.1. The compound of E13, or a pharmaceutically acceptable salt thereof, wherein R9, at each occurrence, is independently selected from the group consisting of fluoro, CH3, and –OCH3.

[0118] E13.2. The compound of E13, or a pharmaceutically acceptable salt thereof, wherein R9, at each occurrence, is independently halogen.

[0119] E13.3. The compound of any of E13-E13.2, or a pharmaceutically acceptable salt thereof, wherein R9, at each occurrence, is fluoro.

[0120] E14. The compound of any of E1-E13.3, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the groupsalt thereof, wherein R8is selected from the group

[0126] E15.2. The compound of E15, or a pharmaceutically acceptable salt thereof, wherein .

[0127] of E15, or a pharmaceutically acceptable salt thereof,wherein .

[0128] of any of E1-E15.3, or a pharmaceutically acceptable saltthereof, from the group consisting of G10, –C(O)NR10aR10b, and C1-4alkyl.

[0129] E16.1. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R10is C1-4alkyl.

[0130] E16.2. The compound of E16.1, or a pharmaceutically acceptable salt thereof, wherein R10is CH3.

[0131] E17. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R10is G10.

[0132] E18. The compound of any of E1-E16 or E17, or a pharmaceutically acceptable salt thereof, wherein G10is the 5- to 10-membered heteroaryl, optionally substituted as defined in E1. E18.1. The compound of any of E1-E16 or E17-E18, or a pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl at G10is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, and optionally substituted as defined in E1.

[0134] E18.2. The compound of any of E1-E16 or E17-E18.1, or a pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl at G10is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl, and optionally substituted as defined in E1.

[0135] E18.3. The compound of any of E1-E16 or E17-E18.2, or a pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl at G10is selected from the group consisting of pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,3-triazol-4-yl, and oxazol-4-yl, pyridin-3-yl, and pyridin-4-yl, and optionally substituted as defined in E1.

[0136] E18.4. The compound of E18.2, or a pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl at G10is pyrazolyl, and optionally substituted as defined in E1.

[0137] E18.5. The compound of E18.3 or E18.4, or a pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl at G10is pyrazol-4-yl, and optionally substituted as defined in E1.

[0138] E18.6. The compound of any of E18-E18.5, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl at G10is optionally substituted with 1-3 C1-4alkyl (i.e., the alkyl may be the same or different).

[0139] E18.7. The compound of any of E18-E18.6, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl at G10is optionally substituted with 1-3 CH3.

[0140] E18.8. The compound of any of E1-E16 or E17-E18.7, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl at G10is unsubstituted.

[0141] E18.9. The compound of any of E18-E18.8, or a pharmaceutically acceptable salt thereof, wherein G10is selected from the group consisting ,.acceptable salt thereof, wherein G10is selected from the group consisting ,.salt thereof, wherein .

[0144] E18.12. The compound of any of E18.10 or E18.11, or a pharmaceutically acceptable salt thereof, wherein G10.

[0145] E18.13. The or a pharmaceutically acceptable salt thereof,wherein .

[0146] of E16, or a pharmaceutically acceptable salt thereof,wherein R10is –C(O)

[0147] E20. The compound of any of E1-E16 or E19, or a pharmaceutically acceptable salt thereof, wherein R10ais C1-4alkyl.

[0148] E20.1. The compound of E20, or a pharmaceutically acceptable salt thereof, wherein R10ais CH3.

[0149] E21. The compound of any of E1-E16 or E19-E20.1, or a pharmaceutically acceptable salt thereof, wherein R10bis H.

[0150] E22. The compound of any of E1-E16 or E19-E21, or a pharmaceutically acceptable salt thereof, wherein R10is –C(O)NHCH3.

[0151] E22.1. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein .

[0152] of E22, or a pharmaceutically acceptable salt thereof, wherein .

[0153] E22.3. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein .

[0154] of any of E1-E22.3, or a pharmaceutically acceptable saltthereof, wherein R8is selected from the group ,. of any of E1-E9, or a pharmaceutically acceptable salt.salt thereof, wherein .

[0157] of E24 or E24.1, or a pharmaceutically acceptable salt thereof, wherein Z2, Z3, Z4, and Z5are independently CH or CR9.

[0158] E24.3. The compound of E24.2, or a pharmaceutically acceptable salt thereof, wherein one of Z2, Z3, Z4, and Z5is CR9and the others are CH.

[0159] E24.4. The compound of E24.3, or a pharmaceutically acceptable salt thereof, wherein .

[0160] E24.5. The compound of E24.4, or a pharmaceutically acceptable salt thereof,6- R14,wherein the heterocyclic ring contains 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

[0163] E24.8. The compound of E24.7, or a pharmaceutically acceptable salt thereof, wherein .

[0164] of E1-E9, E24, or E24.6-E24.8, or a pharmaceutically acceptable salt thereof, wherein R14, at each occurrence, is independently methyl or –OCH3.

[0165] E24.10. The compound of any of E1-E9, E24, or E24.6-E24.9, or a pharmaceutically acceptable salt thereof, ).

[0166] E24.11. The compound of any ofa pharmaceutically acceptable salt thereof, wherein o is 1.

[0167] E24.12. The compound of any of E1-E9, E24, or E24.6-E24.9, or a pharmaceutically acceptable salt thereof, wherein o is 2.

[0168] E25. The compound of E1, selected from a compound of any of Tables 8, 9, or 10, or a pharmaceutically acceptable salt thereof.

[0169] E25.1. The compound of E1 or E25 selected from the group consisting of 4- (((2S)-10-chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0170] E25.2. The compound of E1 or E25 selected from the group consisting of (2S)-8- (4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0171] E25.3. The compound of E1 or E25 selected from the group consisting of (2S)- 10-chloro-9-methyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0172] E25.4. The compound of E1 or E25 selected from the group consisting of (2S)- 10-chloro-9-methyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0173] E25.5. The compound of E1 or E25 selected from the group consisting of (2S)- 10-chloro-9-methyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0174] E25.6. The compound of E1 or E25 selected from the group consisting of 4- (((2S)-10-chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0175] E25.7. The compound of E1 or E25 selected from the group consisting of (2S)- 10-chloro-8-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-9-methyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0176] E25.8. The compound of E1 or E25 selected from the group consisting of (2S)- 10-chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H- 2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0177] E25.9. The compound of E1 or E25 selected from the group consisting of (2S)- 10-chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H- 2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0178] E25.10. The compound of E1 or E25 selected from the group consisting of 4- (((2R)-10-chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0179] E25.11. The compound of E1 or E25 selected from the group consisting of (2R)-8- (4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0180] E25.12. The compound of E1 or E25 selected from the group consisting of (2S)- 9,10-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0181] E25.13. The compound of E1 or E25 selected from the group consisting of (2S)- 9,10-dimethyl-8-(4-(oxazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0182] E25.14. The compound of E1 or E25 selected from the group consisting of (2S)- 9,10-dimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0183] E25.15. The compound of E1 or E25 selected from the group consisting of 4- (((2S)-9,10-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0184] E25.16. The compound of E1 or E25 selected from the group consisting of (2S)-8- (4-(1H-pyrazol-1-yl)benzyl)-9,10-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0185] E25.17. The compound of E1 or E25 selected from the group consisting of (2S)- 9,10-dimethyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0186] E25.18. The compound of E1 or E25 selected from the group consisting of 4- (((2S)-9,10-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0187] E25.19. The compound of E1 or E25 selected from the group consisting of (2S)-8- (3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-9,10-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0188] E25.20. The compound of E1 or E25 selected from the group consisting of (2R)- 9,10-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0189] E25.21. The compound of E1 or E25 selected from the group consisting of (2R)-8- (4-(1H-pyrazol-1-yl)benzyl)-9,10-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0190] E25.22. The compound of E1 or E25 selected from the group consisting of 4- (((2R)-9,10-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0191] E25.23. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0192] E25.24. The compound of E1 or E25 selected from the group consisting of (2S,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0193] E25.25. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0194] E25.26. The compound of E1 or E25 selected from the group consisting of (2S,4R)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0195] E25.27. The compound of E1 or E25 selected from the group consisting of (2S,4R)-10-chloro-4,9-dimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H- 2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0196] E25.28. The compound of E1 or E25 selected from the group consisting of (2S,4R)-4,9,10-trimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0197] E25.29. The compound of E1 or E25 selected from the group consisting of (2S,4R)-4,9,10-trimethyl-8-(4-(oxazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0198] E25.30. The compound of E1 or E25 selected from the group consisting of (2S,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-4,9,10-trimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0199] E25.31. The compound of E1 or E25 selected from the group consisting of N- methyl-4-(((2S,4R)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0200] E25.32. The compound of E1 or E25 selected from the group consisting of 2- fluoro-N-methyl-4-(((2S,4R)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0201] E25.33. The compound of E1 or E25 selected from the group consisting of (2S,4R)-4,9,10-trimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0202] E25.34. The compound of E1 or E25 selected from the group consisting of (2S,4R)-4,9,10-trimethyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0203] E25.35. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0204] E25.36. The compound of E1 or E25 selected from the group consisting of (2S,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0205] E25.37. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0206] E25.38. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H- 2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0207] E25.39. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H- 2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0208] E25.40. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0209] E25.41. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0210] E25.42. The compound of E1 or E25 selected from the group consisting of (2S,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-4,9,10-trimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0211] E25.43. The compound of E1 or E25 selected from the group consisting of (2S,4S)-4,9,10-trimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0212] E25.44. The compound of E1 or E25 selected from the group consisting of 2- fluoro-N-methyl-4-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0213] E25.45. The compound of E1 or E25 selected from the group consisting of N- methyl-4-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0214] E25.46. The compound of E1 or E25 selected from the group consisting of 4- (((2S,3S)-10-chloro-3,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0215] E25.47. The compound of E1 or E25 selected from the group consisting of (2S,3S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-3,9-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0216] E25.48. The compound of E1 or E25 selected from the group consisting of (2S,3S)-10-chloro-3,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0217] E25.49. The compound of E1 or E25 selected from the group consisting of (2S,3S)-10-chloro-3,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0218] E25.50. The compound of E1 or E25 selected from the group consisting of 4- (((2S,3S)-10-chloro-3,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0219] E25.51. The compound of E1 or E25 selected from the group consisting of 4- (((2S,11R)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0220] E25.52. The compound of E1 or E25 selected from the group consisting of (2S,11R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9,11-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0221] E25.53. The compound of E1 or E25 selected from the group consisting of (2S,11R)-10-chloro-9,11-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0222] E25.54. The compound of E1 or E25 selected from the group consisting of (2S,11R)-10-chloro-9,11-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0223] E25.55. The compound of E1 or E25 selected from the group consisting of 4- (((2S,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0224] E25.56. The compound of E1 or E25 selected from the group consisting of (2S,11S)-10-chloro-9,11-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0225] E25.57. The compound of E1 or E25 selected from the group consisting of4- (((2R,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0226] E25.58. The compound of E1 or E25 selected from the group consisting of (2R,11S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9,11-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0227] E25.59. The compound of E1 or E25 selected from the group consisting of (2R,11S)-10-chloro-9,11-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0228] E25.60. The compound of E1 or E25 selected from the group consisting of (2R,11S)-10-chloro-9,11-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0229] E25.61. The compound of E1 or E25 selected from the group consisting of 4- (((2R,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0230] E25.62. The compound of E1 or E25 selected from the group consisting of 4- (((2R,11R)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0231] E25.63. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-((6-methylpyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0232] E25.64. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-((2-methylpyridin-4-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0233] E25.65. The compound of E1 or E25 selected from the group consisting of 5- (((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0234] E25.66. The compound of E1 or E25 selected from the group consisting of 5- (((2S,4S)-10-fluoro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0235] E25.67. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4S)-10-fluoro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0236] E25.68. The compound of E1 or E25 selected from the group consisting of N- methyl-5-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.

[0237] E25.69. The compound of E1 or E25 selected from the group consisting of 5- (((2S,4S)-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0238] E25.70. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4S)-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0239] E25.71. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0240] E25.72. The compound of E1 or E25 selected from the group consisting of 5- (((2R,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0241] E25.73. The compound of E1 or E25 selected from the group consisting of (2S)-9- (4-(1H-pyrazol-1-yl)benzyl)-11-chloro-10-methyl-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-7-one, or a pharmaceutically acceptable salt thereof.

[0242] E25.74. The compound of E1 or E25 selected from the group consisting of (2S)- 11-chloro-10-methyl-9-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,4,5-tetrahydro- 7H-2,6-methanobenzo[b][1,5]oxazonin-7-one, or a pharmaceutically acceptable salt thereof.

[0243] E25.75. The compound of E1 or E25 selected from the group consisting of 4- (((2S)-11-chloro-10-methyl-7-oxo-2,3,4,5-tetrahydro-7H-2,6-methanobenzo[b][1,5]oxazonin-9- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0244] E25.76. The compound of E1 or E25 selected from the group consisting of (2R)- 11-chloro-10-methyl-9-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-7-one, or a pharmaceutically acceptable salt thereof.

[0245] E25.77. The compound of E1 or E25 selected from the group consisting of 4- (((2R)-11-chloro-10-methyl-7-oxo-2,3,4,5-tetrahydro-7H-2,6-methanobenzo[b][1,5]oxazonin-9- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0246] E25.78. The compound of E1 or E25 selected from the group consisting of (2R)-9- (4-(1H-pyrazol-1-yl)benzyl)-11-chloro-10-methyl-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-7-one, or a pharmaceutically acceptable salt thereof.

[0247] E25.79. The compound of E1 or E25 selected from the group consisting of 4- (((2R)-11-chloro-10-methyl-7-oxo-2,3,4,5-tetrahydro-7H-2,6-methanobenzo[b][1,5]oxazonin-9- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0248] E25.80. The compound of E1 or E25 selected from the group consisting of (2R)- 11-chloro-10-methyl-9-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,4,5-tetrahydro- 7H-2,6-methanobenzo[b][1,5]oxazonin-7-one, or a pharmaceutically acceptable salt thereof.

[0249] E25.81. The compound of E1 or E25 selected from the group consisting of 8-(4- (1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0250] E25.82. The compound of E1 or E25 selected from the group consisting of 4-((10- chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-2- fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0251] E25.83. The compound of E1 or E25 selected from the group consisting of 10- chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0252] E25.84. The compound of E1 or E25 selected from the group consisting of 2-(4- (1H-pyrazol-1-yl)benzyl)-4-chloro-3-methyl-6,7,7a,8,9,10-hexahydro-12H-6,10- methanobenzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one, or a pharmaceutically acceptable salt thereof.

[0253] E25.85. The compound of E1 or E25 selected from the group consisting of 4-((4- chloro-3-methyl-12-oxo-6,7,7a,8,9,10-hexahydro-12H-6,10-methanobenzo[b]pyrrolo[1,2- e][1,5]oxazocin-2-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0254] E25.86. The compound of E1 or E25 selected from the group consisting of 4- chloro-3-methyl-2-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-6,7,7a,8,9,10-hexahydro-12H-6,10- methanobenzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one, or a pharmaceutically acceptable salt thereof.

[0255] E25.87. The compound of E1 or E25 selected from the group consisting of 4- chloro-3-methyl-2-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-6,7,7a,8,9,10-hexahydro- 12H-6,10-methanobenzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one or a pharmaceutically acceptable salt thereof.

[0256] E25.88. The compound of E1 or E25 selected from the group consisting of (2S,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0257] E25.89. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0258] E25.90. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0259] E25.91. The compound of E1 or E25 selected from the group consisting of (2S,4S)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0260] E25.92. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0261] E25.93. The compound of E1 or E25 selected from the group consisting of (2R,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0262] E25.94. The compound of E1 or E25 selected from the group consisting of 4- (((2R,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin- 8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0263] E25.95. The compound of E1 or E25 selected from the group consisting of (2R,4R)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0264] E25.96. The compound of E1 or E25 selected from the group consisting of (2R,4R)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0265] E25.97. The compound of E1 or E25 selected from the group consisting of 4- (((2R,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0266] E25.98. The compound of E1 or E25 selected from the group consisting of (2R,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0267] E25.99. The compound of E1 or E25 selected from the group consisting of 4- (((2R,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0268] E25.100. The compound of E1 or E25 selected from the group consisting of (2R,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0269] E25.101. The compound of E1 or E25 selected from the group consisting of (2R,4S)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0270] E25.102. The compound of E1 or E25 selected from the group consisting of 4- (((2R,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0271] E25.103. The compound of E1 or E25 selected from the group consisting of (2S,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0272] E25.104. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0273] E25.105. The compound of E1 or E25 selected from the group consisting of (2S,4R)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0274] E25.106. The compound of E1 or E25 selected from the group consisting of (2S,4R)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0275] E25.107. The compound of E1 or E25 selected from the group consisting of 4- (((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0276] E25.108. The compound of E1 or E25 selected from the group consisting of (S)-4- ((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0277] E25.109. The compound of E1 or E25 selected from the group consisting of (S)-9- chloro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0278] E25.110. The compound of E1 or E25 selected from the group consisting of (S)-9- chloro-8-methyl-7-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0279] E25.111. The compound of E1 or E25 selected from the group consisting of (R)-4- ((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0280] E25.112. The compound of E1 or E25 selected from the group consisting of (R)-4- ((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0281] E25.113. The compound of E1 or E25 selected from the group consisting of (R)-7- (4-(1H-pyrazol-1-yl)benzyl)-9-chloro-8-methyl-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0282] E25.114. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-8-methyl-7-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0283] E25.115. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0284] E25.116. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-8-methyl-7-((6-methylpyridin-3-yl)methyl)-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0285] E25.117. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-8-methyl-7-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0286] E25.118. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-8-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0287] E25.119. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-8-methyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0288] E25.120. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-8-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0289] E25.121. The compound of E1 or E25 selected from the group consisting of (R)-4- ((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0290] E25.122. The compound of E1 or E25 selected from the group consisting of (R)-4- ((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0291] E25.123. The compound of E1 or E25 selected from the group consisting of (R)-7- (4-(1H-pyrazol-1-yl)benzyl)-9-chloro-2,2-difluoro-8-methyl-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0292] E25.124. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-2,2-difluoro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0293] E25.125. The compound of E1 or E25 selected from the group consisting of (R)-9- chloro-2,2-difluoro-8-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0294] E25.126. The compound of E1 or E25 selected from the group consisting of (R)-7- (4-(1H-pyrazol-1-yl)benzyl)-2,2-difluoro-8,9-dimethyl-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0295] E25.127. The compound of E1 or E25 selected from the group consisting of (R)-2,2- difluoro-8,9-dimethyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0296] E25.128. The compound of E1 or E25 selected from the group consisting of (R)-4- ((2,2-difluoro-8,9-dimethyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0297] E25.129. The compound of E1 or E25 selected from the group consisting of (R)-4- ((2,2-difluoro-8,9-dimethyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0298] E25.130. The compound of E1 or E25 selected from the group consisting of (R)-4- ((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0299] E25.131. The compound of E1 or E25 selected from the group consisting of (R)-4- ((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0300] E25.132. The compound of E1 or E25 selected from the group consisting of (R)-8- (4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0301] E25.133. The compound of E1 or E25 selected from the group consisting of (R)-10- chloro-9-methyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0302] E25.134. The compound of E1 or E25 selected from the group consisting of (R)-10- chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4,12,12a-tetrahydro- 1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0303] E25.135. The compound of E1 or E25 selected from the group consisting of (R)-10- chloro-9-methyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0304] E25.136. The compound of E1 or E25 selected from the group consisting of (R)-10- chloro-9-methyl-8-(4-(oxazol-4-yl)benzyl)-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0305] E25.137. The compound of E1 or E25 selected from the group consisting of (R)-10- chloro-9-methyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0306] E25.138. The compound of E1 or E25 selected from the group consisting of (S)-4- ((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0307] E25.139. The compound of E1 or E25 selected from the group consisting of (S)-4- ((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0308] E25.140. The compound of E1 or E25 selected from the group consisting of (S)-8- (4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0309] E25.141. The compound of E1 or E25 selected from the group consisting of (S)-10- chloro-9-methyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0310] E25.142. The compound of E1 or E25 selected from the group consisting of (S)-10- chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4,12,12a-tetrahydro- 1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0311] E25.143. The compound of E1 or E25 selected from the group consisting of (S)-10- chloro-9-methyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0312] E25.144. The compound of E1 or E25 selected from the group consisting of (R)-4- ((10-chloro-2,9-dimethyl-6-oxo-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0313] E25.145. The compound of E1 or E25 selected from the group consisting of (R)-8- (4-(1H-pyrazol-1-yl)benzyl)-10-chloro-2,9-dimethyl-1,2,3,4,12,12a-hexahydro-6H- benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0314] E25.146. The compound of E1 or E25 selected from the group consisting of (R)-10- chloro-2,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1,2,3,4,12,12a- hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0315] E25.147. The compound of E1 or E25 selected from the group consisting of (S)-4- ((10-chloro-2,9-dimethyl-6-oxo-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0316] E25.148. The compound of E1 or E25 selected from the group consisting of (S)-8- (4-(1H-pyrazol-1-yl)benzyl)-10-chloro-2,9-dimethyl-1,2,3,4,12,12a-hexahydro-6H- benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0317] E25.149. The compound of E1 or E25 selected from the group consisting of (S)-10- chloro-2,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1,2,3,4,12,12a- hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one, or a pharmaceutically acceptable salt thereof.

[0318] E25.150. The compound of E1 or E25 selected from the group consisting of (R)-5- ((10-chloro-2,9-dimethyl-6-oxo-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-8-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0319] E25.151. The compound of E1 or E25 selected from the group consisting of (R)-7- ((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-chloro-2,2-difluoro-8-methyl-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0320] E25.152. The compound of E1 or E25 selected from the group consisting of (S)-4- ((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

[0321] E25.153. The compound of E1 or E25 selected from the group consisting of (S)-7- ((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-chloro-2,2-difluoro-8-methyl-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one, or a pharmaceutically acceptable salt thereof.

[0322] E25.154. The compound of E1 or E25 selected from the group consisting of (R)-5- ((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7- yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0323] E25.155. The compound of E1 or E25 selected from the group consisting of (R)-5- ((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0324] E25.156. The compound of E1 or E25 selected from the group consisting of (2S)- 10-chloro-9-methyl-8-(quinolin-6-ylmethyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0325] E25.157. The compound of E1 or E25 selected from the group consisting of (2S)- 9,10-dimethyl-8-(quinolin-6-ylmethyl)-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 6-one, or a pharmaceutically acceptable salt thereof.

[0326] E25.158. The compound of E1 or E25 selected from the group consisting of (2S,4R)-4,9,10-trimethyl-8-(quinolin-6-ylmethyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one, or a pharmaceutically acceptable salt thereof.

[0327] E26. The compound of any of E1-E1.1 or E25-E25.158 selected from the group consisting of: 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,4S)-4,9,10-trimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 2-fluoro-N-methyl-4-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide; 4-(((2S,3S)-10-chloro-3,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide; (R)-4-((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide; (R)-9-chloro-2,2-difluoro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-4-((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-N-methylbenzamide; or a pharmaceutically acceptable salt thereof.

[0328] E27. A compound of any of E1-E26, or a pharmaceutically acceptable salt thereof, that has at least 50% deuterium incorporation at each deuterium label.

[0329] E27.1. The compound of E27, or pharmaceutically acceptable salt thereof, that has at least 75% deuterium incorporation at each deuterium-label.

[0330] E27.2. The compound of E27 or E27.1, or pharmaceutically acceptable salt thereof, that has at least 90% deuterium incorporation at each deuterium-label.

[0331] E27.3. The compound of any of E27-E27.2, or pharmaceutically acceptable salt thereof, that has at least 99% deuterium incorporation at each deuterium-label.

[0332] E27.4. The compound of any of E27-E27.4, or pharmaceutically acceptable salt thereof, that has at least 99.5% deuterium incorporation at each deuterium-label.

[0333] E28. A hydrate, solvate, polymorph, or prodrug of the compound of any of E1- E27.4, or a pharmaceutically acceptable salt thereof.

[0334] E29. A pharmaceutical composition comprising the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E28, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0335] E30. A method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E28, or a pharmaceutically acceptable salt thereof, or the composition of E29.

[0336] E31. The method of E30, wherein the mammal is human.

[0337] E32. The method of E30 or E31, wherein the muscarinic acetylcholine receptor is mAChR M1.

[0338] E33. The method of any of E30-E32, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

[0339] E34. The method of any of E30-E33, further comprising the step of identifying a mammal in need of treatment of the disorder.

[0340] E35. The method of any of E30-E34, wherein the disorder is a neurological disorder or psychiatric disorder, or a combination thereof.

[0341] E36. The method of any of E30-E35, wherein the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe majordepressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, or memory disorders, or a combination thereof.

[0342] E37. The method of any of E30-E36, wherein the disorder is Alzheimer’s disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof.

[0343] E38. The method of E37, wherein the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof.

[0344] E39. The compound, hydrate, solvate, polymorph, or prodrug of any of E1-E28, or a pharmaceutically acceptable salt thereof, or the composition of E29, for use in the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

[0345] E40. Use of the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E28, or a pharmaceutically acceptable salt thereof, or the composition of E29, for the preparation of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

[0346] Compound names and / or structures can be assigned / determined by using the Struct=Name naming algorithm as part of CHEMDRAW®, versions 19.1 or 20.0.

[0347] Compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers includeenantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In the compounds of formula (I) when no specific configuration is indicated at a stereogenic center (e.g., carbon), the compounds include all possible stereoisomers.

[0348] Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.

[0349] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.

[0350] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium) and2H (deuterium). Accordingly, any group comprising one or more hydrogen atoms encompasses corresponding deuterium-labeled versions of the group. For example, “alkyl” encompasses “deuterioalkyl”; “fluoroalkyl” encompasses “fluorodeuterioalkyl”; “–CH2–” encompasses , etc.

[0351] Thealsolabeled compound (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively.

[0352] Isotopically-enriched forms of compounds of formula (I), or any subformulas, may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent ofisotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label).

[0353] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0354] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.3. Pharmaceutical Compositions

[0355] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.

[0356] The pharmaceutical compositions and formulations may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (I)) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0357] For example, a therapeutically effective amount of a compound of formula (I), may be about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0358] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non- toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0359] Thus, the compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0360] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0361] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0362] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin;mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0363] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0364] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0365] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0366] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0367] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0368] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[0369] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[0370] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0371] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0372] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0373] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0374] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed.1975, pp.335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp.236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[0375] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0376] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0377] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0378] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0379] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[0380] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0381] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0382] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0383] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams,ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0384] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0385] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0386] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0387] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specificemollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[0388] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0389] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0390] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0391] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0392] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0393] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[0394] Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. a. Spray-Dried Dispersion Formulations

[0395] The disclosed compounds may be formulated as a spray-dried dispersion (SDD). An SDD is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution with the compound molecularly “dissolved” in a solid matrix. SDDs are obtainedby dissolving drug and a polymer in an organic solvent and then spray-drying the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with increased solubility of Biopharmaceutics Classification System (BCS) class II (high permeability, low solubility) and class IV (low permeability, low solubility) drugs. Formulation and process conditions are selected so that the solvent quickly evaporates from the droplets, thus allowing insufficient time for phase separation or crystallization. SDDs have demonstrated long- term stability and manufacturability. For example, shelf lives of more than 2 years have been demonstrated with SDDs. Advantages of SDDs include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using traditional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable and scalable manufacturing process and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0396] Thus, in one embodiment, the disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I). 4. Therapeutic Uses and Methods

[0397] The disclosed compounds are positive allosteric modulators of mAChR M1. Thus, by positive allosteric modulation, the compounds indirectly activate the muscarinic receptor subtype M1. In one aspect, the disclosed compounds potentiate the agonist response (e.g., acetylcholine) of mAChR M1. In a further aspect, the disclosed compounds increase mAChR M1response to non-maximal concentrations of agonist in the presence of compound compared to the response to agonist in the absence of compound. The potentiation of mAChR M1 activity can be demonstrated by methodology known in the art. For example, activation of mAChR M1activity can be determined by measurement of calcium flux in response to agonist, e.g. acetylcholine, in cells loaded with a Ca2+-sensitive fluorescent dye (e.g., Fluo-4). In a further aspect, the calcium flux was measured as an increase in fluorescent static ratio. In a yet further aspect, positive allosteric modulator activity was analyzed as a concentration-dependent increase in the EC20acetylcholine response (i.e. the response of mAChR M1 at a concentration of acetylcholine that yields 20% of the maximal response).

[0398] In an embodiment, the disclosed compounds may activate mAChR M1response as an increase in calcium fluorescence in mAChR M1-transfected CHO-K1 cells in the presence of thecompound, compared to the response of equivalent CHO-K1 cells in the absence of the compound. For example, a disclosed compound may have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. In an embodiment, the mAChR M1-transfected CHO-K1 cells are transfected with human mAChR M1. In another embodiment, the mAChR M1-transfected CHO-K1 cells are transfected with rat mAChR M1.

[0399] In an embodiment, the disclosed compounds exhibit weak or substantially no agonist activation of mAChR M1response (i.e., lack of activation in the absence of a known agonist such as acetylcholine). Lack of agonist activity may be measured as weak or no increase in calcium fluorescence in mAChR M1-transfected CHO-K1 cells in the presence of the compound, compared to the response of equivalent CHO-K1 cells in the absence of the compound. Lack of mAChR M1agonist activity may be determined as a percent response relative to acetylcholine. For example, a disclosed compound may have less than or equal to 30%, 25%, 20%, 15%, 10%, 5%, or 1% mAChR M1 agonist activity relative to acetylcholine. A disclosed compound may have substantially no mAChR M1agonist activity. In further embodiments, the disclosed compounds exhibit positive allosteric modulation of mAChR M1response to acetylcholine, as described herein, at concentrations that have weak or substantially no agonist activity, as described herein. The absence of mAChR M1agonist activity may contribute to the avoidance of cholinergic adverse effect liability.

[0400] In an embodiment, the disclosed compounds exhibit potentiation of mAChR M1 response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mammalian mAChR M1in the presence of the compound, compared to the response to acetylcholine in the absence of the compound. For example, CHO-K1 cells can be transfected with human mAChR M1. For example, CHO-K1 cells can be transfected with rat mAChR M1. For example, a compound can exhibit positive allosteric modulation of mAChR M1 with an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM. Alternatively, the disclosed compounds exhibit potentiation of mAChR M1response to acetylcholine as an increase in response to non- maximal concentrations of acetylcholine in CHO-K1 cells transfected with human mAChR M1 inthe presence of the compound, compared to the response to acetylcholine in the absence of the compound. For example, a compound can exhibit positive allosteric modulation of mAChR M1 with an EC50of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM.

[0401] In an embodiment, the disclosed compounds exhibit positive allosteric modulation of mAChR M1response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mAChR M1 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound. For example, the disclosed compounds may exhibit positive allosteric modulation of the mAChR M1response to acetylcholine with an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM. In an embodiment, the EC50for positive allosteric modulation is determined in CHO-K1 cells are transfected with a mAChR M1. In another embodiment, the CHO-K1 cells are transfected with a human mAChR M1. In another embodiment, the CHO-K1 cells are transfected with a rat mAChR M1.

[0402] Positive allosteric modulation of the mAChR M1response to acetylcholine with EC50of less than or equal to 0.5 µM, less than or equal to 0.25 µM, or less than or equal to 0.1 µM are all considered potent postive allosteric modulating activity.

[0403] In an embodiment, the compounds activate mAChR M1response in mAChR M1- transfected CHO-K1 cells with an EC50 less than the EC50 for one or more of mAChR M2, mAChR M3, mAChR M4, or mAChR M5response in mAChR M2, M3, M4or M5-transfected CHO-K1 cells. That is, the disclosed compounds can have selectivity for the mAChR M1receptor vis-à-vis one or more of the mAChR M2, M3, M4 or M5 receptors. For example, the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M2, at least 10-fold less than that for mAChR M2, at least 20-fold less than that for mAChR M2, at least 30-fold less than that for mAChR M2, at least 50-fold less than that for mAChR M2, or at least 100-fold less than that for mAChR M2. In another embodiment, the disclosed compounds can activate mAChR M1response with an EC50of at least 5-fold less than that for mAChR M3, at least 10-fold less than that for mAChR M3, at least 20-fold less than that for M3, at least 30-fold less than that for mAChR M3, at least 50-fold less than that for mAChRM3, or at least 100-fold less than that for mAChR M3. In another embodiment, the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M4, at least 10-fold less than that for mAChR M4, at least 20-fold less than that for M4, at least 30-fold less than that for mAChR M4, at least 50-fold less than that for mAChR M4, or at least 100-fold less than that for mAChR M4. In another embodiment, the disclosed compounds can activate mAChR M1response with an EC50of at least 5-fold less than that for mAChR M5, at least 10-fold less than that for mAChR M5, at least 20-fold less than that for mAChR M5, at least 30-fold less than that for mAChR M5, at least 50-fold less than that for mAChR M5, or at least 100-fold less than that for mAChR M5. In another embodiment, the disclosed compounds can activate mAChR M1response with an EC50of at least 5-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 10-fold less than that for the mAChR M2 , M3, M4 or M5 receptors, at least 20-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 30- fold less than that for the mAChR M2, M3, M4or M5receptors, at least 50-fold less than that for the mAChR M2, M3, M4 or M5 receptors, or at least 100-fold less than that for the mAChR M2, M3, M4 or M5 receptors. In another embodiment, the compound activates mAChR M1 response in mAChR M1-transfected CHO-K1 cells and is inactive for one or more of mAChR M1, mAChR M3, mAChR M4, or mAChR M5response in mAChR M2, M3, M4or M5-transfected CHO-K1 cells.

[0404] In an embodiment, the compounds activate mAChR M1response in M1-transfected CHO-K1 cells with an EC50of less than or equal to 10 µM and exhibits a selectivity for the M1receptor vis-à-vis one or more of the mAChR M2, M3, M4 or M5 receptors. For example, the compounds can have an EC50of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M2, at least 10-fold less than that for mAChR M2, at least 20-fold less than that for mAChR M2, at least 30-fold less than that for mAChR M2, or at least 50-fold less than that for mAChR M2. In another embodiment, the compounds can have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of atleast 5-fold less than that for mAChR M3, at least 10-fold less than that for mAChR M3, at least 20-fold less than that for mAChR M3, at least 30-fold less than that for mAChR M3, or at least 50-fold less than that for mAChR M3. In another embodiment, the compounds can have an EC50of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1response with an EC50of at least 5-fold less than that for mAChR M4, of at least 10-fold less than that for mAChR M4, of at least 20-fold less than that for mAChR M4, of at least 30-fold less than that for mAChR M4, or at least 50-fold less than that for mAChR M4. In another embodiment, the compound can have an EC50of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1response with an EC50of at least 5-fold less than that for mAChR M5, of at least 10-fold less than that for mAChR M5, of at least 20-fold less than that for mAChR M5, of at least 30-fold less than that for mAChR M5, or at least 50-fold less than that for mAChR M5. In another embodiment, the compounds can have an EC50of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1response with an EC50of at least 5-fold less than that for the mAChR M2, M3, M4or M5receptors, at least 10-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 20-fold less than that for the mAChR M2, M3, M4or M5receptors, at least 30-fold less than that for the mAChR M2, M3, M4or M5receptors, or at least 50-fold less than that for the mAChR M2, M3, M4or M5receptors.

[0405] The disclosed compounds may be used in methods for treatment of mAChR M1 related medical disorders and / or diseases. The methods of treatment may comprise administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of the compound of formula (I).

[0406] The compounds can be administered to a subject in need thereof to modulate mAChR M1, for a variety of diverse biological processes. The present disclosure is directed to methods for administering the composition to potentiate mAChR M1, a GPCR whose dysfunction is associated with neurological and psychiatric disorders, for example.

[0407] The compounds may be useful for treating and preventing certain diseases and disorders in humans and animals related to mAChR M1 dysfunction. Treatment or prevention of such diseases and disorders can be effected by modulating mAChR M1in a subject, by administering a compound or composition of the disclosure, either alone or in combination with another active agent as part of a therapeutic regimen to a subject in need thereof.

[0408] In combination therapy, the other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.

[0409] In an embodiment, the compounds can be coadministered with anti-Alzheimer’s agents, beta-secretase inhibitors, gamma-secretase inhibitors, orthosteric muscarinic agonists, muscarinic potentiators, cholinesterase inhibitors, HMG-CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies. In a further aspect, the compounds can be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof.

[0410] The compounds may be useful for treating a disease or disorder associated with dysfunction of mAChR M1, wherein the disease or disorder is selected from at least one of Alzheimer’s disease, a sleep disorder, a pain disorder, a cognitive disorder, psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.

[0411] The compounds may be useful for treating a pain disorder, wherein the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof.

[0412] The compounds disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders wherein the patient or subject would benefit from selective positive allosteric modulation of the M1receptor. In one aspect, a treatment can include selective M1receptor modulation to an extent effective to affect cholinergic activity. Thus, a disorder can be associated with cholinergic activity, for example cholinergic hypofunction. In one aspect, provided is a method of treating or preventing a disorder in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and / or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject.

[0413] Also provided is a method for the treatment of one or more disorders, for which muscarinic receptor activation is predicted to be beneficial, in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and / or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject.

[0414] The disclosure is directed to the use of described chemical compositions to treat diseases or disorders in patients (preferably human) wherein muscarinic receptor activation would be predicted to have a therapeutic effect, such as Alzheimer’s disease (both palliative cognitive and disease-modifying), cognitive impairment, schizophrenia, pain disorders (including acute pain, neuropathic pain and inflammatory pain), and sleep disorders, by administering one or more disclosed compounds or products.

[0415] Also provided is a method for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one disclosed compound, composition, or medicament.a. Neurological and Psychiatric Disorders

[0416] The disclosed compounds have utility in treating a variety of neurological and psychiatric disorders, including one or more of the following conditions or diseases: schizophrenia or psychosis including 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, amphetamine and other psychostimulants and cocaine) psychosis psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer’s disease and post-traumatic stress syndrome), including both the positive and the 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- Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age-related cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and compulsive eating disorders; bipolar disorders, mood disorders including depressive disorders; depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders; learning disorders, pervasive developmental disorder including autistic disorder, attention disorders including attention-deficit hyperactivity disorder (ADHD) and conduct disorder; NMDAreceptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson’s disease, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication- induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic- induced tardive dyskinesia and medication-induced postural tremor), Gilles de La Tourette’s syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias including tremor (such as rest tremor, postural tremor and intention tremor), chorea (such as Sydenham’s chorea, Huntington’s disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics),and dystonia (including generalized dystonia such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer’s cramp and hemiplegic dystonia)]; urinary incontinence; neuronal damage including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema; emesis; and sleep disorders including insomnia and narcolepsy. 1. Cognitive Disorders

[0417] The present disclosure provides a method for treating cognitive disorders, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular cognitive disorders are dementia, delirium, amnestic disorders and age-related cognitive decline. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. As used herein, the term “cognitive disorders” includes treatment of those mental disorders as described in DSM-IV-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies andclassification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “cognitive disorders” is intended to include like disorders that are described in other diagnostic sources. 2. Anxiety Disorders

[0418] The present disclosure provides a method for treating anxiety disorders, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder and panic attack. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes anxiety disorders are generalized anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein, the term “anxiety disorders” includes treatment of those mental disorders as described in DSM-IV-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “anxiety disorders” is intended to include like disorders that are described in other diagnostic sources. 3. Alzheimer’s Disease

[0419] Alzheimer’s disease (AD) is a neurodegenerative disease affecting the elderly, which results in progressive impairment of memory, language skills and severe behavioral deficits. Hallmarks of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain and other regions of the brain important for memory and cognition. Other hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau and accumulation of amyloid β peptide (Aβ). Aβ is a 39-43 amino acid peptide produced in the brain by proteolytic processing of β-amyloid precursor protein (APP) by the β-amyloid cleaving enzyme (BACE) and gamma secretase which leads to accumulation of Aβ in the brain, where Aβ 1-40 and 1-42 are the principal aggregate-forming species of Aβ.

[0420] Activation of various muscarinic receptors, particularly the M1 subtype, has been proposed as a mechanism to enhance cognition in disorders such as AD. Thus, without wishing to be bound by theory, it is believed that selective positive allosteric modulators of mAChR subtypes that regulate processes involved in cognitive function could prove superior to AChE inhibitors for treatment of AD and related disorders as it is postulated that these compounds would exhibit improved selectivity for specific mAChRs.

[0421] Phase III clinical trials have shown that orthosteric mAChR activators can have efficacy in improving cognitive performance in AD patients. Moreover, data indicate that administration of M1activators decreases behavioral disturbances, including delusions, hallucinations, outbursts, and other symptoms in patients suffering from neurodegenerative diseases such as Alzheimer’s disease. However, dose limiting adverse effects that may be due to lack of mAChR M1 selectivity led to failed launches of previous M1 agonists. In some cases, evidence suggests that mAChR activation also has the potential to be disease-modifying in that these agents may lower Aβ in AD patients. The M1–selective allosteric agonist TBPB was found to display effects on the processing of APP toward the non-amyloidogenic pathway and decrease Aβ 1−40 and 1-42 production in vitro. These data suggest that selective activation of M1 may provide a novel approach for both symptomatic and disease modifying the treatment of Alzheimer’s disease. 4. Schizophrenia

[0422] Schizophrenia is a debilitating psychiatric disorder characterized by a combination of negative (blunted affect, withdrawal, anhedonia) and positive (paranoia, hallucinations, delusions) symptoms as well as marked cognitive deficits. While schizophrenia remains an idiopathic disorder, it appears to be produced by a complex interaction of biological, environmental, and genetic factors. Over 40 years ago it was found that phencyclidine (PCP) induces a psychotic state in humans that is very similar to that observed in schizophrenic patients. The finding that the main mode of action of PCP is that of a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptor stimulated a series of studies that have led to the development of the NMDA receptor hypofunction model of schizophrenia.

[0423] The present disclosure provides a method for treating schizophrenia or psychosis comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.

[0424] NMDA receptor function can be modulated by activation of G Protein-Coupled Receptors (GPCRs) that are known to physically and / or functionally interact with the NMDA receptor. The NMDA receptor hypofunction hypothesis is a proposal to explain the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents, either directly by action on modulatory sites on the NMDA receptor (e.g., the glycine co-agonist binding site) or indirectly by activation of GPCRs known to potentiate NMDA receptor function (e.g. the mAChR M1), has the potential to ameliorate the symptoms of schizophrenia. In both preclinical and in clinical studies, xanomeline, an M1 / M4preferring orthosteric agonist has proved efficacious with regard to positive, negative and cognitive symptoms, indicating that M1 activation is a reasonable approach to the treatment of schizophrenia. More recently, the selective M1allosteric agonist TBPB demonstrated efficacy in multiple preclinical models of schizophrenia.

[0425] As used herein, the term “schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM-W-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources. 5. Substance-Related Disorders and Addictive Behaviors

[0426] The present disclosure provides a method for treating substance-related disorders and addictive behaviors, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular substance-related disorders and addictive behaviors are persisting dementia, persisting amnestic disorder, psychotic disorder or anxietydisorder induced by substance abuse; and tolerance of, dependence on or withdrawal from substances of abuse. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse; and tolerance of, dependence on or withdrawal from substances of abuse. As used herein, the term “substance- related disorders and addictive behaviors” includes treatment of those mental disorders as described in DSM-IV- TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “substance-related disorders and addictive behaviors” is intended to include like disorders that are described in other diagnostic sources. 6. Pain

[0427] In another aspect, the present disclosure provides a method for treating pain, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain. 7. Obesity and Eating Disorders

[0428] The present disclosure provides a method for treating obesity or eating disorders associated with excessive food intake and complications associated therewith, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD-10) (1992 World Health Organization) as a general medical condition. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition. As used herein, the term “obesity or eating disorders associated with excessive food intake” includes treatment of those medical conditions and disorders described inICD-10 and DSM-W-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for general medical conditions, and that these systems evolve with medical and scientific progress. Thus, the term “obesity or eating disorders associated with excessive food intake” is intended to include like conditions and disorders that are described in other diagnostic sources.

[0429] The compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.

[0430] The present disclosure is further directed to administration of a selective M1 receptor modulator for improving treatment outcomes in the context of cognitive or behavioral therapy. That is, in one aspect, the disclosure relates to a cotherapeutic method comprising the step of administering to a mammal an effective amount and dosage of at least one compound of the disclosure in connection with cognitive or behavioral therapy.

[0431] In another aspect, administration improves treatment outcomes in the context of cognitive or behavioral therapy. Administration in connection with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and / or after therapy. For example, cognitive or behavioral therapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy can be provided within 1, 2, 3, or 4 weeks before or after administration of the compound. As another example, cognitive or behavioral therapy can be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound. b. Modes of Administration

[0432] Methods of treatment may include any number of modes of administering a disclosed composition. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oraladministration, the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non- aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. GelucireTM). In the pharmaceutical composition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.

[0433] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.

[0434] The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. c. Combination Therapies

[0435] In one aspect, the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which disclosed compounds or the other drugs can have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and a disclosed compound is preferred. However, the combination therapy can also include therapies in which a disclosed compound and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other activeingredients, the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.

[0436] Accordingly, the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.

[0437] The above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure.

[0438] The weight ratio of a disclosed compound to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present disclosure is combined with another agent, the weight ratio of a disclosed compound to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present disclosure and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0439] In such combinations disclosed compounds and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0440] Accordingly, the disclosed compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent can be coadministered, either in concomitant therapy or in a fixed combination.

[0441] In an embodiment, the disclosed compounds can be employed in combination with anti- Alzheimer’s agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID’s including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compound can be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, Zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound can be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

[0442] In an embodiment, the disclosed compounds can be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It willbe appreciated that the dopamine agonist can be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.

[0443] In an embodiment, the disclosed compounds can be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound can be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound can be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

[0444] In an embodiment, the disclosed compounds can be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α- adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypicalanti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts. thereof. 5. Kits

[0445] In one aspect, the disclosure provides kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and one or more of:

[0446] (a) at least one agent known to increase mAChR M1activity;

[0447] (b) at least one agent known to decrease mAChR M1 activity;

[0448] (c) at least one agent known to treat a disorder associated with cholinergic activity;

[0449] (d) instructions for treating a disorder associated with cholinergic activity;

[0450] (e) instructions for treating a disorder associated with M1 receptor activity; or

[0451] (f) instructions for administering the compound in connection with cognitive or behavioral therapy.

[0452] In some embodiments, the at least one disclosed compound and the at least one agent are co-formulated. In some embodiments, the at least one disclosed compound and the at least one agent are co-packaged. The kits can also comprise compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0453] That the disclosed kits can be employed in connection with disclosed methods of use.

[0454] The kits may further comprise information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. Inaddition or in the alternative, the kit may include the compound, a composition, or both; and information, instructions, or both, regarding methods of application of compound, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans).

[0455] The compounds and processes of the invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. 6. Chemical Synthesis

[0456] Compounds of formula (I) may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[0457] Compounds of formula (I) may be synthesized as shown in the Schemes and Examples set forth below. Scheme I

[0458] As illustrated in Scheme 1, intermediate i may be subjected to alcohol (e.g. ROH) and acid to provide the ester intermediate ii. The ester may be subjected to standard halogenating conditions (e.g. NBS, CHCl3or Bromine, AcOH) well known to those skilled in the art to provide intermediate iii (wherein X is a halogen). Scheme IIA

[0459] As shown in Scheme IIA, intermediate iii (wherein X is a halogen) may undergo a Mitsunobu reaction with an alcohol iv-a, triphenylphosphine, DtBAD and solvent (e.g. THF) to provide intermediate v-a, followed by deprotection with acid (e.g. TFA or HCl) to afford intermediate vi-a. Intermediate vi-a may be subjected to amide formation conditions (e.g. a base with heating to about 70-90 °C) or (e.g. a 2-step procedure: 1) hydrolysis (e.g. LiOH, solvent, such as THF / water; 2) HATU, base (e.g. DIEA) and solvent (e.g. DMF)) to provide intermediate vii-a. Scheme IIB[00460 s s o c e e , e e ae ee s a aoge ay undergo a Mitsunobu reaction with an alcohol iv-b, triphenylphosphine, DtBAD and solvent (e.g. THF) to provide intermediate v-b, followed by deprotection with acid (e.g. TFA or HCl) to afford intermediate vi-b. Intermediate vi-b may be subjected to amide formation conditions (e.g. a base with heating to about 70-90 °C) or (e.g. a 2-step procedure: 1) hydrolysis (e.g. LiOH, solvent, such as THF / water; 2) HATU, base (e.g. DIEA) and solvent (e.g. DMF)) to provide intermediate vii-b. In Scheme IIB, R2ais H or R2, and L1is a straight chain C1-2alkylene, optionally wherein one methylene of the C1-2alkylene is replaced with an oxygen or nitrogen atom.Scheme IIImay to bis(pinacolato)diboron, palladium catalyst (e.g. Pd(dppf)Cl2, Pd(PPh3)4) in the presence of base (e.g. KOAc) and solvents such as dioxane with heating up to 100 °C to provide intermediate of formula viii. Scheme IVbe subjected to standard Suzuki reaction conditions with a palladium catalyst, such as Pd(PPh3)4, and a base (e.g. Na2CO3, K2CO3, etc.) in a solvent mixture of organic solvent, such as monoglyme or 1,4-dioxane and water with heating to about 80-90 °C to provide compounds of formula ix.Scheme V

[0463] As shown in Scheme V, intermediate of formula x (wherein X is a halogen) may be coupled with a boronic aid or ester under Suzuki coupling conditions, generally known in the art to provide intermediate xi. Coupling reactions may be conducted with a palladium catalyst, such as Pd(dppf)Cl2, and a base (e.g. K2CO3, Cs2CO3) in a solvent mixture of organic solvent, such as DMF or 1,4-dioxane, and water with heating to about 80-90 °C. Reactions may be facilitated with microwave irradiation. Intermediate xii may be formed by subjecting intermediate xi to chlorinating conditions (e.g. SOCl2, DCM) and heat. Scheme VIacid or ester, may be subjected to standard Suzuki reaction conditions with a palladium catalyst, such as Pd(dppf)Cl2, and a base (e.g. K2CO3, Cs2CO3) in a solvent mixture of organic solvent, such as DMF or 1,4-dioxane, and water with heating to about 80-90 °C to provide intermediate xi. Scheme VIIIntermediate xiv (wherein X is a halogen) may undergo a Suzuki reaction with a boronic acid orester, a palladium catalyst (e.g. Pd2(dba)3), and a base (e.g. K2CO3, Cs2CO3) in a solvent mixture of organic solvent, such as toluene and water with heating to about 90-100 °C to obtain methyl ester xv. Intermediate xv may be reduced (e.g. LiAlH4) to provide intermediate xi.

[0466] The general synthetic processes illustrated in the foregoing schemes for preparing compounds of formula (I) wherein Z1is CH, may be adapted to synthesis of compounds of formula (I) wherein Z1is N.

[0467] The compounds and intermediates may be isolated and purified by methods well- known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England.

[0468] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[0469] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in theart from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above-described schemes or the procedures described in the synthetic examples section.

[0470] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0471] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0472] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0473] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0474] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer.1H chemical shifts are reported in δ values in ppm downfield with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs =broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, C18 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in water over 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 µm, 1.0 x 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 ºC. The DAD was set to scan from 190 to 300 nm, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). The MS detector was configured with an electrospray ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles / second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 ºC and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software. Preparation of Intermediates Intermediate Example 1: methyl 5-bromo-3-chloro-2-hydroxy-4-methylbenzoate

[0475] To a(CAS# 39503-57-6, 2.45 g, 10 mmol) in anhydrous DMF (20 mL) at rt was added N-chlorosuccinimide (1.47 g, 11 mmol). After 16 h at rt, the reaction mixture was diluted with EtOAc and 10% aq. Na2S2O3 solution. The layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was sonicated in a minimal amount of iPA and filtered using vacuum filtration to provide the title compound (2.56 g, 92% yield).1H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 7.96 (s, 1H), 3.98 (s, 3H), 2.56 (s, 3H).Intermediate Example 2: methyl 5-bromo-2-hydroxy-3,4-dimethylbenzoate[00 , . g, 30.09 mmol) in methanol (60 mL) was added sulfuric acid (16 mL, 300.88 mmol) dropwise at 0 °C. The resulting solution was stirred at 100 °C in a sealed reaction vessel overnight, poured into ice water and the resulting solid was collected by vacuum filtration. The solid was washed thoroughly with ice water and purified using normal phase chromatography on silica gel (0- 100% EtOAc / hexanes) to give the title compound (4.65 g, 81% yield).1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 3.92 (s, 3H), 2.30 (s, 3H), 2.18 (s, 3H). ES-MS [M+H]+= 181.0.

[0477] To a solution of methyl 2-hydroxy-3,4-dimethylbenzoate (4.62 mg, 25.64 mmol) in chloroform (116 mL) was added bromine (1.84 mL, 35.89 mmol) dropwise at 0 °C. The resulting solution was stirred at 0 °C until the starting material was completely consumed. The reaction mixture was concentrated in vacuo, and the crude residue was purified using normal phase chromatography on silica gel (0-50% EtOAc / hexanes) to afford the title compound (6.40 g, 96% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 10.96 (s, 1H), 7.90 (s, 1H), 3.94 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H). Intermediate Example 3: tert-butyl (R)-2-(hydroxymethyl)-4-methylpiperazine-1- carboxylate

[0478] To a solution of tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (CAS# 1030377-21-9) (800 mg, 3.7 mmol) in DCE (18 mL) was added a solution of formaldehyde (37 wt % in water, 2.75 mL, 37 mmol) followed by acetic acid (0.37 mL). After 5 min, sodium triacetoxyborohydride (3.92 g, 18.5 mmol) was added and the mixture was stirred vigorously at rt. After 5 h, the mixture was diluted with DCM and sat. soln. NaHCO3. The layers wereseparated. The aqueous layer was extracted with DCM (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound, which was carried forward without further purification. ES-MS [M+H]+= 231.2.

[0479] The compounds shown in Table 1 may be prepared similarly to the compound described above, with appropriate starting materials. Table 1 Structure Name1H-NMR and / or ES-MS [M+H]+Interp y , y , , methanobenzo[b][1,5]oxazocin-6-onetert- - - methylphenoxy)pyrrolidine-1-carboxylate. To a solution of methyl-5-bromo-3-chloro-2- hydroxy-4-methylbenzoate (559 mg, 2.0 mmol) in THF (10 mL) at rt was added tert-butyl (R)-3- hydroxypyrrolidine-1-carboxylate (562 mg, 3.0 mmol) and triphenylphosphine (839 mg, 3.2 mmol). The solution was cooled to 0 °C and di-tert-butyl azodicarboxylate (736 mg, 3.2 mmol) was added portion-wise. After 16 h, the reaction mixture was diluted with DCM and water was added. The organic layer was separated. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentratedin vacuo. The resulting residue was purified using normal phase column chromatography on silica gel (0-100% EtOAc / hexanes) to provide the title compound. ES-MS [M+H-tBu]+= 392.0 and 394.0.

[0481] Step 2: Methyl (S)-5-bromo-3-chloro-4-methyl-2-(pyrrolidin-3-yloxy)benzoate. To a solution of tert-butyl (S)-3-(4-bromo-2-chloro-6-(methoxycarbonyl)-3- methylphenoxy)pyrrolidine-1-carboxylate (897 mg, 2.0 mmol) in DCM (13 mL) at 0 °C was added trifluoroacetic acid (1.53 mL, 20.0 mmol). The resulting mixture was stirred at rt for 2 h, concentrated under reduced pressure, and the pH adjusted to basic using sat. soln. NaHCO3. The mixture was extracted with iPA / CHCl3(1:3, 3x). The combined organic extracts were filtered and concentrated in vacuo to give the title compound (696 mg), which was carried forward without further purification. ES-MS [M+H]+= 348.0 and 350.0.

[0482] Step 3: (S)-5-Bromo-3-chloro-4-methyl-2-(pyrrolidin-3-yloxy)benzoic acid. To a solution of methyl (S)-5-bromo-3-chloro-4-methyl-2-(pyrrolidin-3-yloxy)benzoate (696 mg, 2.0 mmol) in THF (10 mL) was added 1N aq. soln. lithium hydroxide (5.0 mL, 5.0 mmol). The resulting mixture was stirred at rt. After 16 h, the reaction mixture was concentrated under reduced pressure to provide the title compound (679 mg), which was carried forward without further purification. ES-MS [M+H]+= 334.0 and 336.0.

[0483] Step 4: (2S)-8-bromo-10-chloro-9-methyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one. To a solution of (S)-5-bromo-3-chloro-4-methyl-2- (pyrrolidin-3-yloxy)benzoic acid (679 mg, 2.0 mmol) in DMF (6.7 mL) was added HATU (760 mg, 2.0 mmol) followed by DIEA (353 µL, 2.1 mmol). The resulting mixture was stirred at rt for 1 h, then diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification using normal phase chromatography on silica gel (0- 100% EtOAc / hexanes) provided the title compound.1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 5.03 (dd, J = 4.8, 2.1 Hz, 1H), 4.40 – 4.29 (m, 1H), 3.95 (dt, J = 14.5, 2.4 Hz, 1H), 3.29 – 3.23 (m, 1H), 2.86 (dd, J = 14.5, 2.2 Hz, 1H), 2.54 (s, 3H), 2.42 – 2.35 (m, 1H), 2.24 – 2.16 (m, 1H); ES-MS [M+H]+= 316.0 and 318.0.

[0484] The compounds shown in Table 2 may be prepared similarly to the compound described above, with appropriate starting materials.Table 2 1H-NMR and / or13C-NMR Structure Name and / or ES-MS [M+H]+(s, – z, = 35 S (s, – z, ), (s, S- (s, 91 m, 64 4, S- (s, – .3 ), dt, z, . (s, 76 m, 56 ), 47 =1H NMR (400 MHz, CDCl3) δ 7.54 (s, (2S,4S)-8-bromo-4,9,10- 1H), 4.79 (dd, J = 4.1, 1.6 Hz, 1H), 4.64 – 451 (m 1H) 384 – 374 (m 1H) 292 = 19 ), ]+= ), 9, z, ), 4, S- (s, = 91 d, 2, = ); (s, 92 = 7, z, .2 nd (s, 21 z, ), z, . (s, – (s, .5 nd (s, 20 z, ), z, .1(2R,11R)-8-bromo-10-chloro- H NMR (400 MHz, CDCl3) δ 7.72 (s, 9,11-dimethyl-3,4-dihydro- 1H), 5.03 (q, J = 3.4 Hz, 1H), 4.29 (dt, J = 117 H 1H 1 2H), d, .0 (s, 50 = z, 20 m, ]+(s, 51 = z, ), ), = (s, m, ), - ad = (s, m, ), ), .3 R 3, 4, S (s, m, ), – .9 z, R 5, 1, S1H NMR (400 MHz, CDCl3) δ 7.45 (s, (2R,4R)-8-bromo-10-chloro-4,9- 1H), 4.95 (dtd, J = 4.2, 3.1, 1.2 Hz, 1H), 358 – 338 (m 2H) 324 (ddd = 144, 19 d, J .0 (s, m, ), – .9 z, R 5, 1, S (s, m, ), – .9 z, S (s, m, m, S- (s, m, m, S- (s, 19 m, m, ), nd1H NMR (400 MHz, CDCl3) δ 8.02 (s, (S)-8-bromo-10-chloro-2,9- 1H), 4.62 (dd, J = 11.6, 9.7 Hz, 1H), 4.20 dimethyl-12341212a- (dd J = 115 36 Hz 1H) 392 – 382 (m, m, ), ndIntermediate Example 5: (R)-7-bromo-9-chloro-8-methyl-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one

[0485] - -3- methylphenoxy)methyl)pyrrolidine-1-carboxylate. To a solution of methyl-5-bromo-3-chloro- 2-hydroxy-4-methylbenzoate (279 mg, 1.0 mmol) in THF (10 mL) at rt was added tert-butyl (R)- 2-(hydroxymethyl)pyrrolidine-1-carboxylate (302 mg, 1.5 mmol) and triphenylphosphine (420 mg, 1.6 mmol). The solution was cooled to 0 °C and di-tert-butyl azodicarboxylate (368 mg, 1.6 mmol) was added portion-wise. After 16 h, the reaction mixture was diluted with DCM and water was added. The organic layer was separated. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified using normal phase column chromatography on silica gel (0-100% EtOAc / hexanes) to provide the title compound. ES-MS [M+H-Boc]+= 362.0 and 364.0.

[0486] Step 2: methyl (R)-5-bromo-3-chloro-4-methyl-2-(pyrrolidin-2- ylmethoxy)benzoate. To a solution of tert-butyl (R)-2-((4-bromo-2-chloro-6- (methoxycarbonyl)-3-methylphenoxy)methyl)pyrrolidine-1-carboxylate (400 mg, 0.86 mmol) in DCM (4.3 mL) at 0 °C was added trifluoroacetic acid (0.66 mL, 8.6 mmol). The resulting mixture stirred at rt for 2 h, concentrated under reduced pressure, and the pH was adjusted to basic using sat. soln. NaHCO3.The mixture was extracted with iPA / CHCl3(1:3, 3x). The combined organic extracts were filtered and concentrated in vacuo to give the title compound (313 mg) and carried forward without further purification. ES-MS [M+H]+= 362.0 and 364.0.

[0487] Step 3: (R)-7-bromo-9-chloro-8-methyl-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one. To a solution of methyl (R)-5-bromo-3-chloro-4- methyl-2-(pyrrolidin-2-ylmethoxy)benzoate (313 mg, 0.86 mmol) in EtOH (3.0 mL) was potassium carbonate (242 mg, 1.72 mmol). The reaction mixture was stirred at 80 °C overnight and concentrated under reduced pressure. The crude material was redissolved in EtOAc, washed with water, brine, dried over Na2SO4, filtered, and concentrated. Purification using normal phase chromatography on silica gel (0-100% EtOAc / hexanes) provided the title compound (263 mg, 92% yield).1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.48 (dd, J = 11.1, 3.2 Hz, 1H), 4.11 (dd, J = 11.1, 10.2 Hz, 1H), 3.92 3.86 (m, 1H), 3.81 - 3.69 (m, 2H), 2.55 (s, 3H), 2.18 (dq, J = 12.7, 7.0 Hz, 1H), 2.10 – 1.88 (m, 2H), 1.70 (dq, J = 13.1, 6.8 Hz, 1H); ES-MS [M+H]+= 330.0 and 332.0.

[0488] The compounds shown in Table 3 may be prepared similarly to the compound described above, with appropriate starting materials. Table 3 Structure Name1H-NMR and / or ES-MS [M+H]+(s, 11 m, 24 70 ]+(R)-7-bromo-9-chloro-2,2-1H NMR (400 MHz, CDCl3) δ 8.08 (s, difl 8 th l 231111 1H) 455 447 ( 1H) 434 426 (m, m, S- (s, 35 73 J S (s, ), m, ), SIntermediate Example 6: (2S)-10-chloro-9-methyl-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one

[0489] To a - 2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one (100 mg, 0.32 mmol) in 1,4-dioxane (2.1 mL) was added bis(pinacolato)diboron (160 mg, 0.64 mmol), KOAc (124 mg, 1.26 mmol), and Pd(dppf)Cl2 (23 mg, 0.032 mmol). The reaction mixture was evacuated and purged with N2(3x) and stirred at 90 °C for 16 h. After cooling to rt, the mixture was filtered through a pad of Celite® which was rinsed thoroughly with EtOAc. The filtrate was concentrated in vacuo to provide the title compound (114 mg), which was carried forward without further purification. ES-MS [M+H]+= 364.2.

[0490] The compounds shown in Table 4 may be prepared similarly to the compound described above, with appropriate starting materials. Table 4 Structure Name1H-NMR and / or ES-MS [M+H]+(2S,4S)-4,9,10-trimethyl-8- (4,4,5,5-tetramethyl-1,3,2-(2R,11S)-10-chloro-9,11- dimethyl-8-(4455-tetramethyl-(2S,4S)-10-chloro-4,9-dimethyl- 8-(4455-tetramethyl-132-(R)-9-chloro-2,2-difluoro-8- thl744 tt thl(S)-10-chloro-2,9-dimethyl-8- (4455 t t th l 132 Interbromopyridin-3-yl)methanol (3.76 g, 20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (4.99 g, 24 mmol), potassium phosphate tribasic (8.61 g, 40 mmol) in 1,4-dioxane (83.3 mL) and water (16.7 mL) was degassed with nitrogen for 3-5 min. Tri(dibenzylideneacetone)dipalladium (1.16 g, 1.0 mmol) and tricyclohexylphosphine (0.7 g, 2.5 mmol) were added. The resulting mixture was subjected to a microwave reactor at 120 °C for 45 min, filtered through a pad of Celite® and concentrated. Purification using normal phase chromatography on silica gel (0-10% MeOH / DCM) provided the title compound (3.27 g, 86%).1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J = 2.3, 0.9 Hz, 1H), 8.24 (d, J = 0.7 Hz, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.71 – 7.64 (m, 1H), 7.59 (dd, J = 8.1, 0.9 Hz, 1H), 5.29 – 5.22 (m, 1H), 4.49 (d, J = 5.3 Hz, 2H), 3.87 (s, 3H); ES-MS [M+H]+= 190.2.

[0492] Step 2: 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine. To a solution of (6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methanol (3.27 g, 17.3 mmol) in DCM (173 mL) at 0 °C was added thionyl chloride (1.88 mL, 26 mmol). After 2 h at rt, the reaction mixture was quenched with sat. soln. NaHCO3, extracted with DCM (3x), dried over Na2SO4, filtered, and concentrated to provide the title compound, which was carried forward without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 1.8 Hz, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.88 (dd, J = 8.2, 2.3 Hz, 1H), 7.74 – 7.67 (m, 1H), 4.81 (s, 2H), 3.89 (s, 3H); ES-MS [M+H]+= 208.1.

[0493] The compounds shown in Table 5 may be prepared similarly to the compound described above, with appropriate starting materials. Table 5 Structure Name1H-NMR and / or ES-MS [M+H]+1H NMR (400 MHz DMSO-d ) δ 867 (t J = , 33 84 .9 d, S-Intermediate Example 8: 4-(4-(chloromethyl)phenyl)-1-methyl-1H-pyrazole(hydroxymethyl)phenyl)boronic acid (4.0 g, 26.3 mmol), 4-bromo-1-methyl-1H-pyrazole (5.3 g, 32.9 mmol) and potassium carbonate (7.4 g, 52.6 mmol) in 1,4-dioxane (105 mL) and water (25 mL) was degassed with nitrogen for 3-5 min. Tetrakis(triphenylphosphine)palladium (0.96 g, 1.32 mmol) was added then stirred at 100 °C for 12 h. After cooling to rt, the mixture was partitioned between water and EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. Purification using normal phase chromatography on silica gel (0-100% EtOAc / hexanes) provided the title compound (3.1 g, 62% yield).1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.82 (s, 1H), 7.51 – 7.43 (m, 2H), 7.28 (d, J = 7.9 Hz, 2H), 5.13 (t, J = 4.2 Hz, 1H), 4.47 (d, J = 4.4 Hz, 2H), 3.85 (s, 3H); ES-MS [M+H]+= 189.2.

[0495] Step 2: 4-(4-(chloromethyl)phenyl)-1-methyl-1H-pyrazole. To a suspension of (4- (1-methyl-1H-pyrazol-4-yl)phenyl)methanol (3.1 g, 16.4 mmol) in DCM (100 mL) at 0 °C was added thionyl chloride (1.79 mL, 24.6 mmol) dropwise. The resulting mixture was stirred at rt for 4-6 h, quenched with sat. soln. NaHCO3, and extracted with DCM (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to provide the title compound, which was carried forward without further purification. ES-MS [M+H]+= 207.1.

[0496] The compounds shown in Table 6 may be prepared similarly to the compound described above, with appropriate starting materials. Table 6 Structure Name1H-NMR and / or ES-MS [M+H]+Intermediate Example 9: 5-(chloromethyl)-2-(1H-imidazol-1-yl)pyridine

[0497] Step 1: 4-(4-bromophenyl)oxazole was prepared according to the procedure from Journal of Medicinal Chemistry (2013), 56(24), 9934-9954.1H NMR (400 MHz, CDCl3) δ 7.95(d, J = 0.9 Hz, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.58 – 7.50 (m, 2H); ES-MS [M+H]+= 223.9 and 225.9.

[0498] Step 2: Preparation of ethyl 4-(oxazol-4-yl)benzoate. To a solution of 4-(4- bromophenyl)oxazole (4.55 g, 20.3 mmol) in ethanol (100 mL) and DMSO (50.8 mL) was added triethylamine (28.3 mL, 203 mmol). Under nitrogen atmosphere, palladium(II)acetate (920 mg, 4.06 mmol) and 1,3-bis(diphenylphosphino)propane (1.68 g, 4.06 mmol) were added. The resulting mixture was purged thoroughly with CO (g) and stirred at 75 °C for 16 h. After cooling to rt, the mixture was diluted with MeOH, filtered through a pad of Celite® and partially concentrated under reduced pressure. The residue was diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification using normal phase chromatography on silica gel (0-50% EtOAc / hexanes) provided the title compound (3.55 g, 80% yield).1H NMR (400 MHz, CDCl3) δ 8.13 – 8.06 (m, 2H), 8.04 (d, J = 0.9 Hz, 1H), 7.97 (d, J = 0.9 Hz, 1H), 7.86 – 7.79 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); ES-MS [M+H]+= 218.2.

[0499] Step 3: Preparation of (4-(oxazol-4-yl)phenyl)methanol. To a solution of lithium aluminum hydride (2M in THF, 24.51 mL, 49.03 mmol) in THF (14.6 mL) at 0 °C was added dropwise a solution of ethyl 4-(oxazol-4-yl)benzoate (3.55 g, 16.34 mmol) in THF (67.3 mL) via a cannula. The resulting mixture was stirred at 0 °C for 1 h. At 0 °C, to the reaction mixture was added 1.86 mL of water dropwise followed by 15% NaOH aq. solution (1.86 mL), then water (5.58 mL). The thick suspension was stirred vigorously at rt for 2 h and filtered through Celite®. The Celite® pad was rinsed thoroughly with EtOAc (200 mL), DCM (100 mL), and then 10% MeOH / DCM (200 mL). The filtrate was concentrated under reduced pressure and the residue was purified using normal phase chromatography on silica gel (0-10% MeOH / DCM) to provide the title compound (2.57 g, 89% yield).1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.0 Hz, 1H), 7.94 (d, J = 0.9 Hz, 1H), 7.79 – 7.71 (m, 2H), 7.46 – 7.38 (m, 2H), 4.73 (d, J = 5.9 Hz, 2H), 1.75 (t, J = 6.0 Hz, 1H); ES-MS [M+H]+= 176.1.

[0500] Step 4: Preparation of 4-(4-(chloromethyl)phenyl)oxazole was prepared in a similar manner as 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine.1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 0.9 Hz, 1H), 7.95 (d, J = 1.0 Hz, 1H), 7.77 – 7.73 (m, 2H), 7.47 – 7.42 (m, 2H), 4.61 (s, 2H); ES-MS [M+H]+= 194.0.Intermediate Example 10: 4-(bromomethyl)-2-fluoro-N-methylbenzamide

[0501] in DCM (25 mL) was added DIEA (1.74 mL, 10 mmol) followed by slow addition of 1- propanephosphonic anhydride (50 wt. % in EtOAc, 5.21 mL, 8.75 mmol). After stirring for 10 min at rt, a solution of methylamine (2 M in THF, 8.75 mL, 17.5 mmol) was added. The resulting mixture was stirred at rt overnight and concentrated under reduced pressure. The resulting oil was redissolved in DCM and washed with water (3x) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound, which was carried forward without further purification. (1.15 g, 93% yield).1H NMR (400 MHz, CDCl3) δ 8.09 (t, J = 8.1 Hz, 1H), 7.27 (dd, J = 9.1, 1.7 Hz, 1H), 7.17 (dd, J = 12.5, 1.7 Hz, 1H), 6.72 (br s, 1H), 4.45 (s, 2H), 3.04 (dd, J = 4.8, 1.2 Hz, 3H); ES-MS [M+H]+= 246.0 and 248.1. Table 7. Commercial Starting Materials No. Structure Name CAS# Supplier s etert-butyl (3R,4S)-3-hydroxy-4- 1290191-90-0 AA Blocks methylpyrrolidine-1-carboxylate s s s s ck ck s exOakwood 2-bromo-1-(4-bromophenyl)ethan-1-one99-73-0Products 4-(chloromethyl)-N-methylbenzamide220875-88-7 Enamine4-(bromomethyl)-2-fluorobenzoic acid477199-77-2 Enamine1-(4-(chloromethyl)phenyl)-1H-pyrazole143426-52-2 Ambeed8 5-(bromomethy Combi- 3 l)-2-methylpyridine 718608-10-7 hydrobromide BlocksPreparation of Representative Compounds Example 1. Preparation of (2S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one (Compound 2)

[0502] - dioxaborolan- 2-yl)-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one (28.5 mg, 0.08 mmol) in 1,4- dioxane (1.0 mL) was added 1-(4-(chloromethyl)phenyl)-1H-pyrazole (30 mg, 0.16 mmol), Cs2CO3(77 mg, 0.24 mmol), Pd(dppf)Cl2(5.7 mg, 0.008 mmol), and H2O (0.2 mL). The reaction mixture was purged with N2and heated to 100 °C. After 3 h, the reaction mixture was diluted with EtOAc and filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-10% MeOH / DCM) then RP-HPLC (15-75% MeCN / 0.05% aq. NH4OH) gave the title compound (13.6 mg, 44% yield).1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 2.5, 0.6 Hz, 1H), 7.71 (dd, J = 1.8, 0.6 Hz, 1H), 7.63 – 7.55 (m, 2H), 7.27 (s, 1H), 7.21 – 7.13 (m, 2H), 6.45 (dd, J = 2.5, 1.8 Hz, 1H), 5.03 (dd, J = 4.7, 2.1 Hz, 1H), 4.42 – 4.30 (m, 1H), 4.09 – 3.96 (m, 3H), 3.27 (ddd, J = 11.9, 9.4, 6.5 Hz, 1H), 2.85 (dd, J = 14.4, 2.2 Hz, 1H), 2.44 – 2.36 (m, 1H), 2.29 (s, 3H), 2.23 – 2.15 (m, 1H); ES-MS [M+H]+= 394.3.

[0503] The compounds shown in Table 8 may be prepared similarly to the compound described above, with appropriate starting materials.Table 8 1 No. STRUCTURE NAME H-NMR and / or ES-MS [M+H]+d, 8, 27 , J .1 – 4, z, ), = , J ), ), – ), .5 ), – .1H NMR (400 MHz, CDCl3) δ 8.03 (t, J = 8.2 Hz, 1H), 7.25 (s, 1H), 7.02 (dd, J = 81 16 Hz 1H) 678 (dd J = 13.1, 05 m, = 8, z, m, , J ), ), z, m, z, ), – . 0 ,1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 2.5, 0.6 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.63 – 7.55 (m, 2H), 7.27 (s, 1H), , = 32 .7 53 = – 96 .2 d, 10 56 z, , J 83 (s, – z, S 09 = .4 ), d, – 78 m, ), ); 37 ), ), ), 12 ), m,1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J = 2.5, 0.6 Hz, 1H), 7.77 – 7.68 (m, (2S)-8-(4-(1H-pyrazol-1- 3H), 7.23 (d, J = 8.5 Hz, 2H), 7.06 (s, 89 77 m, ), = 06 z, , J 82 (s, z, = ); 17 ), – 78 m, ), m, 07 – 92 01 78 m, ), = 32 .7 53 = – 96 .2 d, 12 2. 42 m, (s, 89 77 m, ), =1H NMR (400 MHz, DMSO-d6) δ 8.38 – 8.29 (m, 1H), 7.73 (d, J = 8.3 Hz, 2H), H), ), ), d, ); – 11 1, ), – ), 53 (s, z, S , J 97 ), z, .8 02 = 8, d, );35 = z, 10 (s, .7 d, m, 69 d, = 56 z, , J J 74 56 ), 10 z, S 71 97 40 ), (s, ), 4, 41 7, z, 34 z, (s, 01 ), 4, ), 69 d, =1H NMR (400 MHz, DMSO-d6) δ 8.20 – 8.09 (m, 1H), 7.54 (t, J = 7.9 Hz, 1H), fl h l 7.11 (s, 1H), 7.05 – 6.95 (m, 2H), 4.89 ), h, .1 – J .0 09 = .4 ), , J J 75 = z, ), = .9 , J 98 ), 2, 02 6, ), 75 =1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 7.9 Hz, 2H), hl i hl 7.38 – 7.33 (m, 2H), 7.25 (s, 1H), 4.96 m, (s, 00 J ), d, =1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 2.5, 0.6 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.22 – 7.13 ), – 85 = 0, (s, 34 = , J ), ), – 82 91 J ), 34 = , J 98 ), 1, – z, 93 J ), z, S , J 21 z, m, ), = 0, (s, 33 = , J 97 ), z, = 7, z, ), 27(d, J = 7.2 Hz, 3H); ES-MS [M+H]+= 417.3. , J ), ), z, 80 52 = ), );1H NMR (400 MHz, CDCl3) δ 8.03 (t, J = 8.2 Hz, 1H), 7.24 (s, 1H), 7.05 – 4-(((2S,11R)-10-chloro-9,11- 6.99 (m, 1H), 6.79 (dd, J = 13.0, 1.6 Hz, = 01 ), – 13 = , J ), ), ), ), ), z, , J 97 ), 1, .1 m, 38 (s, S(2S,11S)-10-chloro-9,11-dimethyl- , J J 0, 79 ), = 8, – ); d, 8, 27 , J z, m, z, m, S d, (s, (s, 22 40 22 S-4 2R11 1 hl 11 , J J 1, 04 = 34 z, ), ]+, J 21 96 m, , J 6, 52 3, ); , J ), 4, 94 7, z, z, dt, .9 d, 0, ), (s, 65 ), ), 3, dt, .91H NMR (400 MHz, CDCl3) δ 8.36 – 8.31 (m, 1H), 8.10 (dd, J = 8.0, 0.8 Hz, 1H), 8.00 – 7.88 (m, 1H), 7.53 (dd, J = z, 68 ), – 3, ), d, .2 , J = , J ), ), ), = z, – ), z, .6 ), 5, z, ), ), = z, d, 0, = ), d, 92 d, ), d, .2 – 15 ), – 04 3, = z,1H NMR (400 MHz, CDCl3) δ 7.69 – 7.62 (m, 2H), 7.22 (s, 1H), 7.14 (d, J = hl 8.2 Hz, 2H), 6.09 (br s, 1H), 4.96 (dd, J .5 84 – 3, = z, 72 ), = 76 z, ), z, m, S d, m, 44 .3 7, 0, ), 27 86 , J (s, S 83 = z, = .2 5, 99 ), ), – 83 = z, d, 3, = d, m, ), ), .6Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H); ES- MS [M+H]+= 373.3Example 2: Preparation of (2S,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4- yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one (Compound A18)- 1,3,2- dioxaborolan-2-yl)-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one (30 mg, 0.077 mmol) in 1,4-dioxane (1.5 mL) was added 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4- yl)pyridine (39.7 mg, 0.19 mmol), Cs2CO3(124 mg, 0.38 mmol), Pd(dppf)Cl2(8.4 mg, 0.01 mmol), and H2O (0.3 mL). The reaction mixture was purged with N2 and heated to 100 °C. After 3 h, the reaction mixture was diluted with EtOAc, filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-10% MeOH / DCM) then RP-HPLC (15-75% MeCN / 0.05% aq. NH4OH) to give the title compound (12 mg, 36% yield).1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.90 (d, J = 13.1 Hz, 2H), 7.41 – 7.31 (m, 2H), 7.06 (s, 1H), 4.99 – 4.91 (m, 1H), 3.97 (s, 2H), 3.95 (s, 3H), 3.54 (s, 1H), 3.51 – 3.37 (m, 1H), 3.30 – 3.18 (m, 1H), 2.30 (s, 3H), 2.28 – 2.06 (m, 3H), 1.85 – 1.72 (m, 1H), 1.53 (d, J = 7.1 Hz, 3H); ES-MS [M+H]+= 437.5.

[0505] The compounds shown in Table 9 may be prepared similarly to the compound described above, with appropriate starting materials. Table 9 1 No. STRUCTURE NAME H-NMR and / or ES-MS [M+H]+J ), – ), 3, 1- ), 33 m, ); 32 ), = .2 z, ), d, .0 m, m, (t, 05 ), m, .6 18 ), – e: S 68 m, 51 .9 80 ), 30 m, m,1H NMR (400 MHz, CDCl3) δ 7.67 – 7.61 (m, 2H), 7.23 (s, 1H), 7.14 – 7.08 (m, hl h l 2H), 6.45 – 6.36 (m, 1H), 4.62 (q, J = 2.6 = ), z, 95 ), – S- J ), – ), m, , J 22 0, (s, m, ]+J 99 ), z, .4 80 ), ), – S- J ), (s, 50 95 - ), 30 2, - J ), ), 93 03 .9 );1H NMR (400 MHz, MeOD-d4) δ 7.68 (t, J = 7.9 Hz, 1H), 7.12 (s, 1H), 7.09 - 7.05 hl h l (m, 1H), 6.97 (dd, J = 12.0, 1.2 Hz, 1H), ), 50 ), 30 de = 31 ), = ), ed ), m, m, ). ad 07 68 J ), ), 84 51 48 20 , J ), = (t, 05 ), z, 5, (s, ), ), H d, z, 82 .3 (s, .2 2, 4, m, ), =31 ), = ), (t, (s, m, ), ); J ), z, ), (s, = 26 52 = J 83 99 ), ), (s, m, S (s, – 91 54 18 m, .11H NMR (400 MHz, CDCl3) δ 7.76 – 7.68 (2S,4S)-10-chloro-4,9- (m, 3H), 7.15 (d, J = 8.0 Hz, 2H), 7.07 (s, di thl 41 thl1H 1H 4 4 1 1H 414 H), m, ), ), ]+J ), – ), ), 22 51 = , J ), ), z, ), ), ), 78 ), ]+J 99 ), ), – 7, z, ), z, S J ), – ), ), ), – 5, );1H NMR (400 MHz, CDCl3) δ 7.74 – 7.68 (2R,4R)-10-chloro-4,9- (m, 3H), 7.16 – 7.11 (m, 2H), 7.05 (s, 1H) 4.96 – 4.90 (m 1H) 4.12 (s 3H), – 6, m, .2 S 62 ), (s, m, z, (s, m, S J ), ), 86 m, 8, – = = z, J = ), ), 34 – – = = z, J ), 85 m, d, m, ), 1, );1H NMR (400 MHz, CDCl3) δ 7.75 – 7.70 (m, 2H), 7.71 (s, 1H), 7.19 – 7.13 (m, (2R,4S)-10-chloro-4,9- 2H), 7.09 (s, 1H), 4.87 – 4.83 (m, 1H), (s, ), ), .8 z, S – 12 54 38 (s, ), 4, 1, ); J ), ), 88 02 z, m, 7, 2, ); J = .8 nt, 02 z, 59 26 z, ), ]+J ), 85 m, d, m, ), ), 31 =1H NMR (400 MHz, CDCl3) δ 7.76 – 7.71 (m, 2H), 7.71 (s, 1H), 7.19 – 7.14 (m, (2S,4R)-10-chloro-4,9- 2H), 7.09 (s, 1H), 4.85 (quint, J = 2.9 Hz, ), .2 10 6, 1, ); 62 (s, = (s, ), m, ), ), 31 = Ea pe epaa o o c oo e y oo ,, , a e a y o ,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide (Compound B4)

[0506] a - 2- yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (25 mg, 0.066 mmol) in 1,4-dioxane (1.0 mL) was added 4-(chloromethyl)-N-methylbenzamide (24 mg, 0.13 mmol), Cs2CO3 (65 mg, 0.20 mmol), Pd(dppf)Cl2 (7.3 mg, 0.01 mmol), and H2O (0.2 mL). The reaction mixture was purged with N2, stirred at 100 °C for 3 h, diluted with EtOAc, and filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-10% MeOH / DCM) then RP-HPLC (15-75% MeCN / 0.05% aq. NH4OH) gave the title compound (10 mg, 38% yield).1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.67 – 7.61 (m, 2H), 7.18 – 7.11 (m,2H), 6.13 (d, J = 5.9 Hz, 1H), 4.48 (dd, J = 11.0, 3.3 Hz, 1H), 4.12 (dd, J = 11.1, 10.2 Hz, 1H), 4.04 (d, J = 1.5 Hz, 2H), 3.97 – 3.86 (m, 1H), 3.84 – 3.66 (m, 2H), 2.99 (d, J = 4.8 Hz, 3H), 2.26 (s, 3H), 2.22 – 2.13 (m, 1H), 2.09 – 1.90 (m, 2H), 1.77 – 1.64 (m, 1H); ES-MS [M+H]+= 399.3.

[0507] The compounds shown in Table 10 may be prepared similarly to the compound described above, with appropriate starting materials. Table 10 No. STRUCTURE NAME1H-NMR and / or ES-MS [M+H]+), ), 0, ), ), ), 90 S1H NMR (400 MHz, CDCl3) δ 8.01 (t, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.05 – 6.98 (m, 1H), hl h l 6.79 (dd, J = 13.1, 1.6 Hz, 1H), 6.70 – 6.65 13 .6 m, (s, m, S(R)-9-chloro-8-methyl-7-((2'- ' = z, 81 .3 ), – .2 ), S-1H NMR (400 MHz, CDCl3) δ 8.02 (t, J = 8.2 R 4 hl 22difl H 1H 771 1H 7 1 dd 11.6 68 31 18 ), S = m, m, d, ), ), ), S .6 (s, ), 27 m, 33 ]+66 = ), 98 ), = = ), ), = .1 m, S-1(R)-2,2-difluoro-8,9-dimethyl- H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.2 Hz 1H) 7.89 (s 1H) 7.87 (s 1H) 7.59 = z, 71 (s, .2 .6 73 z, m, – (s, = z, 6, ), ), ), .2 .6 68 ), = 37 = S = – m, m, – – .4 =(R)-10-chloro-9-methyl-8-(4- = z, d, , J ), .7 91 m, S 89 ), ), = 64 =(S)-4-((10-chloro-9-methyl-6- .2 ), = d, z, m, 8, = = ), 14 69 z, m, m, .5 (s, 69 z, ), S1H NMR (400 MHz, CDCl3) δ 8.02 (t, J = 8.2 (R)-4-((10-chloro-2,9- Hz, 1H), 7.66 (s, 1H), 7.02 (dd, J = 8.1, 1.6 Hz 1H) 6.80 (dd J = 13.1 1.6 Hz 1H) 6.67 .6 04 02 ), = = 87 ), = ), 54 m, .2 .6 69 z, d, 02 ), (s, = ), z, 21 .8 ), ), .41H NMR (400 MHz, DMSO-d6) δ 8.73 – 8.66 (R)-5-((10-chloro-2,9- (m, 1H), 8.51 (d, J = 1.9 Hz, 1H), 7.94 (d, J = 8.0 Hz 1H) 7.66 (dd J = 8.0 2.2 Hz 1H), 23 – 61 – 17 = 91 54 6, ), 7, 24 S- 62 ), 02 57 S = – d, .7 36 0, m, = z, 52 1, 89 .1 .9 = ), 72 = ), ), ), SBiological Activity a. Cell Lines Expressing Muscarinic Acetylcholine Receptors

[0508] Chinese hamster ovary (CHO-K1) cells stably expressing rat (r)M1 were purchased from the American Type Culture Collection and cultured according to their indicated protocol. CHO cells stably expressing human (h)M2, hM3, and hM5were described previously (Levey, et al., 1991); hM1and hM4cDNAs were purchased from Missouri S&T cDNA Resource; rM4cDNA was provided by T. I. Bonner (National Institutes of Health, Bethesda, MD). rM2 and rM3 were cloned from a rat brain cDNA library and sequence verified. hM1, rM2, rM3, hM4, and rM4cDNAs were used to stably transfect CHO-K1 cells purchased from the American Type Culture Collection using Lipofectamine2000. To make stable rM2, hM2, rM3, hM4, and rM4 cell lines for use in calcium mobilization assays, these cells also were stably transfected with a chimeric G- protein (Gqi5) (provided by B.R. Conklin, University of California, San Francisco) using Lipofectamine 2000. rM1, hM1, rM3, hM3, rM5, and hM5 cells were grown in Ham’s F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, and 50 µg / mL G418 sulfate. rM2-Gqi5, hM2–Gqi5,and hM4–Gqi5cells were grown in the same medium also containing 500 µg / mL Hygromycin B. Stable rM4–Gqi5cells were grown in DMEM containing 10% heat-inactivated FBS, 20 mM HEPES, 400 μg / mL G418 sulfate, and 500 μg / mL Hygromycin B. b. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor Activity

[0509] For high throughput measurement of agonist-evoked increases in intracellular calcium, CHO-K1 cells stably expressing muscarinic receptors were plated in growth medium lacking G418 and hygromycin at 15,000 cells / 20 μL / well in Greiner 384-well black-walled, tissue culture (TC)-treated, clear-bottom plates (VWR). Cells were incubated overnight at 37 °C and 5% CO2. The next day, cells were washed using an ELX 405 (BioTek) with four washes (80 µL) of assay buffer then aspirated to 20 µL. Next, 20 µL of 16 µM Fluo-4 / acetoxymethyl ester (Invitrogen, Carlsbad, CA) was prepared as a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10% (w / v) Pluronic F-127 and diluted in assay buffer was added to the wells and the cell plates were incubated for 50 min at 37 °C and 5% CO2. Dye was removed by washing with the ELX 405 (four 80µL washes of assay buffer) then aspirated to 20 µL. Compound master plateswere formatted in an 11 point CRC format (1:3 dilutions) in 100% DMSO with a starting concentration of 10 mM using the BRAVO liquid handler (Agilent). Test compound CRCs were then transferred to daughter plates (240 nL) using the Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA) and then diluted into assay buffer (40 µL) to a 2× stock using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).

[0510] Calcium flux was measured using the Functional Drug Screening System (FDSS) 6000 (Hamamatsu Corporation, Tokyo, Japan) as an increase in the fluorescent static ratio. Compounds were applied to cells (20 µL, 2X) using the automated system of the FDSS 6000 at 4 s into the 300 s protocol and the data were collected at 1 Hz. At 144 s into the 300s protocol, 10 µL of an EC20concentration of the muscarinic receptor agonist acetylcholine was added (5X), followed by the addition of 12 µL of an EC80 concentration of acetylcholine at the 230 s time point (5X). Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Emaxvalues for agonist activity are expressed relative to the maximum for acetylcholine. Positive allosteric modulator activity was analyzed as a concentration-dependent increase in the EC20 acetylcholine response. Antagonist activity was analyzed as a concentration-dependent decrease in the EC80acetylcholine response. Concentration-response curves were generated using a four-parameter logistical equation in XLfit curve fitting software (IDBS, Bridgewater, NJ) for Excel (Microsoft, Redmond, WA) or Prism (GraphPad Software, Inc., San Diego, CA).

[0511] The above-described assay was also operated in a second mode where an appropriate fixed concentration of the present compounds were added to the cells after establishment of a fluorescence baseline for about 3 seconds, and the response in cells was measured.140 s later the appropriate concentration of agonist was added and readings taken for an additional 106 s. Data were reduced as described above and the EC50 values for the agonist in the presence of test compound were determined by nonlinear curve fitting. A decrease in the EC50 value of the agonist with increasing concentrations of the present compounds (a leftward shift of the agonist concentration-response curve) is an indication of the degree of muscarinic positive allosteric modulation at a given concentration of the present compound. An increase in the EC50 value of the agonist with increasing concentrations of the present compounds (a rightward shift of the agonist concentration response curve) is an indication of the degree of muscarinic antagonism ata given concentration of the present compound. The second mode also indicates whether the present compounds also affect the maximum response of the muscarinic receptor to agonists. c. Results and Discussion of Biological Activity Data

[0512] Activity (EC50 and Emax) was determined in the mAChR M1 cell-based functional assay as described above and the data are shown in Tables 11, 12, and 13. The compound numbers correspond to the compound numbers used in Tables 8, 9, and 10 above. The data in Tables 11, 12, and 13 demonstrate that the disclosed compounds are positive allosteric modulators of human mAChR M1 and show high PAM activity for the human mAChR M1 receptor(s). Table 11. Biological Activity Data PAM ActivityPAM Activity C dPAM Activity C dPAM ActivityPAM Activity C dTable 13. Biological Activity Data PAM ActivityPAM Activity C dPAM Activity C d

[0513] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0514] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I-a), or a pharmaceutically acceptable salt thereof, whereinn is 1, 2, 3, or 4; R1and one R2, together with the atoms to which each is attached, form a 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle being optionally substituted with 1-4 R3asubstituents independently selected from the group consisting of C1-4alkyl and halogen; or R1and one R2substituted on a non-adjacent carbon atom, together link to form a first C2- 3alkylene bridge, the first C2-3alkylene bridge being optionally substituted with 1-4 R3bsubstituents independently selected from the group consisting of C1-4alkyl and halogen, wherein optionally one R3band a second R2together link to form a second C2-3alkylene bridge; wherein each other occurrence of R2is independently selected from the group consisting of C1-4alkyl and –C1-3alkylene–OC1-4alkyl; wherein two R2, together with the atom(s) to which each is attached, alternatively form a C3-6cycloalkane or oxo; R4is selected from the group consisting of H, C1-4alkyl, halogen, C2-4alkenyl, C1-4fluoroalkyl, CN, NO2, NH2, NHC(O)C1-4alkyl, –OR4a, C3-4cycloalkyl, –CH2OR4a, and –CH2NR4aR4b,wherein R4aand R4bare independently H or C1-4alkyl, or alternatively, R4aand R4b, together with the nitrogen to which each attaches, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, wherein the heterocyclyl is optionally substituted with a first substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, C1-2fluoroalkyl, phenyl, and pyridyl, and optionally substituted with a second substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, and C1-2fluoroalkyl, and optionally substituted with third and fourth substituents independently selected from the group consisting of halogen and C1- 4alkyl; R5is selected from the group consisting of H, C1-4alkyl, halogen, C1-4fluoroalkyl, CN, –OR5a, C3-4cycloalkyl, –CH2OR5a, and –CH2NR5aR5b, wherein R5aand R5bare independently H or C1- 4alkyl, or alternatively, R5aand R5b, together with the nitrogen to which each attaches, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, wherein the heterocyclyl is optionally substituted with a first substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, C1- 2fluoroalkyl, phenyl, and pyridyl, and optionally substituted with a second substituent selected from the group consisting of oxo, cyano, halogen, C1-4alkyl, and C1-2fluoroalkyl, and optionally substituted with third and fourth substituents independently selected from the group consisting of halogen and C1-4alkyl; or alternatively, R4and R5, together with the atoms to which each attaches, form a 5- to 7- membered carbocyclic ring; Z1is CR6or N; R6is H or C1-4alkyl; R7aand R7bare independently selected from the group consisting of H and C1-4alkyl; R8is selected from the group consisting of:nd Z4is CH, CR9, or N; Z5is CH, CR9, or N; wherein 0-2 of Z2, Z3, Z4, and Z5are N; Z6is CH, CR9, or N; Z7is CH, CR14, or N; Z8is C or N; ring 6-membered fully or partially unsaturated heterocyclic ringand / or R15, wherein the heterocyclic ring contains 1-3 heteroatoms independently selected from the group consisting of N, O, and S;ring 6-membered fully or partially unsaturated heterocyclic r h R14and / or R15, wherein the heterocyclic ring contains a first N heteroatom and optionally 1-2 additional heteroatoms independently selected from the group consisting of N, O, and S; R9, at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OC1-4alkyl, and –OC1-4fluoroalkyl; R10is selected from the group consisting of G10, –C(O)NR10aR10b, halogen, cyano, C1-4alkyl, C1- 4fluoroalkyl, –OR10a, –SR10a, –N(R10a)C(O)R10b, –N(R10b)C(O)R10a, –N(R10b)C(O)OR10a, –CO2R10a, –C(O)R10a, –S(O)2NR10aR10b, –S(O)2R10a, –C1-3alkylene–OR10b, and H; R10ais selected from the group consisting of H, C1-4alkyl, C1-4fluoroalkyl, –C1-4alkylene–O–C1- 4alkyl, –C1-4alkylene–C(O)N(C1-4alkyl)2, G12, and –C1-4alkylene–G12; R10bis selected from the group consisting of H and C1-4alkyl; G10and G12are independently selected from the group consisting of a 5- to 10-membered heteroaryl containing 1-3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, phenyl, and C3-6cycloalkyl, the heteroatoms being independently selected from the group consisting of N, O, and S, wherein each is optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, C1-4alkyl, C1- 4fluoroalkyl, –OR11a, –C(O)NR11aR11b, –C1-4alkylene–OR11a, G11, and –C1-3alkylene–G11, and optionally substituted with 1-3 additional substituents independently selected from the group consisting of halogen, oxo, and C1-4alkyl; R11aand R11bare independently selected from the group consisting of hydrogen and C1-4alkyl; G11is C3-6cycloalkyl or 3- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S; R14, at each occurrence is independently selected from the group consisting of halogen, C1-4alkyl, –OC1-4alkyl, and C3-4cycloalkyl; R15is oxo; R16is phenyl or pyridyl; o is 0, 1, or 2; andq is 0 or 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and one R2, together with the atoms to which each is attached, form the 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle being optionally substituted with 1-4 R3asubstituents independently selected from the group consisting of C1-4alkyl and halogen.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (V): ;L1is a straight chain C1-2alkylene, optionally wherein one methylene of the C1-2alkylene is replaced with an oxygen or nitrogen atom.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and one R2substituted on a non-adjacent carbon atom, together link to form the first C2-3alkylene bridge, the first C2-3alkylene bridge being optionally substituted with 1-4 R3bsubstituents independently selected from the group consisting of C1-4alkyl and halogen, wherein optionally one R3band a second R2together link to form a second C2-3alkylene bridge.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula ; n1 is 0, 1, 2, or 3; andL2is the first C2- the 1-4 R3bsubstituents.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of H, C1-4alkyl, and halogen.

7. The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R5is C1-4alkyl.

8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Z1is CH.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R7aand R7bare H.

10. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein , optionally wherein R8is selected from the group, 11. The compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, .

12. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R9, at each occurrence, is independently selected from the group consisting of halogen, C1-4alkyl, and –OC1-4alkyl.

13. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group .

15. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R10is selected from the group consisting of G10, –C(O)NR10aR10b, and C1-4alkyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R10is G10.

17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein G10is the 5- to 10-membered heteroaryl, optionally substituted as defined in claim 1.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R10is –C(O)NR10aR10b.

19. The compound of any of claims 1-15 or 18, or a pharmaceutically acceptable salt thereof, wherein R10ais C1-4alkyl.

20. The compound of any of claims 1-15 or 18-19, or a pharmaceutically acceptable salt thereof, wherein R10bis H.

21. The compound of any of claims 1-15 or 18-20, or a pharmaceutically acceptable salt thereof, wherein R10is –C(O)NHCH3.

22. The compound of any of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group ,23. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein .

24. or a salt thereof, wherein R8is25. The compound of claim 1, selected from the group consisting of: 4-(((2S)-10-chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide; (2S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-10-chloro-9-methyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-10-chloro-9-methyl-8-(4-(oxazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-10-chloro-9-methyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; 4-(((2S)-10-chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S)-10-chloro-8-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-9-methyl-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S)-10-chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S)-10-chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 4-(((2R)-10-chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin- 8-yl)methyl)-2-fluoro-N-methylbenzamide; (2R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-9,10-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S)-9,10-dimethyl-8-(4-(oxazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-9,10-dimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; 4-(((2S)-9,10-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide; (2S)-8-(4-(1H-pyrazol-1-yl)benzyl)-9,10-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-9,10-dimethyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; 4-(((2S)-9,10-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide; (2S)-8-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-9,10-dimethyl-3,4-dihydro-2H,6H- 2,5-methanobenzo[b][1,5]oxazocin-6-one; (2R)-9,10-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2R)-8-(4-(1H-pyrazol-1-yl)benzyl)-9,10-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; 4-(((2R)-9,10-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide; 4-(((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; (2S,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one;4-(((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,4R)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4R)-10-chloro-4,9-dimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4R)-4,9,10-trimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4R)-4,9,10-trimethyl-8-(4-(oxazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-4,9,10-trimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; N-methyl-4-(((2S,4R)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide; 2-fluoro-N-methyl-4-(((2S,4R)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide; (2S,4R)-4,9,10-trimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,4R)-4,9,10-trimethyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-10-chloro-4,9-dimethyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-10-chloro-4,9-dimethyl-8-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-4,9,10-trimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-4,9,10-trimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 2-fluoro-N-methyl-4-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide; N-methyl-4-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide; 4-(((2S,3S)-10-chloro-3,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,3S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-3,9-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,3S)-10-chloro-3,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,3S)-10-chloro-3,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 4-(((2S,3S)-10-chloro-3,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; 4-(((2S,11R)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,11R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9,11-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,11R)-10-chloro-9,11-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2S,11R)-10-chloro-9,11-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 4-(((2S,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide;(2S,11S)-10-chloro-9,11-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 4-(((2R,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2R,11S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9,11-dimethyl-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2R,11S)-10-chloro-9,11-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; (2R,11S)-10-chloro-9,11-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 4-(((2R,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; 4-(((2R,11R)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,4S)-10-chloro-4,9-dimethyl-8-((6-methylpyridin-3-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-10-chloro-4,9-dimethyl-8-((2-methylpyridin-4-yl)methyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; 5-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylpicolinamide; 5-(((2S,4S)-10-fluoro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylpicolinamide; 4-(((2S,4S)-10-fluoro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; N-methyl-5-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)picolinamide; 5-(((2S,4S)-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylpicolinamide; 4-(((2S,4S)-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8- yl)methyl)-N-methylbenzamide; 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; 5-(((2R,11S)-10-chloro-9,11-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylpicolinamide; (2S)-10-chloro-9-methyl-8-(quinolin-6-ylmethyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-9,10-dimethyl-8-(quinolin-6-ylmethyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S,4R)-4,9,10-trimethyl-8-(quinolin-6-ylmethyl)-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-6-one; (2S)-9-(4-(1H-pyrazol-1-yl)benzyl)-11-chloro-10-methyl-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-7-one; (2S)-11-chloro-10-methyl-9-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,4,5- tetrahydro-7H-2,6-methanobenzo[b][1,5]oxazonin-7-one; 4-(((2S)-11-chloro-10-methyl-7-oxo-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-9-yl)methyl)-2-fluoro-N-methylbenzamide; (2R)-11-chloro-10-methyl-9-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3,4,5-tetrahydro- 7H-2,6-methanobenzo[b][1,5]oxazonin-7-one; 4-(((2R)-11-chloro-10-methyl-7-oxo-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-9-yl)methyl)-N-methylbenzamide; (2R)-9-(4-(1H-pyrazol-1-yl)benzyl)-11-chloro-10-methyl-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-7-one; 4-(((2R)-11-chloro-10-methyl-7-oxo-2,3,4,5-tetrahydro-7H-2,6- methanobenzo[b][1,5]oxazonin-9-yl)methyl)-2-fluoro-N-methylbenzamide; (2R)-11-chloro-10-methyl-9-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,4,5- tetrahydro-7H-2,6-methanobenzo[b][1,5]oxazonin-7-one; 8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one; 4-((10-chloro-9-methyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8- yl)methyl)-2-fluoro-N-methylbenzamide; 10-chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one;2-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-3-methyl-6,7,7a,8,9,10-hexahydro-12H-6,10- methanobenzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one; 4-((4-chloro-3-methyl-12-oxo-6,7,7a,8,9,10-hexahydro-12H-6,10- methanobenzo[b]pyrrolo[1,2-e][1,5]oxazocin-2-yl)methyl)-2-fluoro-N-methylbenzamide; 4-chloro-3-methyl-2-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-6,7,7a,8,9,10-hexahydro-12H- 6,10-methanobenzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one; 4-chloro-3-methyl-2-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-6,7,7a,8,9,10- hexahydro-12H-6,10-methanobenzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one; (2S,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; (2S,4S)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; (2R,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2R,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2R,4R)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; (2R,4R)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2R,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; (2R,4S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2R,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2R,4S)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; (2R,4S)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2R,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; (2S,4R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-4,9-dimethyl-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,4R)-10-chloro-4,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; (2S,4R)-10-chloro-4,9-dimethyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydro- 2H,6H-2,5-ethanobenzo[b][1,5]oxazocin-6-one; 4-(((2S,4R)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- ethanobenzo[b][1,5]oxazocin-8-yl)methyl)-N-methylbenzamide; (S)-4-((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide; (S)-9-chloro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (S)-9-chloro-8-methyl-7-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-4-((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide; (R)-4-((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-2-fluoro-N-methylbenzamide; (R)-7-(4-(1H-pyrazol-1-yl)benzyl)-9-chloro-8-methyl-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-8-methyl-7-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one;(R)-9-chloro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-8-methyl-7-((6-methylpyridin-3-yl)methyl)-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-8-methyl-7-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-8-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-8-methyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-8-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-4-((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide; (R)-4-((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7-yl)methyl)-2-fluoro-N-methylbenzamide; (R)-7-(4-(1H-pyrazol-1-yl)benzyl)-9-chloro-2,2-difluoro-8-methyl-2,3,11,11a-tetrahydro- 1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-2,2-difluoro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-9-chloro-2,2-difluoro-8-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,2-difluoro-8,9-dimethyl-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-2,2-difluoro-8,9-dimethyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-4-((2,2-difluoro-8,9-dimethyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-2-fluoro-N-methylbenzamide; (R)-4-((2,2-difluoro-8,9-dimethyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide;(R)-4-((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-N-methylbenzamide; (R)-4-((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (R)-10-chloro-9-methyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4,12,12a-tetrahydro- 1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (R)-10-chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4,12,12a- tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (R)-10-chloro-9-methyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4,12,12a-tetrahydro- 1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (R)-10-chloro-9-methyl-8-(4-(oxazol-4-yl)benzyl)-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (R)-10-chloro-9-methyl-8-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4,12,12a-tetrahydro- 1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (S)-4-((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-N-methylbenzamide; (S)-4-((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-9-methyl-3,4,12,12a-tetrahydro-1H,6H- benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (S)-10-chloro-9-methyl-8-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4,12,12a-tetrahydro- 1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (S)-10-chloro-9-methyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4,12,12a- tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (S)-10-chloro-9-methyl-8-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4,12,12a-tetrahydro- 1H,6H-benzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6-one; (R)-4-((10-chloro-2,9-dimethyl-6-oxo-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide;(R)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-2,9-dimethyl-1,2,3,4,12,12a-hexahydro-6H- benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; (R)-10-chloro-2,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; (S)-4-((10-chloro-2,9-dimethyl-6-oxo-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (S)-8-(4-(1H-pyrazol-1-yl)benzyl)-10-chloro-2,9-dimethyl-1,2,3,4,12,12a-hexahydro-6H- benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; (S)-10-chloro-2,9-dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; (R)-5-((10-chloro-2,9-dimethyl-6-oxo-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-8-yl)methyl)-N-methylpicolinamide; (R)-7-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-chloro-2,2-difluoro-8-methyl-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (S)-4-((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide; (S)-7-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-chloro-2,2-difluoro-8-methyl-2,3,11,11a- tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-5-((9-chloro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylpicolinamide; (R)-5-((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H- benzo[f]pyrrolo[2,1-c][1,4]oxazepin-7-yl)methyl)-N-methylpicolinamide; or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25 selected from the group consisting of: 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; (2S,4S)-4,9,10-trimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydro- 2H,6H-2,5-methanobenzo[b][1,5]oxazocin-6-one; 2-fluoro-N-methyl-4-(((2S,4S)-4,9,10-trimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-methanobenzo[b][1,5]oxazocin-8-yl)methyl)benzamide; 4-(((2S,3S)-10-chloro-3,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5- methanobenzo[b][1,5]oxazocin-8-yl)methyl)-2-fluoro-N-methylbenzamide; 4-(((2S,4S)-10-chloro-4,9-dimethyl-6-oxo-3,4-dihydro-2H,6H-2,5-ethanobenzo[b][1,5]oxazocin- 8-yl)methyl)-N-methylbenzamide; (R)-4-((9-chloro-2,2-difluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1- c][1,4]oxazepin-7-yl)methyl)-N-methylbenzamide; (R)-9-chloro-2,2-difluoro-8-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)- 2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one; (R)-4-((10-chloro-9-methyl-6-oxo-3,4,12,12a-tetrahydro-1H,6H-benzo[f][1,4]oxazino[3,4- c][1,4]oxazepin-8-yl)methyl)-N-methylbenzamide; or a pharmaceutically acceptable salt thereof.

27. A compound of any of claims 1-26, or a pharmaceutically acceptable salt thereof, that has at least 50% deuterium incorporation at each deuterium label.

28. A hydrate, solvate, polymorph, or prodrug of the compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising the compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-28, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. A method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of the compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-28, or a pharmaceutically acceptable salt thereof, or the composition of claim 29.

31. The method of claim 30, wherein the mammal is human.

32. The method of claim 30 or 31, wherein the muscarinic acetylcholine receptor is mAChR M1.

33. The method of any of claims 30-32, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

34. The method of any of claims 30-33, further comprising the step of identifying a mammal in need of treatment of the disorder.

35. The method of any of claims 30-34, wherein the disorder is a neurological disorder or psychiatric disorder, or a combination thereof.

36. The method of any of claims 30-35, wherein the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, or memory disorders, or a combination thereof.

37. The method of any of claims 30-36, wherein the disorder is Alzheimer’s disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof.

38. The method of claim 37, wherein the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof.

39. The compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-28, or a pharmaceutically acceptable salt thereof, or the composition of claim 29, for use in the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

40. Use of the compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-28, or a pharmaceutically acceptable salt thereof, or the composition of claim 29, for the preparation of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

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